Amboss Endocrinology

Antidiabetic drugs Antidiabetic drugs (with the exception of insulin) are all pharmacological agents that have been approved for hyperglycemic treatment in type 2 diabetes mellitus (DM). If lifestyle modifications (weight loss, dietary modification, and exercise) do not sufficiently reduce A1C levels (target level: ∼ 7%), pharmacological treatment with antidiabetic drugs should be initiated. These drugs may be classified according to their mechanism of action as insulinotropic or non-insulinotropic. They are available as monotherapy or combination therapies, with the latter involving two (or, less commonly, three) antidiabetic drugs and/or insulin. The exact treatment algorithms are reviewed in the treatment section of diabetes mellitus. The drug of choice for all type 2 diabetic patients is metformin. This drug has beneficial effects on glucose metabolism and promotes weight loss or at least weight stabilization. In addition, numerous studies have demonstrated that metformin can reduce mortality and the risk of complications. If metformin is contraindicated, not tolerated, or does not sufficiently control blood glucose levels, another class of antidiabetic drug may be administered. Most antidiabetic drugs are not recommended or should be used with caution in patients with moderate or severe renal failure or other significant comorbidities. Oral antidiabetic drugs are not recommended during pregnancy or breastfeeding.

ClassMechanism of actionSide effectsContraindications Biguanide (metformin)Enhances the effect of insulinLactic acidosisWeight lossGastrointestinal complaints are common (e.g. diarrhea, abdominal cramps)Reduced vitamin B12absorptionChronic kidney diseaseLiver failure Metformin must be paused before administration of iodinated contrast medium and major surgery. Sulfonylureas (e.g., glyburide, glimepiride)Increase insulin secretion from pancreaticβ-cellsRisk of hypoglycemiaWeight gainHematological changes: agranulocytosis, hemolysisSevere cardiovascular comorbidity ObesitySulfonamide allergy (particularly long-acting substances) Meglitinides (nateglinide, repaglinide)Increase insulin secretion from pancreaticβ-cells Risk of hypoglycemia Weight gainSevere renal or liver failure DPP-4 inhibitors (saxagliptin, sitagliptin)Inhibit GLP-1 degradation → promotes glucose-dependent insulin secretionGastrointestinal complaintsPancreatitisHeadache, dizzinessArthralgiaLiver failureModerate to severe renal failure GLP-1 agonists (incretin mimetic drugs: exenatide, liraglutide, albiglutide)Direct stimulation of the GLP-1 receptorNausea Increased risk of pancreatitis and possibly pancreatic cancerPreexisting, symptomatic gastrointestinal motility disorders SGLT-2 inhibitors(canagliflozin, dapagliflozin, empagliflozin)Increased glucosuria through the inhibition of SGLT-2 in the kidneyGenital yeast infections and urinary tract infectionsPolyuria and dehydrationDiabetic ketoacidosis Chronic kidney disease Recurrent urinary tract infections Alpha-glucosidase inhibitors(acarbose)Reduce intestinal glucose absorptionGastrointestinal complaints (flatulence, diarrhea, feeling of satiety)Any preexisting intestinal conditions (e.g., inflammatory bowel disease)Severe renal failure Thiazolidinediones(pioglitazone)Reduce insulin resistance through the stimulation of PPARs (peroxisomeproliferator-activated receptors)Increase transcription of adipokinesWeight gainEdemaCardiac failureIncreased risk of bone fractures (osteoporosis)Congestive heart failureLiver failure Amylin analogs (pramlintide) Reduce glucagon releaseReduce gastric emptyingIncrease satietyRisk of hypoglycemiaNauseaGastroparesis Common contraindications of antidiabetic agents Type 1 diabetes mellitus: Patients require insulin therapy (see principles of insulin therapy). Pregnancy and breastfeeding (also see gestational diabetes): All antidiabetic agents are contraindicated. Antidiabetic drugs should be substituted with human insulin as early as possible (ideally prior to the pregnancy). Renal failure : Antidiabetic drugs that may be administered if GFR < 30 mL/min include DPP-4 inhibitors, incretin mimetic drugs, meglitinides, and thiazolidinediones. Morbidity and surgery Pause antidiabetic treatment in the following cases: Major surgery performed under general anesthesiaAcute conditions requiring hospitalization (infections, organ failure)Elective procedures associated with an increased risk of hypoglycemia (periods of fasting, irregular food intake) Sulfonylureas are associated with the highest risk of hypoglycemia. All other substances do not carry a significant risk of hypoglycemia when used as a monotherapy. Combination therapy, particularly with sulfonylurea, significantly increases the risk of hypoglycemia! Effects Insulinotropic agentsMechanism: stimulate the secretion of insulin from pancreatic β-cellsGlucose-independent: Insulin is secreted regardless of the blood glucose level, even if blood glucose levels are low → risk of hypoglycemiaSulfonylurea, meglitinidesGlucose-dependent: Insulin secretion is stimulated by elevated blood glucose levels (postprandially). These antidiabetic agents depend on residual β-cell function.GLP-1 agonists, DPP-4 inhibitors Non-insulinotropic agentsMechanism These agents do not depend on residual insulin production.Effective in patients with nonfunctional endocrine pancreatic β-cellsBiguanides (metformin), SGLT-2 inhibitor, thiazolidinediones, alpha-glucosidase inhibitors Biguanides (metformin) Active agent Metformin Clinical profile Mechanism of action: enhances the effect of insulinReduction in insulin resistance via modification of glucose metabolic pathways Inhibits mitochondrial glycerophosphate dehydrogenase (mGPD)Decreases hepatic gluconeogenesis and intestinal glucose absorptionIncreases peripheral insulin sensitivityLowers postprandial and fasting blood glucose levels Reduces LDL, increases HDL Indications: drug of choice in all patients with type 2 diabetes Clinical characteristicsGlycemic efficacy: lowers HbA1c by 1.2-2% over 3 monthsWeight loss or weight stabilizationNo risk of hypoglycemiaBeneficial effect on dyslipidemiaStudies show metformin reduces the risk of macroangiopathic complications in diabetic patients. Cost-effective Important side effectsMetformin-associated lactic acidosis Incidence: ∼ 8 cases/100,000 patient yearsClinical features: frequently nonspecific Gastrointestinal prodromal symptoms: nausea, vomiting, diarrhea, abdominal painSevere symptoms: muscle cramps, hyperventilation, apathy, disorientation, comaHigh-risk groupsElderly individuals Patients with cardiac or renal insufficiencyDiagnostics Arterial blood gas (ABG): metabolic acidosis and anion gap↑ Serum lactateTreatment: discontinue metformin and treat acidosisGastrointestinal complaints are common: nausea, diarrhea, flatulence Vitamin B12 deficiency Metallic taste in the mouth (dysgeusia) ContraindicationsRenal failure (if creatinine clearance < 30 mL/min)Severe liver failure Intravenous iodinated contrast medium Pause metformin prior to surgeryChronic pancreatitis, starvation ketosis, ketoacidosis, sepsis Heart failure (NYHA III and IV), respiratory failure, shock, sepsis Alcoholism Important interactions: sulfonylureas Metformin treatment must be paused prior to the administration of a contrast medium or scheduled surgery to reduce the risk of lactic acidosis! Because of its favorable risk-benefit ratio, metformin is the drug of choice for monotherapy and combination therapy in all stages of type 2 DM! Thiazolidinediones (glitazones, insulin sensitizers) Active agents Pioglitazone Rosiglitazone Clinical profile Mechanism of action: activation of the transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type) → ↑ transcription of genes involved in glucose and lipid metabolism → ↑ levels of adipokines such as adiponectin → ↑ storage of triglycerides and subsequent reduction of products of lipid metabolism (e.g., free fatty acids) that enhance insulin resistance → glucose utilization is increased and hepatic glucose production reduced Indications: may be considered as a monotherapy in patients with severe renal failure and/or contraindications for insulin therapy Clinical characteristicsGlycemic efficacy: lowers HbA1c by 1% in 3 monthsFavorable effect on lipid metabolism: ↓ triglyceride, ↓ LDL, ↑ HDLNo risk of hypoglycemia Important side effectsFluid retention and edemaWeight gainIncreased risk of heart failureIncreased risk of bone fractures (osteoporosis!) ContraindicationsCongestive heart failure (NYHA III or IV)Liver failurePioglitazone: history of bladder cancer or active bladder cancer; macrohematuria of unknown origin Sulfonylureas Active agents Glyburide: the standard substance of this class with a relatively long half-life Glipizide: a short-acting agent Clinical profile Mechanism of actionSulfonylureas block ATP-sensitive potassium channels of the pancreatic β-cells → depolarization of the cell membrane → calcium influx → insulin secretion Extrapancreatic effect: decreases hepatic gluconeogenesis and increases peripheral insulin sensitivity Indications: particularly suitable for patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine Clinical characteristicsGlycemic efficacy: lowers HbA1c by 1.2% over 3 monthsLong-term experienceLow-cost Important side effectsLife-threatening hypoglycemia Increased risk in patients with renal failure Weight gainHematological changes: granulocytopenia, hemolytic anemiaAllergic skin reactionsAlcohol intolerance Compared to metformin, sulfonylureas are associated with more cardiovascular (macrovascular) complications. ContraindicationsSevere cardiovascular comorbidity ObesitySulfonamide allergy (particularly long-acting substances)Severe liver failureSevere kidney failure Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (→ see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided! Meglitinides (sulfonylurea analogue) Active agents Repaglinide: the leading agent in the class of meglitinides, which is well tolerated by patients with chronic kidney disease Nateglinide Clinical profile Mechanism of actionEnhances insulin secretion (similar mechanism of action to that of the sulfonylureas)Meglitinides should be taken shortly before meals. Indications: particularly suitable for patients with postprandial peaks in blood glucose levels Clinical characteristicsGlycemic efficacy: lowers HbA1c by 0.75% over 3 monthsMore expensive than sulfonylureas Important side effectsLife-threatening hypoglycemia (less risky than sulfonylureas) Increased risk in patients with renal failure Weight gainHepatotoxicity (rare) ContraindicationsSevere liver failureSevere renal failure Interactions: sulfonylureas Incretin mimetics (GLP-1 receptor agonists) Active agents Exenatide Liraglutide: rapid-release formula that is administered daily Albiglutide: extended-release formula that is administered once weekly Dulaglutide Clinical profile Mechanism of action Incretin effect: food intake → activation of enteroendocrine cells in the gastrointestinal tract → release of GLP-1 → GLP-1 degradation via the enzyme DPP-4 → end of the GLP-1 effectIncretin mimetic drugs bind to the GLP-1 receptors and are resistant to degradation by DPP-4 enzyme → increase insulin secretion, decrease glucagon secretion, slow gastric emptying (↑ feeling of satiety, ↓ weight) Clinical characteristicsGlycemic efficacy: lowers HbA1c by 0.5-1.5% over 3 monthsSubcutaneous injectionWeight lossNo risk of hypoglycemia Side effectsGastrointestinal complaints (particularly impaired gastric emptying!) Increased risk of pancreatitis and potentially pancreatic cancer : ContraindicationsPreexisting symptomatic gastrointestinal motility disordersChronic pancreatitis or a family history of pancreatic tumors Dipeptidyl peptidase-4 inhibitors (gliptins) Active agents Sitagliptin Saxagliptin Clinical profile Mechanism of action: Gliptins indirectly increase the endogenous incretin effect by inhibiting the dipeptidyl peptidase-4 enzyme that breaks down glucagon-like peptide 1 → increased insulin secretion, decreased glucagon secretion, delayed gastric emptying Indications: See the antihyperglycemic therapy algorithm for type 2 diabetes. Clinical characteristicsGlycemic efficacy: lowers HbA1c by 0.5-0.75% over 3 monthsNo risk of hypoglycemia unless insulin and/or insulinotropic drugs are used simultaneously Important side effectsGastrointestinal complaints: diarrhea, constipation (milder than in GLP-1 agonist exposure)Nasopharyngitis and upper respiratory tract infectionArthralgiaHeadaches, dizzinessUrinary infections (mild) Increased risk of pancreatitisAcute renal failure ContraindicationsHypersensitivityLiver failure SGLT-2 inhibitors (gliflozins) Active agents Dapagliflozin Empagliflozin Canagliflozin Clinical profile Mechanism of action: reversible inhibition of the sodium-dependent glucose co-transporter (SGLT-2) in the proximaltubule of the kidney → reduced glucose reabsorption in the kidney → glycosuria and polyuria Indications: a treatment option used especially in young patients with treatment-compliant type 2 DM without significant renal failure Clinical characteristicsGlycemic efficacy: lowers HbA1c by 0.6% over 3 monthsPromotes weight lossReduces blood pressure Important side effectsUrinary tract infections, genital infections (vulvovaginitis, balanitis)Dehydration as a result of polyuriaSevere diabetic ketoacidosis ContraindicationsChronic kidney disease Recurrent urinary tract infections (e.g., in patients with anatomical or functional anomalies of the urinary tract) Alpha-glucosidase inhibitors Active agents Acarbose Miglitol Clinical profile Mechanism of actionInhibits alpha-glucosidase → decreased intestinal glucose absorption → The drug is particularly effective in controlling postprandial blood glucose levels.The undigested carbohydrates reach the colon, where they are degraded by intestinal bacteria, resulting in the production of intestinal gas. Clinical characteristicsGlycemic efficacy: lowers HbA1c by 0.8% over 3 monthsNo risk of hypoglycemia Important side effects: gastrointestinal complaints (flatulence, abdominal discomfort, diarrhea) ContraindicationsInflammatory bowel diseaseConditions associated with malabsorptionSevere renal failure

Hyperparathyroidism Hyperparathyroidism (HPT) is characterized by abnormally high parathyroid hormone (PTH) levels in the blood due to overactivity of the parathyroid glands. It is differentiated into three types based on the underlying cause: primary HPT (pHPT), secondary hyperparathyroidism (sHPT), and tertiary hyperparathyroidism (tHPT). pHPT is characterized by elevated parathyroid hormone and calcium levels and is usually caused by parathyroid adenomas (or, in rare cases, by parathyroid carcinomas). Although often asymptomatic, symptoms such as bone pain, gastric ulcers, and/or kidney stonesmay emerge in severe cases. sHPT is characterized by high parathyroid hormone and low calcium levels and may be caused by kidney failure, vitamin D deficiency, or malabsorption. sHPT is also called reactive HPT, as the increase in (parathyroid) hormone production is a physiological response to hypocalcemia and not caused by an abnormality of the parathyroid glands. If sHPT and elevated parathyroid hormone blood levels persist, tHPT may develop, resulting in a shift from low to high calcium blood levels. Hyperparathyroidism is diagnosed and classified by evaluating calcium, phosphorus, and parathyroid hormone levels and, in the case of sHPT, evaluating the underlying disease (e.g., creatininein chronic kidney disease). Surgery is the primary treatment option for symptomatic patients and asymptomatic patients who meet certain criteria. Patients who are not surgical candidates are managed with either calcimimetics or, if osteoporosis is present, bisphosphonates. In sHPT, treatment of the underlying disease is the focus.

Definition All forms of hyperparathyroidism are characterized by elevated PTH levels. Primary hyperparathyroidism (pHPT): Hypercalcemia results from abnormally active parathyroid glands. Secondary hyperparathyroidism (sHPT): Hypocalcemia results in reactive overproduction of PTH. Tertiary hyperparathyroidism (tHPT): Hypercalcemia results from untreated sHPT, with continuously elevated PTHlevels. Epidemiology Primary hyperparathyroidism Lifetime incidence: 1/80 Sex: ♀ > ♂ (3:1) Age: most cases occur after age 50 Prevalence: ∼ 0.1-0.5% Etiology Primary hyperparathyroidism Parathyroid gland adenoma (∼ 85%): benign tumor of the parathyroid glands Hyperplasia and multiple adenomas (∼ 15%) Rarely carcinomas (∼ 0.5%) MEN type 1 or 2 Secondary hyperparathyroidism Chronic kidney disease (most frequent cause) Malnutrition Vitamin D deficiency (e.g., reduced exposure to sunlight, nutritional deficiency, liver cirrhosis) Cholestasis Tertiary hyperparathyroidism Caused by persistent sHPT Pathophysiology Physiological secretion of PTH See disorders of calcium balance. Pathologically increased secretion of PTH Primary hyperparathyroidism: overproduction of PTH by parathyroid chief cellsEffect of PTH on bone → increased bone resorption → ↑ release of calcium phosphate → ↑ calcium levelsInduces RANKL expression in osteoblasts → binding of RANKL to RANK on osteoclasts → activation of osteoclastsInduces IL-1 expression in osteoblasts → activation of osteoclastsEffect of PTH on the kidneys → ↑ phosphate excretion (phosphaturia) Secondary hyperparathyroidism: ↓ calcium and/or ↑ phosphate blood levels → reactive hyperplasia of the parathyroid glands → ↑ PTH secretionChronic kidney disease → impaired renal phosphate excretion → ↑ phosphate blood levels→ ↑ PTH secretionIn addition, CKD → ↓ biosynthesis of active vitamin D → ↓ intestinal calcium resorption + ↓ renal calcium reabsorption → hypocalcemia → ↑ PTH secretion Tertiary hyperparathyroidism: chronic renal disease → refractory and autonomous secretion of PTH → hypercalcemia Renal disease → secondary or tertiary hyperparathyroidism → renal osteodystrophy → bone lesions Familial hypocalciuric hypercalcemia (FHH) is discussed in the learning card Disorders of calcium balance. pHPT develops due to hyperplasia of the parathyroid glands. sHPT develops due to decreased levels of calcium in the blood (reactive HPT)! Clinical features Primary hyperparathyroidism The majority of patients are asymptomatic! Cardiovascular disease KidneyNephrolithiasis, nephrocalcinosis Polyuria, polydipsia Musculoskeletal systemBone, muscle, and joint painPseudogoutOsteitis fibrosa cystica (cyst-like brown tumors) Skull: granular decalcification (salt-and-pepper skull) Digestive tractLack of appetite → weight lossNausea, constipationGastric or duodenal ulcers , pancreatitis Psychological symptoms: depression, fatigue, anxiety, sleep disorders "Stones, bones, abdominal groans, thrones, and psychiatric overtones!" Secondary hyperparathyroidism Symptoms related to the underlying cause of sHPT (commonly renal failure) Bone pain and increased risk of fractures Primary hyperparathyroidism Ca↑Phos↓ALP↑PTH↑ Secondary hyperparathyroidism Can/↓ Phosn/↑ ALP↑PTH↑ Tertiary hyperparathyroidismCa↑Phos↑ ALP↑PTH↑↑ pHPT: hypercalciuria (calcium/creatinine ratio > 0.02), and ↑ cAMP in urine In sHPT, diagnosis focuses on identifying the underlying disease (e.g., creatinine in chronic kidney disease). Hypercalcemic crises may occur in primary and tertiary HPT! Imaging Ultrasound/nuclear imaging (Tc99m-sestamibi scan): only performed prior to surgery to determine the exact location of the abnormal glands Skeletal x-ray: decreased bone mineral density, but usually an incidental finding, as x-ray is not a routine diagnostic tool Cortical thinning: especially prominent in the phalanges of the hand (acroosteolysis) Salt-and-pepper skullRugger-jersey spine sign: Alternating low and high density in the vertebrae produces a banded pattern, similar to a striped rugby jersey. Treatment Primary hyperparathyroidism Surgical Indications Symptomatic patientsAsymptomatic patients who meet at least one of the following criteria: Age < 50 yearsSerum calcium level more than 1 mg/dL higher than the normal upper limitImpaired renal function (eGFR < 60 mL/min)Increased calcium excretion (> 400 mg/day) in combination with an increased risk for nephrolithiasisEvidence of nephrolithiasis or nephrocalcinosis via imagingReduced bone mineral density (T-score < -2.5 at lumbar spine, total hip, femoral neck, or distal third of the radius, or preexisting asymptomatic vertebral fracture)The procedure depends on the pathology: Solitary adenoma: remove only the respective gland (parathyroidectomy)Hyperplasia: remove all four glands (total parathyroidectomy) Half of one of the resected glands can be reimplanted in shallow pockets of the sternocleidomastoid or brachioradialis muscle. A reimplanted gland allows for easier and faster surgical access if intervention due to pHPT relapse is indicated. Carcinoma: resection of tumor, ipsilateral thyroid lobe, and enlarged lymph nodes Nonsurgical: in symptomatic patients who are not able to undergo surgery or asymptomatic patients who do not meet the criteria for surgical therapy Calcimimetics (e.g., cinacalcet) Parathyroid chief cells do not respond adequately to serum calcium changes in pHPT. Calcimimetics are a new class of drugs that increase the calcium sensitivity of parathyroid chief cells and therefore modulate unregulated and excessive PTH secretion in response to the moderate serum calcium changes observed in pHTP. In patients with osteoporosis: bisphosphonates Avoid lithium and thiazide diuretics. For treatment of acute hypercalcemia, see calcium homeostasis. Secondary hyperparathyroidism Treat the underlying condition (e.g., see treatment of chronic kidney disease) and focus on treating hyperphosphatemiaDietary phosphorus restriction (e.g., no soft cheese, nuts)If dietary restriction alone is unsuccessful → add phosphate binders (calcium acetate, calcium carbonate, sevelamer, lanthanum) In case of vitamin D deficiency: substitute with ergocalciferol Tertiary hyperparathyroidism Similar to pHPT

Hypoglycemia Hypoglycemia, or low blood glucose, has many causes, but it most commonly occurs in diabetic patients as a consequence of insulin therapy or other drugs. The onset of hypoglycemic symptoms depends largely on the individual's physiological adaptation mechanisms, although symptoms can start to occur when blood glucose falls below 70 mg/dL. Hypoglycemia manifests with autonomic symptoms (i.e., hunger, sweating, tachycardia) and neuroglycopenic symptoms (i.e., confusion, behavioral changes, somnolence). Since prolonged hypoglycemia can result in acute brain damage, changes in a patient's mental status should prompt immediate fingerstick blood glucose measurement and treatment. Treatment in patients who are still conscious consists of a fast-acting carbohydrate such as glucose tablets, candy, or juice. Unresponsive patients are treated with intravenous dextrose or intramuscular glucagon.

Definition Defining cutoff: There is no specific cutoff that defines hypoglycemia, as there is considerable variability in the serum glucose level at which a person will experience symptoms of hypoglycemia. In patients with diabetes: generally described as ≤ 70 mg/dL (≤ 3.9 mmol/L). [1] Whipple triad [1][2]Low plasma glucose concentration Signs or symptoms consistent with hypoglycemia (see "Clinical features" below)Relief of symptoms when plasma glucose increases after treatment Diabetic patients Causes of hypoglycemia in diabetic patientsInsulin-relatedInsulin excessAccidental overdose of insulin or noninsulin drugs (e.g., sulfonylureas, meglitinides)Wrongly timed medicationDrug interactionsFactitious disorderReactive hypoglycemiaIncreased sensitivity to insulinWeight lossIncrease in activity/exerciseDecreased insulin clearanceRenal failureGlucose-relatedFasting/missed meals Chronic alcohol use Exercise Acute illnessSepsisTraumaBurnsOrgan failure (Relative) overdose of insulin or a noninsulin drug is by far the most common cause of hypoglycemia. Consider factitious disorder in patients with access to insulin and other diabetes medications (e.g., healthcare professionals), for whom there is no other obvious explanation for hypoglycemia. Causes of hypoglycemia in nondiabetic patientsCritical illnessHepatic disease Renal failureHeart failureMalnutritionSepsisTraumaBurnsDrugs that cause hypoglycemia [3] Nonselective beta blockers Antimalarial drugs: quinine, chloroquineAntibiotics: sulfonamides, trimethoprim-sulfamethoxazole, fluoroquinolonesAntifungal drugs: pentamidine, oxalineAnalgesics: indomethacin, propoxyphene/dextropropoxypheneAntihypertensive drugs: ACE-inhibitors, angiotensin receptor antagonistsAntiarrhythmics: cibenzoline, disopyramideOthers: IGF-1, lithium, mifepristone, heparin, 6-mercaptopurineHormone deficienciesHypopituitarismAdrenal insufficiencyEndogenous hyperinsulinism or IGFInsulinomaNoninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)Gastric bypass surgery (late dumping syndrome) Nonislet cell tumor hypoglycemiaExogenous hyperinsulinismFactitious disorderAccidental insulin useAutoimmune causesInsulin autoimmune syndrome (IAS)Anti-insulin receptor autoantibodies Genetic and congenital disorders [4]Congenital hypopituitarismGlycogen storage diseasesFructose intolerance Clinical features Threshold for symptoms Varies greatly, but symptoms have usually occurred by the time serum glucose concentration is < 50 mg/dL(2.8 mmol/L) The threshold at which symptoms may appear in patients with chronic diabetes is especially variable due to hypoglycemia-associated autonomic failure (HAAF). [1]Recurrent hypoglycemia → changes in the counterregulatory response (e.g., decreased epinephrine release) → lower glucose threshold needed to trigger symptoms → asymptomatic hypoglycemiaFor this reason, the initial symptom of hypoglycemia in patients with HAAF is often confusion. The threshold can also vary due to medication: Beta blockers can mask signs of hypoglycemia. Signs and symptoms Neurogenic/autonomicIncreased sympathetic activity: tremor, pallor, anxiety, tachycardia, sweating, and palpitationsIncreased parasympathetic activity: hunger, paresthesias, nausea, and vomiting Neuroglycopenic Agitation, confusion, behavioral changesFatigueSeizure, focal neurological signs Somnolence → obtundation → stupor → coma Beta blockers can mask signs of hypoglycemia. Diagnostics General diagnostic approach Confirm low blood glucose (via fingerstick or BMP) and check for Whipple triad. Rule out acute illness as a cause (e.g., infection, sepsis, burns). Review the patient's medications to rule out medication as a cause (see drugs that cause hypoglycemia). Perform diagnostic workup based on the leading differential diagnosis and whether the patient has diabetes or not. If the Whipple triad is not confirmed, no further workup is indicated. Diabetic patients [1] Hypoglycemia in diabetic patients is almost always due to acute illness and/or medications (e.g., insulin) and further workup is generally not indicated. Initial workup if no obvious trigger identified: Labs: CBC, BMP, LFTs, urinalysisImaging: X-ray chestInfectious workupConsider sulfonylurea and exogenous insulin levels. Nondiabetic patients [2] Rule out acute illness and medication as a cause. Further diagnostic testing should only be pursued if the cause is not evident based on history and examination (and with the guidance of an endocrinologist). The goal is to determine if the hypoglycemia is due to hyperinsulinemia (e.g., insulinoma). Laboratory studies The following labs should be obtained during a hypoglycemic episode (or 72-hour fast if no spontaneous hypoglycemic episode is documented): Insulin antibodiesSulfonylurea level (and any other oral antidiabetic agents)β-hydroxybutyrateProinsulinC-peptideGlucoseInsulin Glucagon tolerance test (see below) Consider also: anti-insulin receptor antibodies, IGF-1/IGF-2, cortisol, glucagon, growth hormone 72-hour fast [2] Procedure: The patient fasts for 72 hours, only drinking noncaloric beverages, and all nonessential medications are discontinued. Measure insulin, C-peptide, and glucose every 4-6 hours. Once plasma glucose < 45 mg/dL or < 55 mg/dL with documented Whipple triad, obtain serum studies (see "Laboratory studies" above).After serum studies have been obtained, continue with a glucagon tolerance test and end the fast.This should be done on an inpatient basis and under the guidance of an endocrinologist. LimitationsResults may be inaccurate if the physiological glucose level is low.Rarely, insulinomas may suppress insulin release in response to hypoglycemia.Insulin levels can be artificially elevated in the presence of circulating anti-insulin antibodies. The 72-hour fast is only necessary if a spontaneous hypoglycemic episode does not occur. Glucagon tolerance test Procedure: After the 72-hour fast has ended, inject glucagon. Measure serum glucose and insulin at baseline, then at 10, 20, and 30 minutes after glucagon injection. Normal response: rapid insulin response, up to 100 uU/mL; glucose peak at 20-30 minutes Insulinoma patients: exaggerated insulin response (exceeding 160 uU/mL); peak insulin at 15 minutes LimitationsUnreliable in patients with malnutrition, hepatic disease, and cirrhosis with portocaval anastomosisMedication interference: diazoxide, hydrochlorothiazide, diphenylhydantoin, sulfonylureas, aminophyllinePatients with nonislet cell tumors can have insulinoma-like responses.The glucagon tolerance test can induce nausea, vomiting, and hypoglycemia.In 8% of insulinomas, the expected peak is not observed. Interpreting the results of fasting labs and the glucagon tolerance test [2][1] Serum levelsHypoglycemia without hyperinsulinismHyperinsulinism (or ↑ IGF)GlucoseLowLowInsulinLow/normalElevatedProinsulin, C peptideLow/normalExogenous: lowEndogenous: normal/highβ-hydroxybutyrateNormalLowGlucose response to glucagonDiminished responseNormal response Nonsuppressed serum insulin concentrations with decreased serum C-peptide and proinsulin concentrations are consistent with exogenous insulin use. Imaging Indications: labs consistent with endogenous hyperinsulinism (e.g., insulinoma) [5] Usually, combined imaging is required to confirm the diagnosis of insulinoma (CT scan and MRI ) Treatment If the patient is conscious:Oral glucose 15-20 gFast-acting carbohydrates (such as glucose tablets, candy, or juice) If the patient is unconscious (or unable to ingest glucose): [2]IV dextrose Subsequent dextrose infusions (D5NS or D10NS infusion) may be needed to maintain glucose levels.Monitor glucose every 2 hours and titrate infusion to maintain serum glucose > 100 mg/dL.IM glucagon: if neither oral or IV routes of administering glucose are feasible Monitoring Recheck POC glucose after 15 minutes.Consider ICU admission with hourly glucose monitoring if hypoglycemia is refractory. Suspected severe hypoglycemia should be treated immediately, without waiting for the results of blood glucose testing!

Metabolic syndrome Metabolic syndrome describes a constellation of medical conditions which increase the risk for several health problems, primarily cardiovascular disease, type 2 diabetes, and fatty liver.These conditions include insulin resistance (considered the main risk factor), hypertension, dyslipidemia, and abdominal obesity. The primary goal in treating metabolic syndrome is therefore to initiate lifestyle changes, which include dietary modifications and physical exercise. These measures often result in lowered blood pressure and triglyceride levels, as well as increased insulin sensitivity. Symptoms that do not respond sufficiently to these changes, such as persistent hypertension or hyperglycemia, are treated with drugs (e.g., ACE inhibitors, metformin).

Definition Metabolic syndrome Presence of ≥ 3 of the following conditions (or already receiving medical treatment for them) Insulin resistance: fasting glucose ≥ 100 mg/dLElevated blood pressure: ≥ 130/85 mm HgElevated triglycerides: ≥ 150 mg/dL Low HDL-C: in men < 40 mg/dL; in women < 50 mg/dLAbdominal obesity: waist circumference ≥ 102 cm in men; ≥ 88 cm in women Weight StatusBody Mass Index (BMI) Underweight< 18.5Normal or Healthy Weight18.5-24.9Overweight≥ 25-29.9Class I Obesity30-34.9Class II Obesity35-39.9Class III Obesity≥ 40 Treatment First-line: lifestyle modificationsDietary changes: calorie restriction, healthy foods (e.g., fruit/vegetables, protein-rich, unsaturated fats, sodium-restricted) Physical activity: minimum of 30 minutes moderate exercise per day (2.5 hours per week) , which increases insulinsensitivity, lowers blood pressure, and promotes weight loss Medical therapy: treat hypertension (e.g., ACE inhibitors), diabetes mellitus, and dyslipidemia (e.g., with statins) Bariatric surgery: if BMI ≥ 40 and no success with dietary and lifestyle changes Sleeve gastrectomy (most common): large part of the greater curvature is removed, so that the remaining stomachresembles a sleeveRoux-en-Y gastric bypass (2nd most common): Roux-en-Y Complications Metabolic syndrome is associated with increased risk of: Cardiovascular disease Type 2 diabetes Non-alcoholic steatohepatitis → increased risk of developing liver cirrhosis and hepatocellular carcinoma

Osteoporosis Osteoporosis is a skeletal condition in which the loss of bone mineral density leads to decreased bone strength and an increased susceptibility to fractures. The disease typically affects postmenopausal women and the elderly, as an abrupt decrease in estrogen and age-related processes play a key role in the development of osteoporosis. Further risk factors include inactivity, smoking, and alcohol consumption. Osteoporosis usually remains asymptomatic until the first occurence of fragility fractures (following minor trauma), particularly of the vertebrae. After repeated vertebral fractures, patients may also develop thoracic hyperkyphosis and lose height. Osteoporosis is diagnosed through a bone density test (dual-energy X-ray absorptiometry), while fractures are usually confirmed through conventional x-ray. Management of osteoporosis includes prophylactic measures and medical therapy. The prophylaxis consists mainly of adequate intake of calcium and vitamin D and regular physical activity with strengthening exercises. Both help to maintain or even increase bone mass and improve balance, thereby reducing the risk of falling. Medical therapy is indicated in cases of severely reduced bone density or osteoporotic fractures. The most commonly used drugs are bisphosphonates, which inhibit bone resorption and can significantly decrease the risk of fractures. There are several other possible medical therapies (e.g., teriparatide, raloxifene), which may be indicated in special cases (e.g., severe osteoporosis, breast cancer prophylaxis required) or if patients have contraindications to bisphosphonates.

Definition Osteoporosis: insufficient bone strength with increased susceptibility to fractures Osteopenia: decreased bone strength but less severe than osteoporosis Epidemiology Sex: ♀ > ♂ (∼ 4:1) Age of onset: 50-70 years Demographics: higher incidence in individuals of Asian, Hispanic and northern European ancestry than in black populations Etiology Primary osteoporosis (most common form)Type I (postmenopausal osteoporosis): postmenopausal womenEstrogen stimulates osteoblasts and inhibits osteoclasts. The decreased estrogen levels following menopauselead to increased bone resorption.Type II (senile osteoporosis): gradual loss of bone mass as patients age (especially > 70 years) Secondary osteoporosisDrug-induced/iatrogenic: especially after systemic long-term therapy with corticosteroids (e.g., in patients with autoimmune disease) Other: Long-term therapy with anticonvulsants, L-thyroxine, anticoagulants,proton-pump inhibitors, aromatase inhibitorsEndocrine/metabolic: hypercortisolism, hypogonadism, hyperthyroidism, hyperparathyroidism, renal diseaseMultiple myelomaImmobilizationAlcohol abuse Risk factorsCigarette smokingFamily history of osteoporosisMalabsorption, malnutrition (e.g., a vegan diet low in calcium and vitamin D)Low body weight Clinical features Mostly asymptomatic Pathological fractures: spontaneous fracture following mild physical exertion or minor trauma (e.g., lifting something, bending over, or sneezing/coughing)Localizations: vertebral (most common) > femoral neck > distal radius (Colles) fracture (Colles fracture), fracturesof the long bones (e.g., humerus)Vertebral compression (crush) fractures are commonly asymptomatic, but may cause acute back pain and possible point tenderness without neurological symptomsLong-term findings after repeated vertebral compression fractures→ Decreased height (loss of 2-3 cm with each fracture)→ Thoracic hyperkyphosis → stooped posture with a "dowager's hump" Diagnostics DXA (dual-energy X-ray absorptiometry)Calculates bone mineral density (BMD) in g/cm2Indications General recommendation for women ≥ 65 years and men ≥ 70 yearsIn younger individuals if additional risk factors are present (e.g., prolonged glucocorticoid use, low BMI(< 21 kg/m2) or weight < 127 lb, alcohol use, smoker, amenorrhea)Results: T-score Osteoporosis: T-score ≤ -2.5 SDOsteopenia: T-score of -1 to -2.5 SD Plain radiographyIf osteoporosis is diagnosed: radiographic assessment of the whole skeletal system is recommended, particularly if a fracture is already suspected or height loss has occurredIncreased radiolucency is detectable in cortical bones once 30-50% of bone mineral has been lost Osteoporosis can be diagnosed if vertebral compression fractures are present Commonly an incidental finding because such fractures are typically asymptomatic Clinical chemistry: usually normal (see Laboratory evaluation of bone disease), but some markers may be used for assessing risk of fracture Urine: ↑ cross-links (e.g., deoxypyridinoline), markers of bone turnover Blood testsPrimary osteoporosis: Alkaline phosphatase possibly elevated Other parameters normal (e.g., serum calcium, phosphate)Secondary osteoporosis: abnormal results depending on underlying disease (e.g., hypercalcemia in hyperparathyroidism) Pathology: Thin, disconnected trabecular structuresAttenuated, pitted cortical boneIncreased osteoclast number and activity Osteoporosis is diagnosed if T-score ≤ -2.5 SD and/or a fragility fracture is present. Differential diagnoses Osteomalacia Hyperparathyroidism Metastases Multiple myeloma Intraosseous hemangioma Treatment Lifestyle measures Diet Avoid alcohol and nicotineSufficient intake of calcium and vitamin D Physical activity with strength and balance training Avoid or minimize glucocorticoids Medical therapy IndicationHistory of fragility fracturesT-scores ≤ -2.5T-score between -1 and -2.5 with severely increased risk of fracture Drugs1st-line treatment: bisphosphonates (alendronate, risedronate); inhibit osteoclasts and therefore bone resorptionAlternative treatment options: in the case of contraindications/unresponsiveness to bisphosphonates or certain risk factors Teriparatide (parathyroid hormone analog): alternative for severe osteoporosis (T-score ≤ -3.5) or for patients with contraindications to bisphosphonates Raloxifene (selective estrogen receptor modulator, SERM) for patients with contraindications to bisphosphonates or those who also require breast cancer prophylaxis (but increases the risk of thromboembolism) Denosumab (monoclonal antibody against RANKL) : for patients with impaired renal function, or no success with bisphosphonates Consider hormonal therapyEstrogens: for women with intolerance to 1st- or 2nd-line treatment options or with persistent menopausalsymptoms Usually in combination with progestinContraindications: breast cancer, coronary heart disease, deep vein thrombosisTestosterone: for men with hypogonadism Bisphosphonates should be taken in the morning and evening at least 30 minutes before meals to prevent bisphosphonatesfrom forming complexes with calcium. To prevent esophagitis, they should also be taken with plenty of water and an upright position should be maintained for at least 30 minutes following intake!

Lipid disorders Lipid disorders encompass a broad spectrum of metabolic conditions that affect blood lipid levels. They are generally characterized by elevated levels of cholesterol, triglycerides, and/or lipoproteins in the blood in association with an increased risk of (or current) cardiovascular disease. The majority of lipid disorders are acquired through unhealthy lifestyles (obesity, inactivity, alcoholism). Congenital causes are less common; examples include familial hypertriglyceridemia, which is associated with extremely high levels of triglycerides that significantly increase the risk of pancreatitis, and familial hypercholesterolemia that results in early atherosclerotic complications. Lipid disorders are usually detected during routine laboratory testing, such as cardiovascular risk factor screening. The blood lipid profile includes total cholesterol, LDL, HDL, and triglycerides. To confirm the diagnosis, a fasting lipid profile must show pathological values on two different occasions. Dyslipidemia is diagnosed if LDL levels > 130 mg/dL and/or HDL levels < 40 mg/dL. The management of lipid disorders involves lifestyle modifications and lipid-lowering agents (primarily statins).

Definition The following terms are often used interchangeably, as they share common causes and are all associated with an increased risk of atherosclerosis and cardiovascular disease. However, the terms have differing meanings. Dyslipidemia: abnormal lipoprotein levels (LDL and HDL) in association with an increased risk of cardiovascular disease or current cardiovascular disease Hyperlipidemia: elevated blood lipid levels (total cholesterol, LDL, triglycerides) Hypercholesterolemia: elevated total cholesterol> 200 mg/dL Hypertriglyceridemia: elevated triglyceride levels Hyperlipoproteinemia: elevated levels of a certain lipoprotein Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease! Epidemiology In the US, an estimated 50% of the population has elevated cholesterol levels. Etiology Congenital (less common)Type I - Hyperchylomicronemia: Autosomal recessive condition that is not associated with an increased risk of atherosclerosis. Patients develop eruptive xanthomas, pancreatitis, and hepatosplenomegaly.Type IIa - Familial hypercholesterolemia: Autosomal dominant condition associated with mutations in the LDL receptor that lead to elevated LDL levels with early atherosclerotic complications (cardiovascular disease)Type III - Familial dysbetalipoproteinemia: Autosomal recessive condition associated with defective ApoE that leads to elevated LDL levels with early atherosclerotic complications (cardiovascular disease)Type IV - Familial hypertriglyceridemia: Autosomal dominant condition associated with an increased risk of acute pancreatitis Acquired (more common) ObesityDiabetes mellitusPhysical inactivityAlcoholismHypothyroidismNephrotic syndrome Cholestatic liver disease Cushing diseaseDrugs: oral contraceptive pill, high-dose diuretic use, metoprolol Fredrickson phenotypeIIIaIIbIIIIVConditionFamilial hyperchylomicronemia [6]Familial hypercholesterolemia[7]Familial combined hyperlipidemia [8]Familial dysbetalipoproteinemia [9]Familial hypertriglyceridemia[10]FrequencyRare∼ 10%1-15%∼ 5%∼ 70%InheritanceAutosomal recessiveAutosomal dominantAutosomal recessiveAutosomal dominantPathogenesisDeficiency of lipoprotein lipaseORDeficiency of apolipoprotein C-IIDefective LDL receptorsORDefective ApoB-100Defective ApoEHepatic overproduction of VLDLClinical manifestationsEruptive xanthomas [6] HepatosplenomegalyRecurrent episodes of acute pancreatitis and/or abdominal pain Lipemia retinalisBile duct stenosisNo increased risk for artherosclerosisPremature atherosclerosis Arcus lipoides Tuberous/tendon xanthomas in type IIaXanthelasma in type IIbPremature atherosclerosisPalmar and tuberoeruptivexanthomasPremature atherosclerosisTuberoeruptive xanthomasAcute pancreatitisFeatures of hyperglycemiaLipoproteindefectChylomicronsLDLLDL and VLDLRemnants of VLDL and chylomicronsVLDLTotal cholesterolNormal to mild ↑ [11]↑↑↑↑↑Normal to mild ↑Total triglycerides↑↑ [11]Normal↑↑↑↑Overnight plasma Creamy top layer [11]ClearClearTurbidTurbid Pathophysiology Elevated LDL and reduced HDL → promote atherosclerosis → increased risk of cardiovascular eventsSee pathogenesis of atherosclerosis for details. Clinical features Typically no specific signs or symptoms Skin manifestations Xanthoma: nodular lipid deposits in the skin and tendonsPathophysiology: Extremely high levels of triglycerides and/or LDL result in extravasation of plasma lipoproteins and their deposition in tissue. Eruptive xanthomas: yellow papules with an erythematous border; located on the buttocks, back, and the extensor surfaces of the extremitiesOccurrence: hypertriglyceridemia (chylomicron or VLDL); also lipoprotein lipase deficiency Tendinous xanthomas: firm nodules, located in tendons (typically extensor tendons of hands and the Achilles tendon)Occurrence: severe hypercholesterinemia, ↑ LDL levelsPalmar xanthomas: yellow plaques on the palms of the handsOccurrence: type III hyperlipoproteinemia, ↑ VLDLXanthelasmas: nodular lipid deposits around the eyelids Typically bilateral, yellow, flat plaques on the upper eyelids (nasal side)Etiology: idiopathic; often occurs in association with hypercholesterolemia (e.g., primary biliary cholangitis), hyperapobetalipoproteinemia, ↑ LDL levelsIncreased incidence in Patients suffering from diabetes mellitusPatients with increased lipoproteins in plasmaUsually affects postmenopausal women Eye manifestations Lipemia retinalis: opaque, white appearance of the retinal vessels, visible on fundoscopic examArcus lipoides corneae Fatty liver (hepatic steatosis) Severe hypertriglyceridemia (typically > 1000 mg/dL) → pancreatitis Atherosclerosis with secondary diseasesCoronary heart diseaseMyocardial infarctionStrokePeripheral arterial diseaseCarotid artery stenosisCholesterol embolization syndrome Diagnostics Laboratory analysisFasting lipid profile : total cholesterol, HDL, and triglycerides are measured LDL level can be measured directly using assays or estimated using the Friedewald formulaPathological values from two different occasions are required to confirm the diagnosis.Dyslipidemia is diagnosed if LDL > 130 mg/dL. and/or if HDL levels < 40 mg/dLIdentify underlying cause Fasting blood glucose level or Hb1AcTSH levelLiver function testsUrine analysis Parameters of fat metabolismLaboratory parameterOptimal level (mg/dL)Pathological (mg/dL)Total cholesterol< 200Borderline: 200-239High: > 240 Triglycerides < 150Borderline: 150-199High: > 200Very high: ≥ 500LDL< 100Near optimal: 100-129Borderline high: > 130High: > 160Very high: ≥ 190HDL≥ 60Low: < 40 ther workup required in patients with confirmed dyslipidemia Assess for cardiovascular disease (CVD)Myocardial infarctionStrokeSymptomatic carotid artery stenosisPeripheral artery diseaseAbdominal aortic aneurysmOr CVD risk equivalents: diabetes mellitus, chronic kidney disease Assess for other major risk factors of CVDSmokingHypertensionElevated total cholesterol, LDL, and/or low HDL Family history of CHD (first degree relative ♂ < 55 years; ♀ < 65 years)Age: ♂ ≥ 45 years; ♀ ≥ 55 years Treatment Goal: Improve serum lipid levels to reduce the risk of cardiovascular disease. General measures: lifestyle modifications Dietary changes: Reduce saturated fat and cholesterol intake. Weight managementPhysical activity Medical therapy StatinsSecond-line lipid-lowering agents Treatment of xanthomas and xanthelasmas: Not required in most cases; Surgical removal for cosmetic reasons is possible but is associated with a high rate of recurrence. Management of congenital disorders: lifestyle modifications and lipid-lowering agents (high-dose statin therapy and ezetimibe for hypercholesterolemia, fibrates for hypertriglyceridemia); LDL apheresis may be required in severe cases. ACC/AHA guidelines Initiate moderate-intensity or high-intensity statin therapy. Clinical atherosclerotic cardiovascular disease (ASCVD) : high-intensity statin therapy (age > 75 years: moderate-intensity statin therapy)LDL ≥ 190: high-intensity statin therapyAge 40-75 years + Diabetes (if LDL 70-189)Age 40-75 years + 10 year ASCVD risk > 7.5% (if LDL 70-189) Risk stratification LDL goal (mg/dL)Lifestyle modifications indicated (mg/dL)Medical therapy indicated (mg/dL)ASCVD or risk equivalents (high risk > 20%)< 100 (or < 70 )> 100> 130≥ 2 Risk factors (moderate risk)< 130> 130> 1600-1 Risk factors (low risk)< 160> 160> 190 Prevention The decision to screen for hyperlipidemia primarily depends on the patient's overall risk for cardiovascular disease. Screening high-risk individuals (i.e., with other risk factors for cardiovascular disease): ♂ > 20-25 years; ♀> 30-35 years Screening low-risk individuals: ♂ > 35 years; ♀ > 45 years Abetalipoproteinemia Etiology deficiency of apolipoproteins (ApoB-48, ApoB-100) Due to mutation in the microsomal triglyceride transfer protein (MTTP) gene Pathophysiology: autosomal recessive disease; deficiency of chylomicrons, VLDL, and LDL. Clinical featuresEarly: steatorrhea, failure to thrive, fat malabsorption, fat-soluble vitamin deficiency, acanthocytosis.Late: developmental delay, retinitis pigmentosa, myopathy, progressive ataxia, spinocerebellar degeneration. DiagnosisExtremely low levels of plasma cholesterol (< 50 mg/dL)Acanthocytes in the bloodAbsent LDL in the bloodOther tests performed include: complete blood count with differential, stool studies, fasting lipid profileConfirmatory test: genetic testing to detect mutations in the MTTP gene.Intestinal biopsy: microscopic evaluation may reveal lipid-laden enterocytes TreatmentRestriction of long-chain fatty acidsLarge doses of oral vitamin E

Bisphosphonates Bisphosphonates (e.g., etidronate, alendronate) are used for the treatment of hypercalcemia and bone metabolism disorders, such as osteoporosis or tumor-induced osteolysis. All bisphosphonates primarily slow down the degradation of bone substance by interfering with osteoclast function. Important side effects of bisphosphonate therapy include hypocalcemia, renal impairment, and aseptic osteonecrosis of the jaw. Therefore, bisphosphonates are contraindicated in patients with hypocalcemia and those with a limited glomerular filtration rate (GFR). Additionally, oral bisphosphonates may cause esophageal damage while IV bisphosphonates can induce flu-like symptoms.

Effects Bisphosphonates bind to hydroxyapatite binding sites on the surface of bone tissue → uptake by osteoclasts during phases of bone resorption → interference with osteoclast function and promotion of osteoclast apoptosis→ reduced bone resorption Also inhibit mineralization Bisphosphonates also reduce bone formation since bone resorption and formation are intrinsically connected! However, bone resorption is reduced more severely than bone formation Side effects General Hypocalcemia and hypophosphatemia (hypocalcemia can also lead to osteomalacia, see osteomalacia and rickets) Aseptic osteonecrosis of the jaw: mostly in high-dose IV administration in tumor patients, but can also occur with oral administration and in other patients Atypical fractures (particularly of the femur)Musculoskeletal painAtrial fibrillationRenal impairmentOcular inflammation and visual disturbances Oral bisphosphonates (alendronate, risedronate, etidronate, tiludronate): esophageal inflammation and cancer IV bisphosphonates (zolendronate): acute-phase reaction with flulike symptoms (e.g., fever, joint, and muscle pain) 24-72 hours after administration Bisphosphonates should be taken in the morning with sufficient water and in an upright position at least 60 minutes before eating! Indications Osteoporosis Hypercalcemia Tumor-induced osteolysis Multiple myeloma Paget's disease of bone Hereditary skeletal disorders Contraindications Reduced GFR (< 30-35 ml/min) Hypocalcemia Esophageal abnormalities (e.g., strictures) Pregnancy/lactation period: no clear contraindications, individual risks/benefits must be weighed

Acromegaly Acromegaly is a condition in which benign pituitary adenomas lead to an excess secretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). In adults, whose epiphyseal plates are closed, the disease causes enlarged hands and feet, coarsened facial features, and pathological growth of internal organs. If the condition occurs in children, before epiphyseal plate closure, it is known as gigantism, which is discussed in a separate learning card. The first step in diagnosing acromegaly is to measure IGF-1 levels. Further testing includes an oral glucose tolerance test (OGTT) with assessment of GH levels, and evaluation of pituitary tumors via cranial MRI. Management consists of transsphenoidal adenomectomy for operable tumors, or GH-inhibiting medication and radiotherapy if surgery is contraindicated or unsuccessful. Adequate treatment is vital to reduce the risk of complications, such as cardiovascular disease and cerebral aneurysms, as these may considerably increase mortality.

Epidemiology Age of onset: 3rd decade of life (mean age at diagnosis usually 40-45 years) Etiology Benign growth hormone-secreting pituitary adenoma (> 95% of cases) Very rare: neuroendocrine or hypothalamic tumors, paraneoplastic syndromesEctopic secretion of growth hormone by neuroendocrine tumors (e.g., small cell lung carcinoma, pancreaticislet-cell tumor (as found in MEN1) ↑ Secretion of growth hormone-releasing hormone (GHRH) from a hypothalamic tumor or in paraneoplastic syndromes (e.g., small cell lung carcinoma, medullary thyroid cancer) Pathophysiology Physiology of GH and IGF-1 GH secretion induced by stress, sport, and hypoglycemia; inhibited especially by hyperglycemia or food intakeHypothalamus secretes GHRH → ↑ secretion of GH → GH induces IGF-1 synthesis → ↑ serum IGF-1 via liversynthesis : → Binds to IGF-1 and insulin receptors → stimulation of cell growth and proliferation, inhibits programmed cell deathProliferative effects especially on bone, cartilage, skeletal muscle, skin, soft tissue, and organsImpaired glucose tolerance caused by binding to insulin receptors→ ↑ Secretion of somatostatin from the hypothalamus → ↓ serum GH and IGF-1 (negative feedback) Effects of a pituitary adenomaOverproduction of GH → abnormally high serum IGF-1 levels → overstimulation of cell growth and proliferation→ symptoms of acromegalyTumor mass compresses neighboring structures (e.g., optic chiasm) → symptoms of mass effectImpaired secretion of other pituitary hormones possible, especially gonadotropins → ↓ LH and FSH → ↓ estrogenand testosterone Excess GH secretion before the conclusion of longitudinal growth (i.e., prior to epiphyseal plate closure) leads to pituitary gigantism with a possible height of ≥ 2 m. After epiphyseal plate closure, GH excess causes acromegaly, but no change in height! Clinical features Tumor mass effects Headache, vision loss (bitemporal hemianopsia), cranial nerve palsies♀: Oligomenorrhea, secondary amenorrhea, galactorrhea, vaginal atrophy♂: Erectile dysfunction, decreased libido, ↓ testicular volume Soft tissue effectsDoughy skin texture, hyperhidrosis Deepening of the voice, macroglossia with fissures, obstructive sleep apnea Carpal tunnel syndrome Skeletal effectsCoarsening of facial features slowly progressing with age : enlarged nose, forehead, and jaw (macrognathia) with diastema Widened hands, fingers, and feet Painful arthropathy (ankles, knees, hips, spine) Cardiovascular disease: hypertension (∼ 30% of cases), left ventricular hypertrophy, cardiomyopathy Organ enlargement: especially kidneys and thyroid gland Effects of impaired glucose tolerance, diabetes mellitus (up to 50% of cases) Increased risk of colorectal polyps and cancer Consider acromegaly in patients who report having had to increase hat, shoe, glove, and ring sizes in the past! Diagnostics Hormone analysis↑ Serum IGF-1 concentration Normal IGF-1 levels rule out acromegalyIf ↑ IGF-1: conduct OGTT with baseline GH and measure GH after 2 hours → If GH suppressed to less than 1 μg/L (2 mU/l): acromegaly ruled out→ If GH not suppressed: confirmed acromegaly; conduct pituitary MRI Pituitary MRIUsually shows a visible mass: confirmed GH-secreting pituitary adenomaIf normal: screen for an extrapituitary cause (e.g., CT scan of the chest and abdomen, measure GHRH) Tumor DNA analysisShows an activating mutation of adenylyl cyclase → overexpression of G-protein coupled receptorFound in 40% of patients Differential diagnoses Gigantism: excess GH secretion in children, before epiphyseal plate closure Marfan syndrome Pseudoacromegaly (e.g., medication-induced): insulin resistance, acromegaloid features, normal GH and IGF-1 Prolactinoma: pituitary tumor; excess of prolactin, not GH Familial tall stature Sotos syndrome McCune-Albright syndrome Treatment Transsphenoidal adenomectomy is the method of choice for treating acromegaly. In patients with inoperable tumors or unsuccessful surgery, medication and radiotherapy are indicated to reduce tumor size and limit the effects of GH and IGF-1. Surgery: transsphenoidal adenomectomy MedicationSomatostatin analogs (e.g., octreotide, lanreotide) Dopamine agonists (e.g., cabergoline): reduce tumor size and GH secretion GH receptor antagonists (e.g., pegvisomant) RadiotherapyConventional fractionated radiotherapy Stereotactic radiosurgery (e.g., Gamma Knife, CyberKnife, proton beam) Danger of hypopituitarism following surgery or radiotherapy! Complications Complications lead to increased mortality Cardiovascular complications (CHF, hypertension, arrhythmia, valvular disease, hypertrophy): the main cause of death Diabetes mellitus Neoplastic disease (e.g., colon cancer, thyroid cancer) Cerebral aneurysm Sleep apnea Hypopituitarism Carpal tunnel syndrome Psychological impairment (↓ quality of life, anxiety, ↓ self-esteem)

Pheochromocytoma A pheochromocytoma is a catecholamine-secreting tumor that typically develops in the adrenal medulla. Pheochromocytomas are usually benign (∼ 90% of cases) but may also be malignant. Classic clinical features are due to excess sympathetic nervous system stimulation and involve episodic blood pressure crises with paroxysmal headaches, diaphoresis, heart palpitations, and pallor. However, pheochromocytomas may also be asymptomatic or manifest with persistent hypertension. Elevated catecholamine metabolites in the plasma or urine confirm the diagnosis, while imaging studies in patients with positive biochemistry are used to determine the location of the tumor. Surgical resection is the treatment of choice but is only carried out once alpha blockade with phenoxybenzamine has become effective.

Epidemiology Age range: 3rd-5th decades of life Present in up to 1% of all hypertensive patients Etiology Tumor arise from chromaffin cells, which are derived from the neural crest. Localization ∼ 90% adrenal medulla (physiologically activated by acetylcholine) ∼ 10% extra-adrenal in the sympathetic ganglia ∼ 10% at multiple locations The majority of pheochromocytomas are benign, unilateral, catecholamine-producing tumors. Rarely, pheochromocytomas also produce other hormones such as EPO. 25% of pheochromocytomas are hereditary. Associations include: Multiple endocrine neoplasia type 2 (MEN 2A, MEN 2B)Neurofibromatosis type 1 (NF1)Von Hippel-Lindau (VHL) disease "10 percent rule": Roughly 10% of pheochromocytomas are extra-adrenal, multiple, bilateral, malignant, pediatric cases, not associated with hypertension, or show calcifications on imaging! Clinical features Clinical presentation is related to fluctuating levels of excess epinephrine, norepinephrine, and dopamine. Episodic hypertension (or persistent hypertension in some cases) ParoxysmalThrobbing headacheDiaphoresisHeart palpitations and tachycardiaPallor Abdominal pain and nauseaAnxiety Weight loss due to increased basal metabolism Hyperglycemia If EPO is secreted, signs of polycythemia Other features consistent with associated familial disorders: MEN 2A: medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasiaMEN 2B: medullary thyroid cancer, pheochromocytoma, oral/intestinal neuromas, and marfanoid habitusNF1: cutaneous neurofibromas, café-au-lait spots, and Lisch nodulesVHL: renal cell carcinoma, hemangioblastoma, angiomatosis, and pheochromocytoma Hypertensive crises can be triggered by palpation of the tumor on abdominal exam! Diagnostics Laboratory tests Whenever possible, all medications should be put on hold one week prior to testing. Best initial test: metanephrines (metabolites of catecholamines) in plasma (high sensitivity) Confirmatory test: metanephrines and catecholamines in 24-hour urine (high specificity) Clonidine suppression test (rarely used) Principle of the test: In healthy patients, clonidine normally significantly decreases plasma catecholamine levels by at least 30%.Evaluation of results: If pheochromocytoma is present, catecholamine levels will fail to decrease upon clonidineadministration, as the tumor will continue to produce catecholamines. Genetic testing: if MEN2A, MEN2B, NF1, or VHL is suspected Other diagnostic tests 24-hour ambulatory blood pressure monitoring Adrenal/abdominal CT or MRI (after positive biochemistry tests to localize tumor) Scintigraphy (MIBG) Other imaging to search for potential additional tumors in patients with pheochromocytoma and MEN2A, MEN2B, NF1, or VHL Differential diagnoses Pheochromocytoma is often referred to as the great mimic because signs and symptoms are similar to those produced by many other clinical conditions. [7] EndocrineHyperthyroidismCarcinoid syndromeHypoglycemiaMedullary thyroid carcinomaMenopauseMastocytosis CardiovascularHeart failureArrhythmiasIschemic heart disease NeurologicalMigraineStrokeMeningioma MiscellaneousPorphyriaPanic disorderAnxiety disordersDrug-induced Monoamine oxidase inhibitorsSympathomimetic drugsWithdrawal of clonidineRecreational drugs (e.g., cocaine)Factitious disorder Treatment Operable disease: Management consists of preoperative blood pressure management and then surgery. Preoperative blood pressure management: combined alpha and beta-adrenergic blockade First, a non-selective alpha blocker is given : phenoxybenzamine blocks alpha-1 and alpha-2 adrenoceptorsequally and irreversibly (see alpha blockers).. After sufficient alpha-adrenergic blockade, a beta blocker may be started for additional blood pressure control and control of tachyarrhythmias.Treatment of choice: laparoscopic tumor resection (adrenalectomy)"No-touch" technique Open surgical resection is reserved for large or invasive tumors. Starting beta blockers before alpha blockade is contraindicated. Beta blockers cancel out the vasodilatory effect of peripheral beta-2 adrenoceptors, potentially leading to unopposed alpha-adrenoceptor stimulation, causing vasoconstriction and ultimately hypertensive crisis. Inoperable disease Benign pheochromocytoma: primary therapy with phenoxybenzamineMalignant pheochromocytoma: MIBG therapy ; otherwise, palliative treatment (chemotherapy, tumorembolization)

Hypothyroidism Hypothyroidism is a condition in which the thyroid gland is underactive, resulting in a deficiency of the thyroid hormonestriiodothyronine (T3) and thyroxine (T4). In rare cases, hormone production may be sufficient, but thyroid hormones may have insufficient peripheral effects. Hypothyroidism may be congenital or acquired. If congenital, it is usually the result of thyroid dysplasia or aplasia. The etiology of acquired hypothyroidism is typically autoimmune (Hashimoto thyroiditis) or iatrogenic. The pathophysiology in hypothyroidism is characterized mainly by a reduction of the basal metabolic rate and generalized myxedema. Typical clinical findings include fatigue, cold intolerance, weight gain, and periorbital edema. More severe manifestations include myxedematous heart disease and myxedema coma, which may be fatal if left untreated. Children with congenital hypothyroidism often have umbilical hernias and, without early treatment, develop congenital iodine deficiency syndrome (intellectual disability, stunted growth). Accordingly, neonatal screening or hypothyroidism 24-48 hours after birth is required by law in most states. In adults, the diagnosis is established based on serum thyroid-stimulating hormone (TSH) and free T4 levels (FT4). Therapy for both acquired and congenital hypothyroidism consists of lifelong treatment with levothyroxine (L-thyroxine) and regular check-ups to monitor disease activity.

Epidemiology Congenital hypothyroidism: ∼ 1/2300 newborns in the US (1/2000 to 1/4000 worldwide) [1] Acquired hypothyroidism: ∼ 3.7% in the US population (1-3% worldwide) Etiology Congenital hypothyroidism Sporadic (∼ 85% of cases) Thyroid hypoplasia or dysplasiaThyroid aplasia (athyroidism) Hereditary (∼ 15% of cases) Defects in thyroid hormone synthesisPeripheral resistance to thyroid hormones Acquired hypothyroidism Primary hypothyroidism: insufficient thyroid hormone productionHashimoto thyroiditisThe most common cause of hypothyroidism in iodine-sufficient regions [5]Associated with other autoimmune diseases (e.g., vitiligo, pernicious anemia, type 1 diabetes mellitus, and systemic lupus erythematosus) Postpartum thyroiditis (subacute lymphocytic thyroiditis) [5] De Quervain thyroiditis (subacute granulomatous thyroiditis) [5]Iatrogenic (e.g., post thyroidectomy, radioiodine therapy, antithyroid medication such as amiodarone and lithium)Nutritional (insufficient intake of iodine): the most common cause of hypothyroidism worldwide, particularly in iodine-deficient regionsRiedel thyroiditisWolff-Chaikoff effect Secondary hypothyroidism: pituitary disorders (e.g., pituitary adenoma) → TSH deficiency Tertiary hypothyroidism: hypothalamic disorders → thyrotropin-releasing hormone (TRH) deficiency (very rare) Pathophysiology Hypothalamic-pituitary-thyroid axis The hypothalamus, anterior pituitary gland, and thyroid gland, together with their respective hormones, comprise a self-regulatory circuit referred to as the hypothalamic-pituitary-thyroid axis. Physiological: See hypothalamic-pituitary axis. HypothyroidismPrimary hypothyroidism: peripheral (thyroid) disorders → T3/T4 are not produced (decreased levels) → compensatory increase of TSHSecondary hypothyroidism: pituitary disorders → decreased TSH levels → decreased T3/T4 levelsTertiary hypothyroidism: hypothalamic disorders → decreased TRH levels → decreased TSH levels → decreased T3/T4 levels Effects of hypothyroidism [9] Generalized decrease in the basal metabolic rate → decreased oxygen and substrate consumption, leading to: CNS: apathy, slowed cognition Skin and appendages: skin dryness, alopeciaLipid profile: ↑ low-density lipoproteins, ↑ triglycerides Decreased sympathetic activity leads to: Decreased sweatingConstipationBradycardia Decreased transcription of sarcolemmal genes (e.g., calcium ATPases) → decreased cardiac output, myopathy Hyperprolactinemia: prolactin production is stimulated by TRH → increased prolactin suppresses LH, FSH, GnRH, and testosterone secretion; also stimulates breast tissue growth Accumulation of glycosaminoglycans and hyaluronic acid within the reticular layer of the dermis → myxedema Complex protein mucopolysaccharides bind water → nonpitting edemaInitially, edema is pretibial, but as the condition progresses it can generalize, resulting in a range of symptoms (see "Clinical features" below). Clinical features General signs and symptoms Symptoms related to decreased metabolic rateFatigue, bradykinesiaCold intoleranceHair loss and cold, dry skinWeight gain (despite poor appetite)ConstipationBradycardiaMyopathy , myalgia, stiffness, cramps, delayed tendon reflex relaxation (Woltman sign), entrapment syndromes(e.g., carpal tunnel syndrome) Symptoms related to generalized myxedemaDoughy skin texture, puffy appearanceMyxedematous heart disease (dilated cardiomyopathy, bradycardia, dyspnea)Myxedema coma (see "Complications" below)Hoarse voice, difficulty articulating wordsPretibial and periorbital edema Symptoms of hyperprolactinemiaAbnormal menstrual cycle (esp. secondary amenorrhea or menorrhagia) Galactorrhea Decreased libido, erectile dysfunction, delayed ejaculation, and infertility in men Further symptomsImpaired cognition (concentration, memory), depression Hypertension [11]Goiter (in Hashimoto thyroiditis) or atrophic thyroid (in atrophic thyroiditis) Older patients may not have typical symptoms of hypothyroidism. Instead, they may appear to have dementia or depression! Congenital hypothyroidism Children with congenital hypothyroidism may have general signs and symptoms of hypothyroidism in addition to those typical in neonates (see below). PostpartumUmbilical herniaProlonged neonatal jaundiceHypotoniaDecreased activity, poor feeding, and adipsia Hoarse cry, macroglossia Congenital iodine deficiency syndrome: impaired development of the brain and skeleton, resulting in skeletal abnormalities (e.g., short stature and delayed fontanelle closure) and intellectual disabilities Most children with congenital hypothyroidism do not have symptoms at the time of birth because the placenta supplies the fetus with maternal thyroid hormone. For this reason, neonatal screening is vital even if children are asymptomatic! Irreversible intellectual disabilities can be avoided through early initiation of adequate therapy! 7 P's for the manifestations of congenital iodine deficiency syndrome: Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protuberant tongue, Poor brain development, and Prolonged neonatal jaundice. Diagnostics Congenital hypothyroidism Neonatal screening to measure TSH levels 24-48 hours after birth is required by law. Increased TSH levels indicate congenital hypothyroidism. Acquired hypothyroidism Basic diagnostic strategy The initial step is to determine TSH levels, which may be followed by measurement of FT4 levels to confirm or rule out the suspected diagnosis. Overt hypothyroidismPrimary hypothyroidism↑ TSH ↓ Free T4 (FT4) and ↓ free T3 (FT3) levels Secondary hypothyroidism↓ TSHTertiary hypothyroidism FT3 levels are not a good indicator of hypothyroidism. Because of the increased conversion of FT4 to FT3, FT3 levels may be normal even in the case of hypothyroidism. Subclinical hypothyroidism Mildly ↑ TSH Normal FT3 and FT4 levels Euthyroid sicksyndromeNormal TSHNormal FT4 and ↓ FT3 levels (low T3 syndrome)↓ FT3 and ↓ FT4 levels (low T3 low T4 syndrome) Further diagnostic considerations Antibody testingTg Ab (thyroglobulin) and TPO Ab (thyroid peroxidase): detectable in most patients with autoimmune hypothyroidism TRAb (TSH receptor) Thyrotropin-binding inhibitory immunoglobulin assay (TBII assay) Can detect antibodies against the TSH receptor, but cannot determine the type of antibody (blocking, neutral, or stimulating)However, if a patient displays symptoms of hypothyroidism and antibodies are detected via the assay, it is highly likely that these are blocking antibodies. Radioactive iodine uptake test Measures the proportion of exogenous iodine that is taken up by the thyroid (normally 10-35%) Decreased uptake indicates hypothyroidism. Associated conditionsHypercholesterolemia (increased LDL), hyperlipidemia, hypoglycemiaIncreased creatine kinaseMild anemia In rare cases: hyponatremia Normal TSH levels very likely rule out primary hypothyroidism and hyperthyroidism and are therefore the decisive parameter in screening for both conditions! Differential diagnoses Euthyroid sick syndrome (ESS) Synonyms: sick euthyroid syndrome (SES), non-thyroidal illness syndrome (NTI) Occurs in severe illness or severe physical stress (most common in intensive care patients) PathophysiologyNormal thyroid function → no symptoms of hyperthyroidism or hypothyroidismCytokines (e.g., interleukin 6) cause various changes in levels of circulating TSH and thyroid hormones. Altered deiodinase enzyme activity ↓ Conversion of T4 to T3↑ Conversion of T4 to reverse T3 (rT3) by thyroxine 5-monodeiodinase↓ Thyroid binding globulin Clinical features: specific to underlying nonthyroidal illness LaboratoryLow T3 syndrome: decrease in both total and FT3 levels; normal FT4 and TSH, and increased reverse T3FT4 levels may be low in prolonged courses of illness (low T3 low T4 syndrome); indicates a poor prognosis TreatmentTreat underlying illnessThyroid hormone replacement is usually not recommended because thyroid function is normal; there isn't conclusive evidence that thyroid hormone substitution is beneficial to patients with ESS Thyroid hormone resistance Definition: insufficient end-organ sensitivity to thyroid hormones Etiology: deficits in thyroid hormone metabolism, transport, or receptor interaction as a result of genetic mutations Clinical features: Symptoms of both hypothyroidism and hyperthyroidism are possible. Laboratory: Persistently elevated FT4 and FT3 and absent TSH suppression is typical. Therapy: No causative therapy is available. Hashimoto thyroiditisMost common cause of hypothyroidism in the US ♀ > ♂ (7:1) Autoimmune thyroiditis Asymptomatic or transient hyperthyroidism→ hypothyroidism Early-stage: rubbery and symmetrically enlarged Late-stage: normal-sized or small if extensive fibrosishas occurred Painless Anti-TPO and TgAb Patchy and irregular Lymphocytic infiltration with germinal centers and oncocytic-metaplastic cells (Hurthle cells) Postpartum thyroiditis Within 1 year of delivery in 5:100 of women Autoimmune thyroiditis Variant of subacute lymphocytic thyroiditisClassic triphasic course: hyperthyroid → hypothyroid → recovery Diffuse and firm Painless Anti-TPO Reduced RAI Lymphocyticinfiltration Subacute granulomatous thyroiditis (De Quervain)[21]Incidence: 12:100,000 per year ♀ > ♂ (3:1)Viral and mycobacterialinfections causing damage to follicular cells Transient hyperthyroidism→ hypothyroidism Diffuse and firm Painful Ab Absent RAI Reduced Multinucleated giant cells and granulomaformation Congenital hypothyroidism Incidence: 1:2300 newborns ♀ > ♂ (2:1) Thyroiddysgenesis Iodine deficiency Asymptomatic at birth→ hypothyroidism Diffuse or nodular Painless TgAb Absent or patchy Riedel thyroiditis Incidence: 1.6:100,000 per year ♀ > ♂ (4:1) Autoimmune thyroiditis Hypothyroidism in 30% of patients Most patients without hypothyroidism remain euthyroid; very few present with hyperthyroidism. Slowly growing and stone-hard Painless Anti-TPO Normal or reduced RAI Dense and white fibrotic tissue Treatment L-thyroxine replacement L-thyroxine (synthetic form of T4): peripherally converted to T3 (biologically active) and rT3 (biologically inactive). General principlesLifelong replacement Prompt initiation L-thyroxine interactions Increased dosage necessaryEstrogenSERM Bile acid-binding resinsOmeprazoleCalcium carbonate PhenytoinCarbamazepine Propranolol Reduced dosage necessary: glucocorticoids Follow-ups with laboratory controls of thyroid function (TSH) at regular intervals; adjustment of dosage if necessary TSHThyroid metabolismT4-dosage↑DecreasedIncrease✓NormalMaintain↓IncreasedReduce Special considerations Children with congenital hypothyroidism: Normalization of thyroid hormone levels within 2-3 weeks is vital to prevent brain damage and developmental disorders. Pregnant women with preexisting hypothyroidism: Levothyroxine dose must be increased but should be reduced to prepregnancy levels after delivery. Elderly patients or patients with preexisting cardiovascular conditions: Initiate levothyroxine with a lower dose and gradually increase the dose. L-thyroxine replacement in subclinical hypothyroidism if:TSH ≥ 10 mU/LTSH 7.0-9.9 mU/L in asymptomatic patients < 70 yearsTSH above the upper limit of normal to 6.9 mU/L in symptomatic patients < 70 years In pregnant women with hypothyroidism, L-thyroxine dose should be increased due to increased demand. Hypothyroidism adversely affects the development of the fetal nervous system! Complications Myxedema coma Myxedema coma is an extremely rare condition caused by decompensation of an existing thyroid hormone deficiency and can be triggered by infections, surgery, and trauma. Myxedema coma is a potentially life-threatening condition and, if left untreated, is fatal in ∼ 40% of cases. Clinical presentationCardinal symptoms: impaired mental status , hypothermia, and concurrent myxedemaHypoventilation with hypercapniaHypotension (possibly shock) and bradycardia TreatmentIV combination of T4 and T3 (plus IV hydrocortisone in some cases) )Patients should be treated and monitored in an ICU. Further complications Primary thyroid lymphoma Hashimoto thyroiditis is the most common cause of hypothyroidism and the only known risk factor for primary thyroid lymphoma. Increased cardiovascular risk Carpal tunnel syndrome

Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism, oligoovulation/anovulation, and/or the presence of polycystic ovaries. The diagnosis of PCOS is made following exclusion of disorders that may present with a similar clinical picture (e.g., congenital adrenal hyperplasia), most commonly by hormone analysis. Up to 50% of PCOS patients have metabolic syndrome, which is associated with obesity, insulin resistance, hypercholesterolemia, and an increased risk for endometrial cancer. PCOS primarily manifests with hirsutism, acne, and virilization. Diagnostic methods include a pelvic exam, blood tests for specific hormones, and ultrasound. Management consists of weight loss via lifestyle changes, and oral contraception pills are indicated in women who do not wish to conceive. The aim of treatment in women who desire to conceive is to normalize ovarian function and stimulate follicular growth (e.g., with clomiphene).

Epidemiology Frequency: 6-10% of women in their reproductive years Pathophysiology The exact pathophysiology is unknown. Reduced insulin sensitivity (peripheral insulin resistance) is present in PCOS, as in metabolic syndrome → hyperinsulinemiaHyperinsulinemia results in:ObesityEpidermal hyperplasia and hyperpigmentation (acanthosis nigricans) Increased androgen production in ovarian theca cells → imbalance between androgen precursors and the resulting estrogen produced in granulosa cellsIncreased LH secretion disrupts the LH/FSH balance → impaired follicle maturation and anovulation/oligoovulationIncreased androgen precursor release → virilization and a reactive increase in estrogen production in adipose tissueInhibits the production of SHBG (sex hormone-binding globulin) in the liver → ↑ free androgens and estrogens Hyperandrogenism in women is most commonly caused by PCOS! Clinical features Onset typically during adolescence Menstrual irregularities (primary or secondary amenorrhea, oligomenorrhea) Difficulties conceiving or infertility Obesity and possibly other signs of metabolic syndrome Hirsutism Androgenic alopecia Acne vulgaris and oily skin Acanthosis nigricans: hyperpigmented, velvety plaques (axilla, neck) Premature adrenarche Voice change may occur in severe forms of PCOS. However, it typically suggests a different underlying cause of hyperandrogenism! Diagnostics Diagnostic criteria According to the American Association of Clinical Endocrinologists, at least two of three of the criteria below are required for diagnosis of PCOS after excluding other causes of irregular bleeding and elevated androgen levels. Hyperandrogenism (clinical or laboratory) Oligo- and/or anovulation Polycystic ovaries on ultrasound Diagnosis of PCOS is possible without the presence of ovarian cysts!Rule out any other causes of hyperandrogenism and anovulation (see "Differential diagnoses" below). Blood hormone levels ↑ Testosterone (both total and free) or free androgen index ↑ LH (LH:FSH ratio > 2:1) Estrogen is normal or slightly elevated A clinical picture of hyperandrogenism overrules any normal hormone levels and can fulfill a diagnostic criterium of PCOS! Evaluate for metabolic disease Test for hypertension Monitor BMI Assess for insulin resistance or type 2 diabetes mellitus → oral glucose tolerance test Assess for hyperlipidemia → measure serum lipids and cholesterol Transvaginal ultrasound Enlarged ovaries with numerous anechoic cysts (polycystic ovaries) "String of pearls" appearance Pathology The histological characteristics of PCOS are: Ovarian hypertrophy with thick capsule Stromal hyperplasia and fibrosis Enlarged, multiple cystic follicles, which are sclerotic Hyperluteinized theca cells Decreased granulosa cell layer Differential diagnoses All conditions that are associated with menstrual cycle changes and signs of virilization should be ruled out before diagnosing PCOS: Pregnancy Thyroid disorder Follicular insufficiency Hyperprolactinemia Congenital adrenal hyperplasia Cushing's disease Pituitary adenoma Androgen-secreting tumors Exogenous androgen intake Exogenous steroid intake Treatment The therapeutic approach in PCOS is broadly based on whether or not the patient is seeking treatment for infertility. If treatment for infertility is not sought: therapy aimed at controlling menstrual, metabolic, and hormonal irregularitiesIf the patient is overweight (BMI ≥ 25 kg/m2)First-line: weight loss via lifestyle changes (e.g., dietary modifications, exercise) Second-line (as an adjunct): combined oral contraceptive therapyIf the patient is not overweight: combined oral contraceptive therapy If seeking treatment for infertilityFirst-lineOvulation induction with clomiphene citrate or letrozole An aromatase inhibitor drug that lowers estrogen levels by inhibiting the conversion of androgens to estrogens. Indicated in the treatment of postmenopausal women with hormone-receptor-positive breast cancer and women with anovulatory cycles, e.g., due to PCOS. Clomiphene inhibits hypothalamic estrogen receptors, thereby blocking the normal negative feedback effect of estrogen → increased pulsatile secretion of GnRH → increased FSH and LH, which stimulates ovulationIf the patient is overweight: advise weight lossSecond-line: ovulation induction with exogenous gonadotropins or laparoscopic ovarian drilling Complications Cardiovascular events Type 2 diabetes mellitus Endometrial cancer Increased miscarriage rate

Graves disease Graves disease is the most common cause of hyperthyroidism and often affects women. It is an autoimmune condition that is associated with circulating TSH receptor autoantibodies leading to overstimulation of the thyroid with excess thyroid hormone production. The classic clinical triad of Graves disease involves a diffuse vascular goiter, ophthalmopathy, and pretibial myxedema, although not all features may be present in a patient. The clinical diagnosis of Graves disease is confirmed via assessment of TSH and T3/T4 levels as well as through detection of thyroid antibodies(TRAbs, anti-TPO, anti-Tg). In addition, a diffuse uptake of 123I may be seen on thyroid scintigraphy. Treatment includesβ-blockers to quickly alleviate symptoms, antithyroid drugs to achieve euthyroid status, and radioiodine ablation or, less commonly, near-total thyroidectomy for definitive control of the disease.

Epidemiology Most common cause of hyperthyroidism in the United States Incidence: ∼ 30 cases per 100,000 people per year Sex: ♀ > ♂ (8:1) Typical age range: 20-40 years Etiology B and T lymphocyte-mediated autoimmune disorder Genetic predisposition: 50% of patients with Graves disease have a family history of autoimmune disorders (e.g., type 1 diabetes mellitus, Hashimoto's disease, pernicious anemia, myasthenia gravis) May be triggered by surgery/trauma of the thyroid gland and possibly severe psychological stress Pathophysiology TSH-receptor stimulating IgG immunoglobulin (TRAb; type II hypersensitivity reaction) → ↑ thyroid function and growth → hyperthyroidism and diffuse goiter TRAb also stimulate:Orbital fibroblasts → fibroblast proliferation, hyaluronic acid synthesis, and differentiation of fibroblasts to adipocytes (opthalmopathy with exophthalmus)Dermal fibroblasts and deposition of glycosaminoglycans in connective tissue (pretibial myxedema) Clinical features Symptoms of hyperthyroidism Triad of Graves diseaseDiffuse goiterSmooth, uniformly enlarged goiterBruit may be heard at the superior poles of the lobes Ophthalmopathy (see Graves ophthalmopathy) ExophthalmosOcular motility disturbancesLid retraction and conjunctival conditionsDermopathy (pretibial myxedema): non-pitting edema and firm plaques on the anterior/lateral aspects of both legs Diagnostics The diagnosis of Graves disease is often apparent on clinical examination and is confirmed through detection of specific thyroid antibodies. Best initial test: ↓/undetectable TSH and ↑ T3/T4 (see "Diagnosis" in hyperthyroidism) Measure thyroid antibodies↑ TRAbs (specific)↑ anti-TPO and anti-Tg (nonspecific) Thyroid scintigraphyIndicated if TRAbs are low to establish a diagnosisShows a diffuse uptake of radioactive iodine (123I)Contraindicated in pregnancy Thyroid ultrasound (with color doppler) Indicated in pregnant women if TRAbs are lowShows an enlarged, hypervascular thyroid Treatment β-blockers: rapid control of hyperthyroidism symptoms Antithyroid drugs: methimazole, propylthiouracilGoal: achieve euthyroid statePatients with a small goiter and mild hyperthyroidism may undergo remission on antithyroid drugs alone (in ∼ 50%of cases).Once remission is achieved, slowly taper and stop. Radioactive iodine ablationFirst-line therapy in nonpregnant patients with small goitersSecond-line therapy in patients who relapse after long-term therapy with antithyroid drugs Surgery: near-total thyroidectomy is rarely done in Graves disease Complications of therapyPermanent hypothyroidism after radioactive iodine ablation or surgery → need for lifelong thyroid replacement therapyNew-onset/exacerbation of Graves ophthalmopathy after radioactive iodine ablation See "Therapy" in hyperthyroidism for more information. See "Graves ophthalmopathy" in orbital disorders for more information,

Pituitary adenoma Pituitary adenomas are benign tumors that often arise sporadically from the anterior pituitary gland. They are classified based on their size as microadenomas or macroadenomas, and whether they produce hormones as secretory (functional) and non-secretory (non-functioning) adenomas. Secretory adenomas produce the pituitary hormone of the corresponding cell type, which results in a state of hyperpituitarism. Non-secretory macroadenomas, however, destroy the surrounding normal pituitary tissue and result in hypopituitarism. Additionally, large macroadenomas compress the optic chiasm and can thus present with signs of mass effect such as bitemporal hemianopsia. The investigation of choice is a contrast-enhanced cranial MRI, which reveals an intrasellar mass. Assays of pituitary hormones are used to evaluate the patient for endocrine abnormalities, and perimetry is required to document visual field defects. Transsphenoidal surgical resection is the first-line therapy for most pituitary adenomas; however, non-secretory microadenomas generally only require follow-up, and prolactin-producing pituitary adenomas (prolactinomas) are best treated with dopamine agonists (e.g., bromocriptine, cabergoline). Pituitary irradiation is indicated only if the pituitary adenomas recur and/or if surgical therapy is contraindicated. NOTES

Epidemiology Pituitary adenomas account for about 15% of primary intracranial tumors. Peak incidence: 35-60 years Prevalence: ∼ 80 cases per 100,000 individuals Etiology Most cases occur sporadically. Some cases (∼ 5%) have a genetic/familial association. Multiple endocrine neoplasia type 1Carney complexThe result of a mutation in the PRKAR1A gene which results in loss of function in a negative regulatory subunit (R1α) of protein kinase A resulting in an increased activity of cAMP.Patients present with cardiac myxomas, spotty skin pigmentation, adrenal gland, testicular, and pituitaryadenomas.Familial isolated pituitary adenoma syndrome: due to a mutation in the AIP genePatients present with somatotroph adenomasMost common familial cause of acromegaly/gigantism Pathophysiology Type of tumor according to size: Pituitary microadenoma: ≤ 10 mmPituitary macroadenoma : > 10 mm Secretory pituitary adenomas (60%): hormone secretion → hyperpituitarismMost secrete one pituitary hormone. The presence of multiple pituitary hormones should also raise the suspicion of atypical pituitary adenomas or pituitary carcinomas. Lactotroph adenoma (prolactinoma)∼ 40%Hyperprolactinemia Somatroph adenoma∼ 15%↑ Growth hormone → acromegaly/gigantismCorticotroph adenoma (Cushing's disease)∼ 5%↑ ACTH → secondary hypercortisolismThyrotroph adenoma∼ 1%[3]↑ TSH → secondary hyperthyroidism Non-secretory pituitary adenomas ∼ 40% of all pituitary adenomas are non-secretory(non-functioning, null-cell) pituitary adenomas; gonadotroph adenomas account for 80-90% of non-secretory pituitary adenomas and are usually chromophobic. Prolactinomas are the most common pituitary adenomas! MicroadenomasThe pituitary hormone which is produced in excess is determined by the histopathology of the pituitaryadenoma (see hyperpituitarism).AsymptomaticMacroadenomasThe hormone which is produced in excess is determined by the histopathology of the pituitary adenoma(see hyperpituitarism); other pituitary hormones may be deficient as a result of pituitary destruction.Mass effects (e.g., headache, bitemporal hemianopsia, diplopia) Hypopituitarism Mass effects (e.g., headache, bitemporal hemianopsia, diplopia) Diagnostics Cranial contrast MRI (initial test) : reveals an intrasellar mass CT scan may be considered Hormone assays [4]Basal prolactin levels (see "Diagnostics" in hyperprolactinemia")Insulin-like growth factor-1 (IGF-1) (see "Diagnostics" in acromegaly")24-hour urine cortisol (see "Diagnostics" in Cushing's syndrome)Thyroid function tests (see "Diagnostics" in hyperthyroidism") Perimetry: to assess visual field defects Differential diagnoses Craniopharyngioma (suprasellar mass): most commonly in children Meningioma (parasellar mass) Lymphocytic histiocytosis ... Treatment ProlactinomasFirst-line: dopamine agonists (e.g., cabergoline, bromocriptine) , which cause the pituitary adenoma to shrink. Second-line: transsphenoidal hypophysectomy ± adjuvant radiotherapy Non-secretory pituitary microadenomas (incidentalomas): no treatment (only follow-up) Other pituitary adenomasFirst-line: transsphenoidal hypophysectomy Second-line: pituitary irradiation Following transsphenoidal resection and/or pituitary irradiation, patients may develop hypopituitarism and potentially require lifelong hormone replacement therapy!

Hyperthyroidism Hyperthyroidism refers to the symptoms caused by excessive circulating thyroid hormones. It is typically caused by thyroid gland hyperactivity, the most common causes of which are Graves disease (most common), toxic multinodular goiter (MNG), and toxic adenoma. In rare cases, hyperthyroidism is caused by TSH-producing pituitary tumors (central hyperthyroidism), excessive production of β-hCG (gestational trophoblastic disease), or oral intake of thyroid hormones(factitious hyperthyroidism). Regardless of the cause, the most common symptoms of hyperthyroidism include fatigue, anxiety, heat intolerance, increased perspiration, palpitations, and significant weight loss despite increased appetite. Serological thyroid hormone assay confirms hyperthyroidism, while measurement of antithyroid antibodies, thyroid ultrasonography, and radioactive iodine uptake tests help identify the etiology. Management of any form of hyperthyroidism involves the initial control of symptoms with beta blockers and antithyroid drugs, followed by definitive therapy either with radioactive iodine ablation of the thyroid gland or surgery.

Epidemiology Prevalence [1]Overt hyperthyroidism: ∼ 1%Subclinical hyperthyroidism: 2-3% Sex: ♀ > ♂ (5:1) Age range at presentation Graves disease: 20-30 years of ageToxic adenoma: 30-50 years of ageToxic multinodular goiter (MNG): peak incidence > 50 years of age Etiology Hyperfunctioning thyroid gland Graves disease (∼ 60-80% of cases) Toxic MNG (∼ 15-20% of cases)Toxic adenoma (3-5% of cases)TSH-producing pituitary adenoma (thyrotropic adenoma)β-hCG-mediated hyperthyroidism (hydatidiform mole, choriocarcinoma) Hashitoxicosis (see Hashimoto thyroiditis) Destruction of the thyroid gland Thyroiditis (see subacute thyroiditis) Subacute granulomatous thyroiditis (de Quervain thyroiditis)Subacute lymphocytic thyroiditis (e.g., post-partum thyroiditis)Drug-induced thyroiditis (e.g., amiodarone, lithium)Contrast-induced thyroiditis (Jod-Basedow phenomenon)Hashimoto thyroiditisRadiation thyroiditisPalpation thyroiditis: due to thyroid gland manipulation during parathyroid surgery. Exogenous hyperthyroidism Ectopic (extrathyroidal) hormone productionStruma ovariiMetastatic follicular thyroid carcinoma Pathophysiology Hypothalamic-pituitary-thyroid axis The hypothalamus, anterior pituitary gland, and thyroid gland, together with their respective hormones, make up a self-regulating circuit known as the hypothalamic-pituitary-thyroid axis. Physiological regulation: See "thyroid gland" in general endocrinology. Hyperthyroidism Disorders of the thyroid gland → excess production of T3/T4 → compensatory decrease of TSHThyrotroph adenoma → ↑ TSH levels → ↑ T3/T4 levels Excess intake/ectopic thyroid hormone production → ↑ levels of circulating T3/T4 → compensatory decrease of TSH Effects of hyperthyroidism Generalized hypermetabolism (increased substrate consumption) Increased number of Na+/K+-ATPase → elevation of basal metabolism → promoted thermogenesisIncreased catecholamine secretion and upregulation of β-adrenergic receptors → hyperstimulation of the sympathetic nervous system Cardiac effectsIncreased numbers of ATPase on cardiac myocytes and decreased amount of phospholamban (PLB) → increased transsarcolemmal Ca2+ movement → enhanced myocardial contractilityHyperadrenergic state → increased cardiac outputDecreased peripheral vascular resistance Clinical features GeneralHeat intoleranceExcessive sweating because of increased cutaneous blood flowWeight loss despite increased appetiteFrequent bowel movements (because of intestinal hypermotility)Weakness, fatigueOnycholysisInfiltrative dermopathy, especially in the pretibial area (pretibial myxedema) EyesLid lag: caused by adrenergic overactivity, which results in spasming of the smooth muscle of the levator palpebrae superiorisLid retraction: "staring look"Graves ophthalmopathy (exophthalmos, edema of the periorbital tissue) Goiter Diffuse, smooth, nontender goiter; often audible bruit at the superior poles Also seen in subacute thyroiditis, toxic adenoma, and toxic MNG Cardiovascular Tachycardia Palpitations, irregular pulse (due to atrial fibrillation/ectopic beats)Hypertension with widened pulse pressureSystolic pressure is increased due to increased heart rate and cardiac output.Diastolic pressure is decreased due to decreased peripheral vascular resistance.Cardiac failure: elderly patients often present with features of cardiac failure (e.g., pedal edema, exertional dyspnea).Abnormal heart rhythms, including atrial fibrillationChest pain MusculoskeletalFine tremor of the outstretched fingers Hyperthyroid myopathy Predominantly affects individuals > 40 years of ageProximal muscles are predominantly affectedSerum creatinine kinase levels are most often normalOsteopathy: osteoporosis due to the direct effect of T3 on osteoclastic bone resorption , fractures (in the elderly) EndocrinologicalFemale: oligo/amenorrhoea, anovulatory infertility, dysfunctional uterine bleeding Male: gynecomastia, decreased libido, infertility, erectile dysfunction Neuropsychiatric systemAnxietyEmotional instabilityDepressionRestlessnessInsomniaTremoulousness (results from the hyperadrenergic state)Hyperreflexia Diagnostics Overview of changes in hormone levels Overt hyperthyroidism Basal TSH ↓ Or undetectable FT3 ↑ FT4 ↑ In 90% of cases Subclinical hyperthyroidism If the negative feedback regulation mechanism is intact, increased FT3 and FT4 lead to suppression of TSH, which in turn leads to reduced stimulation of thyroid follicular cells.Thyroid hormone levels may then be normal. TSH ↓ FT3/FT4 Normal Laboratory studies Thyroid function testsTest of choice: thyroid-stimulating hormone (TSH) levelsTSH is low/undetectable. In pregnancy, levels of β-hCG (similar molecular structure to TSH) peak at the end of the first trimester, which leads to a decrease in serum TSH levels. However, FT3/FT4 levels are normal.Free T3 and free T4 levels: Both are characteristically high. Serum thyroglobulin (Tg)Indicated if exogenous hyperthyroidism is suspectedCharacteristically low levels due to suppression of the production by the administered thyroid hormones Serum thyroid antibodies: if Graves disease/Hashimoto thyroiditis is suspected (see "Overview" in thyroid antibodies) Other: decreased total cholesterol, LDL, and HDL levels Imaging Thyroid ultrasound Can be used to diagnose the underlying cause of hyperthyroidism (e.g., diffuse enlargement, solitary/multiple nodules, increased vascularity of the gland) Thyroid scintigraphy A nuclear medicine imaging technique that allows the structure and function of thyroid tissue to be visualized based on its selective uptake of radioactive iodine (RAI). IndicationsIf etiology of hyperthyroidism is uncertain or if physical examination suggests nodular thyroid disease Identification of ectopic thyroid tissue (e.g., base of tongue masses, which could be lingual thyroid tissue or cases of struma ovarii)Evaluation of thyroglossal cysts Contraindications: pregnant or breast-feeding women Interpretation of resultsOnly the functional part of the gland takes up RAI.Normal thyroid tissue: normal-sized gland with diffuse uptake of RAI Most common findings Graves disease: enlarged gland with diffusely increased RAI uptake Toxic MNG: multiple nodular areas, both cold and hot, resulting in an overall heterogeneous appearance Toxic adenoma: a hot nodule Factitious hyperthyroidism: no uptake of RAI since there is no thyroid gland hyperfunction Differential diagnoses Common differential diagnoses Neuropsychiatric symptoms: anxiety/panic disorders Hyperadrenergic symptoms: intoxication with anticholinergics; cocaine/amphetamine abuse; withdrawal syndromes Weight loss: diabetes mellitus, malignancy Cardiac symptoms: congestive cardiac failure Graves disease Acute to chronic hyperthyroidism Most common cause of hyperthyroidism in the US Peak incidence: 20-30 years of age ♀ > ♂ (8:1)Autoimmunedue to TSH receptorautoantibodies GoiterConsistencyDiffuse and smoothPainless Graves ophthalmopathy Pretibial myxedema Thyroid function tests↓/UndetectableTSH↑ T3/T4 Antibodies↑ TRAbs, anti-TPOantibody, and anti-Tg Iodine uptake on scintigraphyDiffuse Pathologic findingsDiffuse hyperplasia and hypertrophy of follicular cells Toxic multinodular goiterChronic hyperthyroidism Peak incidence: > 50 years of age ♀ > ♂ Chronic iodine deficiency Multinodular Painless ↓ TSH ↑ T3/T4 Absent antibodies RAI Multiple focal areas of increased uptakePatches of enlarged follicular cellsdistended with colloid and flattened epithelium Subacute granulomatous thyroiditis (de Quervain thyroiditis) Transient hyperthyroidism followed by features of hypothyroidism Peak incidence: 30-50 years of age ♀ > ♂ (3:1) Viral and mycobacterialinfections causing damage to follicular cellsDiffuse and firm Painful ↑ ESR Fever, malaise Possible history of upper respiratory tract infections a few weeks prior to the onset of subacute thyroiditis Thyrotoxic phase: ↓ TSH, ↑ T3/T4, and ↑ thyroglobulin Hypothyroid phase: ↑ TSH and ↓ T3/T4 Anti-TPO antibody RAI Reduced Granulomatous inflammation, multinucleated giant cells on histology Subacute lymphocytic thyroiditis (silent thyroiditis)Transient hyperthyroidism followed by features of hypothyroidismPeak incidence: 30-50 years of age ♀ > ♂ (3:1) Postpartumthyroiditis Autoimmune diseases Drugs: α-interferon, lithium, amiodarone, interleukin-2, tyrosine kinase inhibitors Diffuse and firm Painless ↑ ESR unless postpartum Fever, malaise Possible history of upper respiratory tract infections a few weeks prior to the onset of subacute thyroiditis Thyrotoxic phase: ↓ TSH, ↑ T3/T4, and ↑ thyroglobulin Hypothyroid phase: ↑ TSH and ↓ T3/T4 Anti-TPO antibody RAI Reduced Absence of germinal follicles, lymphocyticinfiltration on histology Iodine-induced hyperthyroidismThyrotoxicosis in patients with a preexisting iodine-deficiencythyroid disorderMore common in iodine-deficient regionsIodine excess from diet, contrast, or amiodarone Depends on underlying thyroiddisorder Painless ↓ TSH ↑ T3/T4 Possible ↑ TRAb in patients with Graves disease RAI Reduced Exogenous hyperthyroidism or factitious hyperthyroidism Definition: hyperthyroidism due to excessive intake of thyroid hormone EtiologyIntentionalTherapeutic: suppressive doses of thyroid hormones for thyroid cancer treatmentPatients with psychiatric disorders, like Munchausen syndromePeople who are trying to lose weight UnintentionalIatrogenic Accidental ingestion (primarily in children)Dietary supplement overdose Clinical features: symptoms of hyperthyroidism but no goiter DiagnosticsLow/undetectable TSH, high levels of T4/T3, low Tg levelsLow RAI uptake in scintigraphy TreatmentTaper and stop the exogenous thyroid hormone.Beta blockers: if symptoms are severeCholestyramine: binds to T3 and T4 in the intestine and interrupts the enterohepatic circulation Treatment Symptomatic therapy of thyrotoxicosis Beta blockers provide immediate control of symptoms.Improve tachycardia, hypertension, tremor, and neuropsychiatric symptomsIn high doses, propranolol also decreases the peripheral conversion of T4 to T3 by inhibiting the 5'-monodeiodinaseenzyme. Indication: all symptomatic patients Contraindications: e.g., asthma, Raynaud phenomenon; for more information, see section "Contraindications" in beta blockers. Drugs usedPreferred drug: propranolol (nonselective) Alternatives: atenolol, metoprolol (both have relative beta-1 selectivity), nadolol (nonselective), esmolol(IV administration) Definitive therapy There are currently three effective initial treatment options for Graves disease: antithyroid drugs, radioactive iodine ablation, and surgery. Toxic MNG and toxic adenoma (TA) are not generally treated with antithyroid drugs, but rather with ablation or surgery. Which form of therapy is chosen depends on the individual clinical situation and the patient preference. Antithyroid drugs (ATDs) Antithyroid drugs can effectively render a patient euthyroid; 20-75% of patients achieve permanent remission after 1-2 years of treatment. Some patient groups have a higher likelihood of remission than others. Indications Patients with high likelihood of remission (e.g., small goiter, negative or low TRab titer, women)Active Graves ophthalmopathyChildren age ≤ 5 yearsPregnancyThyroid stormPatient preference Patients who need rapid disease control before further treatment, e.g., achievement of euthyroid state prior to surgeryPatients with an inability to follow radiation safety regulations Contraindications: history of adverse reactions to ATD Adverse effects: See antithyroid drugs. Drugs usedMethimazole Drug of choice, except during the first semester of pregnancy PropylthiouracilDrug of choice in the first trimester of pregnancy and in thyroid stormAlternative drug for patients who are allergic to methimazole or do not tolerate it In rare cases, methimazole can cause cloacal and scalp (cutis aplasia) abnormalities if used in the first trimester. Radioactive iodine ablation (RAIA) Definition: destruction of thyroid tissue using radioactive iodine (iodine 131) through a sodium/iodine symporter Technical background: Radioactive 131I emits both gamma rays and beta rays Gamma rays: diagnostic effect Beta rays: therapeutic effect IndicationsHigh surgical risk; limited life-expectancyLiver diseaseMajor adverse reaction to ATDsPrevious operations or radiation of the neckNo access to a high-volume thyroid surgeonFailure to achieve euthyroidism with ATDsPatient preference Patients with congestive heart failure, right heart failure, pulmonary hypertension, or periodic hypokalemicparalysisRecommended especially for TMNG and toxic adenoma patients with high nodular radioactive iodine uptake ContraindicationsPregnant/breastfeeding womenChildren < 5 yearsConfirmed or suspected thyroid malignancyPatients with moderate to severe Graves ophthalmopathy (GO) ProcedurePre-treatment methimazole: in patients who are at high risk for complications due to worsening of hyperthyroidismFor 4-6 weeks to rapidly achieve a euthyroid state; must be discontinued 2-3 days before RAIA is begun Young or middle-aged patients with mild to moderate symptoms of hyperthyroidism who undergo RAIA do not routinely require pretreatment with methimazole.Avoidance of excess iodine for 7 days prior to RAIA Single oral dose of (131I) → isotope uptake by thyroid gland → emission of β-radiation that slowly destroys the thyroid tissue Post-procedural carePatients with Graves disease become hypothyroid after RAI ablation and require life-long thyroid hormonereplacement. ComplicationsEarly Gastritis Sialadenitis Prophylaxis: suck on sour candies, drink lemon juice, drink plenty of fluids HypothyroidismSurveillance, thyroxine substitutionLate Radiation-induced thyroiditisSecondary malignancy or leukemia (risk of ∼ 1%) Sicca syndrome with dry mouth (xerostomia)In the case of (disseminated) lung metastases: pulmonary fibrosis Thyroid surgery Surgery is rarely indicated IndicationsLarge goiters (≥ 80 g) or obstructive symptoms Confirmed or suspected thyroid malignancyModerate to severe active Graves ophthalmopathyWomen planning to become pregnant in the next < 6 months Large thyroid nodulesPatient preference Access to a high-volume thyroid surgeonRecommended especially for TMNG and TA patients with concomitant hyperparathyroidism, insufficient RAIA, or retrosternal extension ContraindicationsSevere comorbidities that influence surgical risk First and third trimester of pregnancy ProcedureSee "procedure/application" in thyroid surgery.For Graves disease: near total thyroidectomy PrecautionsAntithyroid drugs and beta blockers are given preoperatively for at least 4-8 weeks. Oral potassium iodide administered preoperatively for 10 days (Wolff-Chaikoff effect) Postprocedural care Management of calcium levels: measurement of serum calcium and intact parathyroid hormone levels Weaning of beta blockers Complications Thyroid storm (thyrotoxic crisis) Definition: an acute exacerbation of hyperthyroidism that results in a life-threatening hypermetabolic state EtiologyIatrogenicThyroid surgery RAI ablationDiscontinuation of antithyroid medication Stress-related catecholamine surge Surgery Anesthesia inductionLaborSepsis Clinical features Hyperpyrexia with profuse sweating Tachycardia (> 140 beats/minute) and (possibly severe) arrhythmia (e.g., atrial fibrillation), hypertension (with wide pulse pressure), congestive cardiac failure Severe nausea, vomiting, diarrhea, possibly jaundiceSevere agitation and anxiety, delirium and psychoses, seizures, coma Low/undetectable TSH, elevated free T3/T4 Possible increase of liver function tests TreatmentGeneral measures Intensive care monitoring with fluid and electrolyte substitution Treatment of hyperthermia: ice packs, cooling blankets, and antipyretics (e.g., acetaminophen)Treatment of the underlying conditionBeta blockers (propranolol) should be promptly started. Antithyroid drugs [26]First-line: propylthiouracil Second-line: methimazolePotassium iodide/Lugol iodine: clinical effect is due to the decrease of T4 production in response to iodine load (Wolff-Chaikoff effect) Glucocorticoids: IV hydrocortisone/dexamethasone Plasmapheresis: as a life-saving treatment, rarely needed Treat thyroid storm with PROverbial PROficiency and POetic GLUttony: PROpanolol, PROpylthiouracil, POtassium iodide, and GLUcocorticoids. In the event of simultaneous heart failure, the administration of beta blockers may worsen hemodynamics and is therefore contraindicated! Special patient groups Hyperthyroidism in pregnancy Epidemiology: Hyperthyroidism is rare in pregnancy (< 0.5% of cases). Etiology: Graves disease and β-hCG-mediated hyperthyroidism are the most common causes. Pathogenesisβ-hCG molecule has a similar structure to that of the TSH molecule.β-hCG binds to TSH receptors of the thyroid gland → thyroid stimulation → hyperthyroidism Clinical featuresGraves disease: signs of hyperthyroidism, ophthalmopathyβ-hCG-mediated hyperthyroidism can cause:Subclinical hyperthyroidism Overt (severe) hyperthyroidism in cases of hydatidiform moles/choriocarcinoma (see gestational trophoblastic disease) Diagnosis: same as in non-pregnant patients, but thyroid scintigraphy is contraindicated Treatment Propylthiouracil , methimazole Beta blockers Surgery: if medication cannot be tolerated; safest in second trimester Complications: If left untreated → miscarriage, stillbirth, pre-eclampsia, premature labor, cardiac failure, low birth weight, neonatal hyperthyroidism (see below). Suspect a molar pregnancy or choriocarcinoma if severe hyperthyroidism manifests during pregnancy! Neonatal hyperthyroidism Occurs in ∼ 5% of babies born to mothers with Graves disease Etiology: transplacental passage of maternal TRAbs Clinical featuresHyperthyroidism: irritability, restlessness, tachycardia, diaphoresis, hyperphagia, poor weight gain, diffuse goiter(can cause tracheal compression), microcephaly (due to craniosynostosis)May arise directly after birth or delayed up to 10 days later as a result of transplacental maternal antithyroid medication (including propylthiouracil or carbimazole) TreatmentNeonatal Graves disease resolves within 1-3 months Infants with symptomatic hyperthyroidism: methimazole and propranolol Complications: Untreated symptomatic hyperthyroidism in infants can cause cardiac failure and intellectual disability.

Hashimoto thyroiditis Hashimoto disease is the most common form of autoimmune thyroiditis and the leading cause of hypothyroidism in the United States. Although currently thought to be due to chronic autoimmune-mediated lymphocytic inflammation of the thyroid tissue, the exact pathophysiology remains unclear. Patients are initially asymptomatic or hyperthyroid, progressing to hypothyroidism as the organ parenchyma is destroyed. Diagnosis is based on a combination of specific antibodies, thyroid function tests, and sonography of the thyroid. Treatment involves lifelong hormone replacement therapy with levothyroxine (L-thyroxine).

Epidemiology Prevalence: 5% in the US; Hashimoto disease is the most common form of thyroiditis and the most frequent cause of hypothyroidism in the US. Sex: ♀ > ♂ (7:1) Age of onset: occurs in all age groups, particularly in women aged 30-50 years athophysiology Unknown etiology: Genetic and environmental factors likely play a role. Immunological mechanismsAssociations with HLA-DR3, DR4, and DR5 have been proposedCellular (especially T cells) and humoral immune responses are activated. → active B lymphocytes produce antibodies towards thyroid peroxidase (TPO) and thyroglobulin (Tg) → destruction of thyroid tissue Associations: often associated with Non-Hodgkin lymphoma or autoimmune diseases Associated autoimmune diseases include type 1 diabetes, celiac disease, Grave's disease, autoimmune polyendocrine syndrome, Addison's disease, vitiligo, SLE, suppurative hidradenitis, and Sjögrens syndrome. Clinical features Early-stagePrimarily asymptomaticGoiter: non-tender or painless, rubbery thyroid with moderate and symmetrical enlargementTransient hyperthyroidism (e.g., irritability, heat intolerance, diarrhea) is possible (hashitoxicosis) Late-stageThyroid may be normal-sized or small if extensive fibrosis has occurred. Hypothyroidism (e.g., cold intolerance, constipation, fatigue) Diagnostics Thyroid metabolismEarly-stage: transient hyperthyroidism possible (↓ thyroid stimulating hormone (TSH), ↑ free triiodothyronine(FT3), and ↑ free thyroxine (FT4))Progression: subclinical hypothyroidism (↑ TSH; FT3 and FT4 normal) Late-stage: overt hypothyroidism (↑ TSH; ↓ FT4 and ↓ FT3)[7] Antibody detectionAnti-TPO antibody positive (↑ Anti-microsomal antibodies)Anti-Tg antibody positiveSee thyroid antibodies. Other laboratory testsLipid profile: ↑ LDL and ↓ HDLCBC: ↓ Hb Ultrasound Indications: to assess thyroid size, echotexture, and to exclude thyroid nodules Results depend on the form of Hashimoto's thyroiditis. Atrophic phenotype: reduction in thyroid size (mainly observed)Goitrous phenotype: heterogeneous enlargement Fine-needle aspiration: to exclude malignancy or lymphoma, especially in cases of rapid goiter growth Radioactive iodine uptake test (RIUT): Radioactive iodine uptake is variable, often patchy and irregular with either an increase or decrease in 99mTc uptake. There is ↓ absorption of radioactive technetium (↓ 99mTc uptake) in the thyroid during transient hyperthyroidism Anti-TPO antibodies are also elevated in 70% of patients with Graves disease! Pathology Diffuse lymphocytic infiltration (cytotoxic T lymphocytes) with germinal center, oncocytic-metaplastic cells (Hurthle cells) and fibrotic tissue Oncocytic cells are cells with an acidophilic, granular cytoplasm that appear swollen as a result of the proliferation and enlargement of the mitochondria. In Hashimoto thyroiditis, they are also known as Hurthle cells. Differential diagnoses Subacute thyroiditis (de Quervain thyroiditis) Diffuse toxic goiter/ Graves disease Nontoxic/multinodular goiter Maternal hypothyroidism (cretinism) Riedel thyroiditis ("Riedel struma")Rare, special form of autoimmune thyroiditisInvasive fibrous growth beyond the thyroid tissue into surrounding tissue with destruction of thyroid tissueGoiter; symptoms of compressionSurgery may be necessary because of compression. Acute suppurative thyroiditis Treatment Levothyroxine (T4) replacement therapyLife-long oral administration of L-thyroxine (T4)Commence at a lower and more slow-acting dose with increasing severity of hypothyroidism because of the risk of cardiac side effects. Life-long monitoringDue to decline in T4 production with increasing age Life-long monitoring of thyroid parameters (primarily TSH) is necessary to adjust treatment accordingly and avoid hyperthyroidism Complications Permanent hypothyroidism Myxedema coma Thyroid lymphoma (the risk is 60 times higher in patients with Hashimoto thyroiditis)

Thyroid cancer The majority of thyroid cancers are well-differentiated carcinomas. The principal risk factors are exposure to ionizing radiation and genetic predisposition; thyroid cancers also disproportionately affect women. A distinction is made between well-differentiated thyroid carcinomas (papillary or follicular carcinoma) and poorly differentiated carcinomas(medullary or anaplastic carcinoma); the two groups vary considerably with regard to treatment options, metastaticpathways, and prognosis. Papillary thyroid carcinomas are the most common type of thyroid cancer. Early detection is crucial for improving the prognosis but challenging because symptoms often appear late in the course of the disease. Imaging plays a central role in detection: nodules that appear hypoechoic on ultrasound and cold on scintigraphy should raise suspicion of malignancy. Additional testing is needed to determine the type of thyroid cancer, including measuring hormone levels, tumor markers, and/or biopsy via fine-needle aspiration. Most thyroid cancers are treated surgically (hemithyroidectomy or thyroidectomy), followed by thyroid hormone therapy to replace physiological hormoneproduction and to limit the growth stimulus for any remaining metastases. Further therapeutic measures depend on the type of thyroid cancer involved and include radioiodine therapy and possibly chemotherapy.

Epidemiology Sex Differentiated carcinoma (papillary and follicular): ♀ > ♂ (3:1)Poorly-differentiated carcinoma (medullary and anaplastic): ♀ ≈ ♂ Incidence: ∼ 13.5 new cases per 100,000, per year Etiology Genetic factors: Medullary carcinoma: associated with MEN2 (RET gene mutations) or familial medullary carcinoma.Papillary carcinoma: associated with RET/PTC rearrangements and BRAF mutationsFollicular carcinoma: associated with PAX8-PPAR-γ rearrangement and RAS mutationUndifferentiated/anaplastic carcinoma: associated with TP53 mutation Ionizing radiation (particularly during childhood): mostly associated with papillary carcinoma Thyrocytes Papillary thyroid carcinoma Well-differentiatedMost common type of thyroid cancerPalpable lymph nodes due to metastatic spread (often detected before primary tumor)May be multifocalVery good prognosis∼ 80% of cases30-50 yearsof age Follicular thyroid carcinoma Well-differentiated Hematogenous metastasis especially to LungsBone (lytic lesions) Rarely multifocal Vascular and capsular invasion Good prognosis ∼ 10% of cases 40-60 yearsof age Anaplastic thyroid carcinoma Poorly-differentiated Rapid local growth Symptoms of compression of the structures of the neck (e.g. dysphagia, dyspnea) Lymphatic and hematogenous metastasis Very poor prognosis ∼ 1-2%of cases After 60 years of age Parafollicular cells (C cells)Medullary carcinoma Poorly-differentiated Sometimes a genetic predisposition → multiple endocrine neoplasia type 2 (MEN2) (25% of medullary carcinomas)Sporadic (75% of medullary carcinomas)Produces calcitonin< 10%of cases50-60 yearsof age Remember that Papillary carcinoma is the most Prevalent type of thyroid cancer, that it features Palpable lymph nodes, and that it has the best Prognosis compared to all other types of thyroid cancer. Subtypes and variants Hurthle cell carcinoma3-10% of all well-differentiated thyroid cancersOften classified as subtype of follicular carcinomaThyroid histopathology: hypercellularity with a predominance of Hurthle cells (large, polygonal epithelial cell with eosinophilic granular cytoplasm as a result of numerous altered mitochondria) Hurthle cells are nonspecific and also observed in Hashimoto thyroiditis, Graves disease, previously-irradiated thyroid glands, and in Hurthle cell adenoma (no vascular or capsular invasion; no metastasis)They are also found in the parathyroid glands, salivary glands, and kidneys B-cell lymphoma: usually develops from Hashimoto thyroiditis Sarcoma: rare Metastatic (e.g., breast, renal, melanoma): rare Clinical features Early stages: Often asymptomaticFirm, painless thyroid nodules may be palpated. Late stages: [1]DyspneaDysphagiaHoarseness (vocal cord paresis) Horner syndromePossible obstruction of the superior vena cava Only 25% of thyroid carcinomas detected on ultrasound had previously manifested with clinical signs or symptoms! Laboratory tests Thyroid function tests: Basal TSHfT3 and fT4 Tumor markersThyroglobulin (Tg): should be measured as a follow‑up to thyroidectomy in follicular or papillary thyroid carcinoma CalcitoninFor supporting diagnosis of medullary thyroid carcinoma and follow‑upPatients with medullary thyroid carcinoma often also have elevated levels of carcinoembryonic antigen (CEA) and chromogranin A (which serve to support diagnosis in unclear cases). Imaging Ultrasound [10][11][12] Hypoechoic thyroid lesions with irregular margins > 1 cm are potentially malignant although normal echogenicity does not rule out carcinoma! Malignancies often show microcalcifications (typical for papillary thyroid carcinomas) Thyroid scintigraphy Indications: Thyroid nodule with ↓ TSH levelEvaluation of ectopic thyroid tissue or retrosternal goiter Findings: decreased tracer uptake suggests a malignant non-functioning (cold) nodule. Nodules that appear hypoechoic on ultrasound and cold in scintigraphy are highly suspicious for malignancy! Fine-needle aspiration (FNA) Indicated if malignancy is suspected based on ultrasound or scintigraphyIf biopsy results are unclear or in any way suspicious, surgery is usually recommended. Staging Chest x-ray Abdominal ultrasound Neck CT/MRT Bone scintigraphy or PET for detecting metastases Family screening Pathology Papillary carcinoma Psammoma bodies [18] Morphology: concentric lamellar calcifications Occurrence: seen in diseases associated with calcific degeneration Papillary thyroid carcinomas (evidence of psammoma bodies in thyroid tissue should always raise suspicion of malignancy) [4]Serous papillary cystadenocarcinoma of ovary and endometriumMeningiomasMesotheliomas "Orphan Annie" eyes nuclei Morphology: empty-appearing large oval nuclei with central clearing OccurrencePapillary thyroid carcinomasAutoimmune thyroiditis (e.g., Hashimoto disease, Grave disease) Nuclear grooves [19] Morphology: longitudinal invaginations of nuclear bilayer Occurrence: papillary thyroid carcinomas To memorize that papillary thyroid cancer is histologically characterized by psammoma bodies and Orphan Annie-eye nuclei, imagine that "Papi and Moma adopted Orphan Annie." Follicular carcinoma [20] Uniform follicles Vascular and/or capsular invasion Medullary carcinoma [21] Ovoid cells of C cell origin and therefore without follicle development Amyloid in the stroma (stains with Congo red) Remember that medullary carcinoma is composed of C-cells producing Calcitonin and is characterized by amyloid aCCumulation staining with Congo red. Anaplastic thyroid carcinoma [22] Undifferentiated giant cell (i.e., osteoclast-like cell) Areas of necrosis and hemorrhage Differential diagnoses See learning card on thyroid nodules Thyroid cystUltrasound findingsAnechoic round massIn many cases, dorsal acoustic enhancementRelatively frequent and typically harmless Treatment Well-differentiated cancers Surgical management: primary treatment of choice (see thyroid surgery)Intrathyroidal tumor < 1 cm: hemithyroidectomy Intrathyroidal tumor 1-4 cm: hemithyroidectomy or total thyroidectomy Intrathyroidal tumor > 4 cm, extrathyroidal spread, or metastasis: total thyroidectomy with neck dissectionEvidence of regional lymph node spread: therapeutic neck dissection Postoperative managementRadioiodine therapy : often conducted 4-6 weeks after surgery to destroy remaining thyroid tissue or metastasesThyroid hormone therapy with L-thyroxine after thyroidectomyTSH suppressionReduces the risk of stimulating remaining malignant tissueAdminister the highest possible dose (according to the patient's tolerance) Only administer after radioiodine therapy! Poorly-differentiated cancers Total thyroidectomy with adjuvant radiochemotherapy if operable Radiochemotherapy if locally advanced, inoperable Complications Accidental removal of parathyroid glands → hypocalcemia [25] Transection of superior and recurrent laryngeal nerve → dysphonia (hoarseness), dysphagiaMay occur during ligation of the superior laryngeal artery and inferior thyroid artery due to the proximity of the nerves to the arteries.If only the external branch of the superior laryngeal nerve is damaged, complete loss of voice is unlikely, but a loss of vocal range may occur (with potentially career-damaging consequences for occupational voice users, e.g., singers). Follow-up Physical examination Biochemical tests Neck ultrasound Further imaging, if a relapse is suspected Thyroid cancer 5-year survival rate Papillary > 90% Follicular 50-70% Medullary 50% Anaplastic 5-14%

Hyperprolactinemia Hyperprolactinemia, which refers to the increased production of prolactin by the anterior pituitary, occurs physiologically during pregnancy, lactation, and periods of stress. Pathological hyperprolactinemia is most often the result of pituitary adenomas and less commonly due to primary hypothyroidism and/or dopamine antagonists (e.g., metoclopramide, haloperidol). Women with pathological hyperprolactinemia present with galactorrhea, loss of libido, infertility, menstrual dysfunction, and/or osteoporosis. Men generally present with loss of libido, erectile dysfunction, and/or gynecomastia. The diagnosis is confirmed by repeated measurement of early morning prolactin levels. After ruling out hypothyroidism, a cranial MRI should be performed to detect pituitary adenomas. Management consists of dopamine agonists (e.g., bromocriptine, cabergoline) and treating the underlying cause.

Epidemiology Sex: ♀ > ♂ Prevalence: ∼ 0.4% of the general population Hyperprolactinemia is the most common form of hyperpituitarism. Etiology Prolactin-secreting pituitary adenomas (prolactinomas) Damage to the hypothalamus and/or infundibular stalk Severe primary hypothyroidism: ↓ T3/T4 → ↑ TRH → ↑ prolactin DrugsDopamine antagonists: Antiemetics: metoclopramideAntipsychotics (e.g., haloperidol, risperidone)Certain tricyclic antidepressants: e.g., clomipramine Catecholamine depletors: e.g., reserpineDopamine synthesis inhibitors: α-methyldopa Oral contraceptive pills Verapamil Opiate analgesics Histamine H2-receptor antagonists (cimetidine, ranitidine) Certain types of focal epilepsy: directly after temporal lobe seizures, due to close proximity to the hypothalamus. Chronic renal failure Stimulation of the reflex suckling arc in the chest wall (e.g., following chest wall surgery, post-herpes zoster) Physiological causes: stress, pregnancy, lactation, nipple stimulation, crying baby, sexual orgasm, sleep, exercise Hypothalamic dopamine inhibits prolactin, whereas thyrotropin-releasing hormone (TRH) stimulates prolactin release! Pituitary adenomas are the most common cause (∼ 50%) of pathological hyperprolactinemia! Pathophysiology ↑ Prolactin → galactorrhea ↑ Prolactin → ↑ central dopamine (prolactin-inhibiting hormone) → suppression of GnRH → ↓ LH, ↓ FSH → ↓ estrogen, ↓ testosterone → hypogonadotropic hypogonadism For more details, see hypothalamus and pituitary gland. ↑ ProlactinGalactorrhea (especially premenopausal women) Galactorrhea is rare. ↓ LH + ↓ FSHPrimary and/or secondary amenorrhea, or irregular mensesInfertility Clinical features of ↓ testosterone (see below)↓ TestosteroneLoss of libidoLoss of libido, erectile dysfunction, infertilityGynecomastia Reduced facial and body hairOsteoporosis↓ EstrogenAtrophic endometrium and vaginal atrophy (menopausal symptoms)Osteoporosis (after several years)Little to no noticeable effects Patients with hyperprolactinemia due to a pituitary adenoma may also present with bitemporal hemianopsia and headache (see section on "Clinical features of pituitary adenomas") Diagnostics Laboratory testsBasal prolactin level Prolactinoma is the most likely cause if the prolactin blood level is permanently > 200 ng/mL. Hypothyroidism and drug-induced hyperprolactinemia (with the exception of risperidone) usually result in mild elevations of prolactin (< 100 ng/mL).Prolactin stimulation test : a prolactinoma is the most likely diagnosis if the prolactin blood level does not increase TSH, T4 levels: to exclude primary hypothyroidismIn premenopausal women: pregnancy test Cranial contrast MRI: to rule out pituitary adenomas (see "Diagnostics" in pituitary adenomas) Treatment Dopamine agonists (treatment of choice): bromocriptine, cabergoline, quinagolide Treat the underlying causeTranssphenoidal resection of the pituitary adenoma (see "Therapy" in pituitary adenomas)Discontinue or lower the dose of the offending drugTreatment of primary hypothyroidismRenal transplant for patients with CRF

Goiter Goiter is any abnormal enlargement of the thyroid gland. The condition has various causes, with the most common worldwide being iodine deficiency. In the US, however, Hashimoto's and Graves' disease are more common etiologies. Goiters can be classified based on their morphology, function, or dignity (benign or malignant). Symptoms depend on etiology and are often absent. However, patients may present with hyperthyroidism or hypothyroidism. Large goiters may also cause obstructive symptoms due to compression of the trachea and/or the esophagus. Diagnosis is established based on clinical examination, laboratory tests, and imaging techniques. Management depends on the underlying condition and may include administering iodine (for treating nontoxic euthyroid goiter) or performing surgery (e.g., for treating local compression or thyroid cancers).

Epidemiology Sex: ♀ > ♂ (4:1) Frequency: decreases with age Etiology Iodine deficiency (leading cause of goiter worldwide) Inflammation (e.g., Hashimoto's thyroiditis, subacute granulomatous thyroiditis) Graves' disease Thyroid cysts (e.g., thyroglossal cyst) Thyroid adenomas Thyroid carcinomas Ingestion of goitrogens (e.g., lithium carbonate) Elevated TSH production (e.g., pituitary adenoma Congenital goiter Classification Thyroid gland versus goiter Normal adult thyroid gland Weight: ∼ 10-20 gVolume: ∼ 7-10 mLLocation: caudal to larynx surrounding the anterolateral part of the trachea GoiterEnlarged volume of thyroid gland Goiters can be differentiated based on Morphology (growth pattern, size)Thyroid functionBenignity/malignancy Morphology Growth pattern of goiterDiffuse goiter: diffusely enlarged thyroidGraves' disease Inflammation (e.g., Hashimoto's thyroiditis)Iodine deficiencyNodular goiter: irregular enlarged thyroid due to nodule formation Uninodular goiter (e.g., cysts, adenoma)Multinodular goiter Goiter size: see "Classification of goiter by palpation" below. Thyroid function of goiter Nontoxic goiter: normal TSH, fT3, and fT4 levelsE.g., Hashimoto's disease Toxic goiter: increased thyroid hormone productionE.g., Graves' disease, toxic multinodular goiter Hypothyroid goiter: decreased thyroid hormone productionE.g., Hashimoto's disease, congenital hypothyroid goiter Dignity of goiter Malignant goiter: e.g., thyroid carcinoma Benign (bland) goiter: benign thyroid enlargement Clinical features Patients are commonly asymptomatic. Altered hormone metabolism may occur Symptoms of hyperthyroidism Symptoms of hypothyroidism Obstructive symptoms Compression of the trachea → exertional dyspnea and, in severe cases, stridor or wheezingCompression of the esophagus → dysphagia Potentially, lymph node enlargement (e.g., cervical lymph nodes) in malignant infiltration Diagnostics Best initial step: palpation of thyroid gland (see "Classification of goiter by palpation" below) Laboratory testsInitial workup: TSH levels Possible screen for thyroid antibodies (see thyroid antibodies)If medullary carcinoma is suspected, check calcitonin levels (see thyroid cancer). Imaging: determination of goiter size, nodularity, and consistency UltrasoundFurther evaluation may include: CT, MRI InterventionsDepend on the suspected pathologyFine-needle biopsy for cytology Classification of goiter by palpation According to the World Health Organization (WHO) classification: Grade 0: no goiter is palpable or visible. Grade 1: palpable goiter, not visible when neck is held in normal position Grade 2: a clearly swollen neck (also visible in normal position of the neck) that is consistent with a goiter on palpation Treatment Nontoxic goiterTreatment is not needed if the patient is asymptomatic.Schedule follow-ups for possible dysfunctional thyroid and/or obstructive symptoms. Large goiter (> 80 mL)Surgery is preferred to avoid complications (e.g., obstructive symptoms).Alternatively, radioiodine therapy Iodine deficiency: iodine supplementation In other cases, goiter treatment varies depending on the exact etiology (see "Etiology" above).

Thyroid nodules Thyroid nodules are abnormal growths within the thyroid gland. They are present in approx. 50% of the general population but only palpable in 5-10% of the population. They are more common in women, especially in iodine-deficientregions, and their incidence increases with age. Thyroid nodules are the clinical manifestation of various underlying thyroid diseases. The majority of them are benign (∼ 95%), with colloid cysts, follicular adenomas, and Hashimoto's thyroiditis being the most common causes. Approx. 5% of thyroid nodules are malignant, with papillary carcinoma being the most common. Thyroid hormone assay is the best initial test in the evaluation of thyroid nodules. Thyroid ultrasonography can detect features suspicious of malignancy in a nodule and the diagnosis can be confirmed on ultrasound-guided fine needle aspiration cytology. Radioiodine uptake scan (thyroid scintigraphy) is used to evaluate nodules in patients with hyperthyroidism, to localize the autonomously functioning tissue. Based on their iodine uptake on radioiodine scans, thyroid nodules may be autonomous/hot (increased uptake) or non-functional/cold (decreased uptake). The most common hot nodules are toxic adenomas and dominant nodules of toxic multinodular goiters. With a 5-15% risk of malignancy, cold nodules are clinically significant. Treatment depends on the underlying etiology and includes, e.g., surgery (thyroidectomy) for malignant and autonomous nodules, fine needle aspiration for thyroid cysts, and observation for small, benign nodules.

Epidemiology Sex: ♀ > ♂ (4:1) Incidence: increases with age Geographic distribution: most common in inland regions without iodine fortification programs, where iodine content in food and water is low Etiology Benign thyroid nodules (∼ 95% of cases) Thyroid adenomasFollicular adenoma (most common)Hürthle cell adenoma Toxic adenomaPapillary adenoma (least common) Thyroid cysts Dominant nodules of multinodular goiters Hashimoto's thyroiditis Malignant thyroid nodules (∼ 5% of cases) Thyroid carcinoma Thyroid lymphoma Metastatic cancer from breast/renal carcinoma (rare) Risk factors for malignancyMale genderExtremes in age (< 20 years and > 65 years)History of radiation to the head or neckFamily history of thyroid cancer or polyposisSolid nodule Cold nodule Diagnostic steps for a solitary thyroid nodule Nodule revealed during physical examination or incidentally on imaging Initial tests: thyroid ultrasound and TSH levels↑ or normal TSH → consider FNA based on sonographic criteria or follow-up if criteria are not met↓ TSH → thyroid scintigraphyHot nodule → check T3 and FT4 to assess cause of hyperthyroidismCold nodule → consider either FNA (based on sonographic criteria) or monitoring (with repeat ultrasounds) if criteria are not met Sonographic criteria for fine-needle aspiration (FNA)Solid nodule with suspicious appearance (e.g., oval shape, irregular border, calcifications) that are ≥ 1 cm in diameterNodules ≤ 1 cm in patients with risk factors for malignancy (see "Etiology" above)Large thyroid nodules (≥ 1.5-2 cm), even if they appear benign Follicular adenoma EpidemiologyFollicular adenoma is the most common type of thyroid adenoma10-15% of follicular neoplasms are malignant Clinical featuresOften presents as a slow-growing solitary noduleThe nodule can develop into a toxic adenoma, which produces thyroid hormones autonomously DiagnosticsFNA cannot distinguish between follicular adenoma and carcinomaThyroid surgery is therefore always indicated both for treatment and definitive diagnosisFollicular adenoma histology shows normal follicular structure with no tumor invasion into the surrounding tissues (e.g., capsule, blood vessels) TreatmentLobectomy with histologic analysis of frozen-section specimenThyroidectomy in the case of follicular carcinoma Toxic adenoma EpidemiologyAccounts for ∼ 5-10% of hyperthyroidism cases♀ > ♂Seen mostly in patients 30-50 years of age PathophysiologyGain-of-function mutations of TSH receptor gene in a single precursor cell → autonomous functioning of the thyroid follicular cells of a single nodule → focal hyperplasia of thyroid follicular cells → toxic adenomaThe autonomous thyroid nodule overproduces thyroid hormones → hyperthyroidism → decrease in pituitary TSHsecretion → suppression of hormone production from the rest of the gland Clinical features: hyperthyroidism Diagnostics↑ T3 and ↓ TSHThyroid scintigraphy: solitary, hot noduleShows radioiodine uptake by the hyperfunctioning nodules with suppression of rest of the gland TreatmentControl symptoms with beta-blockers and thioamides until euthyroidism is achieved, followed by tapering of beta-blockersDefinitive treatment Radioactive iodine ablation orLobectomy or hemi-thyroidectomy for pure toxic adenomas Toxic multinodular goiter EpidemiologySex: ♀ > ♂Age: often > 60 years Second most common cause of hyperthyroidism Develops in 10% of patients with a long-standing nodular goiterMore prevalent in iodine-deficient areas PathophysiologyChronic iodine deficiency/thyroid dysfunction → decreased hormone production → increased hypothalamic TRHsecretion → persistent TSH stimulation of the thyroid gland → hyperplasia of thyroid nodules, some more active than others → multinodular goiter (non-toxic MNG)Multiple somatic mutations occur in long-standing goiters → autonomous functioning of some nodules (toxic MNG) → hyperthyroidism Clinical features: hyperthyroidism and multinodular goiter Diagnostics↑ T3 with ↓ TSHThyroid scintigraphy: shows radioiodine uptake by the hyperfunctioning nodules with suppression of the rest of the glandHistopathology: patches of enlarged follicular cells distended with colloid and with flattened epithelium Treatment: same as for toxic adenoma; surgery, if required, involves a near-total or total thyroidectomy Thyroid cysts ClassificationSimple cysts are exclusively fluid-filled nodules lined by benign epithelial cells.Complex cysts are partly solid and partly cystic and carry a 5-10% risk of malignancy. Etiology∼ 50% are due to cystic degeneration of thyroid tissue (colloid cyst)∼ 40% are due to involution of a follicular adenoma∼ 10% are due to thyroid cancer Clinical featuresHemorrhage into a cyst → pain and rapid enlargement of the noduleA large cyst or extensive hemorrhage can cause compression symptoms (e.g., hoarseness, dysphagia) DiagnosticsUltrasound to assess size and appearance If low suspicion of malignancy but size > 2 cm → FNAIf high suspicion of malignancy and size > 1 cm → FNA : TreatmentBenign cyst Aspiration may be curative in some casesSurgery if aspiration is not effectiveFor malignant cysts , see thyroid cancer A complex cyst, especially if the solid component makes up > 50% of the cyst

Diabetes mellitus Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic hyperglycemia (elevated blood glucose levels). The two most common forms are type 1 and type 2 diabetes mellitus. Type 1 is the result of an autoimmune response that triggers the destruction of insulin-producing β cells in the pancreas and results in an absolute insulin deficiency. Type 2, which is much more common, has a strong genetic component as well as a significant association with obesity and sedentary lifestyles. Type 2 diabetes is characterized by insulin resistance (insufficient response of peripheral cells to insulin) and pancreatic β cell dysfunction (impaired insulin secretion), resulting in relative insulin deficiency. This form of diabetes usually remains clinically inapparent for many years. However, abnormal metabolism (prediabetic state or impaired glucose intolerance), which is associated with chronic hyperglycemia, causes microvascular and macrovascular changes that eventually result in cardiovascular, renal, retinal, and neurological complications. In addition, type 2 diabetic patients often present with other conditions (e.g. hypertension, dyslipidemia, obesity) that increase the risk of cardiovascular disease (e.g., myocardial infarction). Renal insufficiency is primarily responsible for the reduced life expectancy of patients with DM. Because of the chronic, progressive nature of type 1 and type 2 diabetes mellitus, a comprehensive treatment approach is necessary. The primary treatment goals for type 2 diabetes are the normalization of glucose metabolism and the management of risk factors (e.g., arterial hypertension). In theory, weight normalization, physical activity, and a balanced diet should be sufficient to prevent the manifestation of diabetes in prediabetic patients or delay the progression of disease in diabetic patients. Unfortunately, these general measures alone are rarely successful, and treatment with oral antidiabetic drugs and/or insulin injections is often required for optimal glycemic control. In type 1 diabetes, insulinreplacement therapy is essential and patients must learn to coordinate insulin injections and dietary carbohydrates. Both type 1 and type 2 diabetic patients require regular self-management training to improve glycemic control, reduce the risk of life-threatening hypoglycemia or hyperglycemia, and prevent diabetic complications.

Epidemiology Type 1: ∼ 5% of all patients with diabetes Childhood onset: typically < 20 years but can occur at any age; peaks at age 4-6 years and 10-14 yearsHighest prevalence in non-Hispanic whites Type 2: The estimated prevalence in the US is 9.1%. Adult onset: typically > 40 years ; mean age of onset is decreasingHighest prevalence in Hispanics, Native Americans, Asian Americans, African Americans, and Pacific Islanders Etiology Type 1Autoimmune β cell destruction in genetically susceptible individualsHLA association. HLA-DR3 and HLA-DR4 positive patients are 4-6 times more likely to develop type 1 diabetes. Association with other autoimmune conditionsHashimoto thyroiditisType A gastritisCeliac diseasePrimary adrenal insufficiency Type 2Hereditary and environmental factors Association with metabolic syndromeRisk factorsObesity, high-calorie dietHigh waist-to-hip ratio (visceral fat accumulation)Physical inactivityFirst-degree relative with diabetesEthnicity HypertensionDyslipidemiaHistory of gestational diabetes Classification Classification according to the WHO and American Diabetes Association (ADA) Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitusAutoimmune (type 1A) Idiopathic (type 1B) Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus Other types of diabetes mellitusGenetic defects in the β cell function: MODY (maturity onset diabetes of the young)Different forms of autosomal dominant inherited diabetes mellitus that manifest before the age of 25 yearsand are not associated with obesity or autoantibodies6 subtypes, the most common being MODY II and MODY IIICaused by genetic defects in the glucokinase gene and hepatocyte nuclear factor-1-α, respectivelyIn contrast to all other subtypes, MODY II is not associated with an increased risk of microvascular disease and can be managed with diet alone, despite stable hyperglycemia and chronically elevated HbA1C levelsAll other subtypes require medical treatment, either with insulin or sulfonylureasGenetic defects in insulin functionDiseases of the exocrine pancreas (pancreoprivic diabetes mellitus) Endocrinopathies: Cushing disease, acromegalyDrug-induced diabetes: e.g., corticosteroidsInfections: e.g., congenital rubella infectionRare immunological diseases: stiff person syndrome Gestational diabetes Pathophysiology Normal insulin physiology Secretion: Insulin is synthesized in the β cells of the islets of Langerhans. The cleavage of proinsulin (precursor molecule of insulin) produces the C-peptide (connecting peptide) and insulin, which consists of two peptide chains (A and B chains). Action: Insulin has a variety of metabolic effects on the body, primarily contributing to the generation of energy reserves and glycemic control. Carbohydrate metabolism: Insulin is the only hormone in the body that lowers the blood glucose level. Protein metabolism: stimulates protein synthesis Stimulates amino acid uptake into cells; inhibits proteolysisLipid metabolism: maintains a fat depot and has an antiketogenic effect Electrolyte regulation: stimulates intracellular potassium accumulation Type 1 diabetes Genetic susceptibility Environmental trigger (often associated with previous viral infection) → Autoimmune response with production of autoantibodies, e.g., Anti-glutamic acid decarboxylase antibody (Anti-GAD), that target insulin-producing cells → progressive destruction of insulin-producing β cells in the pancreatic isletsby autoreactive T cells → destruction of 80-90% of β cells → Absolute insulin deficiency → elevated blood glucose levels Type 2 diabetes Two major mechanisms: Peripheral insulin resistanceNumerous genetic and environmental factors Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes Increased serine kinase activity in liver, fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for PI3K → decreased expression of GLUT4 channels→ decreased cellular glucose uptake Pancreatic β cell dysfunctionAccumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulinproduction Initially, insulin resistance is compensated by increased insulin and amylin secretion. Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines. After a period of impaired glucose tolerance with isolated postprandial hyperglycemia, diabetes manifests with fastinghyperglycemia. Type 1 diabetesSudden; diabetic ketoacidosis is often the first manifestation Alternatively, children may present with acute illness and classic symptoms (see "Characteristic features" below) Weight loss; a thin appearance is typical for type 1 diabetic patients Type 2 diabetes Gradual; the majority of patients are asymptomatic Benign acanthosis nigricans Hyperosmolar hyperglycemic state (in elderly especially, signs of dehydration) Symptoms of complications may be the first clinical sign of disease Characteristic featuresClassic Polyuria Secondary enuresis and nocturia in childrenPolydipsia PolyphagiaNonspecific FatigueVisual disturbances: blurred vision Calf crampsPoor wound healingPruritus Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis, dermatophyte infections, gangrene, pneumonia (particularly TB reactivation), influenza, genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia. Indication for testingDiagnostic criteriaSymptomatic patientsSymptoms or signs of diabetes A single random blood glucose level ≥ 200 mg/dL is sufficient for diagnosis.Alternatively, a pathological fasting plasma glucose (FPG) test, oral glucose tolerance test(OGTT) , or hemoglobin A1C (HbA1C) test establishes the diagnosis (see table below) If hyperglycemia is high enough to suggest but not confirm a diagnosis of DM, two similar test results, either from the same sample or from a separate test sample, will confirm the diagnosis. Asymptomatic patients< 45 years of age who are obese and have one other risk factor for diabetes (see "Etiology" above)> 45 years of age Results (venous blood plasma)Diabetes mellitusPrediabetes HealthyFasting plasma glucose (FPG) in mg/dL (mmol/L) ≥ 126 (≥ 7.0)100-125 (5.6-6.9) = impaired fasting glucose< 100(< 5.6)2-hour glucose value after oral glucose tolerance test (OGTT) in mg/dL (mmol/L) ≥ 200 (≥ 11.1)140-199 (7.8-11.0) = impaired glucose tolerance< 140(< 7.8)Hemoglobin A1C (HbA1c or A1C) in % ≥ 6.55.7-6.4 < 5.7 Additional tests Specific autoantibodies for diabetes mellitus type 1Anti-GAD antibodiesAnti-tyrosine phosphatase-related islet antigen (IA-2) Islet cell surface antibody (ICSA; against ganglioside) C-peptide↓ C-peptide levels indicate an absolute insulin deficiency → type 1 diabetes↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetesUrine analysisMicroalbuminuria: an early sign of diabetic nephropathy Glucosuria: Testing urine for glucose does not suffice to establish the diagnosis of diabetes mellitus. Ketone bodies (usually accompanied by glucosuria): positive in acute metabolic decompensation in diabetes mellitus (diabetic ketoacidosis) Type 1Type 2Relative frequency10-20%80-90%GeneticsPositive HLA associationNegative HLA association; strong genetic predispositionPathogenesisAbsolute insulin deficiencyInsulin resistanceAssociation with obesityNoYesOnsetAcute decompensation, typically at age < 20 yearsGradual; usually at age > 40 yearsC-peptide (Insulin)Decreased or absentInitially elevatedMetabolismUnstableStableRisk of ketoacidosisHighLowTreatmentInsulin therapyLifestyle changes → oral antidiabetic drugs → insulin therapy Glucagonoma Definition: a rare neuroendocrine tumor of the pancreas that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis. Clinical findings: nonspecific symptoms, weight loss (80%), necrolytic migratory erythema (70%), impaired glucose tolerance or diabetes mellitus (75-95%), chronic diarrhea (30%), deep vein thrombosis, and depression Necrolytic migratory erythemaA cutaneous paraneoplastic syndrome that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinomaOccurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities Develop into painful and pruritic crusty patches with central areas of bronze-colored indurationTend to resolve and reappear in a different locationSkin biopsy shows epidermal necrosis Diagnostics: requires a high index of suspicion to make the diagnosis Laboratory findings: ↑ glucagon, ↑ blood glucose levels, normocytic normochromic anemia (90%)Imaging (CT): locate the tumor TreatmentGlycemic controlOctreotide (somatostatin)Pancreatic resection Somatostatinoma Definition: a rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin. Clinical findingsAbdominal painWeight lossClassic triadGlucose intolerance Cholelithiasis Steatorrhea Achlorhydria DiagnosticsLaboratory findings: ↑ somatostatin, ↑ blood glucose levelsImaging: locate the tumor TreatmentOctreotide → inhibition of somatostatin secretionPancreatic resection: curative if no metastases are presentChemotherapy Aspects of treatmentApproachIndividual treatment targetsBlood glucose control and regular glycemic monitoring: A1C values Weight loss : Type 2 diabetic patients with a BMI of 27-35 benefit from a weight reduction of 5%; in patients with a BMI > 35 kg/m2, weight reduction of > 10% is recommended.Blood pressure control Improved blood lipid profile with statin therapy Low dose aspirin for men > 50 years and women > 60 years with cardiovascular risk factorsLifestyle modification↑ Physical activity → ↓ blood glucose and ↑ insulin sensitivity Smoking cessationBalanced diet and nutrition Small, frequent mealsDiet: ∼ 55% carbohydrates (replace simple carbohydrates such as glucose and sucrose with complex carbohydrates), 30% fat, 15% proteinHigh-fiber diet Alcohol should (if possible) be consumed with carbohydrates to avoid hypoglycemia. Self-managementeducationDSME/S programsMedical treatmentOral antidiabetic drugs (see below)Insulin therapy (see below)Patients with prediabetes usually do not require medical treatment but do benefit from a healthy diet, weight loss, and exercise.Monitoring complicationsRegular monitoring of weight, abdominal circumference, blood pressure, blood lipids, renal retention parameters (creatinine, electrolytes), injection site in patients receiving insulin therapyYearly eye exam (type 1: after 5 years with diabetes mellitus or after the age of 11 years); more frequently in patients with abnormal findings or diagnosed retinopathyAnnual urine testing for microalbuminuria Foot exam for neuropathy and ulcers; advise patients to wear appropriate footwear and avoid injuryRoutine screening for psychosocial problems, including signs of depression and cognitive impairmentPneumococcal vaccines Antihyperglycemic therapy algorithm for type 2 diabetes HbA1C target for adults: < 7% (53 mmol/mol) The guidelines for the treatment of DM recommend an individualized treatment strategy. If the target A1C is not reached within 3 months with conservative measures (e.g., diet, exercise), the next step in the therapeutic algorithm should be initiated. General measuresWeight reduction, exercise , medical nutrition therapy, self-management education Monotherapy The drug of choice is metformin. Dual therapy Metformin +A second oral antidiabetic drug: dipeptidyl peptidase-4 inhibitor, sulfonylureas, thiazolidinedione, meglitinides, SGLT-2 inhibitors, alpha-glucosidase inhibitors, amylin analogs GLP-1 receptor agonists (incretin mimetics) Basal insulin Triple therapy Add a third oral antidiabetic drug, nightly basal insulin, or injectable GLP-1 receptor agonistCombination injectable therapy Metformin + basal insulin + mealtime insulin or GLP-1 receptor agonistOnly consider the substitution of drugs in cases in which the drug is not tolerated or side effects occur. Oral antidiabetic drugs should be avoided in patients undergoing surgery or suffering from severe illness. Instead, insulin therapy should be initiated! Total daily requirement of insulinOn average, the body requires 40 USP units of insulin daily. 20 units for basic metabolism → basal insulin20 units for calorie consumption → bolus insulinInsulin correction factor1 unit of insulin lowers the blood glucose level by 30-40 mg/dL (1.7-2.2 mmol/L) Carbohydrate counting10 g of carbohydrates increases the blood glucose level by 30-40 mg/dL (1.7-2.2 mmol/L).Insulin-to-carbohydrate ratioOn average, 1 unit of insulin is required for 15 g carbs = 1 carb serving (carb unit); however, this varies greatly from patient to patient.Insulin sensitivity fluctuates over the course of a day → Insulin-to-carbohydrate ratio changes over the course of a day. Morning hours: 2 units insulin, lunchtime: 1 unit, evening hours: 1.5 unitsType 1 diabetesInsulin replacement therapy: The exogenous insulin requirement depends on the residual insulin production of the pancreas.The initial total daily dose (TDD) of insulin should be 0.6-1.0 U/kg.After beginning insulin treatment, there is often a temporary reduction in exogenous insulin demand. Type 2 diabetesResidual endogenous insulin production is augmented with exogenous insulin, depending on the extent of insulin resistance(which in turn depends on the level of obesity).The TDD of insulin should be 0.1-0.2 U/kg. Indications for insulin therapy Newly diagnosed patients with significantly elevated A1C levels (> 8.5%) or symptomatic diabetes: Initiate insulin therapy with or without an antidiabetic drug. Patients with insufficient glycemic control (target A1C not reached) over a 3-month treatment period with metforminor another antidiabetic drug: Initiate basal insulin supported oral therapy (BOT).Consider initiating insulin therapy. Pregestational and gestational diabetes Patients with end stage renal failure (oral antidiabetic drugs are contraindicated in this case) Regimens of insulin therapy Conventional insulin therapy Fixed regimen of insulin injections: usually twice daily injection of insulin (mixture of 30% regular insulin and 70% intermediate insulin) with self-monitoring of blood glucose levels Advantages: simple regimen, requiring minimal patient education, not very time-consuming Disadvantages: patients must adhere to a rigid diet and exercise plan. Snacks may be required between meals to avoid hypoglycemia. Intensive insulin therapy The goal is to simulate physiological glucose metabolism by keeping fasting blood glucose levels < 100 mg/dL(5.6 mmol/L) and postprandial blood glucose levels < 140 mg/dL (< 7.8 mmol/L) Intensified conventional therapyBasal-bolus regimen: basal insulin 1-2 times daily, + bolus insulin injection 30-45 minutes before mealsadjusted to preprandial blood glucose measurements The bolus insulin dose depends on the preprandial blood glucose level, meal size and time of dayIndication: type 1 diabetes; insulin-dependent type 2 diabetes with a high degree of compliance Insulin pumpContinuous subcutaneous insulin infusion (regular or rapid-acting insulin analogs)Basal and bolus insulin may be managed individually Indication: type 1 diabetes, children, pregnancy, dawn phenomenon (see "Problems" below) AdvantagesOptimal glycemic control and reduced risk of complications in patients with good complianceMore flexibility in the daily diet and exercise plan DisadvantagesComplex and time-consuming therapy; requires frequent blood glucose measurementsHigh risk of hypoglycemiaPatients require intensive education and must be motivated and committed. Basal supported oral therapy (BOT) Alternative to conventional or intensive insulin therapy Indication: combination therapy for type 2 diabetic patients with persistently elevated A1C levels despite oral antidiabetic regimen Regimen: long-acting insulin injection (e.g., glargine) before bedtime combined with an oral antidiabetic drug regimen Types of insulin (see insulin) Problems: early-morning hyperglycemia Dawn phenomenonA common problem (especially in young type 1 diabetic patients)Definition: early-morning hyperglycemia occurs because of the physiological increase of growth hormone levels in the early morning hours, which stimulates hepatic gluconeogenesis. The subsequent increase in insulin demand cannot be met in insulin-dependent patients, resulting in elevated blood glucose levels in the morning.Treatment: measurement of nocturnal blood glucose levels before initiating insulin therapy. The long-acting insulindose may be given later (around 11 p.m.) or increased under careful glycemic control. Treatment with an insulin pump may be considered in children. Somogyi effectRareDefinition: early-morning hyperglycemia because of a counterregulatory secretion of hormones that is triggered by nocturnal hypoglycemia secondary to an evening insulin injectionTreatment: reduction of the evening dose of the long-acting insulin For additional side effects, see insulin. Conditions that require insulin adjustments Physical activity: decreases insulin by 1-2 units per 20-30 minutes activity Illness, stress, and changes in dietIncrease in insulin demand: many illnesses are associated with elevated blood glucose levels due to an acute stress reaction. The subsequent increase in insulin demand cannot be met by patients with insulin deficiency. A higher insulin dose is required.Decrease in insulin demand: vomiting and diarrhea lead to decreased glucose uptake, increasing the risk of hypoglycemia. Surgery: ⅓-½ of the usual daily requirement with frequent monitoring Insulin purging Definition: attempting to lose weight by purposefully not injecting insulin after meals Population: young patients with type 1 diabetes with eating disorders use insulin purging as an alternative to fasting, vomiting, and other methods of weight loss Result: self-induced insulin deficiency reduces insulin-dependent glucose uptake in cells and reduces the anaboliceffect of insulin. Poor glycemic controlIncreased risk of hyperglycemic coma AcuteHyperglycemic crisis: undiagnosed or insufficiently treated diabetes mellitus may result in severe hyperglycemia, potentially culminating in a comaHyperosmolar hyperglycemic state (HHS)Diabetic ketoacidosis (DKA)Life-threatening hypoglycemia: secondary to inappropriate insulin therapyLong-termMacrovascular diseaseMore common in patients with type 2 diabetesPathophysiology: The major determinants are metabolic risk factors, which include obesity, dyslipidemia, and arterial hypertension. Hyperglycemia may be less related to the development of macrovascular disease.ManifestationsCoronary heart disease (CHD)Cerebrovascular diseasePeripheral artery disease (PAD)Mönckeberg arteriosclerosis (medial calcific sclerosis = variant of PAD) PAD diagnostic tools are unreliable in patients with Mönckeberg's arteriosclerosis Microvascular diseaseOnset: typically arises 5-10 years after onset of diseasePathophysiology: Chronic hyperglycemia is the primary factor influencing the development of microvascular disease; results in glycation of proteins and lipids with subsequent impaired protein and cell membrane function and tissue damage Manifestations Diabetic nephropathyDiabetic retinopathyDiabetic neuropathyDiabetic footDiabetic cardiomyopathyDiabetic fatty liver diseaseHyporeninemic hypoaldosteronismLimited joint mobility (formerly known as diabetic cheiroarthropathy) SialadenosisIncreased risk of infection Strict glycemic control is crucial in preventing microvascular disease. Other complications Necrobiosis lipoidicaDefinition: inflammatory granulomatous disorder of the skin; characterized by collagen degeneration and lipid accumulation in the surface of the skin.Epidemiology> 60% association with DM ♀ >> ♂SymptomsRash: circumscribed, erythematous plaques with atrophic centers and irregular marginsCommon sites: pretibial regionUsually asymptomaticUlcerations with subsequent scarring may occurHistopathology: necrobiotic palisading granulomaLymphohistiocytic infiltration with plasma cells, foam cells, and giant cellsWall thickening and occlusion of small blood vesselsDestruction of collagen fibers in the entire coriumTreatment: Corticosteroids may be effective (e.g., intralesional corticosteroid injections). Mucormycosis (zygomycosis)Definition: rare fungal infection, primarily affecting immunocompromised patients and patients with diabetes mellitusEtiology: fungi of the order Mucorales, most commonly Rhizopus oryzae; ubiquitous fungi found in vegetation and soilPathophysiology: Inhalation of the spores into the nose and maxillary sinus (diabetic ketoacidosis stimulates fungal growth) causes sinusitis, tissue necrosis, and contiguous spread to the orbit, brain, and palate. Inhalation of the spores into the pulmonary system may lead to contiguous spread to the mediastinum and heart.Risk factorsDiabetes mellitus, particularly type 1 (ketoacidosis)Immunosuppression: hematologic malignancies, stem cell or solid organ transplantation, treatment with glucocorticoids, AIDSIron overload or treatment with deferoxamineSymptoms and clinical findingsRhino-orbital-cerebral mucormycosis: the most common form; presents with sinusitis, fever, headache Pulmonary mucormycosis: aggressive infection of the bronchioli and alveoli, presenting with fever and hemoptysisDisseminated mucormycosis: (rare) invasion of the vasculature with subsequent dissemination; may affect any organDiagnosticsBiopsy: broad, nonseptate hyphae, with right-angle branching on microscopy Imaging: assess the extent of tissue damage and organ involvementTreatmentAntifungal treatment: amphotericin B, step-down therapy with oral azole Surgical debridementElimination of risk factors, aggressive blood glucose controlComplications: palatal eschars , cerebritis, mediastinitis, cardiac involvement Diabetic nephropathy A major cause of end stage renal disease (ESRD) Pathophysiology: chronic hyperglycemia → non-enzymatic glycosylation (NEG) of the basement membrane (protein glycation) → increased permeability and thickening of the basement membrane and stiffening of the efferent arteriole→ hyperfiltration (increase in GFR) → increase in intraglomerular pressure → progressive glomerular hypertrophyand increased renal size → worsening of filtration capacity PathologyThree major histological changes occur: Mesangial expansionGlomerular basement membrane thickeningGlomerulosclerosis (later stages): may be diffuse (most common) or pathognomonic nodular glomerulosclerosis(Kimmelstiel-Wilson nodules) Clinical findingsOften asymptomatic; patients may complain of foamy urineProgressive diabetic kidney disease with signs of renal failure and risk of uremia (e.g., uremic polyneuropathy)Arterial hypertension Urine analysisProteinuriaInitially moderately increased albuminuria (microalbuminuria) ,Eventually significantly increased albuminuria (macroalbuminuria): nephrotic syndrome may develop. Differential diagnoses: other causes of chronic kidney disease (e.g., hypertensive nephropathy) and nephrotic syndrome Prevention and managementStringent glycemic control Antihypertensive treatment: ACE inhibitors OR angiotensin-receptor blockers are the first-line antihypertensive drugs in diabetic patients. Second line agents to be added to ACE inhibitors or ARBs to further control hypertension include diuretics or calcium channel blockersDietary modification: daily salt intake < 5-6 g/day; phosphorus and potassium intake restriction in advanced nephropathy; protein restriction Microalbuminuria is the earliest clinical sign of diabetic nephropathy. The extent of albuminuria correlates with the risk of cardiovascular disease! Early antihypertensive treatment delays the progression of diabetic nephropathy! Diabetic retinopathy EpidemiologyAfter 15 years with disease, approx. 90% of type 1 diabetic patients and approx. 25% of type 2 diabetic patientsdevelop diabetic retinopathy.The most common cause of visual impairment and blindness in patients aged 25-74 years in the US Symptoms: asymptomatic until very late stages of diseaseVisual impairmentProgression to blindness Ophthalmological findings and classification of diabetic retinopathy Nonproliferative retinopathy (mild, moderate, severe): accounts for most cases of diabetic retinopathyFindings: intraretinal microvascular abnormalities (IRMA), including microaneurysms; caliber changes in venous vessels; intraretinal hemorrhage; hard exudates retinal edema, and cotton-wool spots Visual loss, most commonly due to macular edemaProliferative retinopathyFindings: Preretinal neovascularization is the hallmark of PDR , fibrovascular proliferation , vitreous hemorrhage, traction retinal detachment , rubeosis iridis → secondary glaucoma. Additionally, findings of nonproliferative retinopathy are usually present.Visual loss may be due to vitreous hemorrhage, retinal detachment, or neovascular glaucoma.Macular edemaFindings: clinically significant retinal thickening and edema involving the macula, hard exudates, macular ischemia May occur in all stages of NPDR and PDR TreatmentNonproliferative retinopathyLaser treatment: focal photocoagulationIntravitreal anti-vascular endothelial growth factor (VEGF) injectionProliferative retinopathy and severe nonproliferative retinopathyLaser treatment: panretinal photocoagulation over the course of numerous appointments Risks associated with laser treatment: night vision impairment, visual field loss, further fibrosis of the vitreous body with risk of retinal detachmentVitrectomy in case of traction retinal detachment and vitreal hemorrhageMacular edemaVEGF inhibitorsFocal photocoagulation Diabetic neuropathy Distal symmetric polyneuropathy Pathophysiology: Chronic hyperglycemia causes glycation of axon proteins with subsequent development of progressive sensomotoric neuropathy; typically affects multiple peripheral nerves Epidemiology: Diabetic polyneuropathy is the most common form of polyneuropathy in Western countries. Clinical featuresEarly: progressive symmetric loss of sensation in the distal lower extremities A "stocking-glove" sensory loss pattern with proximal progression is typicalDysesthesia (burning feet) may occurA similar sensory loss pattern may occur in the upper extremities.Late: pain at rest and at night (painful diabetic neuropathy), but also decreased pain perception, motor weakness, and areflexia Special types: Mononeuropathy Cranial mononeuropathy Peripheral mononeuropathy Mononeuropathy multiplex: asymmetric neuropathy, affecting the multiple peripheral and cranial nervesDiabetic truncal neuropathy Diabetic lumbosacral plexopathy Screening Tuning fork: decreased vibration senseMonofilament test: decreased pressure sensePinprick (pain assessment) or temperature assessment: decreased sensation TreatmentOptimal glycemic control Pain managementAnticonvulsants: pregabalin (most effective; usually first-choice), gabapentin, and sodium valproateAntidepressantsTricyclic antidepressants: amitriptylineSNRI: duloxetine, venlafaxineMiscellaneous: lidocaine patch, capsaicin spray, isosorbide dinitrate sprayOpioids: dextromethorphan, morphine sulfate, tramadol, and oxycodone Autonomic neuropathy Urogenital systemErectile dysfunction (most common)Bladder dysfunction: urinary retention, incomplete bladder emptying, bladder distention, overflow incontinence, poor urinary streamCardiovascular systemSilent myocardial infarctionDecreased heart variability or fixed rhythmOrthostatic hypotensionPersistent sinus tachycardiaVentricular arrhythmiaGastrointestinal systemGastroparesis (→ delayed gastric emptying, risk of postprandial hypoglycemia): nausea, abdominal bloating, loss of appetite, early satietyDiarrhea, constipation, incontinenceTreatment involves prokinetic agents (e.g., metoclopramide (1st-line), erythromycin, cisapride). Other manifestationsSweat gland dysfunction associated with heat intolerancePupillary dysfunctionRisk of hypoglycemia due to absence of hormonal counterregulation (secretion of cortisol, glucagon, and catecholamines) Neuropathic diabetic foot Ischemic diabetic footClinical featuresWarm, dry skin, foot pulses are palpableCool, pale foot with no palpable pulsesAdditional infoDiagnosticsNeurological examinations: evaluation of peripheral neuropathy Foot ulcer risk assessment (see "Screening" for diabetic polyneuropathy above)ComplicationsMalum perforans: painless neuropathic ulcers (usually located on the plantar pressure points of the foot: over the head of the metatarsal bones or the heel)Complex, multifactorial pathophysiology. Major risk factors include peripheral sensory neuropathy, autonomic neuropathy, microvascular changes , as well as macrovascular disease.Secondary infection of foot ulcers may lead to cellulitis and acute or chronic osteomyelitis.Diabetic neuropathic arthropathy (Charcot foot): deformation of joints and bones Tarsus and tarsometatarsal joints most commonly affectedCoexisting ulcers commonAcute: swelling, warmth, erythemaChronic: painless bony deformities, midfoot collapse, osteolysis, risk of fracturesPreventionGlycemic controlRegular foot examinationsSelf-monitoringand proper foot careTreatment of foot ulcersSurgical debridementRegular wound dressingMechanical offloading: fitting of therapeutic footwear or total contact castAntibiotic therapy if foot ulcers become infectedInterventional or surgical revascularization: in patients with underlying peripheral artery diseaseAmputation if all else fails or severe life-threatening complications arise In about ⅓ of patients with diabetic foot, the underlying cause is both ischemic and neuropathic. Prognosis Diabetes mellitus is one of the leading causes of death in the US; common complications that result in death are myocardial infarction and end stage renal failure. One of the leading causes of blindness, nontraumatic lower limb amputation, end stage renal failure, and cardiovascular disease The prognosis primarily depends on glycemic control and treatment of comorbidities (e.g., hypertension, dyslipidemia). Gestational diabetes mellitusPregestational diabetes mellitusDefinitionImpaired glucose tolerance diagnosed during pregnancy; associated with an increased risk of maternal and fetal morbidityDiabetes mellitus (type 1 or type 2) that is present prior to pregnancy, which is associated with a significantly increased risk for maternal complications during pregnancy and delivery, and congenital malformations!EpidemiologyOccurs in 5-7% of all pregnanciesUsually in the second and third trimesters (less common in the first trimester)Observed in 1% of all pregnanciesPathophysiologyThe insulin requirement varies during pregnancy.In the first trimester, insulin sensitivity increases and there is a tendency towards hypoglycemia.In the second and third trimesters, hormonal changes trigger progressive insulin resistance that results in hyperglycemia, particularly after mealtimes.As for diabetes mellitus type 1 or 2Risk factorsMajor risk factors for type 2 diabetes (see "Etiology" above)Obstetric Gestational diabetes in prior pregnancyRecurrent pregnancy lossAt least one birth of a child diagnosed with fetal macrosomiaAs for diabetes mellitus type 1 or 2Clinical featuresMothers are usually asymptomaticMay present with edema; warning signs include polyhydramnios or large-for-gestational age infants (> 90th percentile)As for diabetes mellitus type 1 or 2Screening and diagnosticsFirst and second trimester (the first 24 weeks of pregnancy): the diagnosis of diabetes mellitus and gestational diabetes is confirmed with two independent measurements ≥ 126 mg/dL and 92-125 mg/dL respectively Third trimester (at 24-28 weeks) Recommended in all pregnancies!Initial screening: 50-g, one-hour oral glucose challenge testblood glucose level should be < 135 mg/dlConfirmation test: 100-g, three-hour oral glucose tolerance test(oGTT)blood glucose level should be < 140 mg/dlMaternal baseline HbA1c, renal function (creatinine clearance, proteinuria, glucosuria), cardiac and ophthalmic testingMonitoring fetal developmentWeeks 18-24: ultrasound to determine fetal age, evaluate fetal growth, screen for congenital anomaliesWeeks 32-36: close surveillance with ultrasound and nonstress testWeek > 36: at least once weekly ultrasound; consider amniocentesis if delivery is to be induced prior to 39 weeks of gestationTreatmentGlycemic controlDietary modifications and regular exercise (walking)Strict blood glucose monitoring (4x daily)Insulin therapy if glycemic control is insufficient with dietary modificationsMetformin and glyburide in patients who refuse insulin therapyRegular ultrasound to evaluate fetal developmentConsider inducing delivery at week 39-40 if glycemic control is poor or if complications occurStringent glycemic control (exercise, diet, insulin therapy)Delivery and postpartumConsider early delivery if the patient has poor glycemic control or preeclampsiaConsider C-section if estimated fetus weight > 4500 gIntrapartum IV insulin and dextrose to avoid blood glucose fluctuations (maintain normoglycemia 80-100 mg/dL; hourly blood glucose measurementsComplicationsMaternalGestational hypertensionPreeclampsia, eclampsia, and HELLP syndromeUrinary tract infection Fetal: Diabetic fetopathyMaternalDiabetic ketoacidosis (in type 1), hyperosmolar hyperglycemic nonketotic coma (in type 2)Gestational hypertensionPreeclampsia, eclampsia, and HELLP syndromeUrinary tract infection Increased risk of premature birthSpontaneous abortionsPostpartum hemorrhagePolyhydramniosFetalDiabetic embryopathy (first trimester)Diabetic fetopathy (second and third trimester)PrognosisIn most cases, gestational diabetes resolves after pregnancy.Increased risk of gestational diabetes recurring in subsequent pregnancies (∼ 50%)Increased risk of developing type 2 diabetes mellitus (up to 50% over 10 years)→ screen for DM 6-12 weeks postpartum (75 g2-hour GTT); repeat every 3 yearsAs for diabetes mellitus type 1 or 2

Primary hyperaldosteronism Primary hyperaldosteronism, sometimes referred to as Conn syndrome, is an excess of aldosterone caused by autonomous overproduction, usually at the adrenal cortex. It is typically due to adrenal hyperplasia or adrenal adenoma. Primary hyperaldosteronism is one of the common causes of secondary hypertension. High systemic aldosterone levels result in increased sodium reabsorption and potassium secretion in the collecting ducts of the kidney, which leads to the retention of water along with sodium, as well as hypokalemia. Patients are often asymptomatic and found to have hypertension at routine health checks. It will often emerge that the patient's hypertension is resistant to pharmaceutical therapy, and they may have other signs suggestive of secondary hypertension, such as an age of onset below 30 years or above 55 years. If symptoms are present, they typically include headache, muscle weakness, and polyuria. Initial labs in primary hyperaldosteronism classically show a hypertensive patient with hypokalemia and metabolic alkalosis, and high plasma aldosterone concentration (PAC) and low plasma renin activity (PRA) (PAC/PRA ratio increased). Following biochemical confirmation of primary hyperaldosteronism with oral or intravenous sodium loading tests, imaging modalities such as CT and adrenal venous sampling are used to locate the source of autonomous aldosterone secretion. Treatment of primary hyperaldosteronism consists of surgical resection of adrenal adenoma or pharmaceutical therapy with aldosterone antagonists (e.g., spironolactone, eplerenone) in cases of bilateral adrenal hyperplasia.

Epidemiology Underdiagnosed, common cause of secondary hypertension Higher prevalence in blacks SexEtiology: aldosterone-producing adenoma ♀ > ♂ (2:1)Etiology: adrenal hyperplasia ♂ > ♀ (4:1) Etiology Autonomous overproduction of aldosterone (a mineralocorticoid) in the zona glomerulosa of one or both adrenal glands (see Physiological effects of adrenal cortex hormones) Bilateral idiopathic hyperplasia of the adrenal glands (most common) Aldosterone-producing adrenal adenoma, or aldosteronoma Less common causes of primary hyperaldosteronism: Unilateral hyperplasia of one adrenal glandFamilial hyperaldosteronismAldosterone-secreting carcinomas of the adrenal cortexEctopic aldosterone-producing tumors (e.g., in the kidneys or ovaries) Pathophysiology Autonomous aldosterone secretion and hypertension Under normal conditions, aldosterone secretion is primarily regulated by the renin-angiotensin-aldosterone system (RAAS) and occurs in response to the detection of low blood pressure in the kidneys. Autonomous overproduction of aldosterone increases sodium reabsorption by the kidneys irrespective of blood pressure and renin activity, resulting in hypertension. ↑ Aldosterone → ↑ open Na+ channels in principle cells of luminal membrane at the cortical collecting ducts of the kidneys → ↑ Na+ reabsorption and retention → water retention → hypertension Aldosterone escapeThe physiological phenomenon that results in a lack of edema formation and frank hypernatremia in primary hyperaldosteronism Probable mechanism: sodium and water retention → volume expansion → secretion of atrial natriuretic peptide(ANP) and pressure natriuresis (other mechanisms may be responsible, although how these operate remains unclear)→ compensatory diuresis → "escape" from edema and formation and frank hypernatremia Hypokalemia and metabolic alkalosis Increased sodium reabsorption leads to hypokalemia: ↑ Na+ reabsorption → electronegative lumen → K+ follows the electrical gradient through open K+ channels → ↑ K+ secretion → hypokalemia Hypokalemia causes metabolic alkalosis via two mechanisms (both of which decrease extracellular H+, thereby increasing extracellular pH): Efflux of K+ from intracellular to extracellular space in exchange for H+↑ H+ secretion in the kidney in order to enable ↑ K+ reabsorption Diabetes insipidus: hypokalemia → desensitization of renal tubules to antidiuretic hormone (ADH) → increased water excretion (polyuria) and excessive thirst (polydipsia) Clinical features HypertensionOther evidence of the presence of secondary hypertension Features of hypokalemia FatigueMuscle weakness, crampingHeadachesPolyuria and polydipsia PalpitationsConstipation Lack of significant edema (explained by aldosterone escape → see "Pathophysiology" above) Paresthesia in severe cases due to metabolic alkalosis The classic clinical picture of primary hyperaldosteronism: a young patient with hypokalemia and drug-resistant hypertension! Diagnostics Screening tests Plasma aldosterone concentration to plasma renin activity (PAC/PRA ratio; aldosterone-to-renin ratio, or ARR) Indicated in patients with: Hypertension and hypokalemia Associated biochemical findings in classic primary hyperaldosteronism Metabolic alkalosisMild hypernatremiaSevere or drug-resistant hypertension (see "Symptoms/clinical findings" above for details) Results ↑ PAC (> 15 ng/dL or 416 pmol/L) and ↓ PRA ↑ PAC/PRA ratio (ratio > 20 ) Confirmatory testing is considered unnecessary in a patient with the following combination: spontaneous hypokalemia, undetectable PRA levels, and PAC > 20 ng/dL Confirmatory tests: several alternatives Oral sodium loading test: high-sodium diet (5000 mg) or oral sodium chloride tablets (2 g taken three times daily) for 3 days, followed by 24-hour urine measurements of aldosterone, sodium (to confirm appropriate sodium loading), and creatinine (to assess adequate urine collection) Healthy individuals: RAAS is physiologically suppressed → inhibition of aldosterone secretionPrimary hyperaldosteronism: failure to suppress aldosterone secretion (high urine aldosterone > 12 mcg/day (and urine sodium > 200 mEq) Saline infusion test: Infusion of 2 L of normal saline over 4 hoursHealthy individuals: RAAS is physiologically suppressed → inhibition of aldosterone secretion to plasma concentration < 5 ng/dL (139 pmol/L)Primary hyperaldosteronism: failure to suppress aldosterone secretion (PAC > 10 ng/dL, or 277 pmol/L) Fludrocortisone suppression test: Administration of fludrocortisone (0.1 mg every 6 h) for a duration of 4 days (with simultaneous replacement of sodium chloride and potassium) Healthy individuals: RAAS is physiologically suppressed → substantial decrease of aldosterone < 50 ng/mL or ≤ 6 ng/dL (measured in upright position at 10am on day 4)Primary hyperaldosteronism: Failure to suppress the aldosterone secretion (serum levels > 50-60 ng/mL or > 6 ng/dL) Captopril suppression test Subtype identification: imaging Adrenal CT: initial test to identify the cause of primary hyperaldosteronism already confirmed biochemically Allows for carcinoma to be excluded (or detected)Allows bilateral adrenal hyperplasia to be differentiated from unilateral adrenal adenoma Adrenal venous samplingCriterion standard for differentiating between unilateral adenoma and bilateral hyperplasiaAdministered if surgical treatment of primary hyperaldosteronism is desiredProcedure: PAC measured via catheter in blood from right adrenal vein, left adrenal vein, and inferior vena cavaUnilateral disease → four-fold increase in PAC compared with the contralateral sideBilateral hyperplasia → small or no difference in PAC between the two sides (i.e. PAC is bilaterally elevated) The PAC/PRA ratio is used to detect primary hyperaldosteronism. Differential diagnoses Secondary hyperaldosteronism: (↑ PAC and ↑ PRA) Renal artery stenosisRenin-secreting tumorChronic kidney diseaseAdvanced CHFLiver cirrhosisDiureticsLaxative abuse Pseudohyperaldosteronism: other causes of hypertension with hypokalemia (↓ PAC and ↓ PRA)Congenital adrenal hyperplasiaExogenous mineralocorticoidCushing's syndromeDOC-producing tumor11-beta-HSD deficiencyAltered aldosterone metabolismLiddle's syndromeGlucocorticoid resistanceExcessive licorice ingestion: Excessive consumption of licorice can lead to inhibition of cortisol degradation and thus to hypertension associated with hypokalemia. Licorice inhibits 11-β-hydroxysteroiddehydrogenase. This enzyme is located at aldosterone-binding sites and causes degradation of cortisol, which binds just as avidly to the mineralocorticoid receptor as aldosterone, to inactive cortisone. Inhibition of the enzyme leads to increased stimulation of mineralocorticoid receptors via pathologically persistent cortisol. Treatment Bilateral adrenal hyperplasia Aldosterone receptor antagonists (epleronone, spironolactone ) Unilateral autonomous aldosterone secretion (adenoma, unilateral hyperplasia, carcinoma) Surgery (adrenalectomy) Prior to surgery, hypokalemia should be corrected with spironolactone and potassium supplementation.Following surgery: monitor for hyperkalemia Aldosterone receptor antagonist therapy may be considered in patients who are poor surgical candidates.

Subacute thyroiditis Subacute thyroiditis refers to a transient patchy inflammation of the thyroid gland that is associated either with granuloma formation (subacute granulomatous thyroiditis) or lymphocytic infiltration (subacute lymphocytic thyroiditis). While subacute granulomatous thyroiditis usually occurs after a viral upper respiratory tract infection, subacute lymphocytic thyroiditis occurs either during the postpartum period, in association with other autoimmune diseases, or as a side effect of certain drugs. Both forms of subacute thyroiditis are more common among women and are characterized by a triphasic clinical course that classically transitions from hyperthyroidism to hypothyroidism, before returning to a euthyroid phase. During the thyrotoxic phase, patients usually complain of fever, malaise, and goiter, which is tender in subacute granulomatous thyroiditis and painless in subacute lymphocytic thyroiditis. Diagnosis is confirmed by a combination of raised ESR and decreased iodine uptake in a radioiodine uptake study. During the thyrotoxic phase, beta blockers may be used to control the symptoms of thyrotoxicosis, and NSAIDs may be used to control pain among patients with subacute granulomatous thyroiditis. Small doses of levothyroxine may be considered during the hypothyroid phase. As spontaneous remission is seen in about 80% of cases, symptomatic treatment is sufficient in most cases.

Epidemiology ♀ > ♂ (3:1) Peak incidence: 30-50 years Etiology Subacute thyroiditis is characterized by transient patchy inflammation of the thyroid gland (transient thyroiditis).Depending on the underlying cause, one of two types of histological changes are seen: Subacute granulomatous thyroiditis (De Quervain thyroiditis) Subacute granulomatous thyroiditis is characterized by damage to follicular cells, the appearance of large multinucleated giant cells, and the formation of granuloma and fibrosis. Viral infections: Mumps virus, Coxsackie virus, influenza virus, echovirus, adenovirus Mycobacterial infections Subacute lymphocytic thyroiditis Subacute lymphocytic thyroiditis is characterized by damage to follicular cells with lymphocytic infiltration resembling Hashimoto's thyroiditis instead of granuloma formation. Drugs: α-interferon, lithium, amiodarone, interleukin-2, tyrosine kinase inhibitors Autoimmune disease Postpartum thyroiditis: affects 5% of women during the postpartum period and is 3 times more common among women with type 1 diabetes mellitus. Pathophysiology Inflammation of the thyroid gland is associated with a triphasic response. The duration of each phase may vary from patient to patient: Thyrotoxic phase (lasts 4-6 weeks): caused by damage to follicular cells and the release of pre-formed colloid (stored thyroid hormones) Hypothyroid phase (lasts 4-6 months): caused by depletion of pre-formed colloid and impaired synthesis of new thyroid hormones as a result of damage to follicular cells Euthyroid phase: Thyroid function recovers and and pathological changes are no longer visible in the thyroid gland. The disease is self-limiting in most cases but a few patients may experience relapses, and permanent hypothyroidism occurs in ∼ 15% of cases! Clinical features Subacute granulomatous thyroiditis (De Quervain thyroiditis) Possible history of upper respiratory tract infections a few weeks prior to the onset of subacute thyroiditis Painful, diffuse, firm goiter Fever and/or malaise may be present. Features of hyperthyroidism followed by features of hypothyroidism Subacute lymphocytic thyroiditis Painless, diffuse, firm goiter Features of hyperthyroidism followed by features of hypothyroidism Diagnostics Thyroid function tests Thyrotoxic phase: ↑ T3 and T4 , ↑ thyroglobulin, ↓ TSHHypothyroid phase: ↓ T3 and T4, ↑ TSH Confirmatory test↑ ESR Radioiodine uptake study : ↓ iodine uptake (< 5%) Thyroid autoantibodies are absent or appear in low titers. Ultrasound: thyroid with poorly defined hypoechoic regions and decreased vascularity, giving rise to a cobblestone appearance Histologic features : Subacute granulomatous thyroiditis: granulomatous inflammation, multinucleated giant cellsSubacute lymphocytic thyroiditis: absence of germinal follicles, lymphocytic infiltration Treatment Thyrotoxic phaseConsider beta-blockers to control symptoms of hyperthyroidism (i.e. palpitations and/or anxiety). NSAIDs: pain control in the case of acute granulomatous thyroiditisOccasionally corticosteroids (i.e. prednisolone) Antithyroid drugs (e.g., methimazole) should not be administered. Hypothyroid phase: levothyroxine Antithyroid drugs should not be administered in the thyrotoxic phase of subacute thyroiditis!

Diabetes insipidus

Etiology Central diabetes insipidus (CDI); most common form: caused by insufficient or absent hypothalamic synthesis or secretion of antidiuretic hormone (ADH) from the posterior pituitaryPrimary (∼ ⅓ of cases)Most cases are idiopathic. The hereditary form is rare. Autoimmune etiology of primary CDI has been suggested [2][3]Secondary (∼ ⅔ of cases)Brain tumors (especially craniopharyngioma) and cerebral metastasis (most common: lung cancer and leukemia/lymphoma) Neurosurgery: usually after the removal of large adenomasTraumatic brain injury, pituitary bleeding, subarachnoid hemorrhagePituitary ischemia (e.g., Sheehan syndrome, ischemic stroke)Infection (e.g., meningitis) Pathophysiology ADH enables the integration of aquaporins into the plasma membrane of collecting duct cells → reabsorption of free water Either ↓ ADH (central DI) or defective renal ADH receptors (nephrogenic DI) → impaired ability of the kidneys to concentrate urine (hypotonic collecting ducts) → dilute urine (low urine osmolarity) Urine osmolality changesNormal: 500-800 mOsmol/kgComplete DI (< 300 mOsmol/kg, often < 100 mOsmol/kg)Partial DI (300-500 mOsmol/kg) Hyperosmotic volume contraction [12]Loss of fluid with urine → increased extracellular fluid osmolarity → passage of fluid from the intracellular to the extracellular space → equalization of the osmolarities of the extracellular and intracellular fluidDue to the loss of fluid, the osmolarities of intracellular and extracellular compartments are now higher (hyperosmotic) than the initial values.The fluid volume is redistributed between the two compartments to equalize the osmolarities and remains lower than the initial values in each of them (volume contraction) Note that in central DI, ADH levels are decreased, while in nephrogenic DI, they are normal or increased to compensate for the high urine output. Clinical features Polyuria with dilute urine Nocturia → restless sleep, daytime sleepiness Polydipsia (excessive thirst) In cases of low water intake → severe dehydration (altered mental status, lethargy, seizures, coma) and hypotension In the absence of nocturia, diabetes insipidus is very unlikely! Central diabetes insipidus Desmopressin: synthetic vasopressin without vasoconstrictive effects Administration: intranasal, subcutaneous, or oralImportant side effect: hyponatremia (→ see syndrome of inappropriate antidiuretic hormone secretion)Other indications besides central diabetes insipidus include:Hemophilia AVon Willebrand diseaseSleep enuresis

Cushing syndrome Cushing's syndrome, or hypercortisolism, is an endocrine disorder that is most often caused iatrogenically by the exogenous administration of glucocorticoids. Less commonly, Cushing's syndrome can result from endogenousoverproduction of cortisol. Primary hypercortisolism is the result of autonomous overproduction of cortisol by the adrenal gland (e.g., adrenal adenoma, adrenal carcinoma). Secondary hypercortisolism, on the other hand, is the result of increased production of adrenocorticotropic hormone (ACTH), either by pituitary microadenomas (Cushing's disease) or by ectopic, paraneoplastic foci (e.g., small cell lung cancer). Typical clinical features include central obesity, thin, easily bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Since serum cortisol levels vary diurnally, 24-hour urine cortisol measurement, midnight saliva cortisol levels, and/or dexamethasone suppression test are used to diagnose hypercortisolism. Serum ACTH levels and CRH stimulation test are used to identify the cause of hypercortisolism, imaging is then employed to localize the tumor. Treatment of endogenous hypercortisolismprimarily involves surgical removal of the source of excessive cortisol (e.g., adrenalectomy) or ACTH (e.g., transsphenoidal hypophysectomy). If surgery is contraindicated, drugs that suppress cortisol synthesis (e.g., metyrapone) may be used instead.

Etiology Exogenous (iatrogenic) Cushing's syndrome Hypercortisolism as a result of prolonged glucocorticoid therapy Most common cause of hypercortisolism Primary hypercortisolism (ACTH-independent Cushing's syndrome) 5-10% ♂ < ♀ (1:4) Autonomous overproduction of cortisol by the adrenal gland → ACTH suppressionAdrenal adenomas Adrenal carcinoma Macronodular adrenal hyperplasia Secondary hypercortisolismPituitary ACTH production (Cushing disease) ∼ 75% ♂ < ♀ (1:4) Pituitary adenomas → ACTHsecretion Ectopic ACTH production ∼ 15% ♂ = ♀ Paraneoplastic syndrome → ACTH secretionSmall cell lung cancerRenal cell carcinoma While the term "Cushing's syndrome" can be applied to any cause of hypercortisolism, "Cushing's disease" refers specifically to secondary hypercortisolism that results from excessive production of ACTH by pituitary adenomas! Secondary hypercortisolism is also called ACTH-dependent Cushing's syndrome because hypercortisolism is the result of increased ACTH levels. Clinical features SkinThin, easily bruisable skin with stretch marks (classically purple abdominal striae) and/or ecchymosesDelayed wound healingFlushing of the faceHirsutismAcneIf secondary hypercortisolism: often hyperpigmentation (darkening of the skin due to an overproduction of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity)Caused by excessive ACTH production because melanocyte stimulating hormone is cleaved from the same precursor as ACTH.Hyperpigmentation is not a feature of primary hypercortisolism. Neuropsychological: lethargy, depression, sleep disturbance, psychosis MusculoskeletalOsteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head Muscle atrophy/weakness Endocrine and metabolicInsulin resistance → hyperglycemia (see diabetes mellitus) → mild polyuria in the case of severe hyperglycemia Dyslipidemia Weight gain characterized by central obesity, moon facies, and a buffalo hump ♂: decreased libido♀: decreased libido, virilization, and/or irregular menstrual cycles Secondary hypertension (∼ 90% of cases) Increased susceptibility to infections Peptic ulcer disease Cataracts "CUSHINGOID" is the acronym for side effects of corticosteroids: C = Cataracts, U = Ulcers, S = Striae/Skin thinning, H = Hypertension/Hirsutism/Hyperglycemia, I = Infections, N = Necrosis (of femoral head), G = Glucose elevation, O = Osteoporosis/Obesity, I = Immunosuppression, D = Depression/Diabetes Consider a diagnosis of hypercortisolism in patients who present with proximal muscle weakness, central obesity, thinning skin, weight gain, sleep disturbance, and/or depression. Patients with secondary hypercortisolism due to ectopic ACTH production may present with rapid onset of hypertension and hypokalemia without other typical features of Cushing's syndrome. Cortisol is normally deactivated by the enzyme 11β-hydroxysteroid dehydrogenase in the epithelialcells of the renal tubule. 11β-hydroxysteroiddehydrogenase converts cortisol to cortisone (which has lesser mineralocorticoid activity). The enzyme also prevents the binding of cortisol to the renal mineralocorticoid receptor. When cortisol levels surge (as occurs with ectopic ACTH production) the enzyme 11β-hydroxysteroid dehydrogenasebecomes saturated. As a result, cortisol that is not inactivated is free to bind to mineralocorticoidreceptors causing hypertension and hypokalemia. Diagnostics General laboratory findings Hypernatremia, hypokalemia, metabolic alkalosis Hyperglycemia: due to stimulation of gluconeogenesis enzymes (e.g., glucose-6-phosphatase) and inhibition of glucose uptake in peripheral tissue Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) Leukocytosis (predominantly neutrophilic), eosinopenia, thrombocytosis Screening for hypercortisolism Any one of the following can be used as an initial screening test ↑ 24-hour urine cortisol ↑ early morning serum cortisol levels following a low-dose dexamethasone suppression test ↑ midnight salivary cortisol↑ midnight serum cortisol A patient with any one of the above findings should be evaluated to identify a possible cause of hypercortisolism. The diagnosis of hypercortisolism is confirmed if at least two of the above-mentioned findings are present Identifying the cause of hypercortisolism Hormone analysis Once glucocorticoid therapy has been ruled out, the following tests are used to identify the cause of hypercortisolism: Serum ACTH levelsLow (< 5 pg/mL): suspect primary hypercortisolism (adrenal adenoma, carcinoma)Normal or elevated(> 20 pg/mL): suspect secondary hypercortisolism If secondary hypercortisolism is suspected: one of the following tests may be used to differentiate between Cushing's disease and ectopic ACTH productionHigh-dose dexamethasone suppression test Adequate suppression of cortisol levels to less than 50% of baseline: Cushing's diseaseNo suppression: ectopic ACTH productionCRH stimulation testACTH and cortisol levels increase further: Cushing's diseaseNo increase in ACTH or cortisol levels: ectopic ACTH production Only Cushing's disease remains (partially) susceptible to suppression (high-dose dexamethasone suppression test) or stimulation (CRH test) of cortisol secretion! ACTHlevels Dexamethasone suppression test Low-dose dexamethasone suppression test High-dose dexamethasone suppression test CRH test Normal↔︎↓ Cortisol↓ Cortisol↑ ACTH,↑ Cortisol Primary hypercortisolism↓↔︎ Cortisol↔︎ Cortisol↔︎ ACTH,↔︎ Cortisol Cushing's disease↑↔︎ Cortisol↓ Cortisol↑ ACTH,↑ Cortisol Ectopic ACTH secretion↑↔︎ Cortisol↔︎ Cortisol↔︎ ACTH,↔︎ Cortisol Imaging to localize the tumor If primary hypercortisolism is suspected: CT and/or MRI of the abdomen for adrenal tumorsThe adrenal cortex contralateral to the tumor shows atrophy due to reduced ACTH stimulation If Cushing's disease is suspected: CT and/or MRI of the skull (see "Diagnostics" in pituitary adenoma)In Cushing's disease, CT and/or MRI of the abdomen shows bilateral hyperplasia of both the zona fasciculata and zona reticularisIf no findings are present on neuroimaging, perform bilateral sampling of the inferior petrosal sinus in order to measure ACTH levels If ectopic ACTH production is suspected: chest x-ray and/or CT, abdominal CT, pelvis CT In the diagnosis of hypercortisolism, hormone analysis always precedes imaging because microadenomas of the pituitary do not always appear upon imaging. Furthermore, imaging can reveal inactive adrenal tumors (incidentalomas) and pituitary tumors in many healthy individuals! Treatment Exogenous Cushing's syndrome Consider lowering the dose of glucocorticoids Consider the use of alternatives to glucocorticoids (e.g., azathioprine) Endogenous Cushing's syndrome Inoperable disease Drugs to suppress cortisol synthesis: metyrapone, mitotane, ketoconazole Operable disease: surgical therapy is the treatment of choice Pituitary adenoma: transsphenoidal resection of the pituitary adenoma (see "Therapy" in pituitary adenoma)ACTH-secreting ectopic tumor: resection of the ectopic foci (e.g., bronchial carcinoid)Adrenocortical tumor: laparoscopic or open adrenalectomy (surgical procedure to remove one or both adrenal glands)Nelson syndrome (or post adrenalectomy syndrome): can occur after bilateral adrenalectomy in patients with a previously undiscovered pituitary adenoma Pathophysiology: bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on hypothalamus → increased CRH production → uncontrolled enlargement of preexisting ACTH-secreting pituitary adenoma → increased secretion of ACTH and melanocyte-stimulating hormone → symptoms of pituitary adenoma and ↑ MSHClinical features: headaches, bitemporal hemianopia, cutaneous hyperpigmentationDiagnostics: high levels of beta-MSH and ACTH; pituitary adenoma on MRI confirms diagnosisTreatment: pituitary radiation therapy or surgery Following surgical therapy, patients who develop adrenal insufficiency require lifelong glucocorticoid replacement therapy! Patients who develop severe hypokalemia due to mineralocorticoid effect of cortisol may be treated with spirolonolactone (aldosterone antagonist)!

Hypogonadism Hypogonadism is a clinical syndrome associated with impaired functional activity of the gonads. Both males and females can be affected. It is classified as either primary or secondary: Primary hypogonadism (hypergonadotropic hypogonadism) is typically caused by congenital disorders of sex development affecting the gonads (e.g., Turner syndrome, Klinefelter syndrome) or acquired gonadal injury (e.g., irradiation, infection). Secondary hypogonadism (hypogonadotropic hypogonadism) is most often caused by pituitary or hypothalamic disorders (e.g, craniopharyngioma, Kallmann syndrome). Characteristic features in males include testicular hypoplasia, gynecomastia, and absent facial hair growth, while females commonly present with amenorrhea. Following clinical evaluation, the diagnosis is confirmed with hormone tests, and genetic testing may be considered. Treatment involves management of the underlying cause and hormone replacement therapy.

Etiology Hypogonadism is a clinical syndrome associated with impaired functional activity of the gonads. Hypergonadotropic hypogonadism (primary hypogonadism) Definition: insufficient sex steroid production in the gonads Primary gonadal insufficiency: Turner syndrome (females), Klinefelter syndrome (males), androgen insensitivity syndrome, anorchia Secondary gonadal insufficiency (damage to leydig cells or ovarian tissue): chemotherapy, pelvic irradiation, trauma/surgery, autoimmune disease, infections (mumps, tuberculosis) Hypogonadotropic hypogonadism (secondary hypogonadism) Definition: insufficient gonadotropin-releasing hormone (GnRH) and/or gonadotropin release at the hypothalamic-pituitary axis Genetic disorders Kallmann syndromeIdiopathic hypogonadotropic hypogonadism (IHH): genetic disorder characterized by a defect in GnRHproduction/action in the absence of anosmiaPrader-Willi syndromeGaucher's disease Hypothalamic and/or pituitary lesions due to Neoplasm (e.g. prolactinoma, craniopharyngioma, astrocytoma)Trauma, surgery, irradiationInfection Eating disorders (functional hypothalamic amenorrhea) Pathophysiology Diminished functional activity of the gonads → reduced biosynthesis of sex hormones → impaired secondary sexual characteristics and infertility Hypergonadotropic hypogonadism: gonadal insufficiency → insufficient sex steroid production (↓ testosterone, ↓ estrogen) → increased gonadotropin secretion (↑ FSH and ↑ LH) from the anterior pituitary → lack of negative feedback from the impaired gonads → further ↑ FSH and ↑ LH levels Hypogonadotropic hypogonadismIn Kallmann syndrome: impaired migration of GnRH cells and defective olfactory bulb → ↓ GnRH in hypothalamus→ ↓ FSH and ↓ LH → ↓ testosterone and ↓ estrogenIn hypothalamic and/or pituitary lesions: ↓ pituitary gonadotropins (↓ FSH and ↓ LH) → ↓ testosterone and ↓ estrogen Clinical features Delayed puberty (see Tanner stages) ♂Testicular hypoplasia↓ Body hair growth (e.g., absent facial hair)High-pitched voiceSmooth skin (no acne)↓ Lean body mass♀: primary amenorrhea Developmental abnormalities with genitalia (undescended testes, hypospadias) Infertility (↓ sperm count), impotence, and/or ↓ libido Secondary amenorrhea Examine patient for features of: Klinefelter syndrome: gynecomastiaTurner syndrome: webbed neck, short statureKallmann syndrome: anosmia, absent breast development, uterus is present, syndactyly, cleft palate or lipPrader-Willi syndrome: muscular hypotonia, short stature, facial dysmorphiaGaucher's disease: hepatomegaly, splenomegaly, painful bone crisis Diagnostics Routine tests↓ Serum testosterone levels (in males; usually < 300 ng/dL) and ↓ serum estrogen levels (in females)Determine if the source is primary or secondary hypogonadism. Hypergonadotropic hypogonadism: ↑ GnRH, ↑ LH/FSHHypogonadotropic hypogonadism: ↓ GnRH, ↓ LH/FSHBone scan may support the diagnosis of hypogonadism (↓ bone density (osteoporosis ) or delayed epiphyseal closure). Further tests: based on suspected etiology Genetic testing (for Klinefelter syndrome, Turner syndrome, Kallmann syndrome)Serum prolactin (↑ in prolactinoma)Pelvic ultrasound (e.g., gonadal dysgenesis in Klinefelter syndrome)Brain MRI (for CNS lesion or Kallmann syndrome )Adrenocorticotropic hormone stimulation test (ACTH stimulation test): to exclude congenital adrenal hyperplasia Treatment Treat underlying cause: e.g., surgical excision of tumors, pharmacotherapy for prolactinomas Hormone replacement therapyTrigger onset of puberty in prepubertal individuals at appropriate age Testosterone replacement therapy in males .Estrogen replacement therapy in femalesTo improve fertility in postpubertal individuals with hypogonadotropic hypogonadism and, if prepubescent, an alternative to triggering onset of puberty and growth Pulsatile luteinizing hormone-releasing hormone (LHRH) or human chorionic gonadotropin (HCG) in males Pulsatile LHRH or gonadotropins in females

Hypopituitarism Hypopituitarism refers to the inadequate production of one or more anterior pituitary hormones as a result of damage to the pituitary gland and/or hypothalamus. These hormones include growth hormone (GH), prolactin, thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle stimulating hormone (FSH), and luteinizing hormone (LH). In some cases, the posterior pituitary hormones (e.g., ADH) may also be affected, which is known as panhypopituitarism. The most common cause of hypopituitarism is compression of the pituitary gland by a non-secretory pituitary macroadenoma. Other common causes include postpartum pituitary necrosis (Sheehan syndrome), traumatic brain injury, hypophysectomy, and/or irradiation of the pituitary gland. Clinical manifestations vary significantly and depend on the specific hormone deficiency, the age of disease onset, the rate at which hypopituitarism develops, and the underlying cause of hypopituitarism: Growth hormone deficiency during childhood presents with growth retardation, while prolactindeficiency manifests as lactation failure among women. Deficiencies of other anterior pituitary hormones, on the other hand, manifest with clinical features of hypogonadotropic hypogonadism, secondary hypothyroidism, and/or secondary adrenal insufficiency. Severe pituitary damage can also result in central diabetes insipidus as a result of ADH deficiency. Diagnosis of hypopituitarism involves measuring specific hormone levels (depending on the underlying hormonedeficiency) and cranial imaging (in order to identify damage to the pituitary gland and/or hypothalamus). Treatment of hypopituitarism consists of hormone replacement therapy and treatment of the underlying disorder (e.g., transsphenoidal resection of pituitary adenomas).

Etiology Intrasellar/parasellar masses Nonsecretory pituitary macroadenomas (≥ 10 mm in diameter) are the most common cause of hypopituitarism among adults (∼ 40% of cases). Less common: internal carotid artery aneurysms, meningiomas, craniopharyngiomas, Rathke's cleft cyst Pituitary apoplexyInfarction of the pituitary gland as a result of ischemia and/or hemorrhage.Most commonly occurs in patients with a pre-existing pituitary adenomaPrimarily affects the anterior pituitary gland because it receives its blood supply from a relatively low-pressurearterial system and is, therefore, vulnerable to ischemia and infarction. Sheehan syndrome: postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage. During pregnancy, hypertrophy of prolactin-producing regions increases the size of the pituitary gland, making it very sensitive to ischemia. Blood loss during delivery/postpartum hemorrhage → hypovolemia → vasospasm of hypophyseal vessels →ischemia of the pituitary gland Traumatic brain injury (especially around the skull base) Iatrogenic causes (e.g., hypophysectomy, pituitary irradiation) Infiltration of the pituitary and/or hypothalamusHemochromatosisInfections: meningitis, TB Empty sella syndrome Congenital deficiency of hypothalamic hormonesGnRH deficiency (Kallmann syndrome) Pathophysiology Hypopituitarism becomes symptomatic when more than 80% of pituitary cells are damaged. In most cases, hypopituitarism develops slowly (e.g., adenomas, post-irradiation) Certain cases of hypopituitarism develop rapidly (e.g., pituitary apoplexy). Hypopituitarism refers to deficiency of one or more anterior pituitary hormones (see general endocrinology for their physiological effects)GH deficiency → growth retardation (during childhood), ↓ bone density, muscle atrophy, hypercholesterolemiaProlactin deficiency → lactation failure following delivery FSH/LH deficiency → hypogonadotropic hypogonadism (secondary hypogonadism)TSH deficiency → secondary hypothyroidismACTH deficiency → secondary adrenal insufficiency In addition to the aforementioned hormone deficiencies, patients with severe pituitary damage (panhypopituitarism) also present with deficiencies of posterior pituitary hormones:ADH deficiency → central diabetes insipidusOxytocin deficiency → no effect Clinical features Symptoms are variable and depend on the specific hormone deficiency, the age of disease onset, the rate at which hypopituitarism develops, and the underlying cause of hypopituitarism. GH deficiencyDuring childhood: short statureDuring adulthood: usually asymptomatic; subtle findings include weight gain, weakness, and depression Prolactin deficiencyFemales: lactation failure following deliveryMales: asymptomatic FSH/LH deficiencyFemales: primary amenorrhea (delayed puberty), secondary amenorrhea, irregular menstrual cycles, infertilityMales: delayed puberty, loss of libido, infertility, testicular atrophy, loss of facial, axillary and/or pubic hair, gynecomastia TSH deficiency: weight gain, cold intolerance, lethargy, constipation, dry skin (see hypothyroidism) ACTH deficiency: weight loss, weakness, hypotension, chronic hyponatremia, hypoglycemia (see adrenal insufficiency) Central diabetes insipidus: polyuria, polydipsia Intrasellar/parasellar masses (e.g., pituitary macroadenomas, craniopharyngiomas) can present with headache, visual field defects (bitemporal hemianopsia), and/or diplopia. Pituitary apoplexy: manifests with acute onset of Severe headacheHypopituitarismBilateral hemianopiaDiplopia (due to damage to CN III) Pituitary apoplexy, which results in acute hypocortisolism and hypothyroidism, can manifest with severe headache, sudden hypotension, and hypovolemic shock! Diagnostics Since the pattern of hormone deficiency may vary, each hormone deficiency must be tested individually. GH deficiency↓ IGF-1 levels (insulin-like growth factor)↓ GH levels (even after administering arginine and exogenous GHRH) Prolactin deficiency: No routine test is available Gonadotropin deficiencyMales↓ Or normal LH, which does not increase even after administering exogenous GnRH (GnRH stimulation test) ↓ DHEA, ↓ testosterone (in a serum sample collected between 8 and 10 am)Females: the presence of regular menstrual cycles effectively rules out gonadotropin deficiency; no further diagnostic test is required. ↓ FSH and ↓ LH and do not rise after a GnRH stimulation test↓ EstradiolLack of withdrawal bleeding after administering medroxyprogesterone acetate for 10 days (progesterone challenge test)However, withdrawal bleeding occurs after administering an estrogen preparation for 21 days followed by a progesterone preparation for 7 days (estrogen/progesterone challenge test) TSH deficiency: ↓ T3, ↓ T4, ↓ or normal TSH (see secondary hypothyroidism) ACTH deficiency (see secondary adrenal insufficiency) Low cortisol levels (see ACTH stimulation test)↓ Serum ACTH Central diabetes insipidus: low urine osmolality (< 300 mOsmol/L) which persists despite water deprivation but increases once exogenous desmopressin is administered (see desmopressin test) If a pituitary hormone deficiency is identified: perform cranial imaging (preferably MRI) to identify pituitary adenomas Treatment Management consists of treating the underlying cause (e.g., transsphenoidal resection in cases of pituitary macroadenomas) and hormone replacement therapy. Growth hormone deficiencyChildren: GH hormone replacement;Adults: GH hormone replacement is usually not required TSH deficiency: administration of levothyroxine (see hypothyroidism) Patients with TSH deficiency should not be treated with levothyroxine until ACTH deficiency has been ruled out and/or treated because levothyroxine increases the clearance of cortisol and may precipitate an adrenal crisis! ACTH deficiency: glucocorticoid replacement therapy with increased dosage during periods of stress (see adrenal insufficiency) Immediate treatment with glucocorticoids, without waiting for diagnostic confirmation, is required when acute ACTH deficiency is suspected (e.g., following pituitary apoplexy) to prevent an adrenal crisis! GnRH deficiencyMales If fertility is desired: exogenous gonadotropins (e.g., hCG) should be administered If fertility is not desired: testosterone replacement therapyFemales: estrogen replacement therapy with/without progesterone Prolactin deficiency: no treatment is required Central diabetes insipidus: desmopressin In addition to hormone replacement therapy, the underlying cause of hypopituitarism should be treated, e.g., via transsphenoidal resection in the case of pituitary macroadenomas!

Hyperglycemic crises Acute hyperglycemia, or high blood glucose, may be either the initial presentation of diabetes mellitus or a complication arising during the course of another disease. Inadequate insulin replacement (e.g., noncompliance with treatment) or increased insulin demand (e.g., during times of acute illness, surgery, or stress) may lead to acute hyperglycemia. In diabetic ketoacidosis (DKA), which is more common in patients with type 1 diabetes, no insulin is available to suppress lipolysis, resulting in ketone formation and acidosis. In a hyperosmolar hyperglycemic state (HHS), which is more common in patients with type 2 diabetes, there is still some insulin available and so there is minimal or no ketone formation. Clinical features of both DKA and HHS include polyuria, polydipsia, nausea and vomiting, volume depletion (e.g., dry oral mucosa, decreased skin turgor), and eventually mental status changes and coma. Features unique to DKA include a fruity odor to the breath, hyperventilation, and abdominal pain. Patients with HHS typically present with more extreme volume depletion than those with DKA. The mainstay of treatment for both DKA and HHS consists primarily of IV fluid resuscitation, electrolyte repletion, and insulin therapy.

Etiology Lack of or insufficient insulin replacement therapyUndiagnosed, untreated diabetes mellitusTreatment failure in known diabetics: insulin pump failure, forgotten insulin injection, noncompliance with insulin therapy Increased insulin demandStress: infections, surgery, trauma, myocardial infarctionDrugs: glucocorticoid therapy, cocaine use, alcohol abuse DKA, oftentimes precipitated by infection (e.g., pneumonia, urinary tract infection), is often the initial manifestation of type 1 diabetes mellitus (∼ 30% of cases)! Pathophysiology Diabetic ketoacidosis (DKA) Primarily affects patients with type 1 diabetes Osmotic diuresis and hypovolemia Insulin normally elevates cellular uptake of glucose from the blood. In the insulin-deficient state of DKA, hyperglycemia occurs. Hyperglycemia, in turn, leads to progressive volume depletion via osmotic diuresis. Insulin deficiency → hyperglycemia → hyperosmolality → osmotic diuresis and loss of electrolytes → hypovolemia Hypovolemia resulting from DKA can lead to acute kidney injury (AKI) due to decreased renal blood flow! Hypovolemic shockmay also develop. Metabolic acidosis with increased anion gap Insulin deficiency also increases fat breakdown (lipolysis). Metabolic acidosis develops as the free fatty acids generated by lipolysis become ketones, two of which are acidic (acetoacetic acid and beta-hydroxybutyric acid). Serum bicarbonate is consumed as a buffer for the acidic ketones. Metabolic acidosis with an elevated anion gap is therefore characteristic of DKA. Insulin deficiency → ↑ lipolysis → ↑ free fatty acids → hepatic ketone production (ketogenesis) → ketosis → bicarbonate consumption (as a buffer) → anion gap metabolic acidosis DKA is an important cause of anion gap metabolic acidosis with respiratory compensation. Intracellular potassium deficit As a result of hyperglycemic hyperosmolality, potassium shifts along with water from inside cells to the extracellular space and is lost in the urine. Insulin normally promotes cellular potassium uptake but is absent in DKA, compounding the problem. A total body potassium deficit develops in the body, although serum potassium may be normal or even paradoxically elevated. Insulin deficiency → hyperosmolality → K+ shift out of cells + lack of insulin to promote K+ uptake → intracellular K+depleted → total body K+ deficit despite normal or even elevated serum K+ There is a total body potassium deficit in DKA. This becomes important during treatment, when insulin replacement leads to rapid potassium uptake by depleted cells and patients may require potassium replacement. Hyperosmolar hyperglycemic state (HHS) Primarily affects patients with type 2 diabetes The pathophysiology of HHS is similar to that of DKA. However, in HHS, there are still small amounts of insulin being secreted by the pancreas, and this is sufficient toprevent DKA by suppressing lipolysis and, in turn, ketogenesis. HHS is characterized by symptoms of marked dehydration (and loss of electrolytes) due to the predominating hyperglycemia and osmotic diuresis. Clinical features Signs and symptoms of both DKA and HHSPolyuria PolydipsiaRecent weight lossNausea and vomiting Signs of volume depletion (i.e., dry mucous membranes, decreased skin turgor), hypotension, circulatory collapse Neurological abnormalitiesAltered mental statusLethargyComaOther neurological exam abnormalities, e.g., blurred vision and weakness Signs and symptoms specific to DKARapid onset (< 24 h) in contrast to HHS Abdominal pain Fruity odor on the breath (from exhaled acetone) Hyperventilation: long, deep breaths (Kussmaul respirations) Clinical findings of DKA versus HHSDKAHHSDiabetesType 1Type 2History of severe stress, illness, hospitalization++Polyuria, polydipsia++Nausea, vomiting++/-Dehydration+++ (Profound)Altered mental statusPossiblePossibleHyperventilation+-Fruity breath+-Severe abdominal pain+-OnsetRapid (< 24 h)Insidious (days) Known diabetics who present with nausea and vomiting should be immediately assessed for DKA/HHS! Because patients with type 2 diabetes can still produce small amounts of insulin in some cases, acute hyperglycemia progresses more slowly and serum glucose is significantly elevated compared with patients with type 1 diabetes in DKA (> 600 mg/dL versus > 250 mg/dL). Diagnostics Diagnostic approach [5][6] Check serum glucose to confirm hyperglycemia. Check BMP for serum bicarbonate, anion gap, electrolytes, and renal function. Check for the presence of ketones. Urine ketones: Standard urine dipstick assays detect acetoacetate and acetone but not beta-hydroxybutyrate.Serum beta-hydroxybutyrate [7] Check blood gas analysis for pH. [8] Diagnostic workup to evaluate the underlying cause: HbA1c, CBC, ECG, infectious workup Overview of laboratory findings in hyperglycemic crises [5] DKA: hyperglycemia, high anion gap metabolic acidosis, ketonuria/ketonemia HHS: hyperglycemia, hyperosmolality, and dehydration without ketonuria Laboratory testDKAHHSBMPGlucose< 600 mg/dL (< 33.3 mmol/L) About 10% of patients with DKA will be euglycemic (e.g., glucose ≤ 250 mg/dL) [5]> 600 mg/dL (> 33.3 mmol/L)Bicarbonate< 18 mEq/L (< 18 mmol/L)> 18 mEq/L (> 18 mmol/L)Anion gap Elevated anion gap > 10 mEq/L (> 10 mmol/L)Normal anion gap < 10 mEq/L(< 10 mmol/L) UrinalysisModerate-large urine ketones (ketonuria)GlucosuriaNegative or small ketonesGlucosuriaSerum β-hydroxybutyrateElevatedNormalBlood gaspH < 7.30pH > 7.30Serum osmolalityNormalElevated > 320 mosm/kg (> 320 mmol/kg) DKA is the diagnosis in patients with type 1 diabetes who have hyperglycemia, ketonuria, and high anion gap metabolic acidosis with decreased bicarbonate! HHS is the diagnosis in patients with type 2 diabetes who have hyperglycemia and hyperosmolality! Ketone levels should be ordered in all patients with high anion gap metabolic acidosis to evaluate for euglycemic DKA. Electrolytes and renal function [5][6] Sodium: Hyponatremia is common in both DKA and HHS, due to hypovolemic hyponatremia and hypertonic hyponatremia Always check corrected sodium for hyperglycemia. As a general rule of thumb, 1.6 mEq/L should be added for every 100 mg/dL above a serum glucose of 100 mg/dL. Potassium in DKA: normal or elevated (despite a total body deficit) Magnesium levels are typically low. Phosphorus levels may be falsely elevated despite a total body deficit. BUN and creatinine are often elevated. [9] Additional diagnostic workup [5][10][6] HbA1c Urine pregnancy test [11] Identify the underlying cause. Infection CBC with differential UrinalysisBlood and/or urine culturesSerum procalcitoninSerum lactate X-ray chestCardiac ischemia12-lead ECG Serum troponin Abdominal etiology Serum lipase [12]Serum transaminases Abdominal ultrasound Toxicology screen Infection, myocardial infarction, and pancreatitis should be ruled out in all patients presenting with a hyperglycemic crisis. Severity of DKA Arterial pHSerum bicarbonateAnion gapMental statusMild> 7.2415-18 mEq/L> 10 mEq/LAlertModerate7.0-7.2410-15 mEq/L> 12 mEq/LAlert or drowsySevere< 7.0< 10 mEq/L> 12 mEq/LStuporous All etiologies of altered mental status must be considered in the differential diagnosis of DKA/HHS! Intoxication and other endocrine disorders, as well as gastroenteritis, myocardial infarction, pancreatitis, and other causes of high anion gap metabolic acidosis should all be excluded. Differential diagnosis of DKA/HHS and hypoglycemiaDKA/HHSHypoglycemiaOnsetHours to daysMinutesAppetite∅ (unchanged)↑↑↑↑Thirst↑↑↑↑∅ (unchanged)Muscle tone↓↓↑↑ (tremor)Skin turgor↓↓ (dry skin)↑↑ (moist skin)Respirations↑↑ (Kussmaul respirations with DKA)∅ (unchanged) Treatment Overview IV access with two large-bore peripheral IV lines Assess the severity of DKA. Fluid resuscitation: initially with isotonic saline (0.9% NaCl), then 0.45% or 0.9% depending on corrected serum sodium Electrolyte repletion (especially potassium) Insulin therapy IV bicarbonate (only in severe metabolic acidosis) Identify and treat the underlying cause. Consider admission to the ICU. Treat DKA with normal saline and regular insulin. Fluid resuscitation [5][10][13] First hour: isotonic saline solution (0.9% sodium chloride) at 15-20 mL/kg/hour (∼1000-1500 mL bolus) [5][10][13] Next 48 hours: Adjust IV fluid rate and composition according to CVP, urine output, blood glucose, and corrected sodium levels. Check corrected sodium for hyperglycemia. If corrected serum sodium ≥ 135 mmol/L: 0.45% NaCl If corrected serum sodium < 135 mmol/L: 0.9% NaCl When serum glucose falls to < 200-250 mg/dL, add 5% dextrose to infusion. Electrolyte repletion [5] PotassiumPotassium levels must be ≥ 3.3 mEq/L before insulin therapy is initiatedIf potassium level is < 3.3 mEq/L, potassium should be repleted and rechecked prior to giving any insulin. If potassium level is < 5.3 mEq/L, the patient will likely require potassium repletion once insulin therapy is startedMaintain serum potassium between 4-5 mEq/L.Use extreme caution with potassium repletion in anuric patients. Monitor potassium levels every 2 hours while administering insulin infusion.See also repletion regimens for hypokalemia. Serum K+Recommended dose [14]< 3.3 mEq/LIntravenous potassium chloride via central line Withhold insulin until K+ > 3.3 mEq/L.3.3-5.2 mEq/LIntravenous potassium chloride via central line Or intravenous potassium chloride via peripheral line > 5.2 mEq/LNo repletion recommended Phosphorus: See repletion regimens for hypophosphatemia. Magnesium: See repletion regimens for hypomagnesemia. It is critical that potassium levels are confirmed to be > 3.3 mEq/L before administering insulin, as insulin will lower serum potassium and potentially cause severe hypokalemia. Insulin [5][13][15] The administration of insulin is essential in halting lipolysis and ketoacidosis in patients with DKA. Insulin should be administered intravenously and the initial dose is weight-based. There is some controversy as to whether an initial IV bolus of insulin is necessary. Recommended regimens [5]IV regular insulin bolus , followed by continuous regular insulin IV infusion Or regular insulin continuous IV infusion without a bolus Check glucose level hourly and titrate as needed. The goal is to decrease blood glucose levels by 10% per hour (∼50-75 mg/dL/hour). Treatment with subcutaneous rapid-acting insulin analogues on a regular medical ward may be considered in cases of mild DKA. Acid-base status [5] Acidosis usually resolves with fluids and insulin therapy and the use of IV bicarbonate is usually not necessary If pH < 6.9 despite adequate IV fluid resuscitation, administer IV sodium bicarbonate. Monitoring [5][13] [16] Admission to the ICU or closely monitored setting [5] Consider endocrine consult. NPO status in patients with high anion gap metabolic acidosis on insulin infusion Hourly monitoring of vitals and mental status and hydration status POC glucose every 1-2 hours until blood glucose < 250 mg/dL and hourly blood glucose readings are stable for at least 3 hours; then decrease monitoring to every 2-4 hours Serum osmolality every 1-4 hours Blood gas and BMP with electrolytes every 2-4 hours Monitoring of volume status, serum glucose, serum electrolytes, and acid-base status at regular intervals is essential. Criteria for the resolution of hyperglycemic crises [5][6]DKA Glucose < 200 mg/dL PLUS at least two of the following: Venous pH > 7.30Serum bicarbonate ≥ 15 mEq/LAnion gap ≤ 12 mEq/L HHS Normalization of serum osmolality (i.e., < 320 mOsm/kg) Normal mental status Criteria for transitioning to subcutaneous insulin: Resolution of hyperglycemic crisisPrecipitating factor identified and treatedPatient tolerating oral nutrition and eating consistently Procedure for transitioning to subcutaneous insulin: Stop dextrose infusion.Administer long-acting insulin dose. Patients who were on insulin may resume their normal regimen.In insulin-naive patients, initiate subcutaneous insulin at a total daily dose of ∼ 0.6 units/kg/day (see also insulin regimens) [17] [5]Continue IV insulin for 1-2 hours after initiating SQ insulin. Complications Mucormycosis (Mucor and Rhizopus species) Cerebral edema Cardiac arrhythmias Heart failure, respiratory failure Hypoglycemia, hypokalemia

Hypoparathyroidism Hypoparathyroidism may be due to a variety of mechanisms, including destruction of parathyroid glands (autoimmune or surgical), abnormal parathyroid gland development, altered regulation of parathyroid hormone (PTH), or impaired PTHaction on end organs. The resulting hypocalcemia can trigger a variety of symptoms, ranging from muscle cramps to seizures or heart failure. Manifestations of chronic hypoparathyroidism, however, are quite specific, and include basal ganglia calcifications (resulting in movement disorders), cataracts, and skeletal and dental abnormalities. Laboratory findings in hypoparathyroidism include hypocalcemia with low or inappropriately normal PTH, hyperphosphatemia, and normal renal function. Treatment usually includes correcting the hypocalcemia through calcium and vitamin Dsupplementation and treatment of the underlying cause.

Etiology Postoperative: most commonly occurs as the result of accidental injury to parathyroids (or their blood supply) during thyroidectomy, parathyroidectomy, or radical neck dissection Autoimmune: second most common cause Congenital: Parathyroid aplasia or hypoplasia (DiGeorge syndrome)PTH gene mutationAutosomal dominant hypocalcemia Nonautoimmune destruction: Infiltration of parathyroid gland (Wilson's disease, hemochromatosis, granulomas, metastases)Radiation-induced destructionGram-negative sepsisToxic shock syndromeHIV infection Clinical features Acute manifestationsSymptoms of hypocalcemia (e.g., tetany)Chvostek sign: hypocalcemia → hyperexcitable nerves → tapping the facial nerve on the cheek → contraction of facial musclesTrousseau sign: inflate BP cuff → allow for occlusion of brachial artery for a few minutes → carpal spasm Chronic manifestationsExtrapyramidal disorders : symptoms include parkinsonism, dystonia, hemiballismus, choreoathetosis, oculogyric crises, or dementia Secondary to basal ganglia calcification Ocular disease: cataracts, keratoconjunctivitisSkeletal: increased bone mineral density, osteosclerosisDental abnormalities: dental hypoplasia, failure of tooth eruption, defective root formationCutaneous manifestations: dry, puffy, coarse skin Diagnostics Hypocalcemia with low or inappropriately normal PTH Hyperphosphatemia Normal 25-hydroxyvitamin D (25[OH]D) Normal or low 1,25-dihydroxyvitamin D (1,25D): low concentration of PTH cannot stimulate renal production of 1,25D Normal magnesium Normal creatinine Differential diagnoses See differential diagnosis of hypocalcemia. Pseudohypoparathyroidism type 1A: end-organ (i.e., bones and kidneys) resistance to parathyroid hormone (PTH) despite sufficient PTH synthesis due to a defective Gs protein alpha subunit Inheritance: autosomal dominant; gene defect inherited from the mother (GNAS gene imprinting)Pathophysiology: mutations in GNAS1 → α subunit is not encoded → impaired activation of adenylate cyclasewhen PTH binds to Gs → resistance to PTH in kidney and bone tissueClinical features: Albright hereditary osteodystrophyRound faceShort statureObesityBrachydactyly of the 4th and 5th fingersSubcutaneous ossificationsIntellectual disabilityDiagnosticsPersistent hypocalcemia despite increased levels of PTHHyperphosphatemia Pseudopseudohypoparathyroidism: extremely rare condition that mimics PHP type 1a but without end-organresistance to PTHInheritance: autosomal dominant, defective Gs protein alpha subunit is inherited from the father (GNAS geneimprinting). The normal allele from the mother allows for maintaining the responsiveness of the kidneys to PTH.Clinical features: Albright hereditary osteodystrophyDiagnostics: normal calcium, PTH, and phosphate Treatment Treat underlying disease Calcium and vitamin D supplementation

Adrenal insufficiency Adrenal insufficiency is the decreased production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens) and can be primary, secondary, or tertiary. Primary adrenal insufficiency (Addison disease) is caused by a disorder of the adrenal glands. The most frequent cause of primary adrenal insufficiency in the US by far is autoimmune adrenalitis, which may occur sporadically or as a manifestation of polyglandular autoimmune syndromes. Secondary adrenal insufficiency is the result of decreased production of ACTH (adrenocorticotropic hormone) and tertiary adrenal insufficiency is the result of decreased production of CRH (corticotropin-releasing hormone) by the hypothalamus. Decreased levels of ACTH or CRH are seen following sudden cessation of a prolonged glucocorticoidtherapy or in pituitary/hypothalamic diseases. Patients with long-standing adrenal insufficiency can present with postural hypotension, nausea, vomiting, weight loss, anorexia, lethargy, depression, and/or chronic hyponatremia. Patients can also present with loss of libido as a result of hypoandrogenism. Patients with primary adrenal insufficiency also tend to develop hyperpigmentation of the skin, mild hyperkalemia, and metabolic acidosis. Serum cortisol levels that remain low even after the administration of exogenous ACTH (ACTH stimulation test) confirm the diagnosis of primary adrenal insufficiency. Glucocorticoid replacement therapy with hydrocortisone is required for all forms of adrenal insufficiency. The dose of glucocorticoids should be increased during periods of stress (e.g., surgery, trauma, infections) in order to prevent adrenal crisis, which is a severe, acute type of adrenal insufficiency that manifests with shock, fever, impaired consciousness, and severe abdominal pain. Adrenal crisis is life-threatening and should be treated immediately with high doses of hydrocortisone and intravenous fluids.

Etiology Primary adrenal insufficiency (Addison disease) Primary adrenal insufficiency is caused by conditions that directly impair adrenal function. Autoimmune adrenalitisMost common cause in the US (∼ 80-90% of all cases of primary adrenal insufficiency)Associated with other autoimmune endocrinopathies (see autoimmune polyglandular syndromes) Infectious adrenalitisTuberculosis: most common cause worldwide, but rare in the USCMV disease in immunosuppressed states (especially AIDS)Histoplasmosis Adrenal hemorrhage [1][2]Sepsis: especially, meningococcal sepsis → hemorrhagic necrosis (Waterhouse‑Friderichsen syndrome)Disseminated intravascular coagulation (DIC)Anticoagulation: especially heparin (HIT) [3] Infiltration of the adrenal glandsTumors (adrenocortical tumors, lymphomas, metastatic carcinoma)AmyloidosisHemochromatosis Adrenalectomy Impaired activity of enzymes that are responsible for cortisol synthesisCortisol synthesis inhibitors (e.g., rifampin, fluconazole, phenytoin, ketoconazole)21β-hydroxylase deficiency (see congenital adrenal hyperplasia) Vitamin B5 deficiency [4] Secondary adrenal insufficiency Secondary adrenal insufficiency is caused by conditions that decrease ACTH production (impaired hypothalamic-pituitary-adrenal axis). Sudden discontinuation of chronic glucocorticoid therapy or stress (e.g., infection, trauma, surgery) during prolonged glucocorticoid therapyProlonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis Impaired endogenous cortisol production in addition to discontinuation of steroid treatment, decrease in dosage, or increase in requirement (e.g., stress) → acute glucocorticoid deficiency Hypopituitarism: ↓ ACTH → ↓ endogenous cortisol Tertiary adrenal insufficiency Tertiary adrenal insufficiency is caused by conditions that decrease CRH production. The most common cause is sudden discontinuation of chronic glucocorticoid therapy Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, hemorrhage, or anorexia): ↓ CRH → ↓ ACTH → ↓ cortisol release Secondary and tertiary adrenal insufficiency are far more common than primary adrenal insufficiency! Pathophysiology For basic information on the adrenal gland and its functions, see hormones of the adrenal cortex. Primary adrenal insufficiency (Addison disease)Damage to the adrenal gland → hypoandrogenism (most common in female patients) , hypoaldosteronism, and hypocortisolism → ↑ ACTH [7]ACTH is derived from precursor molecule pro-opiomelanocortin (POMC), which is also a precursor for melanocyte-stimulating hormone (MSH).↑ Production of POMC (in order to ↑ ACTH production) → ↑ melanocyte-stimulating hormone (MSH) and hyperpigmentation of the skin (bronze skin) Secondary adrenal insufficiency↓ ACTH → hypoandrogenism and hypocortisolismAldosterone synthesis is not affected (mineralocorticoid production is controlled by RAAS and angiotensin II, not by ACTH). Tertiary adrenal insufficiency↓ CRH → ↓ ACTH → hypoandrogenism and hypocortisolismAldosterone synthesis is not affected. Hormonal changesClinical featuresLaboratory findingsPrimary adrenal insufficiencySecondary adrenal insufficiencyTertiary adrenal insufficiencyHypoaldosteronismHypotensionHyponatremiaHyperkalemiaNormal anion gap metabolic acidosis✓AbsentAbsentHypocortisolismWeight loss, anorexiaFatigue, lethargy, depressionMuscle achesGastrointestinal complaints (e.g., nausea, vomiting, diarrhea)Sugar/salt cravings(Orthostatic) hypotension HypoglycemiaHyponatremia✓✓✓HypoandrogenismLoss of libidoLoss of axillary and pubic hair↓ DHEA-S✓✓✓Elevated ACTHHyperpigmentation of areas that are not normally exposed to sunlight (e.g., palmar creases, mucous membrane of the oral cavity) ↑ MSH✓AbsentAbsent Most cases of adrenal insufficiency are subclinical and only become apparent during periods of stress (e.g., surgery, trauma, infections), when the cortisol requirement is higher! Primary adrenal insufficiency Pigments the skin. Secondary adrenal insufficiency Spares the skin. Tertiary adrenal insufficiency is due to Treatment (cortisol). Diagnostics Diagnosis is based on clinical presentation and confirmed via endocrine evaluation. Diagnosis of adrenal insufficiency General laboratory findings Serum electrolytes HyponatremiaHyperkalemiaNormal anion gap metabolic acidosis Mild hypercalcemia (in up to one-third of cases) Hypoglycemia ↑ Serum creatinine and BUN as a result of hypovolemia Complete blood count: eosinophilia Diagnosis of hypocortisolism Best initial testMorning serum cortisol levels: < 3 μg/dL (< 80 nmol/L) without exogenous glucocorticoid administration confirms adrenal insufficiency. OR morning serum ACTH levels (often not quickly available) ↑ ACTH in primary adrenal insufficiency↓ ACTH in secondary/tertiary adrenal insufficiency Confirmatory testACTH stimulation test (cosyntropin test): measurement of serum cortisol before and 30 minutes after administration of exogenous ACTH (e.g., cosyntropin)Physiological response: exogenous ACTH → ↑ cortisol (failure of cortisol to rise > 20 μg/dL after ACTHadministration confirms primary adrenal insufficiency)In secondary/tertiary adrenal insufficiency: exogenous ACTH → ↑ cortisol (usually a rise in cortisol > 20 μg/dL) OR metyrapone stimulation testMetyrapone inhibits 11β hydroxylase → impaired conversion of 11-deoxycortisol to cortisol (last step of cortisol synthesis)Measurement of 11-deoxycortisol and cortisol after administration of metyrapone: Adrenal insufficiency is diagnosed if the 11-deoxycortisol level does not exceed 70 ng/mL and the cortisol level is < 5 μg/dL. Physiological response: metyrapone → ↓ cortisol synthesis → ↑ CRH and ↑ ACTH (negative feedback) → ↑ adrenal steroidogenesis → ↑ 11-deoxycortisol and ↑ cortisolIn primary adrenal insufficiency: metyrapone → ↓ cortisol synthesis → ↑ in CRH/ACTH → no increase in adrenal steroid production → ↓ 11-deoxycortisol and ↓ cortisolIn secondary/tertiary adrenal insufficiency: metyrapone → ↓ cortisol → ↓ CRH/ACTH → no increase in adrenal steroidogenesis → ↓ 11-deoxycortisol and ↓ cortisol Diagnosis of hypoaldosteronism ↑ Plasma renin concentration ↓ Urine aldosterone levels Diagnosis of adrenal hypoandrogenism ↓ DHEA-S Identifying the underlying cause of adrenal insufficiency Serum ACTH levels: used to distinguish between primary and secondary/tertiary adrenal insufficiency↑ ACTH → primary adrenal insufficiency↓ ACTH → secondary or tertiary adrenal insufficiency CRH stimulation test: used to distinguish between secondary and tertiary adrenal insufficiency [9]↓ ACTH → secondary adrenal insufficiency↑ ACTH → tertiary adrenal insufficiency If primary adrenal insufficiencyScreen for autoantibodies against 21-hydroxylase and other autoantibodies associated with autoimmune adrenalitis Adrenal imaging (ultrasound, MRI, CT): to detect, e.g., a lesion, mass, infection, or hemorrhage of the adrenal glandIf an infectious etiology is suspected: screen for tuberculosis (chest x-ray) and HIV (combination antigen/antibodytests) If secondary adrenal insufficiencyRule out iatrogenic cause: history of long-term cortisol intakeHead MRI: to detect pituitary destruction or compression (e.g., trauma, lesions, hemorrhage, tumors)Test for other pituitary hormone deficiencies (e.g., TSH, GnRH, prolactin, GH) If tertiary adrenal insufficiencyRule out iatrogenic cause: history of long-term cortisol intakeHead MRI: to detect hypothalamic destruction or compression (e.g., trauma, lesions, hemorrhage, tumors)Screen for congenital disorders (e.g., DNA-methylation analysis in Prader-Willi syndrome) Treatment Primary adrenal insufficiency Requires both glucocorticoid and mineralocorticoid replacementGlucocorticoid replacementHydrocortisone : administered in 2-3 doses daily Steroid stress dosing: Increase glucocorticoid dose during stressful situations (e.g., infection, surgery, trauma). Mineralocorticoid replacement Fludrocortisone Loss of libido can be treated with dehydroepiandrosterone (DHEA). Treatment of underlying causes (e.g., antibiotics for TB infection, tumor resection) Secondary and tertiary adrenal insufficiency Only glucocorticoid replacement is necessary: hydrocortisone (as above) Mineralocorticoid production is not ACTH-dependent and therefore unaltered. Loss of libido can be treated with dehydroepiandrosterone (DHEA). Treatment of underlying causes (e.g., tumor resection) In hypopituitarism: substitution of other hormones (e.g., TSH) Glucocorticoid replacement therapy with hydrocortisone is required in all forms of adrenal insufficiency! If the dose of glucocorticoids is not increased during periods of stress, the patient may develop an adrenal crisis! Adrenal crisis (Addisonian crisis) Description: Acute, severe glucocorticoid deficiency that requires immediate emergency treatment. CausesStress (e.g., infection, trauma, surgery) in a patient with underlying adrenal insufficiencySudden discontinuation of glucocorticoids after prolonged glucocorticoid therapyBilateral adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome)Pituitary apoplexy Clinical featuresHypotension, shockImpaired consciousness, comaFeverVomiting, diarrheaSevere abdominal pain (which resembles peritonitis)Hypoglycemia, hyponatremia, hyperkalemia, and metabolic acidosis TherapyAdministration of high doses of hydrocortisone: 100 mg IV every 8 hoursAlternatively: dexamethasone4 mg IV every 12 hoursDoes not interfere with testing, as opposed to hydrocortisone [15]Fluid resuscitation with normal saline to treat hypotension and hyponatremiaCorrect hypoglycemia with 50% dextroseIntensive care monitoring In order to avoid the development of secondary and tertiary adrenal insufficiency, prolonged steroid therapy must be tapered slowly and should never be stopped abruptly. The 5 S's of adrenal crisis treatment are: Salt: 0.9% saline, Sugar: 50% dextrose, Steroids: 100 mg hydrocortisone IV every 8 hours, Support: normal saline to correct hypotension and electrolyte abnormalities, Search for underlying disorder Adrenal crisis can be life-threatening. Therefore, treatment with high doses of hydrocortisone should be started immediately without waiting for diagnostic confirmation of hypocortisolism! Autoimmune polyglandular syndromes Definition: a set of conditions characterized by autoimmune disease that causes multiple endocrine deficiencies, which affect the hormone-producing (endocrine) glands TypesType 1: (APS-1, Whitaker syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED) Less common than APS-2 (1:100,000)Autosomal recessive inheritance; no HLA associationCaused by a mutation in the autoimmune regulator gene (AIRE)Age of onset: usually in childhoodAssociated endocrine deficiencies (two or more of the following should be present) Most commonly Primary adrenal insufficiencyHypoparathyroidismChronic mucocutaneous candidiasisEctodermal dystrophy of skin, nails, and dental enamelLess commonly: hypogonadism, pernicious anemia, alopecia, vitiligo, hepatitisType 2 (APS-2, Schmidt syndrome): defined by the occurrence of primary adrenal insufficiency with thyroidautoimmune disease and/or type 1 diabetes mellitus [16]More common than APS-1 (1:100)Associated with HLA‑DR3 and/or HLA‑DR4 haplotypesAge of onset: usually in adulthoodMain manifestation: primary adrenal insufficiencyAssociated endocrine deficiencies (one or more of the following may be present) Most commonly Thyroid autoimmune disease (e.g., Hashimoto thyroiditis)Type 1 diabetes mellitus Less commonly: celiac disease, pernicious anemia, alopecia areata, vitiligo Diagnostics: condition‑specific antibody tests (e.g., TPO antibodies in Hashimoto thyroiditis, antiparietal cell antibodies in pernicious anemia) Therapy: depends on the endocrine deficiency Replacement of deficient hormones (e.g., thyroxin, hydrocortisone, insulin)Antifungal therapy in chronic mucocutaneous candidiasisVitamin B12 supplementation in pernicious anemia; vitamin D in hypoparathyroidismImmunosuppressive therapy for, e.g., hepatitis, nephritis, pneumonitis

Osteomalacia and rickets Osteomalacia is a disorder of impaired mineralization of the osteoid; rickets is a disorder of impaired mineralization of cartilaginous growth plates. Adults have fused growth plates so they are only affected by osteomalacia. In children, whose growth plates are open, the disorders can occur simultaneously. The most common cause of both osteomalaciaand rickets is vitamin D deficiency resulting from inadequate intake, malabsorption, or lack of exposure to sunlight. Patients with osteomalacia usually present with bone pain and tenderness, while patients with rickets exhibit bone deformities and impaired growth. Over time, both conditions may lead to bending of the long bones or even pathologic fractures. Treatment consists of administering vitamin D and ensuring sufficient calcium intake.

Etiology Vitamin D‑dependent forms Vitamin D deficiencyLow exposure to UV radiation Low oral intakeLow dietary intake Infants younger than 1 year: breast milk has low amounts of vitamin D (see the learning card on breast milk) Low intestinal absorptionCystic fibrosis, chronic pancreatitis Celiac disease Gastrectomy Dark skin Premature birth Defective vitamin D metabolismLiver cirrhosis Drugs: cytochrome P450 inducers increase the metabolism of Vitamin DAnticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital)Renal disease (e.g., chronic renal failure)Rare vitamin D-dependent hereditary forms Vitamin D‑independent forms (rare) Partial defects in renal tubular functioning (renal tubular acidosis, Fanconi syndrome) Phosphate deficiency Drugs: BisphosphonatesAluminiumFluoride Pathophysiology For more information on calcium metabolism, see calcium homeostasis. Vitamin D deficiency and defective vitamin D metabolismHypocalcemia → defective bone matrix mineralization (osteomalacia) or growth plate mineralization (rickets) Renal disease → ↓ production of vitamin D and metabolic acidosis → impaired calcification Vitamin D-independent forms Phosphate deficiency → ↓ phosphate blood levels → defective bone matrix mineralization (osteomalacia) or growth plate mineralization (rickets) Clinical features Osteomalacia Occurs in adults and children Bone pain and tenderness Pathologic fractures Waddling gait and difficulty walking Myopathy: muscle weakness, spasms, and/or cramps Bone deformity only in very severe cases of osteomalacia Symptoms of hypocalcemia (see disorders of calcium balance) Rickets Only occurs in children (growth plates have not fused) Bone deformitiesBending of primarily the long bonesDistention of the bone-cartilage junctionsRachitic rosary: distention of the bone-cartilage junctions in the ribsMarfan's sign: distention of the bone-cartilage junctions in the jointsCraniotabes: softening of the occipital bonesVarum/valgus deformities of the knee Harrison's groove: depression of the thoracic outlet due to muscle pulling along the costal insertion of the diaphragm Late closing of fontanelles Impaired growth Symptoms of hypocalcemia (see disorders of calcium balance) Calcium↓Phosphate↓ Alkaline phosphatase↑Parathyroid hormone↑ X‑ray Osteomalacia Low bone mineral density Thin cortices Looser zones (pseudofractures): transverse bands of radiolucency indicating defective calcification of osteoid Rickets Low bone mineral density Thin cortices Growth plates in the metaphysis of the long bones are less defined and show cupping, stippling, and fraying Wide epiphysis In severe cases, looser zones Evidence of bone deformities (see "Clinical features" above) Differential diagnoses For osteomalaciaMalignancyOsteoporosisPaget disease of the bone For ricketsMalignancyDwarfismOsteogenesis imperfectaChild abuse/neglect Treatment Vitamin D deficiency: administration of Vitamin DAlso indicated in infants who are exclusively breastfedThe healing of both osteomalacia and rickets requires adequate daily intake of calcium. Defective vitamin D metabolism or vitamin D‑independent forms Treatment of underlying disease

Second-line lipid-lowering agents Second-line lipid-lowering agents include fibrates, bile acid resins, niacin, and cholesterol absorption inhibitors. These drugs are used concurrently with statins for patients who have hypercholesterolemia that is inadequately controlled with statin monotherapy. They are also used as second-line agents for patients who experience persistent side effects from statins (e.g. myositis, myalgias, and/or myopathy). Each drug targets different steps in cholesterol and lipid metabolism pathway to treat hypercholesterolemia and therefore vary in their effectiveness at decreasing low-density lipoprotein(LDL), increasing high-density lipoprotein (HDL), and decreasing triglycerides. Second-line lipid-lowering agents are rarely indicated for primary prevention of cardiovascular disease because they do not improve cardiovascular outcomes or mortality.

Fibrates (fibric acid derivatives) Agents: bezafibrate, fenofibrate, and gemfibrozil Mechanism of action: activation of the peroxisome proliferator-activated receptor alpha (PPAR-α) →↑ lipoprotein lipase activity → more rapid degradation of LDL and triglycerides and induction of HDL synthesis →↓ LDL, ↑ HDL, ↓↓↓ triglyceride Side effectsDyspepsiaMyopathy, especially in combination with statins CholelithiasisFibrates inhibit cholesterol 7α hydroxylase → decreased bile acid synthesis → supersaturation of bile with cholesterol (↑ cholesterol:bile acid ratio)↑ LFTs Indication: second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides ContraindicationsRenal insufficiency Liver failureGall bladder diseases Interactions: enhance the effect of other drugs by inhibiting hepatic CYP450 (e.g., sulfonylureas, warfarin) The reason for the enhanced effect is the strong binding of fibrates to albumin. The dose of warfarinshould be reduced by 30% when using fibrates. Bile acid resins Drugs: cholestyramine, colestipol, colesevelam Mechanism of actionIon exchange resin binds bile acids in the intestine → interruption of enterohepatic circulation (↓ bile acidabsorption and ↑ bile acid excretion) → lowers cholesterol pool and promotes synthesis of LDL receptors (↓ unbound LDL), slightly ↑ HDL, and slightly ↑ triglycerides Side effectsNausea, abdominal bloating and cramping ↑ LFTsMyalgia IndicationsCombination treatment with statins in hypercholesterinemiaDigitoxin overdosePruritus associated with elevated bile acid levels (cholestasis)Bile acid diarrhea ContraindicationsHypertriglyceridemia > 300-500 mg/dLHypertriglyceridemia-induced pancreatitisBowel obstruction Drug interactions: warfarin, digoxin, fat-soluble vitamins Niacin Mechanism of action: inhibits lipolysis and fatty acid release in adipose tissue, decreases hepatic VLDL synthesis→ ↓ triglyceride and LDL synthesis, ↑ HDL Indication: high LDL cholesterol and lipoprotein(a) levels (> 50 mg/dL) despite statin and ezetimibe therapy (or if statins are contraindicated) Side effectsFlushing and pruritus: ↑ prostaglandin synthesis → peripheral vasodilationPretreatment with aspirin or ibuprofen can minimize prostaglandin-mediated side effectsParesthesiasGI upset (e.g., diarrhea, flatulence, abdominal pain)↑ LFTsHyperglycemiaHyperuricemia and gout (e.g., podagra) ContraindicationsLiver failureGoutHemorrhageGastric ulcerCardiovascular instability Ezetimibe Mechanism of action: selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesteroltransporter NPC1L1) → ↓ LDL IndicationMonotherapy: in contraindications or statin intoleranceCombination therapy (statin and ezetimibe): in insufficient LDL cholesterol reduction by statins Side effects (especially in combination therapy, otherwise rare): ↑ liver enzymes, angioedema, diarrhea, myalgia Contraindication: coadministration with a statin during active liver disease PCSK9 inhibitors Drugs: alirocumab, evolocumab Mechanism of action: monoclonal antibodies that inhibit proprotein convertase subtisilin kexin 9 (PCSK9), an enzyme that degrades the LDL-receptor → increased removal of LDL from the blood stream → ↓↓↓ LDL, ↑ HDL, ↓ triglycerides Side effectsMyalgiaNeurocognitive defects (delirum, dementia)

Adrenal gland The adrenal gland is a paired retroperitoneal organ located on the upper pole of each kidney. It receives its arterial supply from the superior, middle, and inferior suprarenal arteries and drains into the right and left suprarenal veins. The adrenal gland has two layers: the adrenal cortex (outer layer), which is derived from the mesoderm, and the adrenal medulla(inner layer), which is derived from neural crest cells. The adrenal medulla is composed of chromaffin cells, which secrete catecholamines (norepinephrine, epinephrine, dopamine). The adrenal cortex consists of three layers: the zona glomerulosa, the zona fasciculata, and the zona reticularis, which are responsible for the synthesis of mineralocorticoids, glucocorticoids, and androgens (precursors for estrogen and testosterone) respectively. Mineralocorticoids regulate renal sodium and water reabsorption and potassium excretion, while glucocorticoids play an important role in glucose metabolism. Diseases of the adrenal glands include adrenal insufficiency (due to an infection, hemorrhage, autoimmune destruction), hyperaldosteronism (due to hyperplasia, adenoma), and hypercortisolism (due to hyperplasia, adenoma, exogenous administration).

Gross anatomy Overview Two endocrine glands that produce steroid hormones and adrenaline Size: height and thickness ∼ 5 cm; width 1-2 cm Location Primary retroperitoneal organsEach gland is located superior to the upper pole of the kidneyEnclosed by the renal fascia and adipose capsule of the kidney Embryology Adrenal cortex: derived from mesodermAdrenal medulla: derived from the neural crest Function Adrenal cortex: outer layer that produces steroid hormones Adrenal medulla: inner part of the gland that produces catecholamines Vasculature Arterial blood supplySuperior suprarenal artery (from the inferior phrenic artery)Medial suprarenal artery (from the abdominal aorta)Inferior suprarenal artery (from the renal artery) Venous drainageRight suprarenal vein into the inferior cava veinLeft suprarenal vein into the left renal vein Lymph drainage: left aortic lymph nodes; right caval lymph nodes The left suprarenal vein merges into the left renal vein; the right suprarenal vein merges directly into the inferior vena cava! Innervation Sympathetic: major and minor splanchnic nerves Parasympathetic: vagal nerve Microscopic anatomy Adrenal cortex Surrounded by a fibrous capsule Layers of the cortex Zona glomerulosaDescription: cells arranged in oval clusters surrounded by connective tissue from the fibrous capsuleFunction: mineralocorticoid synthesisZona fasciculataDescription: cells arranged in straight columns that are separated by small fibrous septa Function: glucocorticoid synthesisZona reticularisDescription: small cells arranged in an irregular netlike formation surrounded by connective tissue and capillariesFunction: androgen synthesis GFR → MGA = The layers of the adrenal cortex from outside to inside are GFR (G = Zona Glomerulosa, F = Zona Fasciculata, R = Zona Reticularis). They are the Managing General Agents of some hormone synthesis. Adrenal medulla Large chromaffin cells with many secretory granules (catecholamine storage) Chromaffin cells originate in the neural crest and migrate to the paraganglia and adrenal medulla during embryonic development. Tumors originating from chromaffin cells are called pheochromocytomas. Function: synthesis of catecholamines The cells of the adrenal medulla are modified sympathetic cells that are controlled by cholinergic synapses. Mineralocorticoids: aldosterone Zona glomerulosa Regulation of renal sodium and water reabsorption and potassium excretion See the section "Mineralocorticoids" below for details Renin-angiotensin-aldosterone system Primary hyperaldosteronism Adrenal insufficiency Congenital adrenal hyperplasia Glucocorticoids: cortisolZona fasciculata Metabolism: mobilize energy reservesHigh dosage: immunosuppressive and antiphlogistic effectSee cortisol for detailsCRH → ↑ secretion of ACTH in the pituitary gland → ↑ secretion of glucocorticoids and androgens in the adrenal cortexCushing syndromeAdrenal insufficiencyCongenital adrenal hyperplasiaAndrogens: dehydroepiandrosterone(DHEA)Zona reticularis Precursor for estrogen and testosterone See the section "Androgens" for detailsAdrenal insufficiencyCongenital adrenal hyperplasia Going from outside to inside, the hormones produced in each layer: The deeper you go, the sweeter it gets: Salt (Na+ and mineralocorticoids, zona glomerulosa), Sugar (glucocorticoids, zona fasciculata), and Sex (androgens, zona reticularis) The RAAS regulates the release of mineralocorticoids! Mineralocorticoids General Mineralocorticoids: aldosterone Site of synthesis: zona glomerulosa 1.Pregnenolone3β-hydroxysteroid dehydrogenaseProgesterone2.Progesterone21-hydroxylase (defective enzyme results in the most common form of congenital adrenal hyperplasia, with hypoaldosteronism, hypocortisolism, infant salt wasting, female pseudohermaphroditism and precocious puberty in males)11-deoxycorticosterone3. 11-deoxycorticosterone 11β-hydroxylase and aldosterone synthase (defective enzyme results in congenital adrenal hyperplasia, with hypoaldosteronism, hypocortisolism, female pseudohermaphroditism) Corticosterone 4.CorticosteroneAldosterone synthase Aldosterone Regulation: renin-angiotensin-aldosterone system (RAAS) Positive feedback↑ Angiotensin II: renal hypoperfusion (e.g., hypotension, stimulation of β1 receptors in the kidney) → kidneysrelease renin → renin converts angiotensinogen (produced in the liver) to angiotensin I (AT I) → conversion of AT Ito angiotensin II through angiotensin-converting enzyme (ACE, mostly produced in the lungs) → angiotensin II acts as a strong vasoconstrictor and induces the secretion of aldosterone by the adrenal cortex↑ Serum potassium concentration Negative feedback: ANP Function Mechanism: binds to intracellular mineralocorticoid receptors in the distal tubule and collecting duct of the kidney↑ Na+/K+-ATPase in the basolateral membrane → transports Na+ out and K+ into the tubule cells↑ Apical H+-ATPase↑ Na+ channels ENaC (epithelial natrium channel) and K+ channels ROMK (renal outer medullary potassium channel) in the luminal membrane Effect: ↑ Na+ resorption; ↑ H2O resorption; ↑ K+ excretion; ↑ H+ excretion → ↑ extracellular fluid, ↑ blood pressure, ↓ K+, ↑ pH Aldosterone stimulates the sodium and water retention and potassium excretion in the kidney! Glucocorticoids General Glucocorticoids: mainly cortisol Site of synthesis: zona fasciculata Important cofactor: Vitamin C 1.Pregnenolone pathwayPregnenolone17α-hydroxylase17-hydroxypregnenoloneProgesteronepathwayPregnenolone3β-hydroxysteroid dehydrogenaseProgesterone2.Pregnenolone pathway17-hydroxypregnenolone3β-hydroxysteroid dehydrogenase17-hydroxyprogesteroneProgesteronepathwayProgesterone17α-hydroxylase3.Common pathway17-hydroxyprogesterone21-hydroxylase (defective enzyme results in the most common form of congenital adrenal hyperplasia 11-deoxycortisol4.Common pathway11-deoxycortisol11-β-hydroxylase (defective enzyme results in congenital adrenal hyperplasia, with hypoaldosteronism, hypocortisolism, female pseudohermaphroditism) Metyrapone inhibits this reactionCortisol Regulation: hypothalamic-pituitary gland-adrenal cortex feedback mechanism Mechanism: corticotropin-releasing hormone (CRH) → ↑ secretion of adrenocorticotropic hormone (ACTH) in the pituitary gland → ↑ secretion of glucocorticoids in the adrenal cortex Positive feedback: trigger CRH releasePain, stress (psychological/physical)Pyrogens, adrenaline, histamineHypoglycemia, hypotension Negative feedback: glucocorticoids Circadian rhythm: early morning ↑ serum CRH levels → ↑ cortisol levels Cortisol inhibits the secretion of CRH and ACTH via negative feedback, which, in turn, results in a decrease in cortisol secretion. Function Metabolism: mobilize energy reserves↑ Gluconeogenesis: to maintain blood glucose levels↑ Glycogen synthesis: to maintain glucose storage↑ Protein catabolism ↑ Lipolysis↑ Appetite↑ Insulin resistanceInhibitory effect on bone metabolism and stimulation of bone degradation: direct inhibition of osteoblastic activity and inhibition of osteoclast apoptosis Immunosuppression and antiphlogistic effect: complex mechanisms↓ Lymphocytes, eosinophils, and monocytes↑ RBCs, ↑ Platelets, ↑ Neutrophil granulocytes (overall WBC increases)Inhibition of T-cell and B-cell responsesInhibition of cytokine synthesis and secretion (e.g., IL-2)↓ Mast cell activation and histamine release ↓ Wound healing Permissive effect on catecholamines (e.g., increase in blood pressure ) Mild mineralocorticoid effect: increase in blood pressure, potassium excretion Clinical use of glucocorticoids in the treatment of inflammatory and autoimmune conditions and allergic reactions (see learning card on glucocorticoids) Androgens General Androgens: intermediate sex steroids in the adrenal cortex Dehydroepiandrosterone (DHEA)DHEAS (Dehydroepiandrosterone sulfate)Androstenedione Site of synthesis: zona reticularis In both men and women, DHEA and androstenedione are produced in the adrenal cortex, which are precursors for testosteroneand estrogen. Testosterone is produced by Leydig cells in the testes in men and, to a lesser degree, ovarian stroma in women. Synthesis 17α-hydroxylase: converts pregnenolone → 17-hydroxypregnenolone → dehydroepiandrosterone (DHEA)Defective enzyme → rare form of congenital adrenal hyperplasia that results in male pseudohermaphroditism and delayed puberty in females 3β-hydroxysteroid dehydrogenase: converts DHEA → androstenedione DHEA and intermediates (e.g., androstenedione) are secreted by the adrenal cortex Further processing occurs in the target tissue: gonads, brain, adipose tissue , skin, bone, placenta (see function below) Regulation: hypothalamic-pituitary gland-adrenal cortex feedback mechanism Corticotropin-releasing hormone (CRH) → ↑ secretion of adrenocorticotropic hormone (ACTH) in the pituitary gland→ ↑ secretion of androgens in the adrenal cortex Function Mechanism: Adrenal androgens (DHEA and androstenedione) serve as precursors of: More potent androgensAndrostenedione → testosteroneTestosterone → dihydrotestosterone (DHT) via 5α-reductaseDefective 5α-reductase → 5α-reductase deficiency5α-reductase inhibitors (e.g., finasteride) inhibit the conversion → used to treat BPHDHT is a potent form of testosteroneCauses hair follicles to transform into terminal hair in androgen sensitive areasUpper lip, chin, upper abdomen, and back.Idiopathic hirsutism affects 5-10% of female patients10% of cases arise from hyperandrogenism of adrenal originsEstrogen (in men and postmenopausal women ) Aromatase: converts testosterone → estradiol and androstenedione → estrone Effects of androgensMale sexual differentiation during embryonic development Male pubertal development of secondary sexual characteristics (e.g., growth spurt, increased muscle mass, penile growth, deepening of the voice, Adam's apple growth, acne)SpermatogenesisIncreased libidoAnabolic effects on muscles and bonesStimulate erythropoiesis (↑ RBCs)Influence behavior (e.g., aggression) Effects of estrogenFemale sexual differentiation during embryonic developmentFemale pubertal development of secondary sexual characteristicsSee Estrogen and associated diseases for details Generally, the effects of androgens in women only become apparent in cases of androgen excess (e.g., PCOS, androgen-secreting tumors). Hormones of the adrenal medulla: catecholamines General Catecholamines: norepinephrine, epinephrine, dopamine Site of synthesisRegions of the CNS Chromaffin cells of the adrenal medullaPostganglionic adrenergic neurons StimuliSympathetic activation ("fight and flight")Cortisol from the adrenal cortex 1. 1st Hydroxylation Phenylalanine Phenylalanine hydroxylase Cofactor: Tetrahydrobiopterin (THB) Tyrosine 2. 2nd Hydroxylation Tyrosine Tyrosine hydroxylase Cofactor: THB DOPA (3,4-Dihydroxyphenylalanine) 3. Decarboxylation DOPA DOPA decarboxylase Cofactor: Pyridoxal phosphate (Vitamin B6) Dopamine 4. Hydroxylation of the β-C-Atom Dopamine Dopamine β-monooxygenase Cofactor: vitamin C Norepinephrine 5.Methylation Norepinephrine Phenylethanolamine-N-Methyltransferase (PNMT) Cortisol induces expression of PNMT Cofactor: S-Adenosylmethionine (SAM) Epinephrine Epinephrine has the shortest half-life of the catecholamines. Stress results in an increased production of catecholamines and glucocorticoids. Degradation Enzymatic degradation via catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO)MAO inhibitors (antidepressant drugs) prevent the degradation of catecholamines in the CNS → elevated concentration of catecholamines in synaptic cleft → improve depressive symptoms End-stage metabolite: vanillylmandelic acid (VMA)VMA has diagnostic value: elevated urinary excretion in patients with pheochromocytoma and neuroblastoma The end-stage metabolite of epinephrine and norepinephrine is vanillylmandelic acid. Urinary excretion of VMA has diagnostic value in pheochromocytoma and neuroblastoma! Function Sympathetic activation → fight-or-flight reaction Mechanism: catecholamines bind to various adrenergic receptors (with differing functions depending on the respective G protein; see table below) located on different organs and tissue → trigger specific responses with the ultimate goal to prepare for a fight-or-flight reaction α1 GqStimulation of phospholipase C: PIP2 → IP3 und DAG → ↑ Ca2+Vasculature (skin and GI tract)↑ Contraction of smooth muscles → vasoconstrictionGI tractBladder↑ Constriction of sphinctersα2GiInhibition of adenylate cyclase: ↓ cAMPWhite adipose tissue↓ LipolysisGI tractBladder↓ Muscular contractionPancreas↓ Insulin secretionβ1GsStimulation of adenylate cyclase: ↑ cAMPHeart↑ Heart rate ↑ Contractility ↑ Conductivity Kidney↑ Renin secretionβ2Vasculature (coronary vessels, skeletal muscles)Bronchi↓ Contraction of smooth musculature → vasodilatation and bronchodilatationLiverSkeletal muscles↑ GlycogenolysisWhite adipose tissue↑ LipolysisPancreas↑ Insulin secretionUterusTocolysisβ3Brown adipose tissue ↑ Lipolysis Clinical significance Important diseases associated with the adrenal cortex Hypocortisolism Hypercortisolism Primary hyperaldosteronism (Conn syndrome) Congenital adrenal hyperplasia (CAH) Androgen-secreting tumors Important diseases associated with the adrenal medulla Pheochromocytoma Neuroblastoma

SIADH

Increased pituitary ADH secretionDiseases of the central nervous system (e.g., stroke, bleeding, infection, trauma)Pulmonary disease (pneumonia, COPD)Drugs (e.g., chlorpropamide, carbamazepine, cyclophosphamide, selective serotonin reuptake inhibitors)Endocrine disorders (glucocorticoid deficiency)Neurosurgery (especially: transsphenoidal pituitary surgery) Diagnostics Blood↓ serum osmolality (< 280 mOsm/kg H2O) and ↓ sodium (< 135 mmol/L)Normal renal function (based on creatinine)Normal adrenal function (based on ACTH stimulation test)Normal thyroid function (based on thyroid hormones: TSH, T4, T3)Plasma ADH normal to elevatedFrequently ↓ uric acid values UrineUrine osmolality > 100 mOsm/kg H2O Urinary sodium excretion > 20 mmol/L SIADH patients are usually euvolemic, normotensive, and have no edema. An hyponatremic patient with edema should raise suspicion of other conditions (e.g. congestive heart failure). Treatment Treatment of the underlying condition Asymptomatic patientsFluid restriction!Increased salt intake Symptomatic patientsHypertonic saline administration with ICU monitoring to impede osmotic demyelination syndromeIf severe: consider adding a loop diuretic (e.g., furosemide) to hypertonic saline Most effective if urine osmolality is > 2x the serum osmolality (typically urine osmolality > 500 mOsmol/kg)If initial measures fail, consider demeclocycline or vasopressin antagonists (vaptans): IV conivaptan and PO tolvaptanThe sodium serum levels may increase by a maximum of 10 mmol/L within 24 hours or 0.5 mmol/L per hour. A rapid increase in serum sodium can lead to osmotic demyelination syndrome!

Hormonal contraceptives Hormonal contraceptives involve the use of estrogen and progestin analogs to prevent pregnancy. The contraceptive effect is mediated by negative feedback at the hypothalamus, ultimately leading to reduced pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. Without an LH surge, ovulation does not occur. Progestin also makes implantation less likely, as it causes a thickening of cervical mucus, a decrease in tubal motility, and the inhibition of endometrial proliferation. Oral contraceptives (OCs) are the most common form of hormonal contraception, but other forms of hormone delivery, including patches, injections, and implants, also exist. In combination monophasic OCs, the dose of estrogen and progestin remains constant, while in combination multiphasic OCs it varies over the course of one cycle. The decreased total hormone doses of multiphasic OCs mitigate certain associated side effects and risks. These include bothersome symptoms such as breast tenderness, nausea, bloating, and breakthrough bleeding as well as medical emergencies such as venous thromboembolism. Because of the complications associated with hormonal contraceptives, their use is contraindicated in patients with certain medical conditions and histories, e.g., significant hypertension, ischemic heart disease, venous thromboembolism, and stroke.

Oral contraceptive pillCombined oral contraceptive(COC)Short-acting, reversible oral contraceptivecontaining estrogen and progestin9% (< 1%)ContraceptionHyperandrogenism (e.g., acne, hirsutism)Menstrual cycle disorders (e.g., menorrhagia, dysmenorrhea)Symptom control in endometriosis, leiomyomasProgestin-only contraceptive pills (minipill)Short-acting, reversible oral contraceptivecontaining low doses of norethindrone 9% (< 1%)Contraception for women in whom estrogen-containing contraceptives are contraindicatedContraceptive patchShort-acting, reversible contraceptive transdermal patch that provides sustained low doses of estrogen and progestin 9% (< 1%)Patches are considered as effective as COC pillsOnly require application to the skin once a weekSimilar indications as for COCVaginal ringShort-acting, reversible flexible vaginal ring that contains ethinyl estradiol and etonogestrel 9% (< 1%)Similar indications as for COCInjectable progestinIntramuscular or subcutaneous injection administered every 3 months. 6% (< 1%)Long-term and reversibleIntrauterine device with progestinNeed to be replaced every 3 to 5 years (varies with type of device).< 1%Subdermal progestin implantThe device (flexible plastic rod) is usually inserted subdermally in the upper arm and lasts 3 years.< 1% Emergency contraception Non-hormonal methods: Copper-containing intrauterine devices Added benefit of long-term contraceptionRequires brief, clinical procedure Hormonal methodsMost effective when taken within 3 days of intercourseTypically administered as a single dose or as two doses over one daySignificantly less effective in patients who are obese or overweight Types Levonorgestrel Antiprogestin (e.g., ulipristal acetate) Yuzpe regimen (combination of ethinyl estradiol and levonorgestrel) The rate of pregnancy is ≤ 3.0% if emergency contraception is taken within 72 hours after unprotected sexual intercourse. The earlier it is taken, the lower the likelihood of pregnancy! Effects Mechanisms of action depend on the hormones used in the formulation EstrogenHypothalamus: ↓ release of GnRHPituitary: ↓ LH → inhibits ovulation, ↓ FSH → prevents ovarian folliculogenesis ProgestinInhibits GnRH and LH secretion → suppresses ovulation (main contraceptive mechanism)Inhibits endometrial proliferationChanges cervical mucus (↓ volume and ↑ viscosity) and impairs fallopian tube peristalsis → inhibition of spermascension and egg implantationInhibits follicular maturation Antiprogestin: inhibits or delays ovulation by inhibiting the progesterone receptor Side effects Common side effects Estrogen: Venous thromboembolism (VTE) (increased rate due to estrogen-mediated coagulopathy) Cardiovascular events Hypertension Risk increased in patients with history of HTN during a pregnancy and/or family history of HTNHeadaches Hepatic adenoma development Mastopathy and mastodyniaNausea Progestin: Breakthrough bleeding Follicular cystsVenous thromboembolism (VTE) Weight gain is not a side effect of hormonal contraceptives Indications for immediate discontinuation Sensory disorders (e.g., impaired vision) New or enhanced migraine-like headaches (especially with aura) New or enhanced epilepsy Detection of massesFibroid growthBreast lump growth Jaundice Pregnancy Suspected thromboembolism or thrombophlebitis Studies have shown that women taking estrogen-progestin combination OCPs before menopause have an increased risk of cervical carcinoma but a decreased risk of endometrial and ovarian carcinoma. Indications Contraceptive indications Patients desiring pregnancy in 1-2 yearsShort-acting reversible options include OCPs, patches, and vaginal ringsDMPA (Progestin-only contraceptive that is typically injected and provides relatively long (up to 3 months) but reversible protection) is not appropriate for patients who wish to regain fertility soon Implants and IUDs can be used but may not be cost-effective Postpartum contraception: All contraceptive options except for combination OCPs can be considered in the postpartum periodOCPs containing estrogen should not be given if breastfeeding (estrogen may reduce breast milk production and enter the milk itself)Combination OCPs may only be used after 4-6 weeks postpartum Non-contraceptive indications Symptomatic treatment in menorrhagia and dysmenorrhea Polycystic ovary syndrome (PCOS) Menstrual migraine Premenstrual dysphoric disorder (PMDD) HyperandrogenismAcneHirsutism Pelvic pain due to endometriosis Contraindications Absolute contraindications for estrogen-containing OCPs CardiovascularThromboembolismCoagulopathy, antiphospholipid antibodiesCoronary heart diseaseStrokeArterial hypertension (> 160/95 mm Hg)Heart defects MetabolicPronounced hypertriglyceridemiaMetabolic disorders of the liverInsulin-dependent diabetes mellitus OncologicHepatic tumorsEstrogen-dependent tumors InflammatoryAcute pancreatitisLupus erythematodesVasculitisAfter herpes gestationis Smoking > 35 years of age Genital bleeding of unknown cause Pregnancy Women who smoke and are > 35 years old should not be prescribed OCPs because of increased risk of cardiovascular side effects! Relative contraindications for estrogen-containing OCPs CardiovascularSuperficial venous thrombosisThrombophlebitisSevere varicosis MetabolicHypercholesterinemiaMorbid obesityDiabetes mellitus Age > 40 years Epilepsy Migraines Smoking Lactation (progestin-only preparations permitted) Uterine leiomyomas (especially intracavitary) Gastric/duodenal ulcer Ulcerative colitis Special patient groups Minors In the United States, laws allowing minors to consent to contraceptive health care are determined by individual states. Most states allow adolescents to receive medical care related to pregnancy prevention without parental consent.

General endocrinology Endocrinology is the field of medicine concerned with endocrine tissue (e.g., the pituitary gland, thyroid gland, adrenals, testicles, and ovaries), metabolic diseases, and to an extent, nutritional medicine. Endocrine tissue is responsible for producing and secreting hormones, which influence the function of certain cells and organs. Hormone secretion is controlled by highly regulated pathways that involve cell signaling and positive or negative feedback. Disruption to these pathways can lead to an imbalance of hormones, resulting in various pathological conditions involving hyperactive or hypoactive glands (e.g., hyperthyroidism or hypothyroidism, respectively). One complex pathway is known as the hypothalamic-pituitary axis, which is the main focus in this learning card. An understanding of these hormone pathways is important for determining the next best step of management, particularly when interpreting changes in hormone levels and the results of suppression or stimulation tests.

Overview of endocrinological diseases This learning card focuses on the hypothalamic-pituitary axis. Other important hormones and metabolic diseases are discussed in their respective learning cards. Metabolic diseasesDiabetes mellitusOsteoporosis (see calcium homeostasis)Metabolic syndrome Diseases of the endocrine glands of the hypothalamic-pituitary axisPituitary glandHypopituitarismProlactinomaAcromegalyDiabetes insipidusAdrenal cortexHypocortisolismHypercortisolismPrimary hyperaldosteronismCongenital adrenal hyperplasiaThyroid glandHypothyroidismHyperthyroidismGonadsHypogonadotropic hypogonadismHypergonadotropic hypogonadism Aging endocrine system Basics of endocrinology Hormone Definition: Hormones are endogenous messengers that are produced in glands or single cells. They are responsible for signal transduction and influence the function and metabolic rate of other organs and cells. Complex regulatory circuits normally control their secretion. Hormones can be categorized based on their signaling pathways: Paracrine hormones: affect the neighboring cells through diffusion Autocrine hormones: affect the secreting cell itself Endocrine hormones: are secreted into the bloodstream to reach their targets Based on their chemical nature: Steroid hormones: derived from cholesterol (e.g., testosterone, progesterone, estrogen, glucocorticoids, mineralocorticoids)Amine hormones: derived from a single amino acid such as phenylalanine, tyrosine, or tryptophan (e.g., catecholamines, thyroid hormones (T3 and T4))Peptide/protein hormones: derived from a few or many amino acids (e.g., oxytocin, vasopressin, prolactin, glucagon, insulin) Based on their biochemical properties: Lipophilic hormones: steroid hormones and thyroid hormones Hydrophilic hormones: peptide/protein hormones and amine hormones (except for thyroid hormones!) Hydrophilic hormones (e.g., catecholamines) are stored in secretory granules and are released when needed. Lipophilic hormones (e.g., adrenocortical steroid hormones) pass into the bloodstream once synthesized. They are not stored by cells. Degradation of hormones Steroid hormones and thyroid hormones: inactivation and conjugation in the liver and excretion in bile Catecholamines: enzymatic degradation and excretion in urine (e.g., vanillylmandelic acid) Peptide/protein hormones: proteolytic degradation mainly in the liver and kidneys Feedback control mechanisms Hormones are controlled by different feedback mechanisms. Take the simplified feedback mechanism of the antidiuretic hormone (ADH) as an example: Receptors in the hypothalamus measure plasma osmolality (measuring system). If the osmolality exceeds a set point, the neural pituitary gland excretes ADH (controlled variable). ADH increases renal reabsorption of water (process unit). Receptors in the hypothalamus detect falling osmolality and reduce ADH secretion, which decreases the amount of water reabsorption in the kidneys. Diagnosis of endocrine diseases The following methods may be used: Direct measurement of hormone blood levels (e.g., measuring prolactin blood level upon clinical suspicion of prolactinoma) Stimulation of glands to detect underactivity (e.g., ACTH stimulation test for Addison's disease = chronic adrenal insufficiency) Inhibition of glands to detect hyperactivity (e.g., dexamethasone suppression test for Cushing's syndrome = hypercortisolism) Imaging of glands to determine: Morphological abnormalities (e.g., thyroid ultrasound )Functional abnormalities (e.g., thyroid scintigraphy for autonomous thyroid nodule) Specific laboratory studies (e.g., determination of thyrotropin receptor antibodies, or HbA1c for diabetes mellitus) Hypothalamus and pituitary gland Hypothalamus Ventral part of the diencephalon (forebrain) composed of several nuclei Regulates hormonal pathways and autonomic functions (e.g., control of body temperature and food intake) Hormones of the hypothalamus mostly affect hormonal secretion of the anterior pituitary gland. Exceptions: antidiuretic hormone (ADH) and oxytocinProduced in the hypothalamus → axonal transport in association with neurophysins to posterior pituitary glandfor storage → released into circulation as needed There are two types of hormones: releasing hormones (increase hormonal secretion from the pituitary gland) and inhibiting hormones (decrease hormonal secretion from the pituitary gland) For more information on the anatomy of the hypothalamus, see the learning card for diencephalon. Pituitary gland (hypophysis) Located in a midline depression of the sphenoid bone (sella turcica) in the middle cranial fossa Connects to the hypothalamus through the pituitary stalk (infundibulum) Divided into two parts:Anterior pituitary gland (= adenohypophysis) Posterior pituitary gland (= neurohypophysis) Overview of hypothalamic-pituitary axis Hypothalamic-(anterior) pituitary axis The anterior pituitary produces two different types of hormones: Tropic hormones → affect cells indirectly by stimulating other endocrine glands firstNontropic hormones → direct effect on cells Hypothalamic-pituitary-adrenal axisCRH (corticotropin-releasing hormone)ACTH (adrenocorticotropic hormone)Adrenal cortexHypothalamic-pituitary-thyroid axisTRH (thyrotropin-releasing hormone)TSH (thyroid-stimulating hormone)Thyroid glandHypothalamic-pituitary-gonadal axisGnRH (gonadotropin-releasing hormone)GonadotropinsLH (luteinizing hormone)FSH (follicle-stimulating hormone)Gonads♀: Ovaries♂: Testicles Hypothalamic-pituitary-somatotropic axis GHRH (growth hormone-releasing hormone) GH (growth hormone, somatotropin) Stimulates growth and has an anabolic effect on the body Direct effects of GH: ↓ Glucose uptake into cells↑ Lipolysis↑ Protein synthesis in muscle↑ Production of IGF Somatostatin (growth hormone-inhibiting hormone) Inhibits release of GH Opposes effects of GHRH GI tract: suppresses release of: gastrin, cholecystokinin, secretin, VIP Hypothalamic-pituitary-prolactin axisTRH (thyrotropin-releasing hormone, thyroliberin): stimulates secretion of prolactin in the pituitary gland Prolactin (secreted by lactotropic cells) Breast tissue: growth and lactation Dopamine, also called PIH (prolactin-inhibiting hormone): inhibits secretion of prolactin in the pituitary gland MSH-RH (melanocyte-stimulating hormone-releasing hormone) MSH (melanocyte-stimulating hormone) Skin: hyperpigmentation due to stimulation of melanocytes Melanocyte-inhibiting hormone Hormones of the hypothalamus-(posterior) pituitary axis The posterior pituitary gland (= neurohypophysis) stores and secretes two peptide hormones from the hypothalamusAntidiuretic hormone (ADH, vasopressin): regulation of free water balance (and blood pressure) Reabsorption of water (→ antidiuretic effect) via insertion of water channels (aquaporins) into the renal convoluted tubule (through V2 receptors)At higher levels: vasoconstriction (through V1 receptors) Oxytocin: induces uterine contractions and the release of milk Important diseases associated with the hypothalamus and pituitary gland Hypopituitarism Prolactinoma Acromegaly Diabetes insipidus SIADH Adrenal cortex The adrenal cortex consists of three distinct layers Zona glomerulosa: produces mineralocorticoids Zona fasciculata: produces glucocorticoids (see cortisol for effects) Zona reticularis: produces androgens (see dehydroepiandrosterone for effects) For more information see the learning card for hormones of the adrenal cortex Thyroid gland Thyroid hormones The thyroid gland secretes two thyroid hormones: T3 (triiodothyronine) and T4 (thyroxine, tetraiodothyronine). More T4 is produced than T3 but T4 is less potent. Peripheral 5'-deiodinase in the blood converts T4 into the biologically active T3. T4 is therefore considered a hormonal precursor (prohormone). Half of the T4 is processed into biologically inactive T3 (reverse T3). The half-life of T3 is about one day (∼ 20 hours), whereas the half-life of T4 is about one week (∼ 190 hours). This longer half life makes T4 suitable for use as a depot form that can be used replacement therapy. Furthermore, the C cells of the thyroid gland produce calcitonin, which regulates calcium balance. Physiological effects of thyroid hormones ↑ Basal metabolic rate (↑ oxygen consumption, and ↑ body temperature) Stimulation of carbohydrate metabolism Anabolism of proteins (in high doses: catabolism of proteins) Induces either lipolysis or liponeogenesis depending on metabolic status Permissive effect on catecholamines (particularly via β receptors) In children: stimulation of bone growth CNS effectsPerinatal period: maturation of the brain (therefore, hypothyroidism screening is very important!)Adulthood: Hyperthyroidism: hyperexcitability, irritabilityHypothyroidism: somnolence, slowed speech, impaired memory Reproductive effectsFertilityOvulation and menstruation Feedback control mechanisms Hypothalamus: TRH (thyrotropin-releasing hormone, thyroliberin) → stimulates secretion of TSH (thyroid-stimulatinghormone, thyrotropin) in the pituitary gland → stimulates release of T3 (triiodothyronine) and T4 (thyroxine, tetraiodothyronine) in the thyroid glandStimuli: exposure to extreme cold, stressInhibition T3/T4 inhibit TRH and TSH, which as a result inhibits T3/T4 secretion and iodine uptake Somatostatin, dopamine, and glucocorticoids inhibit the production of TSH. Important diseases associated with the thyroid gland Hypothyroidism Hyperthyroidism Gonads Physiological effects of LH, FSH, and sex hormones ♀: OvariesFSH: follicular maturation → ↑ estrogen (see effects of estrogen and associated diseases) LH: ↑ estrogen, ovulation, and ↑ progesterone ♂: TesticlesFSH: production of sperm, ↑ inhibinLH: stimulation of Leydig cells → ↑ production of testosteroneEffects of testosteroneDevelopment of male sexual characteristics during pubertySpermatogenesisIncreased libidoAnabolic effectsBone formation, growth Muscle-building effects Feedback control mechanisms Hypothalamus: GnRH → stimulates release of FSH (follicle-stimulating hormone) and LH (luteinizing hormone) in the pituitary gland → the effects of LH and FSH on the gonads are different in men and women Stimuli: pulsatile release of GnRH starting at pubertyInhibition of GnRH, LH, and FSH secretion by: Androgen, estrogen, progesteroneInhibin Secretion is regulated by central neuromodulators. Important diseases associated with the gonads Hypogonadotropic hypogonadism Hypergonadotropic hypogonadism Drugs that act on the hypothalamic-pituitary-gonadal axis GnRh agonists GnRh antagonists OCPs Spironolactone Ketoconazole SERM Anastrazole Finasteride Flutamide Clomiphene Cyproterone Regulation of appetite Key hormones: Leptin: A hormone predominantly produced in adipose tissue that is a key mediator of long-term regulation of food intake and body weight and inhibits hunger.Neuropeptide Y (NPY): A neurotransmitter primarily stored in the hypothalamus that has several functions in the central and peripheral nervous systems, including:Appetite stimulationRegulation of anxiety-related behaviorNeuronal excitabilityGhrelin: A hormone secreted by the stomach that stimulates appetite. Levels increase during fasting states and decrease after intake of food.Regulation of hunger: occurs in the lateral nucleus of the hypothalamusStimulated by:GhrelinNeuropeptide Y (NPY)Inhibited by: leptin (produced in adipose tissue) → decreases NPY Regulation of satiety: occurs in the ventromedial nucleus of the hypothalamusStimulated by:Cholecystokinin (short-term effect via inhibition of gastric emptying and food intake)Leptin (long-term) Polyphagia: excessive hunger (e.g., due to hyperthyroidism, hypoglycemia) Ghrelin makes you a gluttonous gremlin. Leptin makes you thin!

Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive defects in the enzymes that are responsible for cortisol, aldosterone, and, in very rare cases, androgen synthesis. All forms of CAH are characterized by low levels of cortisol, high levels of ACTH, and adrenal hyperplasia. The exact clinical manifestations depend on the enzyme defect. The most common form of CAH is caused by a deficiency of 21β-hydroxylase and manifests with hypotension, ambiguous genitalia, virilization (in the female genotype), and/or precocious puberty (in both males and females). All newborn infants in the US are screened for 21β-hydroxylase deficiency by measuring 17-hydroxyprogesterone in a blood sample obtained from a heel prick. CAH treatment involves lifelong glucocorticoidand fludrocortisone replacement therapy. Certain rare forms of CAH (e.g., 11β-hydroxylase and 17α-hydroxylasedeficiencies) manifest with symptoms of mineralocorticoid excess (e.g., hypertension) and therefore require spironolactone (aldosterone receptor inhibitor) in addition to glucocorticoid replacement. Individuals with a virilizing form of CAH have an increased likelihood of experiencing gender dysphoria. Intersex medical interventions may be considered in cases of ambiguous genitalia. Complications of CAH include severe hypoglycemia, adrenal insufficiency, and failure to thrive.

Pathophysiology CAH is caused by autosomal recessive defects in enzymes that are responsible for the production of cortisol. There are three subtypes of CAH: 21β-hydroxylase (∼ 95% of CAH)11β-hydroxylase (∼ 5% of CAH)17α-hydroxylase (rare) Low levels of cortisol → lack of negative feedback to the pituitary → increased ACTH → adrenal hyperplasia and increased synthesis of adrenal precursor steroids Depending on which enzyme is affected, the following endocrine changes are seen: Enzyme deficiency Cortisol Aldosterone 11-Deoxycorticosterone (DOC) Androgens 21-hydroxylase Ct↓ Ald↓DOC↓ And↑ 11β-hydroxylase Ct↓ Ald↓ DOC↑ And↑ 17α-hydroxylase Ct↓ Ald↓ DOC↑ And↓ A deficiency in both 17α-hydroxylase and 11β-hydroxylase tends to result in overproduction of mineralocorticoids like DOCand underproduction of aldosterone. "1 DOC:" If the deficient enzyme starts with 1 (11β-, 17‑), there is increased DOC."AND 1:" If the deficient enzyme ends with 1 (21-, 11β‑), androgens are increased. 21β-hydroxylase Hypotension Female pseudohermaphroditism: clitoromegalyand/or male external genitalia along with a uterusand ovaries Precocious puberty Virilization, irregular menstrual cycles, infertility Normal male external genitalia at birth Precocious puberty 11β-hydroxylase Hypertension Female pseudohermaphroditism: clitoromegalyand/or male external genitalia along with a uterusand ovaries Precocious puberty Virilization, irregular menstrual cycles, infertility Normal male external genitalia at birth Precocious puberty 17α-hydroxylase Hypertension Normal female external genitalia at birth Delayed puberty (primary amenorrhea) or sexual infantilism Male pseudohermaphroditism: female external genitaliawith a blind-ending vagina and intra-abdominal testes at birth Delayed puberty or sexual infantilism Hypoglycemia Adrenal crisis → vomiting and diarrhea → dehydration Failure to thrive Hyperpigmentation in areas that are not exposed to sunlight (e.g., palm creases, mucous membranes of the oral cavity, genitalia) is a common feature in all forms of CAH. Infants with 21β-hydroxylase deficiency can present with shock within the first few weeks of life because of severe dehydrationdue to an adrenal crisis and salt-wasting due to hypoaldosteronism. Different types of mutations on the CYP21A2 gene (which codes for 21β-hydroxylase) are associated with different levels of disease severity. Classic CAHNonclassic CAH21β-hydroxylasedeficiencySevereMildDetection by neonatal screeningYesNoPrevalenceLess commonMore commonOnset of symptomsEarly onset (during the neonatal period or early infancy)Late onset (manifests during late childhood, adolescence, or adulthood)Clinical manifestationsSalt-wasting type∼ 67% of all classic forms7-14 days after birth, males present with failure to thrive, dehydration, vomiting, and shock.Females present with ambiguous genitalia.Non-salt-wasting type (simple virilizing) ∼ 33% of all classic formsNo signs of shockMales present with precocious puberty at age 2-4.Females present with ambiguous genitalia.Normal external genitalia at birth in both genotypesPrecocious pubertyAcneInfertilityFemales may also have irregular menstrual cycles and hirsutism.May even be asymptomaticEthnic predispositionInuit and Alaska native populationsAshkenazi and white populations Individuals with a virilizing form of CAH have an increased likelihood of experiencing gender dysphoria. Differential diagnoses Precocious pseudopuberty Primary adrenal insufficiency PCOS Hyperprolactinemia Cushing Syndrome Diagnostics Increased specific steroid precursors in blood and/or urine samples (see the table below) Screening is conducted by measuring 17-hydroxyprogesterone (also for newborns). If steroid precursors are not elevated at baseline but CAH is still suspected, administer exogenous ACTH(cosyntropin) and measure again (see ACTH stimulation test). Hypocortisolism is seen in all forms of CAH, and cortisol levels remain low even after administration of cosyntropin. Specific patterns of electrolyte and/or acid-base disorders are associated with specific enzyme deficiencies. 21β-hydroxylase 17-Hydroxyprogesterone 21β-hydroxylase↑↑ 11β-hydroxylase↑ 17α-hydroxylase↓ 11-Deoxycorticosterone (DOC) 21β-hydroxylase ↓ 11β-hydroxylase ↑↑ 17α-hydroxylase↑ Corticosterone 21β-hydroxylase↓ 11β-hydroxylase↓ 17α-hydroxylase↑↑ Sodium 21β-hydroxylase↓ 11β-hydroxylase↑ 17α-hydroxylase↑ Potassium 21β-hydroxylase ↑ 11β-hydroxylase↓ 17α-hydroxylase↓ Acid-base disorders 21β-hydroxylase Metabolic acidosis 11β-hydroxylase Metabolic alkalosis 17α-hydroxylaseMetabolic alkalosis All newborns in the US are screened for CAH by measuring changes in 17-hydroxyprogesterone levels from a heel prick blood sample. Treatment General approachTherapy aims to replace deficient hormones and reduce excess androgen production.Glucocorticoid replacement therapy is indicated in all forms of CAH. Lifelong daily regimen Hydrocortisone in neonates and childrenPrednisolone or dexamethasone in adolescents and adultsSteroid stress dosing Specific treatment21β-hydroxylase deficiencyLifelong fludrocortisone therapy (aldosterone substitution)Sodium chloride (salt) supplements, especially during infancy and childhood11β-hydroxylase deficiencySpironolactone to block mineralocorticoid receptorsReduced dietary sodium intake17α-hydroxylase deficiencySpironolactone to block mineralocorticoid receptorsEstrogen replacement therapy for female genotype; may be started in early pubertyReduced dietary sodium intakeSalt-wasting CAHFluid resuscitation with intravenous normal salineIntravenous dextrose in patients with significant hypoglycemiaImmediate administration of glucocorticoid replacement therapy Additional considerationsIntersex medical intervention may be considered in children with ambiguous genitalia.Patients that experience gender dysphoria may benefit from counseling. The dose of glucocorticoids must be increased during severe infection, critical illness, and perioperatively to meet increased demands to prevent adrenal crisis. Prenatal diagnosis and treatment of CAH Prenatal testing is recommended in mothers who have previously given birth to a child with 21β-hydroxylasedeficiency. Chorionic villus sampling Increased 17α-hydroxyprogesterone in amniotic fluid If a defect in 21β-hydroxylase is diagnosed prenatally: Prophylactic treatment of the mother with dexamethasone soon after conception Dexamethasone therapy should be discontinued if the fetus has a male genotype (revealed by karyotyping).

Insulin Insulin is an anabolic peptide hormone that is produced and secreted from beta cells located in the islets of Langerhans of the pancreas. It has important metabolic functions, which include promoting the storage of carbohydrates, amino acids, and fat in the liver, skeletal muscle, and adipose tissues. By modulating glucose absorption from the blood, insulin lowers blood glucose levels. Insulin therapy is an important part of treatment for individuals with insufficient or absent insulin production (e.g., diabetes mellitus, gestational diabetes). Several insulin analogs (e.g., insulin glargine) are available that are related to human insulin but have a different molecular structure and differ in onset, peak, and duration compared to human insulin. It is crucial that patients receiving insulin therapy undergo in-depth training to prevent potentially life-threatening conditions such as hypoglycemia as a result of an insulin overdose or drug interactions. For further information on insulin therapy and regimens, see insulin therapy.

Rapid-acting insulinInsulin lisproOnset: 5-30 minPeak: 30 min-3 hDuration: 3-5 hIntensified conventional insulin therapyInjected before a meal time Used in combination with longer-acting insulin Insulin aspartInsulin glulisine Short-acting insulinRegular insulinOnset: ∼30 minPeak: 2.5-5 hDuration: 4-24 h"Standard insulin" for lowering blood glucose levels in an acute settingConventional insulin therapy Intensified conventional insulin therapyMandatory interval between injections and meal times: ∼30 minUsed in combination with longer-acting insulinIntravenous therapy available (only for this type of insulin) Intermediate-acting insulinNPH insulinOnset: 1-2 hPeak: 4-12 hDuration: 14-24 hConventional insulin therapy Component of basal supported oral therapy (BOT) for treatment-resistant type 2 diabetes mellitusCrystalline suspension Mandatory interval between injections and meal times: 30-60 minUsed in combination with rapid or short-actinginsulinUsually administered twice daily Long-acting insulinInsulin glargineOnset: 1.5-4 hPeak: flat; not definedDuration: ∼ 24 h Intensified conventional insulin therapy Component of basal supported oral therapy (BOT) for treatment-resistant type 2 diabetes mellitus Insulin analogs More consistent efficacy profile and longer duration of effect compared to NPH insulin Used in combination with rapid or short-actinginsulin Administered once or twice daily Insulin detemirInsulin degludecUltralente insulin Mixed insulinMixed insulinBiphasic effectShort-term effect like that of regular insulin/lispro/aspartLong-term effect like that of NPH insulinConventional insulin therapyContains regular insulin and NPH insulin mixed according to a defined ratio Example: Actraphane® 30/70, contains 30% regular insulin and 70% NPH insulinAdministered two or three times a day Effects Insulin is an anabolic peptide hormone that is produced and secreted from beta cells in the islets of Langerhans of the pancreas in response to a rise in blood glucose Several insulin analogs (e.g., insulin glargine) are available that are related to human insulin but have a different molecular structure; after injection they exert the same actions but differ in onset, peak and duration compared to human insulin Insulin binds to insulin receptors (a type of tyrosine kinase receptor) located in various tissues in the body (e.g., liver, skeletal muscle, adipose tissue) and has the following actions: Carbohydrate metabolism Increases Uptake of glucose into cellGlycogenesisGlycolysis Decreases Glycogenolysis Gluconeogenesis: via dephosphorylation of fructose-1,6-bisphosphatase Lipid metabolism Increases Lipid synthesis Decreases Lipolysis Ketogenesis Protein metabolism Increases Protein synthesis Uptake of amino acids Decreases Proteolysis Other effects Secretion of gastric acidCell growth and differentiationUptake of potassium Side effects Hypoglycemia Weight gain Lipodystrophy at the injection site Pain and erythema at injection site Hypokalemia Allergic reactions (rare) Edema (rare) Indications Type 1 diabetes mellitus Type 2 diabetes mellitus, if weight normalization, physical activity, and oral antidiabetic drugs do not keep blood glucose levels in the target rangeAll type 2 diabetic patients with end stage renal failure (oral antidiabetic drugs are contraindicated in this case) Pancreatic insufficiency with secondary diabetes Gestational diabetes, if change of diet is not sufficient Acute hyperkalemia: A drip containing regular insulin and a solution of glucose reduces blood potassium levels. See also "insulin therapy" in diabetes mellitus. Insulin regimens Basal-bolus insulin regimen [3][4] Calculate the total daily dose of insulin (TDD) needed. If the patient is already on a correction scale: Increase or decrease total daily dose by 10-20% as needed.If the patient is lean, has T1DM, age ≥ 70 years, and/or GFR < 60 mL/min: 0.2-0.3 units/kgIf none of the above criteria applies, use the blood glucose level: BG 140-200 mg/dL: 0.4 units/kgBG > 200 mg/dL: 0.5 units/kg Divide the total daily dose of insulin into basal insulin (50%) and nutritional insulin (50%). Basal insulin: Administer as long-acting insulin (e.g., glargine) at bedtime.Nutritional insulin: Administer as rapid-acting insulin (e.g., lispro) in equally divided doses before meals. Add sliding scale insulin as supplemental insulin. Take 5% of the TDD (e.g., 50 → 2.5).Round down to the safest whole number (e.g., 2.5 → 2).For every 40 mg/dL (2.2 mmol/L) above the goal serum glucose of 140 mg/dL, increase the nutritional insulin scale by this increment. Adjust as needed. If glucose persistently > 140 mg/dL and no episodes of hypoglycemia: Increase basal insulin by 20% and/or increase sliding scale insulin by 2 units.In cases of hypoglycemia < 70 mg/dL: Reduce basal insulin by 20% and/or sliding scale insulin by 2 units. Decrease or hold nutritional insulin if the patient is NPO. Sliding scale insulin regimen [4] If the patient is eating all or most of each meal: administer as short-acting insulin (or rapid-acting insulin) before each meal and at bedtime If the patient is not eating: administer as short-acting insulin every 6 hours 71-140000141-180246181-220468221-2606810261-30081012301-350101214351-400121416 If the blood glucose is < 70 mg/dL, hold all insulin and administer hypoglycemia measures. Weight-based NPH insulin regimen for glucocorticoid-induced hyperglycemia [5] Convert glucocorticoid to equivalent prednisone dose (see glucocorticoids). Calculate daily NPH dose based on prednisone dose equivalent and patient weight. Administer glucocorticoid with NPH as a single dose in the morning. Prednisone dose equivalent (mg/day)NPH (units/kg/day)100.1200.2300.3≥ 400.4 NPH doses should be administered in addition to usual basal insulin in patients who are already receiving insul Consider using glargine or detemir in patients receiving dexamethasone. Dexamethasone has a longer hyperglycemic effect than prednisone and most other commonly used systemic glucocorticoids. Insulin regimens for enteral and parenteral nutrition Enteral nutrition [6][7] Determine basal insulin needs. For patients already on insulin: Continue prior dose or administer 30-50% of the total daily dose as long-acting insulin (e.g., glargine) daily.For patients not already on insulin, consider: 5 units of NPH every 12 hoursor 10 units of glargine (or equivalent) daily Add nutritional insulinFor patients receiving continuous tube feedings Calculate the total daily nutritional insulin dose: 1 unit of insulin per 10-15 g of carbohydrates per dayor 50-70% of the total daily doseAdminister as rapid-acting insulin (e.g., lispro) in divided doses every 4-6 hours.For patients receiving bolus feeding Calculate the nutritional insulin dose to cover each meal: 1 unit of insulin per 10-15 g of carbohydrates per mealAdminister as rapid-acting insulin (e.g., lispro) before each feeding. Add sliding scale insulin as supplemental insulin. For patients on continuous tube feedings: Administer rapid-acting insulin (e.g., lispro) every 4 hours or regular insulin every 6 hours.For patients receiving bolus feedings: Administer rapid-acting insulin before every meal. Adjust as needed to glycemic targets, changes in medication, and changes in nutrition. Patients with type 1 diabetes mellitus require basal insulin even if (enteral) feeding is discontinued. Total parenteral nutrition (TPN) [6][8] Add short-acting insulin to IV parenteral nutrition solution. Diabetic patient: 1 unit per 10-15 g dextroseNondiabetic patient: 0.5 units per 10 g dextrose Add sliding scale insulin as supplemental insulin: Administer as short-acting insulin (e.g., regular insulin) every 6 hoursor rapid-acting insulin (e.g., lispro) every 4 hours. Adapt protocol to glycemic targets, changes in medication, and changes in nutrition.

Laboratory evaluation of bone disease Laboratory evaluation of serological and urinary markers is important in the diagnosis of suspected bone disease. An increase or decrease in calcium, phosphate, creatinine, or parathormone may provide important information for differential diagnosis. Elevated serum alkaline phosphatase, which originates from several tissues (e.g., liver and bone) indicates increased bone formation (e.g., after a pathological fracture, in bone metastasis, or Paget disease), once liverdisease is ruled out. Elevated urinary hydroxyproline, a specific marker of collagen synthesis and breakdown, is a typical finding in patients with Paget disease.

Serum calcium Serum phosphateParathormone(PTH)Additional lab values Osteoporosis Ca n Phos n PTH n Elevated serum alkaline phosphatase after pathological fractures Osteomalacia and Rickets↓n/↓↑ ↓Vitamin D Paget diseasennn↑↑ Serum alkaline phosphatase↑ Urine hydroxyproline Primary hyperparathyroidism↑↓↑Hypercalciuria Secondary hyperparathyroidism/renal osteodystrophy ↓n/↑ ↑↑ Creatinine (in renal osteopathy) Tertiary hyperparathyroidism↑↑↑ Osteolytic metastasis↑n/↓n/↓↑ Serum alkaline phosphatase Hypoparathyroidism↓↑↓↓ Magnesium Pseudohypoparathyroidism↓↑↑

Thyroid antibodiesAntithyroid antibodies are autoantibodies that target one or more components of the thyroid gland and can act as markers to help diagnose autoimmune thyroid conditions. For example, thyroid stimulating hormone receptor antibodies(TRAb) are seen mostly in Graves' disease, while thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies(TgAb) are typical for Hashimoto's thyroiditis (but may also be present in Graves' disease). However, elevated thyroidantibodies do not always indicate disease, as somewhat increased levels may also be present in healthy individuals.

TSH receptor antibodies(TRAb) Thyroid peroxidase antibodies(TPOAb) Thyroglobulin antibodies (TgAb) Graves' disease TRab∼ 90% TPOAb∼ 70% TgAb ∼ 50-70% Hashimoto's thyroiditis TRab∼ 10-15% TPOAb> 90% TgAb > 80% Thyroid cancer TRab No association TPOab Sporadic TgAb ∼ 25% (important for follow-up!) Other conditions TRab ∼ 15% in multinodular goiter TPOAb > 60% in postpartum thyroiditis TgAb∼ 40% in other autoimmune diseases (eg, type 1 diabetes mellitus) General population TRAb Negative TPOAb ∼ 5% TgAb ∼ 5% Pathophysiology TSH receptor antibodies (TRAbs): There are three types of antibodies that may have either a stimulating (most common), blocking, or neutral effect on the TSH receptors. In Graves' disease: stimulating TRAbs (thyroid stimulating immunoglobulin, TSI) → ↑ thyroid function and growth→ hyperthyroidism and diffuse goiterIn Hashimoto's thyroiditis: blocking TRAbs → competitively block the activity of TSH on the receptor → hypothyroidismNeutral TRAbs have no effect on the thyrotropin receptors and their clinical and physiological relevance remains unclear. Thyroid peroxidase antibodies (TPOAb) TPO functions as a catalyst to the organification and coupling reactions in thyroxine production. TPOAbs prevent it from doing so.In Hashimoto's thyroiditis: TPOAbs cause a fall in thyroid hormone production → hypothyroidismIn Graves' disease: TPOAbs have a complement fixing and cytotoxic capacity and are not known to play a role in pathogenesis of Graves' disease, but are seen as a result of the autoimmune nature of the disease. Thyroglobulin antibodies (TgAb) Thyroglobulin (Tg) is a protein produced in thyroid cells, which is involved in the synthesis of thyroid hormone and is normally found only in low concentrations in the bloodstream.Destructive thyroid processes (i.e., Hashimoto's thyroiditis) and/or rapid disordered growth of thyroid tissue (e.g., Graves' disease, follicular thyroid cancer) → release of circulating free Tg into the bloodstream → TgAb induction

Antithyroid drugs Antithyroid drugs are drugs that either decrease thyroid hormone synthesis (thionamides) or thyroid hormone release (iodides). The most important group of antithyroid drugs are thionamides, which include methimazole, carbimazole, and propylthiouracil. Thionamides decrease thyroid hormone synthesis by inhibiting thyroid peroxidase, an essential enzyme involved in multiple steps of thyroid hormone synthesis. Thionamides play a significant role in the treatment of hyperthyroidism and thyroid storm. Iodides are solutions containing potassium iodide that inhibit the release of thyroid hormones into the circulation. They are, therefore, a useful adjunct treatment in the management of thyroid storm, but their main clinical use is for the preoperative preparation of a patient with Graves' disease, because they decrease the vascularity of the thyroid gland.

Thionamides(sulfur-containing) MethimazoleCarbimazolePropylthiouracil Inhibit thyroid peroxidase enzyme → inhibits thyroid hormone synthesis Propylthiouracil also inhibits the peripheral conversion of T4 to T3. Slow onset of action (3-4 weeks) Methimazole has a faster onset of action and fewer side effects than propylthiouracil Hyperthyroidism Thyroid storm After radioactive iodine treatment Before radioactive iodine treatment or thyroidectomy Potassium iodidesLugol's iodine(oral potassium iodide)Saturated solution of potassium iodide(SSKI) Inhibit proteolytic cleavage of T3 and T4 from thyroglobulin → inhibits thyroid hormone release Also decrease thyroid vascularity and decrease the size of the gland Rapid onset of action (within a week) Pretreatment before thyroid surgery Adjunctive therapy in thyroid storm Adjunctive therapy in hyperthyroidism Used as prophylaxis to decrease radioactive iodine uptake in the thyroid gland Side effects Thionamides Allergy/hypersensitivityThe most common side effect is a pruritic rash (particularly with methimazole)Rarely, severe effects such as exfoliative dermatitis,vasculitis, polyserositis, and acute arthralgia occurIf mild, switch to propylthiouracil; if severe, avoid thioamides because of the risk of cross-sensitivities Agranulocytosis Rare but dangerous (affects ∼ 0.5% of patients; more common in elderly and those taking high doses)Rapidly reversible with discontinuation of treatment Hepatotoxicity (seen with propylthiouracil use): HepatitisCholestatic jaundiceLiver failure TeratogenicityMethimazole and carbimazole are teratogenic; propylthiouracil is therefore recommended in the first trimesterAfter the first trimester, switch back to carbimazole/methimazole because of the hepatotoxic effects of propylthiouracil Diffuse goiter Impaired sense of taste (dysgeusia) Iodides Side-effects are rare and often mild. Oral/gastric mucosal irritation (e.g., aphthous ulcers, metallic taste): To avoid mucosal irritation, iodides should be consumed with food or diluted with fluids. Allergy/hypersensitivity: rash, angioedema; rarely, severe anaphylactic reactions can occur Teratogenicity: contraindicated in pregnancy because they can cross the placental barrier and cause fetal goiter Iodides delay and decrease the effects of radioactive iodine. They must be stopped at least a week before radioactive iodine ablation. Complete blood counts should be monitored in patients taking antithyroid drugs because of the risk of agranulocytosis/aplastic anemia. Liver function tests should be monitored in patients taking propylthiouracil because of the risk of hepatotoxicity.

Thyroid surgery Thyroid surgery is a procedure commonly performed to treat benign and malignant thyroid disorders. Total thyroidectomyentails the removal of the entire thyroid gland and is indicated in the management of thyroid cancer or benign thyroidconditions that affect the entire gland (e.g., Graves' disease, multinodular goiter). A small cuff of tissue adjacent to the tracheoesophageal groove is spared in near-total and subtotal thyroidectomy in order to protect the parathyroid glandsand the adjacent nerves. Lobectomy (removal of a single lobe) or hemithyroidectomy (removal of a single lobe with the isthmus) is performed for unilateral benign thyroid disorders (e.g., toxic adenoma, recurrent thyroid cysts) and for small, low-risk differentiated thyroid cancers. Postoperative complications include hematoma formation, hypoparathyroidism, nerve palsy (recurrent/superior laryngeal nerve), and hypothyroidism. The greater the extent of resection, the greater the risk of complications. However, the most extensive resections (total thyroidectomy) are associated with the lowest rates of recurrent disease.

Thyroid gland anatomy See thyroid gland and parathyroid glands. Nerves in close proximity to the thyroid gland Recurrent laryngeal nerve (close to the inferior thyroid artery) Superior laryngeal nerve (close to the superior thyroid artery Preparation Achieve euthyroid status preoperatively. In hyperthyroidism to minimize the risk of thyroid stormThioamidesIodides (potassium iodide) Beta blockers (e.g., propranolol)In hypothyroidism: thyroid hormone replacement Preoperative oral calcium and vitamin D supplementation Preoperative direct/indirect laryngoscopy Total thyroidectomy The entire thyroid gland is removed. Thyroid cancer Some cases of Graves' disease and toxic multinodular goiter Large goiter causing obstructive symptoms or physical disfigurement Near-total thyroidectomy A small cuff of thyroid tissue is left behind Benign thyroid conditions that affect the entire gland (e.g., large goiter, toxic MNG, Graves' disease) Subtotal thyroidectomyA larger cuff of thyroid tissue is left behind Thyroid lobectomyRemoval of the affected thyroid lobeLow-risk differentiated thyroid cancer Follicular adenoma Toxic adenoma Thyroid cysts HemithyroidectomyThe affected lobe with the isthmus is removed. Complications Transient/permanent postoperative hypoparathyroidism (most common) or hypothyroidism Hematoma Transient/permanent RLN palsy Superior laryngeal nerve palsy → paralysis of cricothyroid muscle → easy voice fatigability; change in the timbre of voice Thyroid storm: if the surgery was performed in inadequately treated patients with hyperthyroidism (see "complications" of hyperthyroidism for further details) Unilateral RLN palsy Clinical features Husky/hoarse voiceIneffective coughRisk of aspiration pneumonia Bilateral RLN palsy Immediate postoperative dyspnea, stridor (on extubation)