Endocrinology Exam 2

Evaluate the roles of the 3 types of deiodinase enzymes in thyroid hormone metabolism.

1. Deiodinase 1 (D1): produces T3 (greatest biologic activity) in circulation, it is found most abundantly in the liver, kidney, skeletal muscle, and thyroid. "Step up" from T4 to T3 (increase in biologic activity) 2. Deiodinase 2 (D2): maintains a constant level of intracellular T3 in the brain and pituitary to ensure local T3 production 3. Deiodinase 3 (D3): Inactivates T4, T3 in the placenta, and glial cells of the CNS. Found in the brain, placenta, and fetal tissues. "Step down" from T4 to reverse T3 (decrease in biologic activity)

List the three major "ketone bodies" that are formed and excreted into the urine in the absence of adequate insulin.

1. β-hydroxybutyrate 2. Acetoacetate 3. Acetone

What is the significance of a cold nodule on a thyroid scan?

10-20% are malignant

What do pharyngeal pouches 3 and 4 develop into?

3rd pouch: Inferior Parathyroid + Thymus 4th pouch: Superior Parathyroid + Ultimobranchial body (forms C-cells/ parafollicular cells)

In general, what size of Adrenal lesion is highly suspicious for malignancy?

> 4cm

What is the size of a Microadenoma of the pituitary?

< 10mm

What is the size of a Macroadenoma of the pituitary?

> 10mm Can manifest itself due to compression on other structures

Describe the stimuli for glucagon secretion and its physiological actions.

A decrease in blood glucose levels results in an increase in glucagon release from α-cells of the pancreas, promoting the mobilization and utilization of metabolic fuels (mainly from the liver). Glucagon will bind the glucagon receptor in the liver, which is Gs coupled and will increase AC and cAMP, in turn activating PKA. Activate PKA, will inactivate glycogen synthase (to stop production of glycogen), activate phosphorylase kinase which will phosphorylate glycogen phosphorylase, activating it, and promoting to breakdown to glycogen into glucose. The overall effect is an increase in glycogenolysis, increased gluconeogenesis, increased lipolysis, and increased ketoacid production which are the source of fuel for the muscle/heart cells during times of starvation

Thyroglossal duct cyst

A palpable cystic midline mass in the neck due to incomplete closure of the thyroglossal duct.

Diabetic ketoacidosis (DKA) Define and include development, precipitating factors, signs/symptoms, diagnostic criteria, lab abnormalities, management, and when it is considered resolved.

A state of uncontrolled catabolism triggered by relative or absolute deficiency of circulating insulin. Development/Pathophysiology: acute insulin deficiency results in rapid mobilization of energy from stores in muscle and fat depots leading to an increased flux of amino acids to the liver for conversion to glucose and of fatty acids for conversion to ketones Precipitants: ∙ Interruptions in normal insulin delivery ∙ Reduced insulin sensitivity (infection, MI, burns, trauma, pregnancy) Signs/ Symptoms: a day or more of- ∙ Triad of symptoms: (1) Metabolic acidosis (2) Hyperglycemia (>250 mg/dL) (3) Positive ketones in the urine or blood ∙ Polyuria ∙ Polydipsia ∙ Marked fatigue ∙ Nausea/ Vomiting ∙ Mental stupor ∙ Dry mucous membranes ∙ Orthostatic hypotension ∙ Labored breathing (Kussmaul's) ∙ Fruity odor of breath Diagnosis: characterized metabolically by hyperglycemia and ketoacidosis ∙ Plasma glucose high (> 250mg/dL) ∙ Positive serum ketones ∙ Low arterial blood pH (< 7.3) ∙ High serum and urinary ketones ∙ Hyponatremia ∙ Hyperkalemia: impaired insulin action + hyperglycemia results in decreased potassium uptake by the skeletal muscle and efflux of potassium from cells ∙ Plasma bicarbonate < 18 mEq/L ∙ Elevated anion gap ∙ Elevated BUN and Creatinine Treatment: 1. Hydration: with IV fluids 2. Restore electrolyte homeostasis, correct acidemia, normalize serum glucose (ensure potassium > 3.3 mEq/L) no more than 100mg/dL/hr (if BG is < 250 mg/dL with acidosis still present, add dextrose to IV fluids to maintain insulin infusion), eliminate underlying cause This includes Fluid administration, Insulin administration, Potassium Chloride, and Sodium Bicarbonate Resolution: DKA is considered to be resolved only when: ∙ Blood glucose < 200-250 mg/dL ∙ Serum bicarbonate > 15 mEq/L ∙ Venous blood pH > 7.30 ∙ Anion gap is < 12

The pharyngeal clefts are lined by A, while the pharyngeal pouches are lined by B.

A. Ectoderm B. Endoderm

Explain generally the relationship of TSH to FT4 in patients with primary hypothyroidism, Euthyroidism, and non-pituitary hyperthyroidism.

A. Euthyroidism (Normal Thyroid Function) ∙ TSH: Normal ∙ Free T4: Normal B. Hypothyroidism ∙ TSH: Increased ∙ Free T4: Decreased C. Non-pituitary Hyperthyroidism ∙ TSH: Normal ∙ Free T4: Increased

CaSR Mutations Identify the subtypes and the result of each

A. Familial Hypocalciuric hypercalcemia (FHH): Autosomal dominant Inactivating mutation in the CaSR, which increases the Ca2+ set point, resulting in higher than normal levels of blood calcium needed to suppress PTH secretion. PTH concentrations are inappropriately normal or high in the presence of mild hypercalcemia ∙ Check 24 hour urine for calcium/creatinine excretion ratio ∙ No end organ damage and no treatment is required B. Autosomal Dominant Hypocalcemia (ADH): Activating mutation in the CaSR which results in serum PTH concentrations that are inappropriately normal or low despite the presence of mild/severe hypocalcemia

Describe the effects of a high-carbohydrate vs. high-protein meal on serum levels of glucose, insulin, and glucagon.

A. High-Carbohydrate ∙ Glucose: Increase ∙ Insulin: Increase ∙ Glucagon: Decreases B. High-Protein ∙ Glucose: N/A ∙ Insulin: Small Increase ∙ Glucagon: Increase

Discuss the common etiologies and potential consequences of hypocalcemia and hypercalcemia

A. Hypocalcemia: i. Etiology ∙ Lack of PTH (hypoparathyroidism) ∙ Lack of Vitamin D (dietary deficiency, malabsorption, inadequate sunlight) ∙ Increased calcium complexation with phosphate ii. Consequences ∙ Hyperexcitability of the Neuromuscular junction ∙ Muscle spasm ∙ Tetany B. Hypercalcemia: less common than hypocalcemia i. Etiology ∙ Excess of PTH (hyperparathyroidism) -- typically mild, asymptomatic, & sustained for years ∙ Excess of Vitamin D (Vitamin D intoxication) ∙ Increased bone resorption ∙ Increase intestinal absorption of calcium ∙ Decreased renal excretion of calcium (thiazide) → this is why thiazide diuretics are contraindicated in patients with hypercalcemia ii. Consequences ∙ Precipitation of salt in tissues (i.e.- renal stones) ∙ Weakness ∙ Generalized musculoskeletal pain

Analyze the metabolic effects of thyroid hormone action.

A. Liver: Increase glycolysis & cholesterol synthesis, which indirectly increased hepatic glucose and triglyceride production B. Adipocytes: Increase in glucose availability to adipocytes C. Skeletal Muscle: stimulates glucose uptake and glycolysis in the muscle, while also stimulating protein synthesis and muscle growth D. Pancreas: Increase sensitivity of beta cells to stimuli that promote insulin release

Identify and describe different modalities for monitoring glycemic control. List the glycemic goals for nonpregnant adults with diabetes mellitus

A. Patient self monitoring (SMBG): use of at-home glucometer to measure BGL ∙ Patients using insulin regimens B. Interstitial Glucose: Continuous glucose monitor ∙ Real time: continuously reports glucose levels and alarms for hyperglycemia or hypoglycemia ∙ Intermittently scanning measures levels continuously but only displays when swiped by a reader or smart phone C. A1C: reflects average glycemic control over ~3 months. Glycemic Control Goals: ∙ Pre-prandial capillary plasma glucose: 80-130 mg/dL ∙ Peak post-prandial (2 hours) capillary plasma glucose: < 180 mg/dL ∙ A1C < 7.0%

Describe the production and roles of calcitonin in regulating calcium, as well as its clinical relevance.

A. Production: Secreted by thyroid C-cells B. Roles: Counteracts a lot of the effects of PTH. It will inhibit osteoclast mediated bone resorption, inhibit phosphate resorption in the kidney, and inhibit calcium absorption in the intestine. Clinical Relevance: Can be used as a tumor marker in medullary carcinoma of thyroid C-cell malignancy or as an inhibitor of bone resorption (i.e.- Paget's disease or patients unable to tolerate bisphosphonates)

Explain the clinical utility for radionuclide imaging, thyroid ultrasonography, and thyroid biopsy.

A. Radionuclide Imaging: useful for determining the functional activity and morphology (size, shape) of the thyroid gland. This is useful in differentiating among the causes of thyrotoxicosis ∙ Graves Disease: enlarged gland with intense homogenous concentration of tracer ∙ Toxic nodular goiter: one or more discrete regions of tracer activity corresponding to palpable nodules B. Thyroid Ultrasonography: useful for determining the side and characteristics of nodular lesions. Able to differentiate solid nodules from cystic nodules, and can be used to monitor size over time C. Thyroid Biopsy: best used for differentiating benign from malignant thyroid nodules and diffuse goiters

Euthyroid Sick Syndrome

AKA "Low T3 Syndrome" It is abnormal (low) thyroid hormone levels due to an acute, severe illness, even though the thyroid is normal. Following the illness, thyroid levels will return to normal. Patients do not require treatment, but labs should be re-ordered after illness resolves.

De Quervain's Thyroiditis

AKA Granulomatous Thyroiditis This is a painful thyroiditis which is more common in females than males and is preceded by a viral illness typically respiratory in nature (i.e.- Coxsackie, mumps, measles). Patients will complain of anterior neck pain and occurrence typically peaks in the summer. Initially, patients have a Thyrotoxic (hyperthyroid) phase for 3-6 weeks, followed by a euthyroid phase for 6-12 months, and initially hypothyroid which lasts weeks to months Morphology: note scattered follicles replaced by neutrophils, with aggregated of lymphocytes/ macrophages/ plasma cells later in the disease. Multinucleated giant cells enclose colloid Treatment ∙ NSAISs to relieve pain ∙ Steroids

Thyroid Storm Define, and include common causes, possible precipitants, diagnosis, and treatment

AKA Thyrotoxic crisis, it is an acute life-threatening exacerbation of thyrotoxicosis. Patients present with acute onset of hyperpyrexia (>40°C), sweating, marked tachycardia often with a-fib, nausea, vomiting, diarrhea, agitation, tremulousness, delirium. Causes ∙ Patients with history of Graves disease who have discontinued anti-thyroid medication ∙ Previously undiagnosed hyperthyroidism Precipitants ∙ Severe infection ∙ DKA ∙ MI ∙ CVA ∙ Surgery ∙ Trauma Diagnosis: based largely on clinical findings ∙ Elevated Serum T4, Free T4, T3, and Free T3 ∙ Decreased TSH Treatment 1. Supportive Care: fluids, oxygen, cooling blanket, acetaminophen, multivitamins, antibiotics (if indicated) 2. Specific measures: Anti-thyroid medication to block further synthesis and secretion of thyroid hormone, Beta-blockers (propranolol), Dexamethasone (reduce conversion of T4 to T3)

Plummer Disease

AKA Toxic Multinodular Goiter, it occurs in older patients with longstanding euthyroid multinodular goiters and can be precipitated by iodide load leading to hyperthyroidism Signs/Symptoms ∙ Tachycardia ∙ Heart Failure ∙ Arrhythmias ∙ TSH: decreased ∙ T3/T4: Increased ∙ *Pemberton's Sign: when patient raises arms above their head, it results in a superior vena cava syndrome and patient's face will become red

Follicular adenoma vs. Follicular carcinoma of the thyroid

Adenoma: well-formed capsule encircling the tumor that does not invade the capsule (A) Carcinoma: invasion of the capsule (B)

Pramlintide Include the Clinical Use, Mechanism of action, and Adverse Effects

Amylin Analogue; Amylin is responsible for β-cell mass and function, helping to regulate postprandial glucose levels Clinical use: Insulin treated Type I and Type II DM who are unable to achieve target post-prandial blood glucose levels MOA: (1) Suppresses appetite, (2) slows gastric emptying, and (3) inhibits glucagon release Adverse Effects: ∙ Nausea, Vomiting, Anorexia ∙ Weight loss

Myxedema Coma Define and include the clinical presentation

An acute hypothyroid crisis which is rare but has a high mortality rate due to decreased cardiac output which leads to decreased tissue perfusion, brain and organ depletion, and multi-organ failure Presentation ∙ Altered mentation/ Disorientation ∙ Hypothermia ∙ Bradycardia, low voltage\ ∙ Coarse skin ∙ Thin Hair ∙ Brittle nails ∙ Facial Edema Treatment: Levothyroxine IV bolus + IV corticosteroids

What is the initial question following discovery of an "Incidentaloma"?

Are there previous films?

Understand the basal-bolus regimen, differentiate the onset of action and duration of action for different insulin analogs: A. Short-acting B. Fast-acting C. Intermediate D. Long-acting E. Ultra-long acting Identify the insulin analogs when they are used in combination in different dosing regimens, which insulin is used for diabetic ketoacidosis, and the adverse effects of insulin.

Basal-Bolus Regimen: Used to treat Type I DM it is insulin replacement in which "Basal" is given in order to provide a constant "low-level" of insulin (intermediate and long acting), while "Bolus" is to increase insulin to mimic secretion after a meal (rapid and short acting) A. Short-acting: ∙ Type: Regular (Novolin) ∙ Clinical Indication: Bolus insulin that is injected 30-45 minutes before a meal; this is used for Diabetic Ketoacidosis ∙ Onset: 30 minutes ∙ Duration: 5-8 hours B. Fast-acting: ∙ Type: Lispro, Aspart, Glulisine ∙ Clinical Use: Preferred prandial hyperglycemic control; injected just before (<10 min) a meal ∙ Onset: 3-15 minutes ∙ Duration: 2-4 hours C. Intermediate: ∙ Type: Neutral Protamine Hagedorn (NPH); Used in combination with Lispro (Humalog) or Novolin (regular) ∙ Clinical Use: Injected twice daily at breakfast and lunch thereby decreasing the number of injections needed each day ∙ Onset: 2 hours ∙ Duration: 12 hours D. Long-acting: ∙ Type: Detemir (Levemir), Glargine (Lantus) ∙ Clinical Use: Glargine will act as a peakless insulin, and Detemir slows down the absorption; these act as basal insulin, which fast acting insulin can then be added onto ∙ Onset: 2 hours ∙ Duration: Detemir (6-24 hours), Glargine (20- >24 hours) E. Ultra-long acting: ∙ Type: Degludec ∙ Clinical Use: basal insulin injected daily ∙ Onset: 2 hours ∙ Duration: > 40 hours Adverse Effects ∙ Hypoglycemia: tachycardia, palpitations, sweating, confusion, agitation ∙ Weight Gain: promotes protein and fatty acid synthesis and storage ∙ Hypokalemia: activates the Na+/K+ ATPase ∙ Hypersensitivity ∙ Lipodystrophy

On non-contrast CT an adrenal nodule with HU of < 10 is most likely?

Benign (non-malignant)

The superior thyroid artery runs with what nerve? What muscle does this innervate?

External laryngeal n. (innervates cricothyroid m.)

Identify the target organs and physiological functions and mechanisms of action of active vitamin D [Calcitriol, 1,25(OH2)D3] in modulation of plasma calcium and phosphate.

Calcitriol (produced by the kidneys) is a steroid hormone that is made as needed and will have longer-term regulation since it circulates bound to protein carriers. It is responsible for raising plasma calcium and raising PO43-. It does this by acting at the following locations: 1. Intestine: Increases calcium and phosphate absorption ∙ Increases calcium channels on luminal side of calcium, the bring in more calcium ∙ Increases expression of sodium/phosphate co-transporter on luminal side of intestine to bring in more phosphate 2. Kidney: Increases calcium absorption and phosphate absorption 3. Bone: Promotes PTH action, increasing osteoclast activity to increase Ca2+ resorption An increase in Active vitamin D [Calcitriol, 1,25(OH2)D3] will inhibit PTH production, decreasing overall PTH

List the organs and hormones involved in calcium and phosphate absorption, storage, and excretion. Identify which organs are the primary sites of calcium and phosphate regulation.

Calcium and phosphate are absorbed in the gut and enters the extracellular fluid, where it will undergo exchange in the kidneys and bones Calcium is primarily regulated through the gut, while phosphate is primarily regulated through the kidney.

Describe the relationship between plasma calcium and parathyroid hormone (PTH) secretion, including the mechanisms by which PTH secretion is regulated.

Calcium ions will regulate a number of hormones. A decrease in blood calcium stimulates the parathyroid gland to release parathyroid hormone (PTH). Overall effect is to increase plasma calcium and decrease plasma phosphate. Parathyroid hormone is a peptide hormone which can be made before it is used, and have a rapid response resulting in short term regulation. PTH will stimulate: 1. Bones: increases calcium resorption ∙ Osteoblasts form RANKL and OPG; under normal conditions, OPG binds RANKL to inhibit it ∙ Free RANKL can bind receptors on the osteoclasts to increase bone resorption ∙ PTH binds receptors on osteoblasts, stimulating production of RANKL and inhibiting production of OPG allowing for increased osteoclast formation to resorb bone 2. Kidney: A. Increase calcium reabsorption at distal tubule and loop of Henle via the PMCA and NaCX transporters B. Decrease PO43- reabsorption at proximal tubule by activating Gs & Gq, inhibiting the sodium-phosphate transporters C. Activate renal 1α-hydroxylate (converts inactive Vitamin D to active vitamin D [calcitriol] in proximal tubule 3. Intestines: Calcitriol (from the kidney) Increase Ca2+ uptake

Glinides Include Clinical indications, Mechanism of action, adverse effects, and contraindications.

Clinical Use: Type II DM MOA: Binds ATP-dependent K+ channels to cause depolarization in order to increase Ca2+ influx into the β-cells thereby enhancing the secretion of already made insulin Adverse Effects: ∙ Hypoglycemia ∙ Weight gain Contraindications: ∙ Should not be used with Sulfonylureas since they have the same mechanism of action and can lead to severe hypoglycemia

List the target organs of parathyroid hormone and describe its effects and mechanisms of action in each organ as they pertain to regulation of plasma calcium and phosphate.

Chief cells in the parathyroid gland are responsible for synthesizing and secreting parathyroid hormone (PTH) whose overall effect is to increase plasma calcium. An increase in blood calcium will decrease PTH while a decrease in blood calcium will increase PTH. In chief cells, plasma calcium will bind the calcium sensing receptor (CaSR) which activates Gq → PLC → PIP2 + DAG → PKC → which increases intracellular calcium → Inhibits the secretion of PTH When calcium levels drop, the inhibition of PTH will be released

Hashimoto's Disease Include definition, lab findings, and morphology

Chronic autoimmune thyroiditis which is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. There is a higher frequency in females than males, and results from autoimmune destruction of the thyroid follicles. Labs ∙ Thyroid peroxidase antibodies (TPO Ab) ∙ Thyroglobulin Antibodies (Tg Ab) ∙ Lymphocytic infiltration Results in gradual loss of thyroid function over time T3/T4: Decreased TSH: Increased TRH: Increased Morphology: The thyroid is "pale, yellow-tan, firm, and nodular." There are mononuclear inflammatory infiltrates with well-developed germinal centers. May note Hurthle cells (presence of abundant eosinophilic, granular cytoplasm)

List three pharmacologic approaches to prevent and modify the metabolic sequelae of chronic kidney disease

Chronic kidney disease leads to decreased calcitriol levels and phosphate retention. This will lead to hypocalcemia and secondary hyperparathyroidism. This can lead to renal osteodystrophy (osteomalacia or osteitis fibrosis cystica) 1. Phosphate Binders 2. Calcitriol & Analogues 3. Cinacalcet

Explain the rationale to control hyperphosphatemia in patients with chronic kidney disease and identify three agents that are used as oral phosphate binders

Chronic kidney disease leads to decreased calcitriol levels and phosphate retention. This will lead to hypocalcemia and secondary hyperparathyroidism. This can lead to renal osteodystrophy (osteomalacia or osteitis fibrosis cystica) Oral phosphate binders will bind dietary phosphates to prevents phosphate absorption 1. Aluminum-Based: Aluminum hydroxide ∙ reserved for refractory hyperphosphatemia ∙ not commonly used 2. Calcium-Based: Calcium acetate, Calcium carbonate ∙ Can lead to hypercalcemia 3. Sevelamer ∙ Non-absorbable cationic ion-exchange resin that decreases cholesterol absorption

Describe the biochemical effects of chronic hyperglycemia.

Chronically high blood glucose levels leads to nonenzymatic glycation which results in glucose molecules becoming covalently attached to protein in the blood. One of these proteins is hemoglobin. (HbA1c is hemoglobin that is nonenzymatically glycosylated). An HbA1c > 6.4% is indicative of diabetes. Long term, this distorts the protein structure and therefore function. This leads to long-term microvascular problems (diabetic retinopathy, nephropathy, neuropathy) as well as long-term macrovascular problems (arterial disease, CAD, atherosclerosis)

Bisphosphonates Include the Clinical Use, compare and contrast the Mechanism of action between 1st generation and 2nd generation, pharmacokinetics, and Adverse Effects

Clinical Use 1. Osteoporosis (T score < 2.5) 2. Malignancy-related hypercalcemia 3. Paget disease (increased bone resorption followed by excessive bone formation but bone is deformed) Mechanism of Action: Analogue of pyrophosphate, they decrease bone resorption by inducing apoptosis in osteoclasts, thereby inhibiting osteoclast function and decreasing the cholesterol biosynthetic pathway A. First Generation (Etidronate, Tiludronate): Non-nitrogen containing; less potent B. Second Generation (Pamidronate, Alendronate, Ibandronate): Nitrogen containing; nitrogen group increases potency Pharmacokinetics: ∙ Poor intestinal absorption; must take in the morning with a full glass of water after an overnight fast then wait 30-60 minutes before eating, drinking, or taking any other medications ∙ Excreted by glomerular filtration: in renally impaired patients, reduce or avoid use Adverse Effects: A. Oral: Esophagitis & Esophageal erosion → sit upright or stand for 30-60 minutes after taking to avoid B. IV: Flu-like symptoms (treat with acetaminophen), Acute renal failure, Hepatitis (prevent with slow infusion), Osteonecrosis of the jaw (after oral surgery) C. Both: Subtrochanteric femur fractures (atypical fracture) seen in long term use of bisphosphonates

Denosumab Include clinical use, mechanism of action, and adverse effects

Clinical Use 1. Osteoporosis: second line after bisphosphonates 2. Hypercalcemia of malignancy: refractory to bisphosphonate therapy MOA: A fully human monoclonal antibody, it with bind RANKL, preventing it from binding RANK and inhibiting osteoclast formation and activity thereby reducing bone resorption and increasing bone mass Adverse Effects: ∙ Increased risk of infection: RANKL and RANK are expressed on B- and T-cells, affecting B- and T-cell activation ∙ Osteonecrosis of the jaw ∙ Atypical fractures ∙ Transient hypocalcemia ∙ Endocarditis, cellulitis, pancreatitis, hypersensitivity reaction

Calcitonin Include clinical use, mechanism of action, and adverse effects

Clinical Use 1. Postmenopausal osteoporosis: short term treatment; provides analgesic effect 2. Paget's Disease in those who are intolerant or non-responsive to alternative therapy 3. Emergent Hypercalcemia (those associated with malignancy): patients become refractory after a few days MOA: Binds the calcitonin receptor on osteoclasts, inhibiting osteoclast-mediated bone resorption. Adverse Effects: ∙ Increased incidence of cancer ∙ Hypersensitivity

Potassium iodide Include clinical use, Mechanism of action, and predict its effects

Clinical Use: Hyperthyroidism (in those who do not want to use anti-thyroid agents, or radioactive iodine therapy) MOA: Inhibits organification and hormone release due to Wolff-Chaikoff effect Effects: ∙ Can result in severe exacerbation of thyrotoxicosis ∙ Crosses the placenta and can cause fetal goiter

Radioactive Iodide (131-I) Include clinical use, mechanism of action, and contraindications

Clinical Use: Hyperthyroidism → preferred treatment of choice for patients > 21 years old MOA: destroys the thyroid gland because it is rapidly absorbed and concentrated by the thyroid and incorporated into storage follicles by emitting β rays that destroy the thyroid parenchyma Contraindications: Pregnant or nursing mothers (crosses the placenta and is excreted in breast milk) and can destroy the fetal and infant thyroid gland

Levothyroxine and Liothyronine Identify the clinical uses of based on their pharmacokinetic profile and potential adverse effects

Clinical Use: Hypothyroidism (i.e.-Hashimoto's, Pregnancy, Drug-induced [Rifampin, Phenytoin]) Levothyroxine: T4 replacement, it is the treatment of choice for hypothyroidism due to its long half-life (7 days) and low cost; once daily dosing Liothyronine: T3 replacement, it has a shorter half life (24 hours), requiring multiple daily doses with a higher cost ∙ For patient's with Myxedema coma, where faster onset of T3 can enhance rate of recovery from life-threatening hypothyroidism, this is the drug of choice Adverse Effects: Can precipitate angina, MI, arrhythmia, Decreased bone density, and seizures, and therefore should use lowest initial dose possible

Raloxifene Include clinical use, mechanism of action, and adverse effects

Clinical Use: Postmenopausal osteoporosis (especially in those with high risk of breast cancer) Mechanism of Action: A selective estrogen receptor modulator, it acts as an estrogen agonist in bone and estrogen antagonist in the breast and endometrium. This will increase bone mass while decreasing the risk of breast cancer Adverse Effects ∙ Hot flashes ∙ Venus thrombosis

Cinacalcet Include the Clinical Use, Mechanism of Action, and Adverse Effects

Clinical Use: Primary and Secondary hyperparathyroidism Mechanism of Action: Increases the calcium-sensing receptor (CaSR) sensitivity to extracellular calcium, which decreases parathyroid synthesis and secretion Adverse Effects: Hypocalcemia ∙ Check calcium level ∙ Hungry bone syndrome

Teriparatide Include Clinical use, Mechanism of action, Pharmacokinetics, and Adverse Effects

Clinical Use: Severe osteoporosis with high risk of fracture ∙ Given for those who cannot tolerate bisphosphonates, have contraindications to bisphosphonate use, or fail osteoporosis therapy MOA: Human PTH analog (fragment of PTH), in which intermittent exposure favors bone anabolism Pharmacokinetics: Given subcutaneously once/day for < 2 years Adverse Effects: ∙ Black Box Warning: Osteosarcoma caused in rodents ∙ Hypersensitivity

Acarbose Include Clinical indications, Mechanism of action, adverse effects, and contraindications

Clinical Use: Type II DM MOA: completely inhibits α-glucosidase in the intestinal brush border to decrease sugar hydrolysis, glucose absorption, and post-prandial blood glucose increase Adverse Effects: occur due to increased carbohydrates in the GI tract ∙ Flatulence ∙ Diarrhea ∙ Abdominal pain Contraindications: ∙ Inflammatory bowel disease ∙ Intestinal obstruction

Metformin Include clinical indication, mechanism of action, pharmacokinetics, and adverse effects

Clinical Use: Type II DM, Polycystic ovarian syndrome MOA: Increases insulin sensitivity at the liver and muscle in order to increase glucose uptake and decrease hepatic glucose production Pharmacokinetics: Eliminated by renal excretion (should not be used in end-stage renal disease) Adverse Effects: ∙ Lactic acidosis: Myalgia, abdominal discomfort, malaise, daytime somnolence; risk factors include moderate to severe renal insufficiency, CHF, shock, septicemia, chronic alcohol abuse ∙ GI Discomfort, diarrhea ∙ Metabolic taste ∙ Vitamin B12 deficiency: can aggravate peripheral neuropathy

Natpara Include Clinical use, Mechanism of action, and Adverse Effects

Clinical Use: Used as an adjunct to calcium and vitamin D for hypoparathyroidism MOA: Recombinant Human PTH Adverse Effects: Osteosarcoma in rodents

Thyrotoxicosis Define and describe the signs and symptoms

Clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormones, resulting in the acceleration of metabolic processes. Typically, it is due to hyperactivity of the thyroid gland (hyperthyroidism) but it can be due to excessive ingestion of thyroid hormone or excessive excretion of thyroid hormones from ovarian tumors. Thyrotoxicosis' include: A. Graves Disease (diffuse toxic goiter) B. Plummer disease (toxic multinodular goiter) C. Diffuse multinodular goiter D. Ectopic thyroid tissue E. TSH-secreting pituitary adenomas Signs/Symptoms: due to hypermetabolic state ∙ Nervousness ∙ Malaise ∙ Palpitations ∙ Heat intolerance, Sweating ∙ Weight loss ∙ Inability to concentration ∙ Tachycardia ∙ Increased Systolic BP ∙ Goiter Treatment ∙ Regulate heart rate (Beta-adrenergic blockers)

Recognize malignancy-related hypercalcemia and respective pharmacologic approaches

Clinical: Seen in 20% of cancer patients, it can be caused by malignancies that secrete PTH or PTH-related peptide, malignancies involving the bone marrow, malignancies metastatic to the bone, or certain lymphoma and breast cancers which hypersecrete calcitriol. Hypercalcemia is rapidly progressive Pharmacologic Approaches: Saline + IV Bisphosphonates (pamidronate/ Zoledronate)

Explain the role of measuring thyroid autoantibodies.

Detection of thyroid autoantibodies is helpful in establishing the diagnosis of autoimmune thyroid disease (Hashimoto) or Graves Disease. This can be useful in patients who present with signs of thyrotoxicosis (i.e.- bilateral exophthalmos) without obvious signs or laboratory manifestations of Graves disease.

List and distinguish between the types/classes of diabetes mellitus.

Diabetes mellitus is a syndrome of disordered metabolism with inappropriate hyperglycemia due to an absolute or relative deficiency of insulin. A. Type 1 Diabetes: Typically has an onset in childhood and adolescence, and results from pancreatic islet β-cell destruction, most commonly caused by an autoimmune process. Circulating insulin is virtually absent, glucagon is elevated, and β-cells fail to respond to known insulinogenic stimuli. ∙ Prone to developing DKA ∙ Require insulin replacement ∙ Autoimmune markers include: GAD65, ICA, IAA ∙ Signs/ Symptoms: polydipsia, polyphagia, polyuria, weight loss, prolonged wound healing, cardiovascular symptoms (chest pain, neurologic deficits) B. Type 2 Diabetes: Most common onset is in adulthood, it is the most prevalent form of diabetes. Heterogenous disorder that is associated with a relative insulin deficiency (at time of diagnosis, 50% of β-cell activity is lost) ∙ Commonly overweight → obesity leads to an inflammatory state in the peripheral tissues which results in insulin resistance ∙ Prone to developing Nonketotic hyperosmolar coma ∙ May note Acanthosis nigricans: darkened areas/ velvety patches on the skin C. Gestational Diabetes: glucose intolerance that develops or is first recognized during pregnancy; insulin resistance is greatest in the 3rd trimester D. Other specific Types: Includes MODY which is a subgroup characterized by the onset of diabetes in late childhood or before the age of 25 as a result of partial defect in glucose-induced insulin release ∙ Generally non-obese and lack insulin resistance

Diabetes Mellitus (DM) Include criteria for diagnosis, patients at risk, who should be screened, prevention of Type 2 DM, Evaluation, Management, and potential complications

Diagnosis 1. Fasting blood glucose (FBG) > 126 mg/dL on more than one occasion = diabetes ∙ No caloric intake for > 8 hours 2. 2h oral glucose tolerance test (2h OGTT) > 200 mg/dL at 2 hours = diabetes ∙ Patient presents fasting, BGL is drawn, and 75g of sugared drink is consumed and BGL is drawn 2 hours later 3. HbA1c > 6.5% = diabetes ∙ Obtained from lab 4. Non-fasting/random blood glucose > 200 mg/dL = diabetes ∙ With symptoms (polyuria, polydipsia, polyphagia, unintended weight loss, blurred vision, fatigue) ∙ On > 2 occasions At-Risk ∙ Physically inactive ∙ First degree relative with DM ∙ Ethnicity: African American, Latino, Native American, Pacific Islander, Asian American ∙ History of CVD ∙ HTN ∙ Women with polycystic ovarian syndrome ∙ Severe obesity, acanthosis nigricans Screening: ∙ Overweight or Obese ∙ Patients with pre-diabetes → Impaired fasting glucose: 100-125mg/dl → Impaired glucose tolerance 2 hour test: 140-199 mg/dL → HbA1C 5.7-6.4% ∙ > 45 years old Prevention: ∙ Weight loss; lifestyle modification ∙ Metformin for those at high risk ∙ Screen and treat modifiable risk factors: obesity, HTN, tobacco use Evaluation: Patient centered collaborative care ∙ Diabetes self-management education (DSME) ∙ Medical nutrition therapy: individualized meal planning ∙ Physical activity ∙ Smoking cessation counseling ∙ Psychosocial assessment and care: depression, anxiety, eating disorders Treatment: 1. Lifestyle Management 2. Pharmacologic Therapy ∙ Insulin is essential for Type I DM ∙ Metformin monotherapy should be started at diagnosis of Type II DM unless the patient has a contraindication Complications: ∙ Eyes: Diabetic retinopathy, Cataracts ∙ Kidney: Nephropathy, Infection, Renal Tubular Necrosis ∙ Nervous System: Peripheral neuropathy, motor neuropathy, autonomic neuropathy ∙ Skin: Candidiasis, Ulcers ∙ Cardiovascular: Heart disease, CVD, PVD ∙ Bones & Joints: Osteomyelitis, carpal tunnel ∙ Infections: Necrotizing fasciitis, Mucor meningitis

Explain how estrogen reduces bone resorption and identify adverse of estrogen therapy

Estrogen inhibits the apoptosis of osteoblasts and osteocytes while promoting the apoptosis of osteoclasts. It will decrease differentiation of osteoclasts, by decreasing the production of RANKL and cytokines (IL-6) and increasing the production of osteoprotegerin (OPG) which prevents RANKL from binding RANK Clinical Use: Postmenopausal osteoporosis (given in combination with progesterone) ∙ Not first line (Raloxifene is better option) Adverse Effects: ∙ Vaginal bleeding ∙ Breast tenderness ∙ Venous thromboembolism ∙ Increased long-term risk of breast cancer

Sulfonylureas Identify 1st and 2nd generation, and describe their clinical indications, Mechanism of action and adverse effects

Examples A. First Generation: Tolbutamide, Chlorpropamide B. Second Generation: Glyburide, Glipizide, Glimepiride Clinical Use: Type II DM of relatively recent onset (<5 years) MOA: Binds ATP-dependent K+ channels to cause depolarization in order to increase Ca2+ influx into the β-cells thereby enhancing the secretion of already made insulin Adverse Effects: ∙ First Generation: disulfiram-like reactions ∙ Hypoglycemia ∙ Weight gain ∙ Sulfa allergy

SGLT-2 inhibitors Include Examples, Clinical Use, Mechanism of action, and Adverse Effects

Examples: -gliflozin medications Clinical use: Type II DM; thought to reduce major adverse cardiovascular events MOA: Sodium-glucose co-transporter 2 (SGLT2) inhibitors, they will decrease glucose reabsorption in the the proximal convoluted tubule of the kidney, thereby increasing urinary glucose excretion Adverse Effects: ∙ UTI ∙ Genital infection

Thiazolidinediones Include examples, clinical indications, mechanism of action, adverse effects, and contraindications

Examples: -glitazone medications Clinical Use: Type II DM MOA: Activates peroxisome proliferator-activated receptor-gamma (PPAR-ɣ) which indirectly increases insulin sensitivity at the liver, muscle, and fat tissue by increasing adipocyte formation and redistributing fatty acids Adverse Effects: ∙ Weight gain ∙ Edema ∙ Anemia ∙ Exacerbation of heart failure ∙ Increased risk of fracture in postmenopausal women Contraindications: ∙ NYHA Class III and IV heart failure ∙ Women with low bone density

Anti-thyroid agents Include examples, clinical use, mechanism of action, and adverse effects

Examples: Methimazole, Propylthiouracil (PTU) Clinical Use: Hyperthyroidism (i.e.-Grave's Disease) → most useful in young patients with small glands and mild disease MOA: Inhibits thyroid peroxidase, blocking iodine organification and coupling reactions thereby preventing thyroid hormone synthesis ∙ PTU also inhibits peripheral deiodination of T4 to T3 Pharmacokinetics: ∙ Methimazole: 10x more potent, it is 1st line for children and adults with a faster onset of action and more rapid achievement of Euthyroidism, but it is a teratogen ∙ Propylthiouracil (PTU): used for pregnant women during their 1st trimester, life threatening thyrotoxicosis, or those with adverse reactions to methimazole Adverse Effects: ∙ Common: Rash, altered sense of taste or smell (methimazole) ∙ Serious: Reversible Agranulocytosis, Hepatotoxicity, Vasculitis, Hepatic necrosis & liver failure (PTU)

What are the preferred pharmacological agents for gestational diabetes?

Gestational diabetes is a diabetes diagnosed during pregnancy. Excess glucose can pass through the placenta, and stimulate hyperglycemia in the fetus. This results in hyperplasia of the fetus' islet cells, and leads to increased insulin secretion by the fetus' pancreas which leads to severe hypoglycemia following birth when glucose levels drop. The baby's that are born will suffer from macrosomia (large baby). Treatment ∙ Insulin ∙ Metformin

Describe the relationship between blood glucose concentrations and insulin/glucagon secretion

High blood glucose levels activate β-cells of the pancreas which secrete insulin When blood glucose levels are low, this activates α-cells of the pancreas which secrete glucagon

Explain how a goiter can be formed in both hyper- and hypo-thyroid conditions.

Hyperthyroidism (i.e.- Graves Disease): autoantibody binds TSH receptors and acts how TSH would, increasing T3 and T4, decreasing plasma TSH levels with continues activation of the TSH receptor by the autoantibodies Hypothyroidism: decreased iodide in the diet will decrease T3/T4 production, which results in increased plasma TSH, that binds to thyroid cells that results in the growth of the thyroid

What lab tests are used to assess thyroid function?

Hypothalamus-Pituitary- Thyroid Axis: A. Hypothalamus: Thyrotropin Releasing Hormone (TRH) B. Anterior Pituitary: Thyroid stimulating hormone (TSH) C. Thyroid: Thyroxine (T4) and Triiodothyronine (T3) A. Serum TSH: High sensitivity, widely available, and low cost. TSH is produced by thyrotrophs, and stimulates all aspects of thyroid gland function, including - hormone synthesis, secretion, hyperplasia, hypertrophy, and vascularization. TSH is produced by the anterior pituitary gland and is responsible for binding the TSH receptor on the thyroid to release Thyroxine (T4) and Triiodothyronine (T3) B. Free T4: Used when suspicion of thyroid disease is moderate to high. More T4 than T4 is produced, which is typically inactive, but is converted to the more active T3 in the liver and other tissues. Almost all T4 is bound to protein and inactive; free T4 is biologically active. High free T4 levels are associated with hyperthyroidism and low free T4 levels are associated with hypothyroidism C. Serum T3: Used when thyroid dysfunction is clinically obvious or already biochemically confirmed (by the above two tests) in order to identify the underlying cause and plan appropriate therapy.

Describe the role of iodine in the generation of thyroid hormones and discuss, in detail, the cellular mechanisms and locations involved in the biosynthesis, storage, and secretion of tri-iodothyronine (T3) and thyroxine (T4).

In order to make Thyroid Hormones, both tyrosine and Iodine are needed. Tyrosine + one I2 = monoiodotyrosine (MIT) Tyrosine + two I2 = di-iodotyrosine (DIT) DIT + DIT = Thyroxine (T4) DIT + MIT = Triiodothyronine (T3) 1. Iodide (I-) from the blood, comes into the follicular epithelial cells via the sodium/iodine symporter (NIS) where it is "trapped" inside the follicular cells 2. Iodide (I-) will leave the thyroid follicular cells, and enter the colloid via the pendrin transporter 3. Follicular epithelial cells will produce thyroglobulin (TG) and thyroid peroxidase (TPO) which will be exocytosed into the colloid 4. In the colloid, thyroid peroxidase (TPO) converts iodide (I-) to Iodine (I2), and add together Tyrosine and I2 then couple them appropriately to form T3 and T4. These will be stored in the colloid 5. When T3 or T4 are needed, they will be endocytosed by the follicular epithelial cells and then degraded in order to be able to be released into the blood.

Discuss the cascading perfusion of the pancreas

In the majority of the islets, arterioles will enter at the periphery of the islet and then branch into fenestrated capillaries, first perfusing the peripheral A and D cells B-cells will receive blood that is first perfuses A and D cells, and therefore, the inhibitory effect of insulin on glucagon secretion is carried out by the insulin in general circulation

Psuedohyperparathyroidism Define and include causes, clinical findings, and treatment

Increased secretion of PTH as a result of target tissue unresponsiveness to PTH (problem with PTH receptors) Causes ∙ Type I: GNAS1 gene mutation Clinical ∙ Serum Calcium: Decreased ∙ Serum Phosphate: Increased ∙ PTH: Increased ∙ Calcitriol: -- ∙ Bone: Variable ∙ Kidney: Decreased phosphate excretion, decreased calcium reabsorption Treatment ∙ Vitamin D ∙ Calcium ∙ Low phosphate diet and phosphate binder

Explain the role of incretin in the pathogenesis of Type 2 Diabetes Mellitus GLP-1 receptor agonists and DPP-4 inhibitors Include Examples of each, and describe Mechanism of Action, Adverse effects, and contraindications

Incretins are a group of metabolic hormones (GLP-1 & GIP) that are secreted by intestinal cells following a meal which will stimulate insulin release. Glucagon-like peptide-1 (GLP-1) promotes insulin secretion after the ingestion of food, and is then rapidly degraded by dipeptidyl peptidase-4 (DPP-4) GLP-1 Receptor Agonists: includes Exenatide (hela monster), Lixisenatide, Liraglutide, Albiglutide A. Mechanism of Action: (1) increases glucose-dependent insulin release, (2) decreases postprandial glucagon release, (3) decreases gastric emptying, and (4) decreases appetite B. Adverse effects: ∙ Nausea, Vomiting ∙ Weight loss ∙ Acute pancreatitis ∙ Medullary thyroid cancer C. Contraindications: ∙ Pancreatic disease ∙ Medullary thyroid carcinoma, MEN DPP-4 Inhibitors: -gliptin medications A. Mechanism of Action: Inhibits DPP-4 to increase endogenous incretin, which will act on the pancreas to (1) increase glucose-dependent insulin release and (2) decrease glucagon release B. Adverse effects: ∙ Headache ∙ Increased risk of URI due to decreased activity of T-cells ∙ Hypersensitivity C. Contraindications:

Medullary Thyroid Cancer

Neuroendocrine tumor of parafollicular C cells of thyroid that results in high calcitonin levels and present as solitary thyroid nodules in 70-95% patients. Associated with Men 2A and MEN 2B. Prognosis is variable

What are the majority of adrenal nodules?

Non-hormonally active Adenoma's.

Describe the mechanism of action of insulin. List the major target organs and cell types for insulin and the major effects of insulin on carbohydrate, fat, and protein metabolism in each organ.

Insulin is a pre-pro hormone made in pancreatic β-cells whose goal is the rapid uptake, storage, and use of glucose by almost all body tissues (especially muscle, adipose tissue, liver) It will deplete plasma glucose, fatty acids, and amino acids MOA: High levels of blood glucose leads to the release of insulin from β-cells of the pancreas, which will bind insulin receptors (tyrosine kinase) on the cell membrane. This results in autophosphorylation of the beta subunits of the receptor, and the phosphorylation of IRS which activates at least 3 pathways (Ras & MAPK, PI3K, and PLCɣ). Down-stream phosphorylation will stimulate protein synthesis, fat synthesis, glycogen synthesis, and growth and increase in gene expression, as well as the increase of GLUT4 transporters Major Effects on Target Tissues 1. Adipose Tissue: Increase glucose uptake, increase lipogenesis, decrease lipolysis 2. Striated Muscle: Increase glucose uptake, increase glycogen synthesis, increase protein synthesis 3. Liver: decrease gluconeogenesis, increase glycogen synthesis, increase lipogenesis Major Effects on Metabolism A. Carbohydrates ∙ Muscle: increase glucose uptake (GLUT4), glycolysis, and promote the formation of glycogen ∙ Liver: Absorbs glucose and stores it as glycogen, excess is converted into fatty acids and stored as triglycerides in adipose tissues, inhibit gluconeogenesis ∙ Adipose: Increase glucose uptake (GLUT4), used as substrate for glycerol of fatty acid B. Fats ∙ Liver: Increase glucose uptake and convert excess glucose into fatty acids to be stored as triglycerides in the adipose tissue ∙ Adipose: i. Activates LPL to split triglycerides into fatty acids so they can be absorbed and stored ii. Activates FAS to promote lipogenesis iii. Inhibits HSL to release fatty acids from adipose tissue iv. Promotes glucose transport (GLUT4), used for glycerol C. Protein ∙ Muscle: Increases amino acid uptake, inhibits catabolism of proteins ∙ Liver: Inhibits gluconeogenesis

Assess the value of determining the plasma concentration of C-peptide

Insulin is first produced as a pre-prohormone with multiple cysteine residues. When the pre-prohormone is processed, it is cleaved into C-peptide as well as Insulin. The C-peptide will be contained in the secretory vesicle with insulin. The amount of C-peptide can be measured to determine the amount of endogenous insulin production

Pendred Syndrome

Mutation in the SLC26A4 gene which is responsible for pendrin production which results in hypothyroidism resulting in hearing loss, goiter, and defects in iodide organification.

Hypoglycemia Define, and Include symptomatology, common etiologies, classification in those with diabetes, and treatment

Low BGL levels Symptoms: Whipple's Triad 1. Documented low blood sugar 2. Signs and symptoms of hypoglycemia (weakness, confusion, sweating, hunger, anxiety, loss of consciousness) 2. Reversal of symptoms with glucose Etiologies: ∙ Antidiabetic agents ∙ Postprandial ∙ Factitious ∙ Insulinoma ∙ Adrenal insufficiency Classification 1. Severe: Event requiring assistance of another person to administer corrective action; Actual blood glucose may not be measured 2. Documented symptomatic hypoglycemia: Event with typical symptoms of hypoglycemia + measured glucose of ≤ 70 mg/dl 3. Asymptomatic hypoglycemia: Event not accompanied by symptoms but with measured glucose of ≤ 70 mg/dl 4. Probable symptomatic hypoglycemia: Event with typical symptoms of hypoglycemia but no glucose determination 5. Pseudohypoglycemia: Typical symptoms of hypoglycemia with measured glucose >70 mg/dl Treatment: ∙ 15-20 grams of glucose preferred tx for conscious individual ∙ 15 grams simple carbohydrates ∙ Glucagon ∙ IV dextrose in unconscious patients

Explain mechanisms of action of vitamin D analogues in relation to parathyroid hormone and list three vitamin D analogues

MOA: Binds to and activates Vitamin D receptors in the chief cells, decreasing PTH gene transcription and therefore PTH as well as parathyroid hyperplasia. This will also decrease dietary absorption of calcium to increase plasma calcium levels which will decrease overall PTH secretion. 1. Paricalcitol 2. Oxacalcitriol 3. Doxercalciferol Adverse Effects: Hypercalcemia, Hyperphosphatemia

Describe the most common mutations leading to MODY and neonatal diabetes.

MODY (maturity onset diabetes of the young): typically presents in patients in the 2nd-3rd decade of life. There is a mutation in the pancreatic glucokinase resulting in higher glucose levels needed to activate insulin secretion ∙ Insulin independent ∙ No autoantibodies to pancreatic antigens ∙ Normal lipid levels Neonatal Diabetes: very rare, it can be transient or permanent. If permanent, the mutation that is most common is that in KCNJ11 which results in the K+ ATP channel which is always open, and therefore no release of insulin

What is the imaging modality of choice for evaluation of the Pituitary gland?

MRI

What are the regulators of glucagon release?

Major 1. Glucose: inhibits release 2. Insulin: inhibits release 3. Amino Acids: stimulates release Minor 4. Cortisol: stimulates release 5. Neural (stress): stimulates release 6. Epinephrine: stimulates release

Parathyroid Carcinoma

Malignant tumor of the parathyroid capsule which can exceed 10 gms in weight. Typically contain uniform cells and invades surrounding tissues. Will contain a dense fibrous capsule.

Describe the different staining methods of the endocrine pancreas

Mallory-Azan Staining: will distinguish (4) cell types of the Langerhans islets 1. A (alpha) cells: red in color, located in the periphery, and responsible for mainly secreting glucagon but can also secrete gastric inhibitory peptide, CCK, endorphins, & gastrin 2. B (beta) cells: brownish-orange in color, located in the center, they secrete insulin and will contain secretory granules 3. D (delta) cells: blue in color, located in the periphery, they secrete somatostatin 4. Other ("pale cells"): remain unstained, they include F-cells (secrete pancreatic peptide), D-1 cells (secrete vasoactive intestinal peptide), and EC cells (secrete substance P, secretin, and motilin)

Hyperosmolar Hyperglycemic Syndrome (HHS) Define and include the work-up and treatment

Marked hyperglycemia (>600 mg/dL) in the absence of ketoacidosis. Typically more common in elderly patients with or without a history of Type 2 DM. Acidosis does not occur because there is still some circulating insulin Diagnosis: ∙ Plasma glucose > 600 mg/dL ∙ Profound dehydration ∙ Serum pH > 7.30 ∙ Bicarbonate concentration > 15 mEq/L Treatment: 1. Fluid Resuscitation 2. Correction of hyperglycemia and electrolyte imbalances

Describe and differentiate between the Wolff-Chaikoff and Jod-Basedow effects.

Mechanisms used by the body to assure iodine regulation A. Wolff-Chaikoff: This is a normal adaptation to iodine intake. When there is sudden exposure to excess serum iodine, there will be a decrease in thyroid hormone production (temporary hypothyroidism). Following 2-4 weeks of excess iodide exposure, thyroid hormone biosynthesis will resume due to a decrease in the sodium/iodine symporter (NIS) expression B. Jod-Basedow: Increased iodine supply leads to increased thyroid hormone production independent of normal regulatory mechanisms (Iodine-induced hyperthyroidism). Typically occurs in patients with an underlying thyroid disease (i.e.- nodular goiter)

Branchial Fistula

Open tract from pharynx to lateral neck due to persistence of 2nd pharyngeal cleft. Leads to infection and discharge of saliva.

Explain the reason for the differential response of insulin release with oral versus intravenous glucose administration.

Oral: blood levels of glucose gradually rise, creating a large increase in insulin levels. As insulin levels rise, there will be a decrease in blood glucose levels. When BGL increase, the increase in insulin levels are extremely elevated because of the incretin effect in which the beta-cells not only release insulin but the GI tract as well. IV: blood glucose levels rise quickly, resulting in a rapid increase in insulin levels. Insulin will then decline and then increase again (biphasic release). This is due to the beta-cells initially dumping all the insulin that they have. The beta-cells then produce more insulin and secrete these levels again.

Describe the autonomic regulation of the islet activity

Parasympathetic (cholinergic) stimulation: ↑ Glucagon secretion ↑ Insulin secretion Sympathetic (adrenergic) stimulation: ↑ Glucagon secretion ↓ Insulin secretion

Hypoparathyroidism Define and include causes, clinical findings, and treatment

Parathyroid gland fails to produce sufficient amounts of parathyroid hormone or the parathyroid hormone produced lacks biologic activity Causes ∙ Acquired: post-thyroid surgery, radiation, very low magnesium ∙ Hereditary: DiGeorge Syndrome (aplasia of parathyroid gland), Familial isolated hypoparathyroidism (activating mutation of Calcium-sensing receptor [CaSR] gene) Clinical ∙ Serum Calcium: Decreased ∙ Serum Phosphate: Increased ∙ PTH: Decreased ∙ Calcitriol: Decreased ∙ Bone: Decreased resorption ∙ Kidney: Decreased phosphate excretion, decreased calcium reabsorption ∙ Symptoms: bone pain secondary to bone fractures, renal stones, constipation Treatment ∙ Vitamin D ∙ Calcium ∙ Thiazide Diuretic ∙ Low phosphate diet and phosphate binder ∙ Natpara

What is the most common mass of the sella?

Pituitary adenoma

What cardiovascular changes occur in hyperthyroidism?

Positive inotropic and chronotropic effects which increases heart rate and contractility ∙ Increased rate of myocardial diastolic relaxation ∙ Enhanced systolic function ∙ Increased rate of depolarization and repolarization of the SA node

Sheehan Syndrome

Post-partum pituitary necrosis, it occurs due to enlargement of the pituitary gland during pregnancy without increase in blood supply, making it prone to infarction from hypovolemic shock Can present as hypopituitarism or partial deficiency, amenorrhea, oligomenorrhea, or difficulty with lactation (earliest sign)

Hyperparathyroidism Include Subtypes, Etiology, Lab results, Clinical Findings, and Treatment

Primary Hyperparathyroidism: the most common etiology of hypercalcemia A. Etiology: Non-cancerous parathyroid Adenoma or hyperplasia increasing PTH production B. Lab results ∙ Serum Calcium: High → due to excessive renal Ca2+ reabsorption ∙ Serum Phosphate: Low → due to phosphaturia ∙ PTH: Increased ∙ Calcitriol: Increased (PTH stimulates 1α-hydroxylase) ∙ Bone: resorption ∙ Kidney: increased phosphate excretion, Increase calcium reabsorption C. Clinical ∙ On imagining will note less dense areas of bone ∙ Calcium phosphate stones (recurrent flank pain, polyuria, and polydipsia) ∙ "Painful bones, renal stones, abdominal groans, and psychic moans" D. Treatment: Surgery (Parathyroidectomy) → sestamibi scan performed beforehand to accurately localize the adenomas; should consider when serum calcium > 1.0 mg/dL above normal ∙ Vocal cord paralysis can occur ∙ Permanent hypoparathyroidism can occur Secondary Hyperparathyroidism A. Etiology: Diseases outside of the parathyroid gland cause glands to become enlarged or overactive (CKD, Vitamin D Deficiency, Malabsorption) B. Lab Results ∙ Serum Calcium: Low ∙ Serum Phosphate: High ∙ PTH: Increased ∙ Calcitriol: Decreased (due to renal failure) ∙ Bone: resorption, osteomalacia ∙ Kidney: decreased phosphate excretion C. Treatment: Treat underlying cause, Vitamin D, Phosphate Binders, Cinacalcet Tertiary (Refractory) Hyperparathyroidism A. Etiology: End-stage renal disease B. Lab Results ∙ Serum Calcium: High ∙ Serum Phosphate: High ∙ PTH: Extremely high C. Treatment: Parathyroidectomy, Vitamin D, Phosphate binders, Cinacalcet

What is the prime modality for evaluation of a thyroid nodule? What is needed to establish a histiologic diagnosis?

Prime Modality: Ultrasound -- can characterize and evaluate for other nodules Histiologic Diagnosis: Fine Needle Aspirate (FNA) -- can confirm benign vs. malignant

Anaplastic Thyroid Cancer

Rare, it is the most aggressive thyroid cancer found in those 60-65 years old, and more common in females than males. Patients present with a rapidly enlarging neck mass, dyspnea, dysphagia, and hoarseness. Mortality is 100%.

The inferior thyroid artery runs with what nerve? What muscle does this innervate?

Recurrent laryngeal n. (innervates all laryngeal m. besides the cricothyroid m.)

Hyperthyroidism Include differentiation of primary vs. secondary, hormone levels, and signs/symptoms

Signs/Symptoms ∙ Increased basal metabolic rate (weight loss) ∙ Heat intolerance/ sweating ∙ Goiter (stimulation of TSH receptors) ∙ Tachycardia ∙ Proximal muscle weakness with decreased muscle mass ∙ Ocular changes: wide, staring gaze and lid lag; proptosis Primary Hyperthyroidism: problem with the thyroid gland itself (i.e.-Graves disease, Toxic multinodular goiter, Solitary toxic adenoma) A. Hormone Levels ∙ TRH: Decrease ∙ TSH: Decrease ∙ T3/T4: Increased Secondary Hyperthyroidism: A. Hormone Levels ∙ TRH: Decreased ∙ TSH: Increased ∙ T3/T4: Increased B. Signs/ Symptoms ∙ TRH Stimulation test: injection of TRH followed by an increase in TSH excludes secondary hyperthyroidism

Hypothyroidism Include differentiation of primary vs. secondary, hormone levels, causes, signs/symptoms, and treatment

Signs/Symptoms ∙ Low basal metabolic rate (weight gain) ∙ Cold intolerance/ lethargy/ lowered basal body temp ∙ Goiter (if excessive TSH production) ∙ Galactorrhea ∙ Fatigue ∙ Dry Skin ∙ Eyelid edema ∙ Thickened tongue Primary Hypothyroidism: Thyroid gland is not making enough thyroid hormones (most common) A. Hormone Levels ∙ TRH: Increased ∙ TSH: Increased ∙ T3/T4: Decreased B. Causes ∙ Hashimoto's ∙ Iatrogenic: Thyroidectomy, radioactive iodine, external radiation to the neck ∙ Medications: Iodine excess, amiodarone, checkpoint inhibitors, Biotin, ∙ Congenital: absent or ectopic thyroid ∙ Iodine deficiency Secondary Hypothyroidism: caused by a deficiency in TSH production by the pituitary gland A. Hormone Levels ∙ TRH: Increased ∙ TSH: Decreased ∙ T3/T4: Decreased B. Causes ∙ Hypopituitarism: tumors, surgery, Sheehan's, Trauma Tertiary Hypothyroidism: caused by a deficiency in TRH production by the hypothalamus A. Hormone Levels ∙ TRH: Decreased ∙ TSH: Decreased ∙ T3/T4: Decreased B. Causes ∙ Hypothalamic disease: tumors, trauma, infiltration Treatment ∙ Levothyroxine (synthetic T4)

Review the regulation of thyroid hormone production by the hypothalamus and anterior pituitary gland, including the actions and mechanisms of thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH).

The Hypothalamus produces TRH (peptide hormone) which acts on Thyrotrophs in the Anterior pituitary, which will secrete TSH (peptide hormone) to act on Thyroid follicles by binding the TSH- receptor in the thyroid leading to an increase in Thyroid hormones (T3 + T4) TSH receptor is Gs and Gq linked, and promotes the synthesis/secretion of thyroid hormone, as well as promotion of thyroid size (increased cell size/ number) by activating thyroid peroxidase, increasing thyroglobulin synthesis, and increasing iodide uptake. High levels of TRH can increase prolactin secretion.

Describe the characteristics of the cell types of the endocrine pancreas

The endocrine pancreas is made up of Langerhans islets which are spherical cell masses embedded in the exocrine gland which lightly stain with H&E are consist of cell types that are undistinguishable

Parathyroid Adenoma

The most common cause of primary hyperparathyroidism, it is a solitary lesion that typically lies in close proximity to the thyroid gland Average weight of 0.5-5.0 gms and it is well-circumscribed lesion that is tan to reddish-brown Cells are typically uniform which mitotic figures being rare. There is very little if any adipose tissue

Papillary carcinoma of the thyroid

The most common form of thyroid cancer, it is associated with previous exposure to ionizing radiation Branching papillae will have a fibrovascular stalk which is covered by a single to multiple layer of cuboidal epithelial cells Nuclear features are diagnostic ∙ Optically clear nuclei (Orphan Annie Eye nuclei) ∙ Intranuclear grooving (lines in the nucleus)

Papillary Thyroid Cancer

The most common type of thyroid cancer (60-80%). The diagnosis is made by fine-needle aspiration, and the visualization of characteristic psammoma bodies (collection of calcification). Prognosis is the best

Graves' Disease Define and include its clinical presentation and treatment

The most common thyrotoxicosis, it is an autoimmune disorder which results in symptoms of hyperthyroidism Thyroid stimulating immunoglobulins (TSI) will provide constant stimulation of the thyroid causing excess levels of T3 and T4. Patients may also show thyroperoxidase (TPO) antibodies and Thyrotropin receptor antibodies (TSHR-antibodies) T3/T4: Increased TSH: Decreased TRH: Decreased Clinical: triad of clinical findings 1. Hyperthyroidism 2. Infiltrative ophthalmopathy with resultant exophthalmos 3. Localized, infiltrative dermopathy Morphology: Tall and more crowded follicular epithelial cells in which the colloid does not meet the edge of the cell Treatment ∙ Anti-thyroid drugs (methimazole, propylthiouracil) ∙ I-131 ablation (radioactive iodine) ∙ Surgery

Describe, in detail, the mechanism by which glucose stimulates insulin secretion from pancreatic beta cells. List additional factors that modulate insulin secretion.

The primary regulator of insulin release is glucose. 1. Glucose enters the β-cell of the pancreas through GLUT-2 transporters, where it then enters the glycolysis pathway to form ATP 2. Increased ATP decreases the activity of ATP-sensitive K+ channels of the β-cell. This leads to decreased K+ removal from the cell, leading to the build up of K+ in the cell causing depolarization of the beta-cells 3. Depolarization will lead to the opening of voltage gated Ca2+ channels, increasing intracellular calcium 4. Intracellular calcium triggers the exocytosis of insulin containing vesicles and therefore secretion of insulin Other modulators: Increased blood free fatty acids, CCK, ACh, Glucagon, β-adrenergic agonists, sulfonylurea drugs

Justify the use of β-blockers in hyperthyroidism

Use as off-label therapeutic adjuncts to control symptoms of hyperthyroidism (i.e.- sweating, tremor, tachycardia, SVT) They can reduce peripheral conversion of T4 to T3

List the thyroid autoantibodies that can be detected and identify which thyroid autoantibodies are likely to be present in Hashimoto's thyroiditis and Graves' disease respectively.

Thyroid Autoantibodies 1. Anti-thyroperoxidase (TPO) Antibodies: Thyroperoxidase (TPO) helps produce T4 and T3. Autoantibodies can interfere with TPO's ability to use iodine to produce these hormones, resulting in hypothyroidism. TPO antibodies cause inflammation and can destroy the thyroid gland or cause hyperplasia or nodules to form 2. Thyroid Stimulating Hormone (TSH) receptor (TSHR-Ab) Antibodies: TSH is a hormone released by the pituitary gland that stimulates the thyroid to make thyroid hormone by binding TSH receptors. TSH receptor antibodies (TSHR-Ab) can imitate the action of TSH, causing excess thyroid hormone production 3. Anti-thyroglobulin (anti-Tg) antibodies: Thyroglobulin (Tg) is a protein that helps the thyroid gland function properly Hashimoto's Thyroiditis: Associated with TPO antibodies & anti-Tg antibodies Graves' Disease: Associated with TSHR antibodies & TPO antibodies

Describe the roles of TBG, transthyretin, and albumin with respect to thyroid hormones.

Thyroid hormones are hydrophobic and will be better circulated through the blood through binding proteins 1. Thyroxine-binding globulin (TBG): contains a single binding site for T3 or T4 and will bind them with high affinity 2. Transthyretin (TBPA): 10x greater affinity for T4 >> T3, but has lower affinity than TBG and therefore will rapidly dissociate from thyroid hormones 3. Albumin: found in high concentration in the plasma, it has a low affinity for T3 and T4 allowing for rapid dissociation

Hypercalcemia Define (including ranges), and include signs/symptoms, laboratory evaluation, and treatment

Total serum calcium above the normal range in the presence of normal serum proteins. Most (50%) of calcium is free and it is this calcium which is associated with signs and symptoms. This occurs either from (1) Too much calcium entering the extracellular fluid (increased GI absorption, increased bone resorption) or (2) Insufficient calcium excretion from the kidneys. Normal range is 8.6-10.3 mg/dL. > 14 mg/dL is considered to be a medical emergency and most often occur due to malignancy. Signs/ Symptoms: related to absolute calcium level as well as how fast the rise in serum calcium occurs ∙ Mild, prolonged: produced mild or no symptoms or recurring problems (i.e.- kidney stones) ∙ Sudden, severe: dramatic symptoms (confusion, lethargy, possible sudden death) Laboratory Evaluation: ∙ Total calcium + albumin ∙ Ionized calcium ∙ Repeat for confirmation ∙ Following confirmation of hypercalcemia, check PTH and if high, check 24 hour urine calcium Treatment: ∙ Rehydration and IV bisphosphonate ∙ Calcitonin (directly inhibit osteoclast function) ∙ Bisphosphonates ∙ Denosumab ∙ Parathyroidectomy

Understand the treatment strategy for different types of diabetes mellitus (DM)

Type I DM: occurs due to autoimmune destruction of the pancreatic β-cells and insulin deficiency ∙ Treatment: Insulin Type II DM: occurs due to insulin resistance with relative insulin deficiency ∙ Treatment: oral agents, non-insulin injectable, insulin

What is the significance of a hot nodule on a thyroid scan?

Typically are benign

Differentiate between T3 and T4 in terms of production in the thyroid gland and biological activity. Discuss the physiological effects and mechanism of action of T3.

Tyrosine derived hormones which In a euthyroid (normal) status, T4 > T3. Most of the T3 & T4 is bound to thyroxine binding globulin (TBG), maintaining a large storage pool so the body has enough when it is needed. Altered TBG levels will change total T4 levels, but free T4 levels can remain normal T3: Most biologically active, binds thyroid hormone receptor (TR) within the nucleus, causing the receptor to heterodimerize with the retinoid X receptor (RXR), and allows for gene transcription that will result in -- ∙ Calorigenesis: increased basal metabolic rate (increased O2 consumption, heat production, carbohydrate/protein/lipid metabolism) ∙ Cardiovascular effects: Increases inotropy and chronotropy (increased cardiac output), decreases systemic vascular resistance ∙ Trophic/Growth Effects: bone growth and stimulates GH and IGF-1 production ∙ Nervous system Effects: Normal development, myelination, neuronal differentiation (if T2 is absent or low it leads to mental retardation) T4: Less biologically active, but has a longer half life (7 days) compared to T3 (<1 day) ∙ Increased TBG (increase total T4): pregnancy, estrogen, liver disease ∙ Decreased TBF (decrease total T4): hepatic failure, androgens, anabolic steroids, congenital

Discuss the effects of insulin deficiency on fat metabolism

Unable to take up glucose into the cells, results in the body attempting to use fat from energy. Adipocytes will activate HSL, leading to the breakdown of triglycerides into fatty acids and glycerol and moving them into the bloodstream. This increase of fatty acids and glycerol in the blood stream is what promotes atherosclerosis in severe diabetes. At the same time, the liver will begin producing acetoacetic acid, to produce phospholipids and cholesterol. Some of this acetoacetic acid enters the blood stream and is converted into ketones (this is how DKA occurs)

Osetomalacia Define, include lab results, and symptoms

Vitamin D deficiency in adults that results in impaired mineralization of the bone matrix (deficient vitamin D), bone pain/pathologic fractures ∙ Serum Calcium: Decreased ∙ Serum Phosphate: Decreased ∙ PTH: Increased ∙ Calcitriol: Decreased ∙ Bone: Increased resorption ∙ Kidney: Increased phosphate excretion, increased calcium reabsorption ∙ Symptoms: pain in legs, hips, muscle weakness

Rickets Define, include lab results, and symptoms

Vitamin D deficiency in children that results in deficient mineralization at the growth plate (deficient vitamin D), soft bones ∙ Serum Calcium: Decreased ∙ Serum Phosphate: Decreased ∙ PTH: Increased ∙ Calcitriol: Decreased ∙ Bone: Increased resorption ∙ Kidney: Increased phosphate excretion, increased calcium reabsorption ∙ Symptoms: bow-legged due to bone resorption to try and increase Vitamin D levels

Explain the sources, biochemical forms, and activation of vitamin D.

Vitamin D is synthesized from cholesterol. In the skin, 7-Dehydrocholesterol is exposed to UV light, converting it to Cholecaliferol (D3). Cholecaliferol is converted in the liver to 25-hydroxycholecaliferol. In the kidney, 1α-hydroxylase will activate Vitamin D to its active form Calcitriol Vitamin D can bind intracellular VDR receptors in the intestine which will promote the absorption of calcium and phosphate as well as to regulate the transcription of PTH

What are the symptoms of hyperglycemia?

∙ Polyuria: consequence of osmotic diuresis secondary to sustained hyperglycemia ∙ Blurred vision ∙ Weight loss despite polyphagia ∙ Dizziness/ Weakness ∙ Anorexia, Nausea, Vomiting