Endocrinology

Transgender patients

Awareness of gender identity: -Between 1 and 2 = conscious of physical differences between sexes -At 3 = can label themselves as a girl or boy -By 4 = gender identity is stable and recognize gender constant Etiology: -Recent estimates site prevalence at 0.3-2.7% -Gender identity is not simply a psychosocial construct (genetics, hormones, brain differences) Gender Dysmorphia: -Incongruence between gender identity and assigned sex -Desire to be rid of secondary sex characteristics and desire for those of other gender -Strong desire to be of and treated as other gender -Clinically significant distress (for who?) Treatment-phases of transitioning: -Reversible = clothes, hair, shoes, toys, GnRH analogues, androgen blockers -Partially reversible = mascilizing and feminizing hormone therapy -Irreversible = surgical intervention Puberty blockers: -Continuous GnRH secretion. Suppress FSH and LH. Initial spike followed by desensitized pituitary -Benefits = delay irreversible secondary sex characteristics. Effects fully reversible and allow time for teen to mature and make decision as well as time for parent and social support to develop -Risks = bone mineral density reduced, height reduction if started early, lack of secondary sex characteristics compared to peers, expense/insurance coverage Timing of treatment = recommend Tanner stage II. Increased psych distress. Minimal breast and testicular development can be reversed. GnRH analogues = Leuprorelin, Triptorelin, and Goserelin (monthly and 3-monthly depot preparations. Histrelin implant (lasts 12 months Transgender women are on average 50 times increased risk for HIV infection when compared to the general population. Among transgender individuals, the prevalence of mental health challenges is high (suicide attempt 40%) Key themes: -Social support and safe spaces as facilitators to engagement in care -Frequent lack of respect for identity by provider/clinic as a barrier to engagement in care -Gender affirmation as key to overcoming mental health challenges and engaging in care Feminizing meds: -Estrogens induce development of female secondary sexual characteristics -Anti-angrogen treatment reduces effect of endogenous male sex hormones [spironolactone, finasteride (5-alpha reductase inhibitor) and cyproterone acetate] -Progestins for breast tissue development -No change in voice -Hormones have minimal clinically significant physiologic affects and suggest we can do less labs in the future Masculinizing meds: -Testosterone injections most common. Can have transdermal and pellet preparations -Progestins may be used short term to stop menses and androgenic affects of some progestins also may be desirable -Transgender males may become pregnant bc T is not fail safe contraceptive. May continue to ovulate. T may adversely affect development of fetus

Islets of Langerhans

Constitute 2% of total pancreas. 3 most important cells types of the islets: -Beta = constitute 60-80% of the cells and contain insulin -Alpha = 20-30% of the cells and produces glucagon -Delta = secretes somatostatin which suppresses insulin and glucagon secretion

GLP-1 receptor agonists

GLP-1 increases insulin, lowers glucagon, slows gut motility and induces satiety. DPP-4 inactivates GLP-1 and GIP. >50% of secreted GLP-1 is already degraded before it reaches the general circulation. >40% is already degraded before it reaches beta cells. Incretin effect is diminished in type 2 diabetes. Receptor agonists = exenatide (53% homology), liraglutide (97% homology), albiglutide, dulaglutide. All administered by subQ Can help lose weight. Effects of drugs decline as glucose levels reach normal Exenatide is synthetic version of exendin 4, a protein found in the saliva of the gila monster. It's effect is predominantly *post-meal*. It is a potent glucose-dependent insulin secretion, inhibits glucagon secretion, indirectly slows gastric emptying and stimulates satiety. . Clearance varies and occurs after enzymatically degraded by DPP-4. Side effects include GI bloating, nausea, diarrhea, increased HR. Administered by subQ once weekly, one or twice daily. Contraindication is gastroparesis. *Glucose dependent*, therefore does NOT induce hypoglycemia. Weight loss of 5.3kg. Lowers A1c as much as 1% Liraglutide effect and action in diabetes = evaluation of CV outcome showed decreased CV events and decreased death from CV causes.

Incretin enhancers (DPP-4 inhibitors)

Inhibition of DPP-4 to increase active GLP-1. 80% inhibition at 24 hours. Immediate effect mostly on *post-meal* glucose Sitagliptin and Saxaliptin are not metabolized, excreted unchanged through the kidneys with dose adjusted for renal insufficiency Linagliptin is hepatically metabolized. Administered once daily by mouth. No contraindications. GI adverse effects. Does NOT induce hypoglycemia and is weight neutral. Lowers A1c by about 0.7%

Type 3 diabetes

Latent auto-immune diabetes of adulthood (LADA) Adult age at diagnosis (usually >25). Initial presentation masquerades as non-obese type 2 diabetes (does not present as DKA). Initially can be controlled with meal planning with or without oral glucose lowering pills. Insulin dependency gradually occurs usually within months. Antibody positive, low C-peptide conc, unlikely to have a family history of type 2 diabetes

Growth

Length is different than height! Height is less because of gravity and such. Girls' peak growth rate is 11.5 years. Boys' peak growth rate is 13.5 years. There is a difference between genetic short stature and constitutional delay. Constitutional delay determination will include growth pattern, parental Hx, dentition and bone age (epiphyseal plate) Mid parental height: -Boys = [(M+F) + 5 inches]/2 -Girls = [(M+F) - 5 inches]/2 Processes that affect growth: -Genetic disorders = turner syndrome, down syndrome, skeletal dysplasia, chromosomal disorders, prader-willi syndrome, noonan syndrome, SHOX defect. Down syndrome children have a different growth chart for interpreting growth patterns. -Endocrine disorders = hypothyroidism, excessive steroids, GH deficiency. In child with hypothyroidism, normal weight but short. -GI diseases = malnutrition, malabsorption, IBD, celiac disease -SGA/IUGR = Birth weight/length < -2 SD. ~10% do not catch up -Systemic disorders = pulmonary, immunological, cardiac, hematological, medication related -Psychosocial deprivation = neglect that leads to poor growth due to lack of nurturing and/or nutrition Blood analysis: -Complete blood count -ESR and/or C-reactive protein -Celiac screen -Chemistry, karyotype, GFs, TSH, free T4 Diagnosis of GH deficiency: -History of risk factors -Poor growth velocity -Delayed bone age -Low IGF-1, IGFBP-3 -Failed GH provocative testing -MRI of the pituitary/hypothalamus Puberty: -Sex hormones are active in utero but then go away until puberty -Infant puberty issues = breast development (benign premature thelarche), small phallus -Androgens = pubic hair, body odor, voice, acne, growth surge. DHEA-S, androstenedione, testosterone -Estrogen = breast development, growth surge. Estradiole, estrone -Menarche = 12.16 in black, 12.88 in whites -Precocious puberty: central precocity puberty (CPP) (idiopathic, CNS pathology, hamartoma) and peripheral (ovarian cysts, McCune-Albright, exogenous). CPP is much more common in girls, and in boys required CNS workup. Treatments include leuprolide, triptorelin, histrelin implant (GnRH agonist therapy). -Delayed puberty = boys without testes enlargement by age 14 and girls without breast changes by age 13. Causes are usually secondary (low LH, FSH) can be late bloomer or have central disease. Also primary hypogonadism can be cause

Glucocorticoid-Remediable Aldosteronism

"Hybrid gene". Promoter sequence for *11-beta-hydroxylase* (drives cortisol) attaches to coding sequence of aldosterone synthase. Result is aldosterone controlled by ACTH instead of renin/angiotension II Treatment: -If unilateral aldosterone secreting adenoma, surgical resection often leads to cute -If bilateral adrenal hyperplasia is the cause, treat with a mineralocorticoid antagonist -Glucocorticoid, mineralocorticoid receptor antagonist

Obesity medications

(30+ or BMI of 27+ with co-morbidities) Phentermine (short term only) = sympathomimetic. Side effects include headache, elevated BP, *elevated HR*, insomnia, dry mouth, constipation, anxiety, palpitations, *tachycardia* Orlistat (Xenical) = lipase inhibitor. Decreased absorption of fat-soluble vitamins, steatorrhea, oily spotting, fecal urgency, oily evacuation, *increased defecation* Phentermine/Topiramate ER (Qsymia) = sympathomimetic, GABA receptor modulation, carbonic anhydrase inhibition. Most efficacious. Side effects include those seen in phentermine plus insomnia, dry mouth, constipation, paresthesia, dizziness and dysgeusia Locaserin (Belviq) = 5-HT2c serotonin agonist, little affinity to other serotonin receptor sub-types. Side effects include *headache*, nausea, dry mouth, dizziness, fatigue, constipation Naltrexone/Bupropion SR (Contrave) = DA/NA reuptake inhibitor, opioid receptor antagonist. Side effects include *Nausea*, constipation, headache, vomiting, dizziness Liraglutide (Saxenda) = GLP-1 receptor agonist. Side effects include *Nausea*, vomiting Weight regain occurs when anti-obesity meds are stopped

Bariatric surgery

(40+ or BMI of 35+ with co-morbidities) Contraindications: -Untreated major depression or psychosis -Uncontrolled and untreated eating disorders -Current alcohol or drug abuse -Severe CVD or coagulopathy -Inability to comply with nutritional requirements Types of surgery: -Roux-en-Y gastric bypass (RYGB). Has biggest change in weight. Increases GLP-1 -Vertical sleeve gastrectomy. Causes decrease in ghrelin. -Adjustable gastric band Mechanisms implicated: -Reduced energy intake as a result of altered eating behavior -Changed gut-derived signals as a consequence of altered nutrient and/or biliary flow -Understanding the interplay between gut hormones, bile acids, and the microbiome of nonsurgical treatment options for obesity Benefits: -Decreases weight, fat and diabetes incidence -Reverses sleep apnea -Improves psychosocial health -Associated with reduced all cause mortality, reduced CV events, reduced cancer mortality Complications: -Postoperative complications -Vitamin, iron, Ca deficiencies -Dumping syndrome; flatulence -Recurrent severe hypoglycemia Associated with dramatic and durable improvements in obesity-related complications, which may include reduced mortality

Thyroid histology

*Oncocytic cell* = Hurthle cell. Metaplastic follicular cell with eosinophilic cytoplasm, round nucleus, and prominent nucleolus. Seen in both benign and malignant lesions C-cells = produce calcitonin, located at the lateral aspect of thyroid gland, rarely seen in regular histology until hyperplastic, best seen with immunostains for calcitonin Papillary formation = finger like projections which consist of single or multiple layers of epithelium centered around a core/stalk containing blood vessels and connective tissue Nodular thyroid enlargement: -Can be found in 4-7% of US population -Solitary = neoplastic/benign -Multiple nodules = usually benign? -*Non-toxic nodular goiter* = can be endemic (Iodine deficiency), sporadic, chemically induced, or dyshormonogenetic. Firm gland, diffusely enlarged, cut surface is shiny and amber colored due to increased colloid accumulation. Asymmetric enlargement, multinodular, hemorrhage, calcification, fibrosis (as a function of repair), cystic degeneration. *Heterogenous morphology*. Variable sized follicles lined by tall columnar epithelium and/or flattened low-cuboidal epithelium. Can have papillary hyperplasia in nodular goiter. Diffuse thyroid enlargement: -Usually benign. -*Diffuse toxic goiter (Grave's disease)* = symmetric and diffuse enlargement of the thyroid gland. Red brown cut surface, decreased colloid, increased vascularity. Because there is hyperplasia of collicular cells, usually of increased size, these cannot be accommodated in the follicles in the usual way so papillary infoldings occur. Lymphocytic infiltration is common in the *stroma.* -*Chronic lymphocytic thyroiditis (hashimoto's thyroiditis)* = diffusely enlarged gland, lobulated cut surface. Infiltration of thyroid *gland *by lymphocytes and plasma cells. Follicular atrophy. Hurthle cell/oncocytic metaplasia -Rarely tumors Thyroid neoplasms: -*Follicular adenoma* = benign, primary epithelial neoplasm. Solitary, well circumscribed and encapsulated. Follicular, solid, trabecular growth patterns. No invasion of the capsule or capsular vessels -*Primary malignant epithelial neoplasms* = uncommon (1-2% of all cancers). More common in genetic females. Behave in an indolent fashion. *Irradiation* is the most well known etiological factor for thyroid carcinoma aka *papillary carcinoma* (Ret is rearranged on ch 10). -*Well-differentiated carcinoma* = derived from follicular cells. Papillary carcinoma, follicular carcinoma. Produce THYROGLOBULIN. -*Papillary thyroid carcinoma* (PTC) = the most common type of thyroid cancer. Can occur in *all sizes*, slow growing lesions. Metastasize via *lymphatics*. Nucleus is elongated, chromatin cleared, membrane thickened, intranuclear grooves, intranuclear inclusions. Can see papillary cores. Cleared nuclei distinguishes PTC from papillary formation in graves disease. *Follicular variant* (low risk tumors) forms follicles not papillae and now has new name. In *tall cell variant*, cell height is three times the width. In PTC, 10 yr survival is over 90% but gets more aggressive with older age, males, larger size, tall cell variant and distant metastases. Can present as multiple tumors within thyroid. - *Follicular carcinoma* = 5% of all thyroid carcinomas in US. Increasing incidence with age. Common in iodide deficient regions. Encapsulated tumor with cells invading into tumor capsule and/or vessels, hematogenous spread to* brain lungs and bone*, prognosis dependent upon extent of invasion. Tumor cells invade into capsular blood vessel instead of lymphatics like PTC. Presents as solitary/single tumor nodule - *Medullary carcinoma* = derived from C-cells which produce calcitonin. In familial, MEN2 syndromes. Can be sporadic and lethal. Germ line mutation (whereas in PTC it is mutated only in the tumor) of Ret oncogene on ch 10 in familial cases. 20% are hereditary. Cannot treat with radioactive iodine. Secrete calcitonin. Prognosis is 50% at 5 years. See amyloid, tumor nest, calcitonin. Salt and pepper nuclei bc neuroendocrine tumor -*Anaplastic carcinoma* = fatal tumor. 5% of all thyroid malignancies. Patients over 60, more common in women, often preceded by a history of goiter. Usually invades into the surrounding neck structures. See very pleomorphic tumor cells, can show spindle cells and multinucleated giant cells. DOES NOT produce thyroglobulin. Tumor is hemorrhagic and necrotic and replaces the entire gland

Antihyperglycemic agents for T2D

-Metformin -Insulin secretagogues -Glucosidase inhibitors -Incretin mimetics (GLP-1 agonists) -Incretin enhancers -Sodium glucose transporter inhibitors (SGLT-2) -Thiazolidinediones -Insulin Principles of glucose lowering agents: -Multiple drugs available, each with tissue specific action -All of these drugs, except insulin are used for type 2 diabetes ONLY -All are contraindicated in pregnancy except Glyburide (sulfonylurea) and metformin -Can be used in any combination except sulfonylureas should not be used with meglitinides (cross reactivity) -Metformin is generally first drug of choice -Can start with multiple classes of drugs

Hypoparathyroidism

-Post-surgical = following total thyroidectomy or radical neck dissection -Infiltrative disease = Hemochromatosis, Wilson's disease -Hypomagnesemia = Decreased functional adenylate cyclase leading to decreased PTH activity -Congenital = DiGeorge syndrome, familial, resistance to PTH Albright hereditary osteodystrophy = unique finding in AHO is shortened fourth and fifth digits Hypocalcemia: -Cardiac arryhthmia -Neuromuscular irritability: perioral paresthesias, tingling of the fingers and toes, tetany (Chevostek's sign--facial nerve) (trousseau's sign--carpal spasm) Treatment: -Oral calcium and 1,25 dihydroxy vitamin D -Synthetic PTH (1-84): NATPARA -Monitor = serum and urinary calcium concentration -Goal serum calcium level in a patient with hypoparathyroidism is low normal. You are going to be excreting in the urine what you create. Don't want to form kidney stones

Endodermal progenitor cell transplant

1. Beta cell self-replication 2. Neogenesis 3. Acinar to beta cell transdifferentiation 4. a to B cells reprogramming

Hypothyroidism

10 times more common in women than men. Increased risk among women > 40 years of age Primary: -Autoimmune destruction (Hashimoto's), measure TPO antibodies -Iatrogenic -Dysgenesis/agenesis of the thyroid gland -Defects in biosynthesis -TSH is high and T4 and T3 are low Central: -Pituitary/hypothalamic -TSH is low as are T4, T3 Transient: -Hypothyroid phase of thyroiditis Myxedema coma: -Severe, life-threatening untreated/poorly treated hypothyroidism -RARE -High mortality -Typically elderly patient with pre existing hypothyroidism and precipitating illness such as sepsis or MI; COLD inciting factor -Characterized by altered mental status, hypothermia, bradycardia, hyponatremia, respiratory failure -Coarse/flaky skin, puffy face, droopy eyelids, non-pitting edema, thin hair, hoarse voice, delayed reflexes

Diabetes

A condition in which a person has a high blood sugar level, either because the body doesn't produce enough insulin, or because body cells do not properly respond to the insulin that is produced. Insulin = a hormone produced in the pancreas which enables body cells to absorb glucose and utilize as energy If the body cells do not absorb the glucose, the glucose accumulates in the blood, leading to vascular, nerve and other complications Number 1 cause of renal failure, new cases of blindness, and nontraumatic amputations Specific signs and symptoms: -Polyuria/polydispia -Weight loss -Polyphagia -Diabetic ketoacidosis -Coma Non-specific signs and symptoms: -Fatigue -Blurry vision -Dry mouth -Dry or itchy skin -Vaginal candidiasis -Poor healing of wounds -Excessive/unusual infections (bacteria love glucose) -Hyperglycemia--> immunosuppression Elevated fasting a post prandial glucoses increase CV risk

Obesity

A disease associated with substantial burden of morbidity and premature death. Medical complications include pulmonary disease, pancreatitis, nonalcoholic fatty liver, gall bladder disease, cancer, skin, gout, phlebitis, osteoarthritis, gynecologic abnormalities, diabetes, dyslipidemia, HTN, CVD, intracranial HTN Caused by ingesting more energy than is expended over a long period of time. Pathophysiology includes, stomach, SI, LI, pancreas and adipose SI hormones: -CCK, GLP-1, OXM, PYY -Peripheral effect on food intake is decrease. Anorexic effects Adipocyte hormones: -Leptin (weight loss, satiety), adiponectin (insulin sensitization), inflammatory cytokines Arcuate nucleus: -Part of the hypothalamus near the base -Located near the BBB -Takes in peripheral circulating signals and relays them to the CNS -Takes in GI and adipocyte hormones, glucose, FAs, amino acids Obesity treatment strategy: 1. Self-directed lifestyle change 2. Professionally-directed lifestyle change 3. Pharmacotherapy (30+ or BMI of 27+ with co-morbidities) 4. Weight loss surgery (40+ or BMI of 35+ with co-morbidities) 5. Post-surgical combinations Patients at risk have a BMI of 25-29.9, 30+. Waist circumference (W 35, M 40). Patients should be counseled about benefits of 3-10% weight loss. There is wide variation in response to specific diets. Combination of pharmacotherapy and lifestyle modification has an additive effect. Lifestyle modification program: -Diet, physical activity, and behavioral change -Reduced calorie diet. Try for 500-750 kcal/day energy deficit. -Physical activity -Behavioral therapy = structured program that includes regular monitoring of food intake, activity and weight with personalized feedback from a trained interventionist -Can induce weight loss of 7-10%

Type 2 diabetes

A metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbs, fat and protein metabolism resulting from defects in insulin secretion, insulin action and multiple other pathophysiologic defects 90% of cases of diabetes. Effects of DM include long term damage, dysfunction and failure of various organs. It is a disease of middle age. Develops when the insulin secretory capacity can no longer compensate for the obesity-related insulin resistance The *earliest detectable abnormality is an increase in insulin secretion*. As insulin resistance increases, a healthy beta cell makes more insulin, which overcomes the insulin resistance. As a consequences, blood glucose remains in the normal range, both after a meal and fasting. As time goes on, beta cells cannot keep producing this amount of insulin. As the beta cells start to fail, *postmeal glucose goes up first*. As the decline of insulin production continues, the liver starts producing glucose and the glucagon secreted helps sustain the hyperglycemia. At the time of diagnosis, people with diabetes have already lost 50% of beta cell function. Ominous octet: -Increased hepatic glucose production -Neurotransmitter dysfunction at the brain -Decreased glucose uptake at the muscles -Increased glucose reabsorption at the kidneys -Increased lipolysis and reduced glucose uptake at the fat -Decreased incretin effect in the GI -Impaired insulin secretion by the pancreas -Increased glucagon secretion by the pancrease Incretins = intestinal hormones, released in response to food ingestions. Accounts for 60-70% of postprandial insulin response Incretin effect = insulin secretion is relatively enhanced after oral vs parenteral glucose administration As T2DM progresses, additional therapies are required. T2DM is increasing in the youth Risk factors: -Family history of diabetes -Overweight -Habitual physical inactivity -Race/ethnicity (native americans) -HTN, HDL cholesterol, PCOS Screening: -Screen at any age for those with risk factors -In those without risk factors, begin testing at 45 -If normal, repeat testing at least every 3 years -If prediabetes, consider screening yearly if at the highest risk Glycemic goals are all about individualization Early tight glycemic control reduces microvascular disease in the short and long term and macrovascular disease over the long term Implications for treatment: -Effects of early intensive treatment persist for years -Prior poor control can cause damage that is difficult to reverse -In older patients with long-standing diabetes, with complications, aggressive DM treatment may be ineffective (or even harmful) -Aggressive management of other risk factors for CVD is critical!!! (smoking cessation, BP control, lipid lowering) Treatment strategies: -Lifestyle changes!! -Oral meds and non insulin injections -Insulin -Additional weight loss strategies -Meds for CV risk factor modification

Insulin

A peptide hormone secreted by B-cells in the pancreatic islets of Langerhans. Key anabolic hormone critical for glucose uptake and utilization, lipid and protein synthesis, and an essential growth factor for normal development It is a major *anabolic* hormone. It is necessary for: -Transmembrane transport of glucose and aminoacids -Glycogen formation in the liver and skeletal muscles -Glucose conversion to triglycerides -Nucleic acid synthesis -Protein synthesis Its principle metabolic function is to increase the rate of glucose transport into certain cells in the body. These are the striated muscles cells, including myocardial cells, fibroblasts, and fat cells, representing collectively about 2/3 of the entire bodyweight Intact insulin function requires: -Islet B-cell mass -Insulin synthesis -Glucose-dependent insulin secretion -Insulin signaling at target cells Secretory vesicles: -Each B-cell contains ~10,000 secretory granules. -Granules also contain Zn, unprocessed proinsulin, proteolytic enzymes, Islet Amyloid Polypeptide Synthesis: -It is synthesized as inactive, precursor form (preproinsulin). A signal sequence is removed from preproinsulin following insertion into the endoplasmic reticulum, resulting in proinsulin. -Proinsulin is further processed to form insulin and a by product, C peptide, both of which are packaged into secretory vesicles -The mature insulin mc comprises two peptide chains (A and B) linked together by two disulfide bonds Metabolism: -The major regulator of insulin secretion is glucose which acts both directly and by augmenting the action of other insulin secretagogues -A rise in the blood glucose levels causes an immediate release of insulin that is stored in the beta cell granules -If the secretory stimulus persists, a delayed response follows, which involves active synthesis of insulin; the constitutive pathway

Hypoglycemia

A sign not a diagnosis. It is not possible to define as a single plasma glucose value. Thresholds for specific brain responses to hypoglycemia occur across a range of plasma glucose concentrations. @ 80-85 mg/dL, suppression of insulin secretion. @ 65-70 mg/dL, increased glucagon, epi, cortisol and GH secretion. @50-55 mg/dL, awareness of symptoms. < 50 mg/dL, impaired cognition. Must satisfy Whipple's triad: 1. Symptoms and/or signs are compatible with hypoglycemia 2. A low measured plasma glucose concentration 3. Resolution of symptoms and signs when plasma glucose is restored to normal Symptoms/signs: -Symptoms are characteristic but not specific -Neurogenic (autonomic) = the result of the perception of physiological changes caused by CNS-mediated sympathetic nervous discharge triggered by hypoglycemia. Include adrenergic and cholinergic responses -Neuroglycopenic = arise from the failure of brain function caused by deficient glucose:confusion, dizziness, fatigue, inability to concentrate, blurred vision, headache, focal neurological signs, loss of consciousness, seizures, depression of respiration, death -Neurogenic symptoms usually precede neuroglycopenic symptoms -Previous episodes of hypoglycemia may modify the response to a later episode, typically attenuating the adrenergic response (hypoglycemia unawareness of hypoglycemia-associated autonomic failure) Glucose measurements: -Need accurate measurement of plasma glucose (glucose meters not accurate enough -While blood glucose 15% lower than serum and plasma, venous is 10% lower than arterial -Glucose concentration decreases over time in collection tubes not containing inhibitors of glycolysis from utilization of glucose by red and white cells Fasting hypoglycemia: -*Insulin-mediated* = hyperinsulinism, insulinomas, exogenous insulin or insulin secretagogues, autoimmune hypoglycemia -*Failure of counter-regulation* = growth hormone deficiency, cortisol deficiency -*Congenital errors of metabolism* = impaired glycogenolysis, impaired gluconeogenesis, impaired ketogenesis Differential diagnosis: -Insulin mediated = *high* insulin, low FFAs, *low* ketones, low lactate, high GH and cortisol -Defect of counter-regulation = low insulin, high FFAs, high ketones, low lactate, *low* GH and cortisol -Defect of gluconeogenesis = low insulin, high FFAs, high ketones, *high* lactate, high GH and cortisol -Defect of glycogenolysis = low insulin, high FFAs, *high* ketones, low lactate, high GH and cortisol -Defect of fatty acid oxidation = low insulin, *high* FFAs, *low* ketones, low lactate, high GH and cortisol

Conn's syndrome

Aldosterone excess. Causes: -Adenoma (65%) -Bilateral hyperplasia (35%) -Carcinoma (rare) Adrenal cortical adenoma = benign neoplastic proliferation of adrenal cortical tissue. Unilateral and solitary and well circumscribed. Variety of cell types. Most have cells resembling zona fasciculala with minority having features of zona glomerulosa cells Clinical features: -HTN -Muscle weakness, fatigue and polyuria -Periodic paralysis Increased cardiac arrhythmias

Synthetic insulin

All packaged at neutral pH except Glargine (4). Bolus = rapid-acting human analogs. Aspart, lispro, glulisine, inhaled insulin. Short-acting regular. Used for coverage of food intake or correction of hyperglycemia. Short acting regular human insulin has peak time in 2-4 hours. Rapid acting has peak time in 1 hr Basal = long acting human analogs. Glargine, detemir, degludec. NPH-complexed with protamine. Maintains euglycemia in the fasting state. NPH is intermediate and dosed one or twice daily, peaks in 4-8 hours. Glargine, detemir, degludec are long acting and dosed once daily, always flat with no peak. Aspart/Lispro/Glulisine: -Insulin molecule manipulation through recombinant DNA technology -Disrupts monomer-monomer interaction -Decreased hexamer formation, leading to more rapid absorption and action -Have faster onset of action and shorter duration of action than regular analogues. Also have 2x higher peak conc. Inhaled insulin: -Rapid acting insulin absorbed onto carrier particles delivered via inhalation -Mediation time for max effect is 53 min -Duration of action is 160 min -Dosed in 4 unit increments NPH-intermediate acting: -A suspension of crystalline zinc insulin combined with the positively charged polypeptide, *protamine* -Advantage = can be combined with other insulins -Disadvantage = peak in action increases risk of hypoglyemia -Inexpensive Glargine: -Peakless 24 hours insulin -Insulin molecule modifications -Unique release pattern at injection site -Acidic pH so precipitates in blood. The slow break down is the precipitate slowly dissociating Detemir: -A soluble, long-acting basal insulin analog with a relatively flat action profile -Acylation with myristic acid -Remains as solution after injection, neutral pH, duration of action is dose dependent up to 24 hours -c max is reached 6-8 hours after administration Degludec: -Long-acting basal human insulin analog -Side chain attached at B29 -Conc reached steady state after 3-4 DAYS of administration -Dosed every 24 hours, glucose lowering effects seen up to 42 hours Insulin administration: -Long or intermediate acting only -Twice daily mixed split -Twice daily 70/30 or 75/25 -Rapid acting insulin before each meal + long acting insulin once daily -Continuous insulin infusion using a pump that administers insulin through a catheter in the abdominal fat to help control a person's blood sugar levels. Uses only regular or very rapid insulin. Uses 1 injection site and eliminates most of the subcutaneous insulin depot. Programmable basal and bolus delivery simulates normal pancreatic function -With the twice daily split mixed regimen, include times of hyperglycemia. Dawn phenomenon is the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients Insulin complications: -Hypoglycemia. Higher rates with low HbA1c. -Insulin lipodystrophies. Localized loss of subQ fat at injection sites. Lipohypertrophy, swelling of subcutaneous fat at injection sites -Allergy -Insulin resistance. IgG mediated. All treated and some untreated diabetics have anti-insulin IgG but Ab mediated resistance is rare

Androgenital syndrome

Androgen/sex steroid excess. Congenital adrenal hyperplasia (CAH). Inherited disorder caused by deficiency of enzymes required for the biosynthesis of glucocorticoids and mineralocorticoids. This *leads to androgen excess*. Have enlarged/hyperplastic adrenal glands Clinical features: -Females = male hair pattern with facial hair -Males = fast body growth and testicular atrophy

Immune-mediated hypoglycemia

Antibodies to the insulin receptor. Act as an insulin agonist to cause hypoglycemia. Can also act as an insulin-antagonist to cause hyperglycemia Disease tends to be self-limited. Immunosuppression, steroid and plasmapheresis generally is unsuccessful. Antibodies to insulin (Hirata's disease). Associated with other autoimmune diseases. No previous history of insulin exposure. Sudden and unpredictable dissociation of insulin from its antibody results in fasting or postprandial hypoglycemia

Pheochromocytoma

Catecholamine secreting tumor arising from the Chromaffin cells of the adrenal medulla. Rare in children. Other sympathetic ganglia may also be affected Clinical features: -so called 10% rule = 10% bilateral 10% extra adrenal 10% malignant 10% familial and 10% children. WRONG. MANY MORE are FAMILIAL than thought, somewhere between 20-35%. Mutations are passed on in an autosomal dominant fashion -Excess catecholamines = HTN, palpations, headaches, diaphoresis, flushing, anxiety, nausea, constipation, pain and epistaxis -Elevated urine catecholamines Gross findings: -In sporadic = unilateral -In familial = bilateral or multiple tumors -Well circumscribed -Average size is 6cm -Firm cut surface, vascular Microscopic findings: -Growth pattern = nested, trabecular or solid -Zellballen or Organoid pattern = the round groups of tumor cells supported by a rish vascular network and a delicate spindle cell sustentacular network -Nuclei = *"salt and pepper"* aka neuroendocrine chromatin -Malignancy = associated with necrosis, mitoses, vascular invasion

Diabetic ketoacidosis (DKA)

Cellular starvation state. Body perceives state of starvation because absolutely no insulin in synthesized or detected by the liver, muscle, adipose Compensation is to utilize fuel sources in normal progression: 1. *Liver* (anti-glucose production) --> increase plasma glucose --> glucosuria --> polysuria --> dehydration 2. *Muscle* (glucose uptake, protein synthesis) --> increase plasma glucose and muscle wasting --> weight loss 3. *Adipose tissue* (anti-lipolytic) --> increase plasma FFA --> increase plasma B-hydroxybutyrate and acetoacetate --> acidosis Symptoms: -Nausea/vomiting -Thirst/Polyuria -Weakness/Anorexia -Abdominal pain -Visual disturbances -Somnolence Signs: -Tachycardia -Hypotension -Dehydration -Hyperventilation -Weight loss -Fruity odor on breath -Altered mental status Treatment = *Insulin* then replacement and correction of fluid and electrolyte imbalances

a-Glucosidase inhibitors

Competitively inhibit the ability of enzymes in the SI brush border to break down oligosaccharides and disaccharides into monosaccharides -Delays gut carb absorption, increases GLP-1 -Affects *post-prandial* glucose only -Pills are taken with meals -Side effect = flatulance, abdominal bloating -Contraindications = GI disorders especially IBD -Titrate dose slowly to minimize GI side effects -Renally excreted as unchanged drug -Does NOT induce low glucose -Lowers A1c by about 0.4%

Synthetic glucocorticoids

Developed to exploit the anti-inflammatory and immunosuppressant effects of glucocorticoids Dexamethasone has highest anti inflammatory and HPA suppression with no mineralocorticoid activation

Pancreas

During embryonic development, the pancreas actually develops as two separate buds. The ventral bud is a subdivision of the hepatic diverticulum, a growth of duodenal endoderm that fills in the ventral mesentery. The hepatic diverticulum also gives rise to the liver and gallbladder as well as the biliary tree. The dorsal bud emerges separately as a growth of duodenal endoderm into the dorsal mesentery. As the buds form, the ventral bud begins to rotate clockwise around the duodenum, carry the billiary tree with it. The two buds meet to the left of the duodenum and fuse together. Acinar cells = exocrine, produce digestive zymogens Islet cells = endocrine, produce metabolic hormones -a-cells = glucagon -B-cells = insulin -delta cells = somatostatin

Soluble cell signaling

Endocrine = signal (hormone) travels through blood stream to reach distant target cell Paracrine = signal travels through extracellular space to reach nearby target cell Autocrine = signal travels through extracellular space and binds to the cell producing it The capillaries of endocrine tissues have fenestrated endothelial cell linings. A given endocrine tissue generally produces *one biochemical type* of hormone. A given endocrine tissue may produce more than one specific hormone, but *each cell* in that tissue generally produces only one hormone

Type 1 Diabetes

Epidemiology: -Most common in northern Europe -Peak ages = 5-7 yr and at onset of puberty; 1/3 of cases after age 18 -Onset is more common in winter "cold" season -Incidence is increasing worldwide Risk factors: -Viral infections -Exposure to cow's milk at an early age -Higher socioeconomic status -Obesity -Vitamin D deficiency -Perinatal factors such as maternal age, history of preeclampsia, and neonatal jaundice -Low birth weight decreases the risk of developing it though Several clinically useful serum autoantibodies can be detected during the preclinical period of type 1 diabetes. 60=80% of patients with newly diagnosed type 1 have *ZnT8* autoantibodies. Inaddition, 26% of subjects with antibody neg type 1 diabetes have ZnT8 autoantibodies Path: -Chronic *auto-immune* insulitis involving genetic predisposition, environmental trigger (virus) and beta cell injury---> islet cell antigen release---> B cell production of antibodies---> destruction of beta cells -*Concurrence of other auto-immunity* before or after development of type 1 diabetes such as thyroiditis, addison's disease, celiac disease After-meal glucoses get elevated before fasting glucoses Treatment: -Insulin replacement therapy -Adjust doses according to carb intake, exercise regiment, blood glucose profile -Test blood glucose levels and adjust insulin appropriately -Monitor for complications -The Basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating -Early control in the disease is important for long term outcomes (70% risk reduction in intensive care tactics). Intensive therapy significantly reduced CV incidences, retinopathy, nephropathy and neuropathy

Medium-chain acyl-CoA dehydrogenase deficiency

Fatty acid oxidation defect. Hypoketotic hypoglycemia. Mimics reye's syndrome with elevated liver anzymes and ammonia Newborn screening by MS acylcarnitine profile. Treatment is limit fasting to less than 12 hours start to see hypoglycemia 12-16 hours after eating

Multiple endocrine neoplasia syndromes (MEN)

Genetically defined, multiple endocrine organs involved, signs and symptoms cary with organs involved, may also have lesions in non endocrine systems Men 1 (Wermer syndrome): -Multifocal hyperplasia and neoplasia of *pituitary, parathyroid, and pancreatic islets* -Different family members may manifest different symptoms due to organ involved -Gene involved MENIN with multiple sites of mutation -Clinical prognosis *usually related to pancreatic lesions which can be malignant* MEN2 = mutations in *ret protooncogene*. *Medullary thyroid carcinoma* is the most prognostically important lesion bc can be fatal Men 2A (Sipple syndrome): -Consists of neoplasia and hyperplasia of *thyroid C cells adrenal medulla and parathyroids* Men 2B -Consists of neoplasia and hyperplasia of *thyroid C cells, adrenal medulla AND neural tissue of oral and GI systems* -Skeletal and eye lens abnormalities (Marfanoid Habitus) -96% of these patients show mutation in ret codon 918

Glucose homeostasis

Glucose production = ingestion, glycogenolysis, gluconeogenesis Glucose utilization = brain, muscle, red and white blood cells, renal medulla Plasma glucose is maintained within a narrow range of 70-100mg/dL Fasting systems: -Hepatic glycogenolysis -Hepatic gluconeogenesis -FAO and ketogenesis -Hormonal integration

Primary hyperaldosteronism

HTN, hypokalemia, mild hypernatremia, metabolic alkalosis, muscle weakness can occur. K may fall to severely low levels. Causes: -Elevated aldosterone with *elevated plasma renin activity*. Likely renal cause (secondary) -Elevated aldosterone with *suppressed plasma renin activity*. Aldosterone-secreting tumor, glucocorticoid-remediable aldosteronism. -Elevated deoxycorticosterone (aldosterone effect) with *suppressed plasma renin activity*. Tumor, CAH, glucocorticoid resistance. Diagnosis: -Check early morning aldosterone:renin ratio. -Ratio > 20 suggestive but not diagnostic of primary hyperaldosteronism -Aldosterone > 15 and suppressed renin are also suggestive -Consider salt-loading to demonstrate inappropriate aldosterone secretion-caution in severely HTN patients Once biochemical diagnosis certain, CT should be performed to help differentiate between an adenoma and hyperplasia. Most patients (over age 35) should have adrenal vein sampling prior to surgery to further differentiate since adenomas are common *Spironolactone*: -Mineralocorticoid antagonist. Also blocks androgen and progesterone receptors. -Is a K sparing diuretic. Used for essential HTN, congestive heart failure, cirrhosis, nephrosis, primary hyperaldosteronism, PCOS/hirsutism -Side effects: Hyperkalemia, Volume depletion, gynecomastia, impaired libido and impotence in men, Menstrual irregularities in women and teratogenic -Contraindications = renal impairment, hyperkalemia, and pregnancy Eplerenone: -Mineralocorticoid antagonist. Highly selective and more expensive. NOT used for antiandrogenic effects -Uses = K sparing diuretic, primary hyperaldosteronism -Contraindications = renal impairment, hyperkalemia, pregnancy Amiloride: -K sparing diuretic -Weak diuretic and weak antihypertensive effect -Uses = K sparing diuretic -Contraindications = renal impairment and hyperkalemia

Prediabetes diagnostic criteria

HbA1c 5.7-6.4% or Fasting plasma glucose is 100-125mg/dL or 2 hour plasma glucose is 140-199 mg/dL People with prediabetes can have impaired fasting glucose, impaired glucose tolerance or both

Molecular basis for T2D

Hyperinsulinemic-Euglycemic clamp: -Measures glucose disposal and insulin resistance -The more resistant to insulin a subject is, the less glucose is needed to maintain this predetermined glucose level -Skeletal muscle accounts for most glucose uptake and most of the post-meal defect in T2D -More insulin sensitive subjects have a *higher glucose infusion rate* The liver maintains fasting glucose levels Cardinal abnormalities: -Decreased glucose uptake in skeletal muscle -Increased glucose production by the liver (inappropriate gluconeogenesis). -Dysfunctional adipose tissue with increased lipolysis -Defective insulin secretion from pancreatic B-cell -Diabetes resembles starvation. *Both insulin resistance and B-cell failure are necessary to develop T2D*. Skeletal muscle insulin resistance: -The defect lies downstream of the insulin receptor and upstream of GLUT4 translocation -The central kinase in insulin signaling is *AKT* -Even in insulin resistance, exercise can stimulate glucose uptake via *AMPK* Selective liver insulin resistance: -Liver relies on special properties of *GLUT2 and GCK* for sensing of high glucose and for glucose export when low -Insulin normally turns off gluconeogenesis via blocking *FOX1* -Insulin normally stimulates lipogenesis via *SREBP1c* -Insulin resistance is apparently selective in that there is *persistent lipogenesis yet a failure to suppress gluconeogenesis* -T2D is marked by fatty liver -Patients with diabetes due to insulin receptor mutations do NOT develop a fatty liver -Nonalcoholic fatty liver disease and dyslipidemia are integral parts of insulin resistance. There is a positive correlation between plasma triglycerides and insulin resistance. In addition to storage in hepatocytes, excess triglycerides is also secreted to the blood in VLDL particles Adipocyte insulin resistance: -Insulin normally increases lipid synthesis via *ChREBP* and *SREBP1* and uptake via *LPL* -Insulin normally represses lipolysis by inhibiting *HSL* activity -Insulin resistance results in increased lipolysis and free fatty acid release from adipose tissue -T2D is marked by elevated serum FFA Ectopic lipid deposition: -Increased serum FFAs and intramyocellular triglycerides correlate with insulin resistance -Adipose tissue is not the problem; DYSFUNCTIONAL adipose tissue is. -Adipose tissue cannot accommodate lipid storing needs so lipids get abnormally stored in liver and skeletal muscle -Obesity ultimately results in dysfunctional and inflamed adipose tissue with release of FFAs and inflammatory cytokines. Skeletal muscle and liver insulin resistance is due to effect of ectopic lipids and inflammation. Targeting fat to improve insulin sensitivity: -Thiazolidinediones (TZDs) are the only current antidiabetic drugs that act primarily by increasing insulin sensitivity -Agonists for *PPARy*, the adipocyte master regulator -Causes weight gain, less adipose inflammation, higher adiponectin, lower serum FFAs, and less ectopic lipid Brown fat: -While white adipocytes store energy, brown/beige adipocytes function to burn energy. Uncoupled mitochondrial respiration by *Ucp1* generates heat -Increased by TZDs, cold exposure, thyroid hormone, catecholamines -Potentially powerful treatments for obesity and T2D Adipose quantity and distribution: -Relative risk of T2D increases markedly with increasing BMI -At any BMI, *abdominal distribution* correlates with diabetes and CV risk -SQ fat may be protective while visceral fat leads to insulin resistance B-cell function and failure: -B cells have constitutive glucose uptake by *GLUT1/2*. Glycolysis generates ATP. Inhibition of the *ATP-sensitive K+ channel*. Membrane depolarization results in opening of voltage-dependent Ca2+ channels. Increased intracellular Ca2+ results in fusion of readily releasable insulin secretory granules with the cell membrane -First phase of insulin secretion is lost earlier in T2D. Second phase is due to priming and recruitment of reserve pool of secretory granules. -*Insulin resistance initially leads to hyperinsulinemia and islet hypertrophy* and proliferation -B cells later fail due to chronic glucolipotoxicity. Hyperstimulation and exhaustion. ER stress (adaptive initially but if unresolved, apoptosis), oxidative stress (mitochondrial dysfunction and ROS), and inflammation Other organ systems: -The gut = incretin effects and the microbiome -Pancreatic a-cell = failure to suppress postprandial glucagon -Nephron = new SGLT2 inhibitors target glucose reabsorption -Brain = obesity due to hypothalamic circuits, also autonomic nervous system -Effects of circadian rhythm Genetics: -Monogenic diabetes is uncommon -Insulin resistance, defective insulin secretion -Runs in families but polygenic -Lifetime risk of developing T2D is 7% in general -Risk increases to 30-40% in individuals with one parents with T2D, up to 70% if both parents have T2D. Monozygotic twins is 90%. -SNP1, TCF7L2, none are immune-related. GWAS loci tend to be named by the nearest genes to the lead SNP but regulatory regions do not always affect the nearest gene. Lead SNPs fall in inron of FTO. Recent studies show that nearby IRX3 is the target of regulatory SNPs and associated with obesity -YET, the incidence has increased drastically, far too short a time for genes to have changed -Due to effects of environment on genetically susceptible individuals

Glucose-6-phosphatase deficiency

Impaired gluconeogenesis and glycogenolysis Treatment = frequent cardohydrate rich meals, intragstric dextrose, uncooked cornstarch, no lactose/fructose Late = hepatic tumors, nephropathy start to see hypoglycemia 2-4 hours after eating

Fructose-1,6-diphosphatase deficiency

Impaired gluconeogenesis. Attacks of hypoglycemia, metabolic acidemia, lactic acidemia, hyperuricemia Triggers = fasting or fructose Treatment = limit lasting < 8-12 hr, no fructose/sucrose start to see hypoglycemia 8-12 hours after eating

Glycogen debrancher deficiency

Impaired glycogenolysis. Failure to thrive, hepatomegaly, muscle weakness Hypoglycemia, hyperketonemia, elevated liver enzymes Treatment = frequent carbohydrate feeds, increased protein intake, intragastric dextrose, uncooked cornstarch Late = cardiomyopathy (30%), myopathy (30%) start to see hypoglycemia 4-8 hours after eating

Adiponectin

Improves insulin sensitivity. Synthesized exclusively in white adipose tissue. Most abundantly secreted adipocyte hormone. Levels are *inversely related to body fat mass* (higher body fate, lower adiponectin) Obesity is associated with lower levels

Iodide and thyroid

In normal thyroid, iodide uptake is mediated by Na/I symporter (NIS). It is highly regulated to allow adaptions to variations in dietary supply (low iodide increases NIS, high iodide decreases NIS). Highly expressed in thyroid, low levels in salivary glands, lactating breast, placenta. Allows radioactive iodine scanning and therapy of thyroid in a selective manner. Intake is 100-150mcg/day. A prolonged decrease of <40 mcg/day can cause an endemic goiter or cretinism. The effect of iodine on the thyroid gland depends on the state of the underlying gland, whether it is normal or abnormal. Wolff-Chaikoff effect: -Excess iodide transiently inhibits thyroid iodide organification (step 2) -In individuals with a normal thyroid, the gland escapes from this inhibitory effect -In individuals with underlying autoimmune thyroid disease, the suppressive effect may persist Jod-Basedow phenomenon: -Hyperthyroidism produced by iodine exposure -Occurs in *nodular thyroid glands* Radioiodine (131-I): -Emits gamma rays and beta particles -Used in low doses for diagnostic purposes, higher doses for therapy -Effects dose dependent -Do not give to breast-feeding or pregnant women, children -Need to stop antithyroid drugs 5 days prior -Need 24 hr uptake first -Goal in grave's disease is hypothyroidism (5-10% require a second dose) -Necrosis of follicular cells followed by disappearance of colloid and fibrosis of gland over months -Contact precautions after treatment Amiodarone: -Used to treat arrhythmias -37% by weight is organic iodine. -Can cause hypothyroidism -Can cause hyperthyroidism: *Type 1* in patients with underlying thyroid nodular disease of Grave's Disease--unmasks hyperthyroidism, increased thyroid hormone production, *iodine effect*. *Type 2* in patients with normal thyroids--destructive thyroiditis--increased thyroid hormone release, direct *toxic effect* of amiodarone. Recombinant TSH (rTSH): -TSH stimulates thyroid tissue and increases iodine uptake. -RTSH used in thyroid cancer patients to stimulate thyroid tissue for diagnostic thyroglobulin measurement and radioiodine scanning -Increases TSH transiently to improve detection of residual thyroid tissue -Patients stay on thyroid hormone therapy -Avoids the need to withdraw thyroid medication and cause hypothyroidism to raise TSH

Thyroid

In the 3rd week gestation, is an outpouching of foregut at the foramen cecum. It descends anterior to the trachea and bifurcates into two lobes. Thyroid remains connected to foramen cecum by the thryoglossal duct which regresses at 8 weeks. Ectopic thyroid tissue can arise along this path as well as sublingually. The inferior end of the thyroglossal duct forms the pyramidal lobe Thyroid hormone = animo acid derived hormone-precursor is tyrosine. Thyroid gland produces two types of thyroid hormones. Thyroxine (T4) is made exclusively in thyroid gland. Triiodothyronine (T3) is made in thyroid and by extra-thyroidal conversion (80%) of T4 to T3. T3 is biologically active hormone, T4 is more of a precursor. Thyroid hormone acts on thyroid hormone receptor nuclear receptor. Thyroid hormone is critical for brain development, skeletal function and growth in infants/children. Regulates metabolic activity in all tissues except BRAIN/SPLEEN/TESTES. Increases basal metabolic rate and oxygen consumption. Heat production by stimulation of Na-K ATPase. Affects function of virtually all tissues. Thyroid hormone synthesis: -Iodine = micronutrient in food. Pregnant and lactating women need more. -Thyroglobulin = large glycoprotein made by rough ER of thyroid follicular epithelial cells, stored in vesicles and exocytosed into colloid -Contain Tyrosine residues sterically oriented for thyroid hormone production. -*Step 1: Iodide transport*. I- is transported across the basolateral membrane of the follicular cells by Na/I symporters (NIS). This is active transport with Na gradient generated from Na/K ATPase. At the apical border of the follicular cells, an iodide/chloride transporter (pendrin) transports I- across the apical membrane -*Step 2: Oxidation of iodide to iodine*. On the apical membrane of the follicular cell, I- is converted to I2 in the presence of H2O2 catalyzed by thyroid peroxidase (TPO). I2 combines with tyrosine residues of thyroglobulin, catalyzed by TPO. Two products are formed: monoiodotyrosine (MIT) or diiodityrosine (DIT). -*Step 3: Coupling*. Either 2 mcs of DIT combine (T4) or one DIT and one MIT combine (T3), catalyzed by TPO. T4, T3 and uncoupled DIT.MIT stay bound to thyroglobulin and are stored in the lumen as colloid. Production of T4 is 10x faster than T3. -*Step 4: Proteolysis of thyroglobulin*.Under TSH stimulation, colloid is taken up in vesicles via pinocytosis back into the follicular cell. Vesicles fuse with lysosomes, which contain proteases that cleave T3, T4, inactive iodotyrosine, peptides and amino acids -*Step 5: Secretion of thyroid hormone*. T4 and T3 diffuse across the basolateral membrane into capillaries and enter the circulation T3 from T4: -Deiodinases = enzymes that cleave iodine from T4 -ACTIVATING = outer ring cleavage -INACTIVATING = inner ring makes reverse T3. Biologically inactive Most of hormones are bound the TBG, albumin and transthyretin. Free hormone is the active and regulated hormone. TBG is made in the liver. Have increased TBG with estrogen (COC, pregnancy) and acute hepatitis. Have decreased TBG with chronic liver disease, malnutrition, nephrotic syndrome, glucocorticoid therapy. Total hormone conc will increase with increased TBG but free amount will reach new steady state and remain stable. There is a long-linear inverse relationship between TSH and T4. There is wide variation of individual set point. Specific TSH:T4 set point for each individual. *TSH assay is the optimal screening test in ambulatory healthy patients* Goiters: -Enlarged thyroid gland. Normal gland is 15-20grams -Can be endemic or non-endemic, diffuse or nodular, solitary or multi-nodular, toxic or non-toxic -Cretinism in endemic severe iodine deficiency. Iodine deficiency during pregnancy in BOTH mom AND baby causes baby to have coarse facial features, umbilical hernia, large fontanelles, macroglossia. Continued iodine deficiency postnatally can cause severely stunted physical growth and cognitive and neurologic development Thyroid nodules: -Palpable mass, nodule documented by imaging -6.4% of women, 1.5% of men ages 30-60 with annual incidence of 0.1% -Age = older. More common in women -Benign (90%) = colloid nodules, follicular/Hurthle cell adenomas, lymphocytic thyroiditis -Malignant (5-10%) = papillary (75%), follicular (15%), medullary (5%), lymphoma, anaplastic, metastases to thyroid -Obtain TSH and ultrasound. If low TSH, uptake and scan. -If not functional, US appearance of nodule determines risk of malignancy then biopsy or observe -Managing after FNA = Benign is just observe, non-diagnostic is repeat FNA, indeterminate is molecular testing or surgery, cancer is thyroidectomy.

Pancreas Transplant

In type 1 diabetes, there is defective glucose counter regulation. There is near total B cell loss and hypoglycemia-associated autonomic failure (HAAF). For HAAF, responses become impaired over time after hypoglycemic episodes. Vicious cycle of hypoglycemia begets hypoglycemia due to blunted sympathoadrenal responses Pancreas-kidney transplant: -Whole organ, vascularized, composite tissue graft -Usually done with kidney transplant -Indications = T1D requiring kidney transplantation in the absence of a living kidney donor, already committed to surgery and immunosuppression, acceptable risk of more extensive surgery -Benefits = prolongs deceased donor kidney graft and consequently patient survival, stabilizes glycemia with elimination of hypoglycemia, majority independent from insulin Pancreas-after-kidney transplant: -Indications = T1D with a stable, functioning kidney graft and unstable glycemic control, already committed to immunosuppression, acceptable risk of additional major intra-abdominal surgery -Benefits = may prolong kidney graft survival, stabilizes glycemia with elimination of hypoglycemia, lesser majority independent from insulin (more immunologic graft loss) Pancreas alone transplant: -Indications = unstable glycemic control including hypoglycemia unawareness, severe hypoglycemia episodes, and less commonly recurrent diabetic ketoacidosis. Acceptable risk of immunosuppression -Benefits = stabilizes glycemia with elimination of hypoglycemia, lesser majority independent from insulin (more immunologic graft loss) Contraindications for and risks of pancreas transplantation: -Age > 50 years -BMI > 28 kg/m2 -Insulin requirement > 1 unit/kg per day (insulin resistance) -CVD -Surgical risks = 5% technical failure, 40% re-operation There is normal insulin secretory reserve with successful pancreas transplant. Islet cell responses to defend against hypoglycemia are restored. Sympathoadrenal responses to defend against hypoglycemia are improved. Endogenous glucose production response to hypoglycemia is normalized.

Antithyroid drugs

Interfere with 2 steps of thyroid hormone synthesis by affecting thyroid peroxidase: intrathyroidal iodine utilization and iodotyrosine coupling Use in graves disease for children and adolescents, adults who may achieve remission (use for 1-2 years) or to "cool the patient down" prior to radioactive iodine or surgery (use for several months). Must be sure of the diagnosis. Many TSH and free T4 assays use a biotinstreptavidin separation system. Patients who are taking high doses of biotin can have spuriously abnormal results. We advise patients to stop high dose biotin (vit B7) for 2 days prior to thyroid testing. Antithyroid drugs: -1/2 life *PTU* is 1 hr, *methimazole* 4-6 hrs. Intrathyroidal duration of action longer. -There is latent period before improvement (2-4 weeks) -PTU protein-bound, methimazole not -PTU also decreases T4 to T3 conversion -Side effects = agranulocytosis (neutropenia) 0.1-0.5%. THIS CAN KILL. Can occur at any time at any dose. Methimazole (First line): -*Daily* -Starting dose 10-30mg -6-12 weeks to euthyroid -*Frequency of side effects are dose related* -*Fewer drug-induced lupus, vasculitis, hepatitis* -Used in ALL Grave's Disease patients EXCEPT during the *first trimester of pregnancy*, during a thyroid storm or if have adverse reactions to methimazole PTU: -Three times a day -Starting dose 100mg -6-12 weeks to euthyroid -No dose relationship of side effects -Can cause hepatitis 0.1-0.2% of the time Drugs that inhibit T4 to T3 conversion: -PTU -Glucocorticoids -Propanolol Other drugs: -Beta blockers for thyrotoxicosis of any etiology. -NSAID in subacute thyroiditis -Iodine or glucocorticoids, in addition to antithyroid drugs, in severe thyrotoxicosis Treatment of thyroid storm (severe hyperthyroidism): -Antithyroid drugs = PTU -Beta blocker = propranolol or esmolol -Glucocorticoid = hydrocortisone -Iodine = potassium iodide drops

Diabetes criteria

Symptoms or diabetes plus a random plasma glucose conc of >200 mg/dL or Fasting plasma glucose concentration >126 mg/dL or 2-hour plasma glucose concentration >200 mg/dL during an oral glucose tolerance test or A1c > 6.5%

Islet transplant

Isolated, high purity cellular preparation, intact islet tissue. Islet transplant alone: -Indications = unstable glycemic control including hypoglycemia unawareness, severe hypoglycemia episodes, and less commonly recurrent diabetic ketoacidosis. Acceptable risk of immunosuppression -Benefits = stabilizes glycemia with elimination of hypoglycemia, 50% independent from insulin (lower engrafted islet mass), significantly improved health-related quality of life Islet-after-kidney transplant: -Indications = type 1 diabetes with a stable, functioning kidney graft and poor or unstable glycemic control. Already committed to immunosuppression -Benefits = stabilizes glycemia with elimination of hypoglycemia, 50% independent from insulin (lower engrafted islet mass), significantly improved health-related quality of life Contraindications for and risks: -BMI > 28 kg/m2 -Insulin requirement > 1 unit/kg per day (insulin resistance) -Procedural risks = <10% intra-abdominal bleeding and <5% portal (branch) vein thrombosis There is reduced insulin secretory reserve compared to normal with successful islet transplant, but it is still elevated. Islet cell response to defend against hypoglycemia is restored. Sympathoadrenal responses to defend against hypoglycemia are improved. Endogenous glucose production response to hypoglycemia is normalized

Adrenal medulla

Modified sympathetic ganglion. Preganglionic sympathetic nerve fibers (using ACh as a neurotransmitter) directly makes contact with postganglionic cells...the Chromaffin cells Upon stimulus, Chromaffin cells secrete catecholamines directly into the circulation 90% of the adrenal medullary cells are the epinephrine secreting type and 10% are the NE secreting type Causes of hyperfunction: -neoplasm (pheochromocytoma) -hyperplasia -neuroblastoma

Diabetes complications

Most common cause of new cases of blindness in adults 20-74. Most common cause of kidney failure. 60% of all non-traumatic lower-limb amputations. 67% have hypertension. 2-4 times higher death rates due to heart disease than adults without diabetes. 7th leading cause of death in the US. Hyperglycemia is strongly correlated with microvascular disease. Causes derangements in molecular pathways, leading to tissue damage. *Retinopathy:* -Onset is 3-5 years after diagnosis for type 1 with nearly all patients affected after 20 yrs -For type 2, prevalence is about 20% at the time of diagnosis. Onset averages 4-7 years *before* diagnosis. -Hyperglycemia causes dysregulated retinal blood flow, oxidative stress and inflammation, increased vascular permeability, microthrombosis, ischemia, growth factor proliferation -Increased incidence in first degree relatives -Association with nephropathy in type 1 -HTN, dyslipidemia, medications -Two major categories = non-proliferative and proliferative -*Proliferative* = neovascularization. These new vessels are fragile and leakage results in hemorrhage. Preretinal and vitreous hemorrhage causes acute vision loss that often resolves spontaneously. Fibrosis can cause retinal traction and detachment. Ischemia. -*Macular edema* = biggest cause of blindness in DM. Can occur at ANY stage of retinopathy. Edema and thickening of the retina. Accounts for 75% of vision loss due to DM. -*Mild* = microaneurysms, dot hemorrhages, hard exudates (lipid leakage within macrophages) -*Moderate/severe *= also have soft exudates (cotton wool spots, nerve fiber layer infarcts). venous beading, intraretinal microvascular abnormalities. 50-75% annual progression to PDR for severe. -*Prevention* = glycemic control, antihypertensive therapy. Good glycemic control is highly effective in *primary prevention* of retinopathy in T1D. Similar but less pronounced effect in slowing progression of mild to moderate nonproliferative retinopathy in T1D. Favorable effect of early intervention may persist as long as 10 years (metabolic memory). Decreases progression of retinopathy in T2D -*Treatment* = Focal laser photocoagulation. Intravitreal glucocorticoids. Vitrectomy. *Nephropathy*: -Onset 5-20 years after DM. Independent risk factor for both CV and overall mortality. -Risk factors = poor glycemic control, HTN, age, genetic factors, face, obesity, tobacco use, retinopathy -Glomerular disease = mesangial expansion, glomerular BM thickening, glomerular sclerosis -Albuminuria = microalbuminuria and proteinuria -Natural history = glomerular hyperfiltration, microalbuminuria, regression to normoalbuminuria, progression to macroalbuminuria, decreased GFR, progression to end-stage kidney failure -*Prevention* = glycemic control, BP control, treatment of dyslipidemia, measurement of spot urine microalbumin to creatine ratio (annually after 5 yr in T1, begin at diagnosis in T2) -*Treatment* = ACE inhibitor or angiotension II receptor blocker, other antihypertensives, dietary restriction (Na and protein), weight loss *Neuropathy*: -Most common microvascular complication. Most common form of neuropathy in developed countries. 50-70% lifetime incidence of at least one form of neuropathy -Risk factors = age, duration of DM, poor glucose control, blood vessel damage, mechanical injury to nerves, genetic susceptibility, HTN, dyslipidemia, tobacco use, excessive alcohol use -Distal symmetric sensorimotor polyneuropathy, autonomic neuropathy, polyradiculopathy, mononeuropathy -Peripheral neuropathy = most common type, Distal, symmetric. Sensory > motor. Symptoms include decreased sensation, paresthesia, hyperesthesia, worse at night -*Treatment* = anticonvulsants, TCA, SNRI, topical agents, opioids, antioxidants, electric nerve stimulation -Type of autonomic neuropathy = CV, gastrointestinal, genitourinary, peripheral -SV autonomic = resting tachycardia, exercise intolerance (fixed HR, inadequate CO), postural hypotension, silent MI -GI autonomic = esophageal enteropathy, gastroparesis, intestinal enteropathy, b=gallbladder atony and enlargement -*Gastroparesis* = delayed gastric emptying. Symptoms include early satiety, nausea, vomiting, worsening of glycemic control, asymptomatic. Treatment include glycemic control, dietary modifications, prokinetic agents. Can have effect on efficacy of insulin injection and lead to hyperglycemia if insulin is used up before the stomach empties. -Genitourinary = urinary retention (UTIs, overflow incontinence) and erectile dysfunction -Peripheral = aka sudomotor. Impaired perspiration, peripheral edema, callus formation (ulcers) and possible contributor to neuroarthropathy (joints) -*Prevention* = glucose control, BP control, treatment of dyslipidemia, smoking cessation, decreased alcohol intake Diabetic foot ulcers = major cause of amputations, sepsis and death. Risk factors include neuropathy, foot deformity (Charcot arthropathy), peripheral vascular disease, and poor glycemic control (impaired wound healing). Macrovascular complications: -Increased mortality of CVD in pre-diabetes -Coronary artery disease, cerebrovascular disease, peripheral vascular disease -CVD and DM = accounts for 75% of all deaths in diabetics. Diabetics have 2-4x higher risk of CVD than people without DM. Most likely to have asymptomatic disease. Diabetes with CVD tends to have worse clinical outcomes -DM increases coronary mortality -Risks for type 1 = duration of diabetes is the most important factor. Higher risk after 20-25 yrs -Risks for type 2 = >50% have pre-existing CVD at the time of diabetes diagnosis. Factors include underlying insulin resistance and presence of multiple CV risk factors -Prevention = glucose control, BP control, lipid control, reduction of microalbuminuria, weight loos and exercise, smoking cessation, aspirin in selected patients Screening: -Retinopathy screening = annual dilated eye exam. For T1D start within 5 yrs, for T2D start at time of diagnosis. Pregnant or planning pregnancy should have comprehensive eye exam and get counseling on risk of progression -Nephropathy screening = annual urine microalbumin and creatinine. For T1D start 5 yrs after diagnosis, for T2D at diagnosis. Confirm abnormal test! Need at least 2 abnormal tests 3-6 months apart. Annual serum creatinine -Neuropathy screening = annual exam, T1D 5 yrs after diagnosis, T2D at diagnosis. Screen for signs and symptoms of CV autonomic neuropathy. Peripheral neuropathy and foot care -CV screening and prevention = check BP at each visit, fasting lipid panel annually, aspirin therapy

Hyperinsulinemic hypoglycemia

Most common cause of persistent hypoglycemia in children and adults. In adults, insulinomas are most common cause. In children, congenital hyperinsulinism is most common cause. Diagnostic criteria: -Increased glucose utilization -During hypoglycemia have hyperinsulinemia, high C-peptide, hypofatty acidemia, hypoketonemia and glycemic response to glucagon Insulinomas: -Most common cause of endogenous hyperinsulinemia hypoglycemia in adults. Typically small. Benign in over 90% of cases. Malignant, larger 6 cm. Solitary. Usually located within the pancreas -Elevated insulin, proinsulin and C-peptide at time of hypoglycemia. Treatment is surgical resection. Congenital hyperinsulinism: -Most common cause of persistent hypoglycemia in neonates and children. Dysregulated insulin secretion. Mutations in 11 different genes involved in the regulation of insulin secretion. Also associated with congenital syndromes (beckwith wiedemann syndrome) -Presentation includes Severe neonatal hypoglycemia, Large birth weight (Insulin promotes fetal growth), High glucose requirements -2 histologic forms: diffuse hyperinsulinism and focal hyperinsulinism. For diffuse, all beta cells are affects. For focal, adenomatous lesion. Treatment: -Pharmacological = inhibitors of insulin secretion. Diazoxide (oral) and somatostatin analogues (subQ injections) -Surgical = partial or near-total pancreatectomy

Hypoglycemia

Most common in patients with type 1 diabetes or patients on insulin due to mismatch of insulin and food or increased activity. The "tighter" the glycemic control, the hight the risk of hypoglycemia The lower the HgbA1c, the higher the risk of hypoglycemia Insulin pump therapy and continuous glucose monitor can help

Hemoglobin A1c

Normal is <5.7% HbA1c = non-enzymatic glycosylation of hemoglobin amino acid residues. Accumulates over 2-3 months life-span of RBC's. Proportional to average plasma glucose level over past 10-12 weeks. Can be monitored routinely in the clinic setting. Provides an objective measure of glycemic control. Useful clinically for encouraging compliance and goal-setting, and used for diagnosis

Hypercalcemia

Organ systems affected = bone, CV, Brain, GI. "Bones, Groans, Stones, Psychic Moans". *Primary hyperparathyroidism*: -Abnormal hypersecretion of PTH leading to hypercalcemia -Solitary adenoma (85%), Diffuse hyperplasia (15%), parathyroid carcinoma (<1%) -Incidence = 5-50 per 10,000 people -Leads to an increase in serum Ca and decrease in serum Pi. Increased urine output of Pi which offsets the absorptive effects of Pi in the intestine and its effect of phosphate resorption from the bone. -Historically, patients presented with significant bones disease -Generalized demineralization of bone, subperiosteal bone resorption, and bone cysts -Osteitis fibrosa cystica -Today, most patients present with elevated serum calcium -Additional signs and symptoms = kidney stones (more Ca deposition in the urine), renal dysfunction, reduced bone mineral density (cortical bone) -Treatment = *parathyroidectomy* in symptomatic patients or asymptomatic patients less than 50 years old, with severe hypercalcemia, reduced creatinine clearance, and osteoporosis. *Pharmacologic* options are hydration and loop diuretic, bisphosphonate, cinacalet (Ca mimetic that decreased PTH production) *Secondary hyperparathyroidism*: -Hyperfunctioning parathyroid glands compensate for hypocalcemia or hyperphosphatemia. Low serum phosphate is usually because of renal insufficiency -Treat the underlying cause: renal insufficiency, calcium malabsorption, vitamin D deficiency *Tertiary hyperparathyroidism*: -Parathyroid gland hyperfunction and hypersecretion due to prolonged secondary hyperparathyroidism -Elevated serum calcium (does not have low serum phos like primary) -Requires surgery if severe Diagnosis: -Hypercalcemia -Measure intact PTH -Inappropriately normal? If blood Ca is elevated, it should be suppressed, not normal Familial hypocalciuric hypercalcemia (FHH): -Autosomal dominant inheritance. -Abnormal calcium sensor causes a shift in the parathyroid cell's set point for calcium -Lab findings = elevated serum calcium, normal or slightly elevated PTH, *low urine calcium* (abnormal receptor is also in the kidney! wants to retain the calcium) -Benign condition, surgery is not necessary

Hyperthyroidism

Overproduction of thyroid hormone (Grave's disease) or leakage of pre-formed thyroid hormone (Thyroiditis). Can cause lid retraction, staring appearance due to increased adrenergic tone stimulating the levator palpebral muscles. TSH is low and T4 and T3 are high in primary disease. TSH is normal to high in central hyperthyroidism and T4 and T3 are high. Grave's disease: -Autoimmune disease -TSH receptor autoantibodies stimulate thyroid hormone production -Ophthalmopathy = proptosis, diplopia, inflammatory changes (conjunctival injection, periorbital edema, chemosis) -Thyroid dermopathy (<5%) -Thyroid acropachy (clubbing of digits) -Onycholysis "plummer's nails" with distal separation of the nail plate from the nail bed. Toxic multinodular goiter (MNG)/toxic adenoma: -Most nodules do not make thyroid hormone -Functional nodules have autonomous production of thyroid hormone WITHOUT regulation by the pituitary (usually mild hyperthyroidism). Iodine exposure may worsen hyperthyroidism. -Toxic MNG typically longstanding goiter in older patient with multiple autonomous nodules -Toxic adenoma solitary functional nodule somatic activating mutations of TSH receptor Thyroiditis: -Damage to the thyroid gland (autoimmune, bacterial/fungal/viral, drugs) -Leakage of stored thyroid hormone causing hyperthyroidism (lasts 6-8 weeks until stored thyroid hormone is depleted) -Treat "adrengergic" symptoms (beta-blocker) -Return to euthyroid state or swing to transient hypothyroidism (Damaged follicular cells need to recover) -*Subacute granulomatous* = painful, viral etiology, negative anti-thyroid antibodies, elevated ESR -*Lymphocytic* (silent/painless) = part of the spectrum of autoimmune thyroid disease. Almost always painless. About 50% TPO antibodies present. Excess iodine intake/cytokines leads to inflammation that activates proteolysis of stored Tg. Permanent hypothyroidism may occur -Low I-123 uptake Thyroid storm: -Extreme manifestation of thyrotoxicosis. Multisystemic disorder from excessive thyroid hormone levels -1-2% patients with thyrotoxicosis progress to thyroid storm -10% mortality -High fever, profound tachycardia, altered mental status, abdominal pain, diarrhea, end organ dysfunction -Often a precipitating event Nonthyroidal illness: -Altered thyroid function tests found in seriously ill or starving patients without preexisting thyroid disease -A time of thyroid hormone INACTIVATION -TFTs = Low T3, high rT3, TSH low but detectable. Low T4 if prolonged -No treatment, protective mechanism to prevent tissue catabolism.

Mineralocorticoid deficiency

Primary adrenal insufficiency. Loss of both glucocorticoids and mineralocorticoids. Hyporeninemia Treated with mineralocorticoid replacement = Fludrocortisone Fludrocortisone: -Synthetic pure mineralocorticoid -Used to control hyperkalemia and maintain intravascular volume -Side effects = hypokalemia, volume overload

Thiazolidinediones (TZDs) (PPARy agonists)

Rarely used Decrease peripheral insulin resistance in skeletal muscle, adipose and liver. Mimic effects of exercise. Bind to nuclear PPARy receptor causing increased transcription of GLUT 4 transporter. Pill by mouth once or twice daily. Lowers *pre-meal and post meal glucose*. Side effects can include weight gain, hepatocellular injury, increased risk of bladder cancer. Contraindications = active liver disease, heart failure, renal insufficiency, history of bladder cancer Reduces plasma triglycerides but increases LDLs and raises HDL. Slow onset of action. Fasting glucose begins to decrease within 5-7 days but does not achieve stead state for 2-3 months Does NOT induce hypoglycemic blood glucose. Lowers A1c up to 1.8%

Adrenals

Receive blood from superior suprarenal artery (branch off inferior phrenic artery), middle surprarenal artery (off aorta) and inferior suprarenal artery (branch off renal artery) Embryo: -Fetal cortex = intermediate mesoderm -Permanent cortex = coelomic mesoderm -Medullar = neural crest Cortex: -*Zona glomerulosa* = SALT. Mineralocorticoids most notably aldosterone under the stimulation of angiotensin II although ACTH also mildly stimulates this layer. Contains small balls of small purple cells -*Zona fasciculata* = SUGAR. Glucocorticoids most notably corticosterone and cortisol under the stimulated of ACTH. Contains cords of pink to clear frothy cells. Froth is lipid vacuoles containing cholesterol ethers -*Zona reitcularis* = SEX. Produces androgens (DHEA and androstenedione) under the stimulation of ACTH. Contains a net-like pattern of small pink cells Medulla: -Chromaffin cell = epi, norepi -Receives innervation from cholinergic splanchnic nerves and are under control of the SNS

Pituitary glands

Reside on the ventral surface of the brain, just inferior to the optic chiasm. They are also just medial to the uncus of the temporal lobe and anterior to the brainstem. Reside in the *sella turnica* of the sphenoid bone AP: -Adenohypophysis. Arises as an outpouching of oral *ectoderm* at the roof of the mouth called *rathke's pouch* -Anterior lobe = pars distalis -Intermediate lobe = pars intermedia -Pars tuberalis surrounds the pituitary stalk and is separated from the anterior lobe by fibrous trabecula PP: -Neurohypophysis. Outpouching of the neural tube from the floor of the third ventricle that retains its connection with the remainder of the central nervous system as it differentiates into the infundibular stalk and pars nervosa -Median eminence accepts the axons of hypothalamic nuclei carrying stimulatory and releasing factors that enter the hypophyseal portal system -Infundibular stalk carries axons arising from hypothalamic nuclei that continue on to the infundibular process Paraventricular nucleus of hypothalamus produces oxytocin, while supraoptic nucleus produces ADH. These are stored and released by PP. Through the hypophyseal portal system, stimulatory and inhibitory hormones travel from the hypothalamus to the AP. Superior hypophysial artery--> capillary bed called primary plexus--> hypophyseal portal veins --> second plexus in the pars distalis of the AP Cells of AP: -Basophil = FSH, LH, ACTH, TSH -Adicophil = Prolactin, GH -Chromophobe = "exhausted" of hormone Cells of PP: -*Herring body* = ADH, Oxytocin -Pituicytes = support

Metformin

Reduces hepatic gluconeogenesis and possibly glycogenolysis, decreases glucose absorption in large intestine. *Hepatic-activation/phosphorylation of AMPK*. Gut mediated-effects of glucose absorption and *activation of GLP-1 *(anorexic effects). Increase in bile acid exposure and altering the microbiome. A delayed-release formulation of metformin with minimal systemic absorption retains its glucose-lowering efficacy. This suggests that the glucose-lowing effects of metformin are strongly influenced by effects on the gut. The gut is also the site of an important adverse reaction to metformin that often limits metformin dosing or use completely. The mechanisms for this intolerance may relate to altered transport of serotonin or histamine, local metformin concentrations in enterocytes, increased bile acid exposure in the colon or an altered microbiome. Second hepatic metformin mechanism observed in rodents. Inhibits mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state. Reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis at lower doses than are required to affect AMPK Improves pre-meal glucose with modest effect on post-prandial. Weight neutral and can induce weight loss because people feel full earlier. It is not metabolized. *renally excreted* unchanged so can accumulate if patient has renal insufficiency. Adverse effects = anorexia, nausea, diarrhea, lactic acidosis(rare) It is the drug of choice for T2D, immediate onset; increase the dose slowly at 1 week intervals to avoid gastrointestinal side effects. Does not cause hypoglycemia Contraindications = prone to metabolic acidosis, hypoxic states, renal failure, cardiac ischemia, T1D. Requires presence of insulin for its action. It can lower A1c as much as 2%. Most commonly prescribed drug for T2D

SGLT-2 inhibitors

Renal reabsorption of glucose = (180 liters/day) x (900mg of glucose per liter) = 162 grams of glucose per day. SGLT2 mediates glucose reabsorption in the kidney. Responsible for 90% of renal glucose reabsorption in the proximal tubule. Canagliflozin, Dapagliflozin, Empagliflozin: -Inhibit Na glucose co-transporter 2 (SGLT2). Excretion of 50-200g/day -Metabolism is mainly hepatic with some metabolites excreted via kidneys -Contraindications = severe renal impairment, ESRD, or on dialysis -Side effects = vulvovaginal candidiasis, vulvovaginal mycotic infection, UTI, polyuria, small risk of euglycemic DKA -Dapa is associated with bladder CA -Lowers Hb A1c by as much as 0.7% with weight loss of 2.2% -CV risk benefit, renal protection

Leptin

Secreted by white adipose tissue adipocytes. Stimulates the anorexigenic neuron system in hypothalamus. Inhibits orexigenic neuron system in hypothalamus Net effect is to *decrease appetite, increase thermogenesis and reduce fat mass*. Circulating levels are directly proportional to body fat mass. Levels decline with weight loss. Congenital leptin deficiency is very rare

Hypoglycemia in growth hormone/cortisol deficiency

Shorten fasting = partial impairment of gluconeogenesis and lipolysis Clinical clues = midline defect, microphallus, cholestatic liver disease, history of pituitary/hypothalamic tumors Treatment = replacement of deficient hormones start to see hypoglycemia 8-16 hr after eating

Osteoporosis

Silent, systemic metabolic bone disease, low bone mass "bone density", micro architectural disruption "bone quality". Increased risk for bone fracture Uncomplicated osteoporosis has no pain or symptoms. Prevalence: -1 of 2 women will experience an osteoporosis related fracture -1 out of 5 men -Affects all ancestry but white and asian have higher risk Fractures: -Vertebral = 2/3 are asymptomatic, chronic pain, deformity, increase in morbidity and mortality -Hip fractures = most are serious, 50% impaired mobility, mortality during first year is 30% in men and 17% in women -19 billion bucks of direct cost Path: -Low peak bone mass "modeling" -Excess bone loss later in life "remodeling" -Increased bone resorption by osteoclasts and decreased bone formation by osteoblasts Causes: -Primary = no known cause seen in postmenopausal women and aging men -Secondary = medications (glucocorticoid) or diseases (hypogonadism). Genetic factors include osteogenesis imperfecta, parental history of hip fracture before 80, idiopathic hypercalciuria. Lifestyle factors include alcohol intake, smoking, inactivity/immobilization, high intake of caffeine soda and salt, low Ca and vit D intake. GI disorders can also cause it. Diagnosis: -Clinically = evidence for low trauma "fragility" fracture particularly at the spine, hip, wrist, humerus, rib and pelvis. Vertebral fractures, hip fractures -Screening DXA = look for areal bone mineral density. Sites used are total hip, femoral neck and lumbar spine. Can use forearm if those done work. -*T-score* = number of SD below the average for a young adult at peak bone density. Normal is -1 and above. -*Z-score* = number of SD below an average person of the same age. Age, race, gender-matched. -Osteoporosis = T score at or below *-2.5* or *history* of low trauma fragility fracture. ONLY FR POST-MENOPAUSAL WOMEN AND MEN >50. -Women >65 and men >70 should be screened. Younger is have clinical risk factors -Fracture risk doubles with every SD decrease in BMD -50% of fractures occur in patients who DO NOT have osteoporosis as defined by DXA Risk factors: -Age, low BMI, previous fracture, FH of hip fracture -Current smoking, alcohol, glucocorticoids, rheumatoid arthritis Who to treat? -Post menopausal women and men older than 50 with a T score less than -2.5 at hip or spine or clinical diagnosis of osteoporosis or high risk of fracture (FRAX) of greater than 20% for all fracture or 3% for hip. Treatment: -Modify risk factors, nutrition, exercise, fall prevention -Pharm = bisphosphonates, denosumab, parathyroid hormone analogs (Teriparatide), Romosozumab, calcitonin, estrogen Bisphosphonates: -Prevention and treatment, first line therapy -Anti-resorptive, inhibits osteoclast activity and promotes osteoclast death -If oral take in morning before breakfast with water and stay upright for at least 30 min -Short term side effects = GI side effects, increase in creatinine, flu-like illness -Long term side effects = atypical fracture of the femur, osteonecrosis of the jaw (reported mainly in cancer patients receiving IV bisphophonates). Denosumab: -First line therapy. -Human monoclonal Ab -Anti-resorptive, inhibits RANK ligand, inhibits osteoclast formation -NOT renally excreted -Adverse effects = hypocalcemia, infections and skin reaction, atypical femur fracture and ONJ reported Parathyroid hormone analogs: -Chronic/continuous exposure to PTH = bone resorption -Intermittent exposure to recombinant PTH or PTHrp = bone formation >>>bone resorption. "Anabolic window". Teriparatide: -Moderate to severe...second line therapy -Anabolic agent that increases osteoblast activity 0It is common practice to follow teriparatide treatment with an antiresorptive agent, usually bisphosphonate, to maintain or further increase BMD -Adverse effects = nausea, headache, leg cramps, hypercalcemia, orthostatic hypotension, palpations. Osteosarcoma. *AVOID* in Paget's disease, high alk phos, hypercalcemia, h/o skeletal malignancy, radiation or mets. Romosozumab: -Osteoanabolic but also decreases bone resorption -Side effects = arthralgia, hypocalcemia, ONJ and AFF have been reported -Increases risk of MI, stroke and CV death -Sclerosteosis and van Buchem disease = loss of function in sclerostin and high bone mass. Stimulates osteoblast activity

Thyroid and parathyroid

Sits on the anterior aspect of the tracheal cartilages and the common carotid arteries. Also present behind each lobe is a recurrent laryngeal nerve. Some people can have a pyramidal lobe. During the fourth week of development, it was an outpouching of oral midline endoderm from the floor of the mouth, called the thyroid diverticulum. Arises at the foramen cecum. The thyroid gland descends in the anterior midline through the thyroglossal duct, past the hyoid bone, thyroid cartilage and cricoid cartilage to find its final position in the anterior inferior neck The parafollicular cells of the thyroid originate from a completely different source--The lateral pharyngeal apparatus. They come from the fourth pharyngeal pouch that gives rise to the ultimobrachial body which travels inferomedially toward the substance of the thyroid gland to give off the cells that travel into the gland and terminally differentiate into C-cells. Sup parathyroid is from 4th pouch, inf parathyroid is from 3rd. Follicular cell = T3, T4 Colloid = thyroglobulin Parafollicular cell = Calcitonin Follicular cells may undergo a metaplastic change to form oncocytes (Hurthle cells). These cells are enlarged follicular cells with bright eosinophilic cytoplasm that may appear somewhat granular. This change is due to the accumulation of a large number of mitochondria. This is response to inflammation Parathyroid: -Glands are made up of two main epithelial cell types and stromal fat cells (appear at puberty and increase with age) -Chief cells = Parathyroid hormone -Oxyphil cells = have very eosinophilic granular cytoplasm. Abundance increases with age

Adrenal glands

Situated in the retroperitoneal tissues at the upper poles of the kidneys and usually weigh *4-6g*. Right adrenal is pyramidal in shape and left adrenal is crescent in shape. Adrenal cortical hyperplasia = bilateral symmetric or nodular enlargement of the adrenal glands. Simple diffuse (65% and female), bilateral nodular (20% and female) or ectopic hyperplasia (15% and male and heaviest weight of 20g+)

Hypoglycemia due to drugs

Sulfonylureas, salicylate overdose (especially children), beta-adrenergic blocking agents (blocks adrenergic warning signs) which impair lipolysis, pentamidine. Alcohol induced: -Depletion of hepatic glycogen is essential -Oxidation of ethanol to acetic acid generates NADH -Increased NADH/NAD ratio inhibits several important gluconeogenic enzymes, most important conversion of lactate and amino acids to pyruvate -Hypoglycemia after 6-36 hours of food deprivation -No correlation with blood ethanol levels -Diabetics on insulin or oral agents are susceptible -Fatalities occur, especially in children

Insulin Secretagogues

Sulfonylureas: -Stimulates pancreatic insulin secretion for *12-24 hours*. -Binds to sulfonyl receptor in beta cell resulting in depolarization of ATP-dependent potassium gated Ca channels. -Immediate effect mostly on *pre-meal* glucose -Metabolized by liver, excreted via kidney with active metabolites so caution in renal impairment -Contraindications = T1D, DKA, sulfa allergy -Adverse effects include hypoglycemia, weight gain, hunger -Lowers Alc up to 1.5% -Should not be used with Meglitinides bc share binding site Meglitinides/Glinides: -Stimulates pancreatic insulin for 3-4 hours -Stimulates insulin release by regulating ATP-sensitive K gated Ca channels on beta cells -Fast onset -Side effects = low glucose 2-4 hours after meal, weight gain -Disadvantage = patient compliance -Contraindications = T1D, liver failure, DKA, sulfa allergy -Metabolized by the liver by cytochrome p450 enzyme system, 96% of metabolites excreted via GI tract -Lowers A1c by about 0.4% so only marginal

Vit D

Synthesis: -Two prehormones -Converted to active form in two steps -Increases absorption of calcium and phosphate from the intestines -Regulation in the kidneys: stimulation is PTH and inhibition is calcium and vit D Adults under 50 need 1,000mg of Ca from all sources and 400-800 units of vit D every day Adults 50 + need 1,200 mg of Ca and 800-1,000 units of vit D every day Vit D enriched foods: -Milk, cereals, yogurt, orange juice -Cheese, fatty fish Vit D deficiency: -Lack of solar irradiation, decreased intake or impaired absorption, metabolic defects in vit D hormone system -Leads to secondary hyperparathyroidism -Metabolic bone disease = Rickets in children, osteomalacia in adults -Widened osteoid seams and impaired mineralization -Risk factor for osteoporosis -Treatment = treat underlying disorder if chronic renal or liver failure. Correction of hypocalcemia and vit D deficiency Vit D intoxication: -Uncommon cause of hypercalcemia -Requires LARGE doses -Symptoms = nausea, vomiting, weakness, altered mental status -Prolonged hypercalcemia = vit D stored in fat -Treatment = hydration, no dietary calcium, maybe glucocorticoids

Insulin Physiology

T1D has absolute insulin deficiency while T2D have insulin resistance with relative insulin deficiency Human proinsulin contains C peptide portion. Exogenous insulin does not have this. Proinsulin is packaged in Golgi apparatus of the pancreatic beta cell. Proteolytic cleavage to C-peptide and insulin. Zinc is added, forming crystalline insulin. Hexamer --> dimer --> monomer (active form) Insulin is stored in granules secreted by exocytosis. Dock and fuse with cell membrane. Mediated by secondary signals altering ionic fluxes across cell membrane--> rise in cytosolic Ca. *Glucose is most potent stimulant for insulin secretion. Regulation: -Stimulatory = nutrient load (glucose, fat/protein), autonomic nervous system (vagal stimulation, cephalic phase), hormonal (incretin hormones GLP-1 and GIP) -Inhibitory = starvation, hypoglycemia, hormonal (glucagon, EPI, growth hormone, cortisol) Mechanisms: -Binds to insulin and IGF-1 receptors with strong affinity and specificity -Interacts with specific cell surface receptors. Protein phosphorylation cascade -Generation of 2nd messengers -Glucose uptake by cell Metabolism: -Endogenous insulin = beta cell --> blood stream --> portal vein --> liver. Most is metabolized by the liver -Exogenous insulin = subcutaneous tissue --> bloodstream --> kidney --> liver. Most is metabolized by kidney Anabolic actions: -Adipose tissue = promotes triglyceride synthesis/storage, glucose uptake, inhibits lipolysis -Muscle tissue = promotes glycogen synthesis and AA uptake/protein synthesis -Liver tissue = promotes glycogen synthesis, FA synthesis, inhibits glucose output/ketogenesis.

Thyroid hormone therapies

T4 = 7 day half life. Free hormone is 0.04 T3 = 1 day half-life and 3x more potent. Free hormone is 0.4 Both are largely protein bound. TSH is high in primary hypothyroidism and low in primary hyperthyroidism Levothyroxine = LT4 Liothyronine = LT3 T4 and T3 mixes (do not use) The aim of therapy is replacement, NOT cure of hypothyroidism. Most patients require lifelong therapy. Hypothyroidism is treated with T4 because of longer half life and peripheral conversion to T3. But some people have persistent symptoms. *T3 is used for myxedema coma*. Side effects due to inappropriate dosing or can have color dye sensitivity. LT4 dosing: -Starting dose depends on age, degree of thyroid failure of patient. Age <60 without cardiac disease gets 50-125mcg. If >60 or cardiac disease, start 25mcg -Average final dose for those without thyroid is 1.6mcg/kg po qd. Lower in elderly -Use 75% of oral dose if given IV TSH monitoring: -Frequency of monitoring is every 6 weeks until normalized -Target range is 0.5-4.5mlU.L. Usual target is 0.5-2.5. Higher target in older people (1-6). Remember, cannot trust the TSH in secondary (pituitary) hypothyroidism -It is easy to get the wrong dose! -If TSH levels on therapy are *higher* than expected, this suggests too low a dose. Can be due to compliance, drugs that decrease LT4 absorption, conditions that decreases LT4 absorption (SI disease), drugs that increase LT4 metabolism, increased TBG (pregnancy) or progression of endogenous thyroid disease. -If TSH levels on therapy are *lower* than expected, this suggests too high a dose. Can be due to decreased TBG, self-administration of excess LT4, significant weight loss, reactivation of grave's disease or development of autonomous nodules. -*TSH levels are particularly important in pregnancy and thyroid cancer* Drugs that cause primary hypothyroidism = aminodarone, lithium interferon-a, interleukin-2, tyrosine kinase inhibitors, checkpoint inhibitor immunotherapy. Drug that causes secondary hypothyroidism = bexarotene Treating myxedema coma (severe hypothyroidism) = LT4 and LT3. Supportive drugs for any associated metabolic disturbances. IV hydrocortisone since there is impaired adrenal reserve in profound hypothyroidism. Treat precipitating factors, especially infection. Be aware of decreased metabolism of most medications, especially avoid sedatives

Ghrelin

The only circulating orexigenic (increases hunger) hormone. Secreted by the *gastric fundus* and proximal SI. When stomach is growling = ghrelin Increases gut motility, decreases insulin secretion. Stimulates increased food intake, increase energy balance, increases weight gain. *Peaks before meals *to stimulate eating, levels drop after meal and nutrient ingestion *Prader-Willi syndrome* = increase in ghrelin causing hyperphagia and severe obesity

Thyrotroph adenomas

Treatment with octreotide

Type 1 vs Type 2 diabetes

Type 1: -Absolute insulin deficiency -Abrupt onset of hyperglycemia and propensity for the development of DKA -Life long insulin injection required -Associated with auto antibodies -Predominant type of diabetes diagnosed in individuals <30 yrs -Family history is rare -First functional abnormality is decrease in insulin secretion Type 2: -Insulin resistance with relative insulin deficiency -Hyperglycemia develops gradually with progressive decline in beta cell function -Can be treated with oral meds -Associated with increasing age and obesity -Hyperosmolar hyperglycemic non-ketosis -Can develop DKA -95% have family history -First functional abnormality is decreased insulin secretion and decreased response to insulin

ACTH

o Adrenocorticotropin. Synthesis and secretion of adrenal cortex steroids (cortisol). Proliferation and survival of adrenal cortex cells. When have deficiency in ACTH, can have adrenal atrophy. Excess ACTH leads to hypertrophic adrenals. o HPA: Hypothalamus releases CRH, which is a stimulatory trophic factor. CRH stimulates pituitary corticotrophs to release ACTH, which is a stimulatory factor on the adrenal cortex and an inhibitory factor on the hypothalamus ACTH stimulates cortisol release from the adrenal cortex which acts as an inhibitory factor on the pituitary corticotrophs and the hypothalamus o Stimuli = CRH, stress, hypoglycemia, anxiety, depression, alpha and beta adrenergic agonists o *Diurnal patter*. Peaks just before awakening. If checking for high levels check at night. If checking for low levels check in morning. o Pusatile o Inhibitor is cortisol

Cushing's syndrome

o An excess in cortisol secretion (regardless of the cause or source). The most common cause is *iatrogenic* from exogenous glucocorticoid use. The effects of the disease are long lived due to the fact that nuclear transcription is affected. MUST rule out exogenous steroid use! o 1. Loss of diurnal variation of cortisol secretion. Now just tonically high. Measure late night salivary cortisol to verify o 2. Autonomy from "central* ACTH control—loss of response to feedback inhibition. Use dexamethasone suppression test to verify (substitutes for endogenous cortisol in suppressing ACTH release). Could be a pituitary adenoma that is resistant to negative feedback from cortisol or an adrenal adenoma that continues to secrete cortisol despite low ACTH concentrations or an ectopic source that is secreting ACTH that is resistant to cortisol feedback o 3. Excess cortisol secretion. Test 24 urinary free cortisol to verify. Leads to impaired immunity, increase in clotting factors, weight gain, obesity, growth retardation, cataract formation, proximal myopathy, osteoporosis and redistribution of body fat. Can also cause HTN, cardiomyopathy, thin skin, easy bruisability, violaceous striae, acne, hyperpigmentation, hirsutism (androgens increase) and a wide variation of psychiatric disturbances o 68% are Cushing's disease (pituitary adenoma) and 12% are ectopic ACTH syndrome (these people are the sickest because *ACTH levels are the highest*). o For adults, 80% of people have bilateral hyperplasia while 10% have adrenal cortical adenomas and 10% have adrenal cortical carcinomas. But for children, 35% are due to hyperplasia, 14% are due to adenoma and *51% are due to carcinoma* o Adrenal cortical adenoma = benign neoplastic proliferation of adrenal cortical tissue. Unilateral and solitary, well circumscribed. Tumor cells grow in mix of growth patterns, usually have clear cytoplasm-resembling cells of zona fasciculata, no mitoses or atypical cells o Adrenal cortical carcinoma = Malignant neoplasm arising from adrenal cortical cells. Large bulky tumor, fleshy cut surface with hemorrhage and necrosis, average size 12 cm and weigh >100g, invasion into adjacent structures/organs (kidney) can be seen. Necrosis, cellular pleomorphism, tumor capsule invasion, vascular invasion and distant metastases o ACTH-dependent Cushing's is characterized by bilateral adrenal hyperplasia. The normal corticotrope cells separate from the adenoma will atrophy because of negative feedback. Pituitary, iatrogenic or ectopic o ACTH-independent Cushing's = prime etiology would be an adrenal adenoma. Can occur bc of iatrogenic steroid use. o Triad of metabolic derangements due to excess corticosteroids: Carbohydrate metabolism = stimulates gluconeogenesis, leading to hyperglycemia Fat Metabolism = increased lipogenesis and insulin resistance, leading to increased FFA's and fat getting added in odd places (dewlap, buffalo hump and supraclavicular fat pads) Protein metabolism = increased gluconeogenesis, leading to catabolism o Treatment: Depends on source of Cushing's. Cure likely in a unilateral adrenal adenoma with adrenalectomy. Trans-sphenoidal hypophysectomy (60-75% cure). Other therapies such as ketoconazole, metyrapone, or bilateral adrenalectomy may be required Symptoms take up to 12 months to resolves. Not all sequelae completely resolve, especially psychiatric complications Mineralocorticoid antagonist or cortisol suppression for when have apparent mineralocorticoid excess driven by high levels of cortisol Medical treatment is second line after surgery: -Decrease production of glucocorticoid bu inhibiting enzymes in steroidogenesis pathway (adrenal) = Metyrapone -Decrease production by inhibiting ACTH secretion (pituitary) = Pasireotide, a somatostain analog. Can cause increase of blood glucose levels, can cause cardiac conduction defects and can cause gallstones

Rhythms in endocrinology

o Circadian rhythms = occur over the course of a day and repeat daily. Characteristic of most endocrine functions o Ultradian rhythms = bursts (spikes, pulses) of hormone secretion. Can be superimposed on circadian rhythms. Physiologically important, particularly in reproduction.

Somatotroph adenomas

o Clinical syndromes = gigantism and acromegaly (large extremities). There is swelling of the hands in a patient with acromegaly which resulted in an increase in glove size and the need to remove rings o Chemical confirmation = lack of suppression of GH to an oral glucose load (normally goes down with glucose). Elevated serum IGF-1 o Path confirmation = histologic appearance of pituitary adenoma. Immunospecific staining for GH o Consequences = arthritis, cancer (esp of the colon, preceded by polyps), CVD, Neuropathy (including carpal tunnel syndrome), obstructive sleep apnea, DM, mortality o Treatment = surgical pharmacological, radiation o Pharm DA agonists (paradoxical effect bc usually stimulates in a normal person) Somatostatin analogs (bind to somatostatin receptors on the somatotroph cell). Octreotide and Lanreotide GH receptor antagonists (bind to growth hormone receptors and prevent GH from binding). *Pegvisomant* binds avidly to one site but does not bind at all to the second receptor therefore it occupies all receptors but does not have biological activity because it doesn't bind to both receptors

Corticotroph adenomas

o Cushing's syndrome (common o Neurologcial symptoms (uncommon)

GH deficiency

o If IGF-1 is low in a patient who has multiple deficiencies of other pituitary hormones, it reliably indicates GH deficiency. If low-normal, may indicate partial GH deficiency o Random growth hormone concentration cannot be used because of physiologic fluctuations during the day o Tests of GH stimulation = insulin-induced hypoglycemia, GHRH, macimorelin (synthetic ghrelin receptor agonist) o GH replacement in adults = GH replacement consistently decreased fat mass and increased muscle mass. Some trials showed an increase in bone mineral density in men. Other effects of GH replacement but not consistent.

Lactotroph adenomas

o In premenopausal women, amenorrhea/oligomenorrhea and galactorrhea. In postmenopausal women, neurological symptoms (can go undetected until causes impaired vision). In men, decreased libido, decreased fertility, and decreased potency o Physiologic causes of hyperprolactinemia = pregnancy, nursing, exercise, physical and psychological stress o Pathologic causes = lactotroph adenomas, DA receptor antagonists, catecholamine inhibitors, H2 antagonists, estrogens, opiates o DA agonists shrinks lactotroph adenoma

GnRH

o LH In females = induces ovulation and progesterone synthesis In males = gametogenesis and stimulates synthesis and secretion of testosterone o FSH In females = stimulates estrogen synthesis, follicle growth In males = promotes spermatogenesis o HPA: Pulsatility and pulse frequency are critical. There is greater frequency and amplitude of pulses in puberty. Pulsatile infusion stimulates LH and FSH secretion Constant infusion inhibits LH and FSH secretion GnRH release from the hypothalamus stimulates the pituitary gonadotrophs to release FSH and LH, which act on the ovary and testis Testosterone and progesterone and inhibin act as negative regulators at the pituitary and hypothalamus. Estrogen acts as a negative regulator as well except when it is during the menstrual cycle in which is can be a positive regulator (E creates LH surges) o Act on gonads to regulate steroidogenesis and gametogenesis.

Gonadotroph adenomas

o Neurological symptoms (most common) = visual field impairment and headaches o Incidental finding on MRI (less common) o Hormonal abnormality (uncommon) = premature puberty in a boy, ovarian hyperstimulation in a premenopausal women Basal secretion = elevated intact FSH but rarely intact LH. Elevated alpha, LHB and FSHB subunits. Stimulated secretion = LHB and, less often, intact FSH response to TRH o Only treatment is surgery

Pituitary tumors

o Only pituitary adenomas can hypersecrete hormones or fragments thereof. Normally there are made by pituitary cells. Any disease of the pituitary or hypothalamus can cause deficiency of any hormone made by the anterior pituitary. Only a disease of the hypothalamus or infundibulum can cause a deficiency of vasopressin(ADH) and thereby cause diabetes insipidus o Prolactin is only hormone that cannot be replaced by drugs

Anterior pituitary

o Outgrowth of oral ectoderm forms Rathke's pouch which become the AP. o Corticotrophs are the first AP cells to undergo terminal differentiation and this is positively regulated by the transcription factor Tpit. PROP1 has both DNA-binding and transcriptional activation ability. Its expression through PIT-1 leads to ontogenesis somatotrophs, lactotrophs, and thyrotrophs. PIT-1 is a pituitary specific positive transcription factor necessary for differentiation of somatotropes, lactotropes and thyrotropes. *Inactivating mutations in genes encoding these TFs are important causes of pituitary hormonal deficiencies.* o Cell types and hormones: -Corticotroph = ACTH -Thyrotroph = TSH -Gonadotroph = LH and FSH -Somatotroph = GH -Lactotroph = Prolactin -ACTH is from large mc POMC -TSH LH and FSH (glycoprotein hormones) all have the same alpha subunit but different beta subunits -GH and prolactin have structural homology and bother can activate prolactin receptor o Feedback regulation = secretion of hormones from the target glands will suppress the release of pituitary and hypothalamic hormones. Loss of feedback inhibition by target hormones results in pituitary trophic hormone hypersecretion and hyperplasia of pituitary cells. Hypothalamic-pituitary regulation serves as interface between nervous and endocrine systems. o Hypothalamic neurons secrete releasing and inhibiting hormones into the hypothalamic pituitary portal system to regulate pituitary function o Portal system = system that consists of two consecutive capillary beds

Addison's Disease

o Primary adrenal failure. Decreased levels of glucocorticoid production which eventually affects production of mineralocorticoids and sex steroids. Typically 90% of cortex is destroyed prior to presentation. You see elevated ACTH concentrations. Course can be acute or indolent depending on the cause. All adrenal hormones can be lost. o In a person with Addison's expect to see hyponatremia and hyperkalemia and hypotension. Clinical characteristics include hyperpigmentation, weight loss, muscle or joint pains, fatigue, nausea, abdominal pain, hypoglycemia can occur and salt craving may occur Etiologies: -Autoimmune destruction of adrenal cortex (60%). Half of people with autoimmune adrenalitis have at least one other autoimmune disorder -Can be associated with *polyglandular syndromes* -Infectious = TB, fungus, HIV -Bilateral hemorrhage/infarction -Metastatic cancer -Drugs Diagnosis: -Early AM cortisol and ACTH conc. -If early AM cortisol is <5mcg/dl with an elevated ACTH, very likely primary adrenal insufficiency -*Cosyntropin* stimulation testing = IM injection of synthetic ACTH. Cortisol measured 30, 60 min later. Serum cortisol after injection excludes adrenal failure -*Metyrapone* testing for secondary adrenal insufficiency = Metyrapone blocks 11-beta hydroxylase to decrease cortisol production. Low cortisol stimulates ACTH under normal conditions. If there is pituitary dysfunction (secondary insufficiency), you do NOT get a build up of cortisol precursor, 11-DOC, which you normally would with this test -If patient is hypotensive with a strong clinical suspicion, treat with glucocorticoids first and make the diagnosis later! -Dexamethasone will not interfere with cortisol assay therefore would be an appropriate initial, short term treatment Treatment = cortisol replacement (hydrocortisone, dexamethasone, prednisone). Double or triple dose when patient is sick of stressed. At doses greater than 60-80mg daily, hydrocortisone has mineralocorticoid activity due to an overwhelmed cortisol cortisone shunt that allows HC to bind and activate MCR. Therefore, in patients with primary adrenal insufficiency requiring stress dose or acute dose steroids, mineralocorticoid replacement with fludrocortisone is not required until the HC dose is <60-80mg daily Adrenal crisis: -Defined as acute deficiency in cortisol and mineralocorticoids -Can be life threatening! Often masquerades as other conditions -Clinical characteristics = hypotension, shock, fatigue, weakness, malaise, fever, lethargy, abdominal pain, nausea, vomiting, anorexia, hypoglycemia -Several etiologies = new primary adrenal failure, known adrenal insufficiency with acute illness or under-replacement of meds, acute withdrawal of high dose glucocorticoids, pituitary apoplexy (least likely) Polyglandular syndromes: -Type 1 = hypoparathyroidism, mucocutaneous candidiasis, primary hypogonadism (AIRE gene) -Type 2 = T1D, autoimmune thyroiditis, vitiligo, hypogonadism (more common)

Adrenocortical hormones

o Steroid hormones synthesized from cholesterol by cytochrome P450 enzymes in the mitochondria and smooth ER of the adrenal gland. Affect gene transcription through binding to specific mineralocorticoid, glucocorticoid and sex hormone nuclear receptors . Affect enzyme activity by binding membrane receptors. First step is side chain cleavage of cholesterol to pregnenolone by CYP11A1 in the mitochondria o *Aldosterone* is released in response to increased angiotensin II, increased serum potassium and increased ACTH (lesser stimulus). Binds minderalocorticoid receptor to regulate blood volume and salt/water homeostasis Juxtaglomerular cells can sense tension and blood pressure in the kidneys. *Renin* is released in response to decreased afferent arteriole volume (low renal perfusion) and decreased distal tubule Na conc (tubuloglomerular feedback). Renin is decreased in response to increased afferent arteriole volume (high renal perfusion pressure) and increased distal tubule sodium conc (tubuloglomerular feedback) Binds mineralcorticoid receptor in the distal cortical collecting duct principal cells. Moves to nucleus to stimulate transcription of genes to increase number of Na and K channels. Results in increased Na reabsorption and promotes K and *proton secretion* o *Cortisol* is released in response to increased ACTH and increased arginine vasopressin (lesser stimulus). Binds glucocorticoid receptor to regulate energy balance, cardiovascular, metabolic and immune homeostasis. POMC processing. Cleaved into multiple peptides with one of them being ACTH. ACTH is a melanocyte stimulating hormones. ACTH specific receptor is melanocortin 2 receptor on adrenal tissue and functions to increase LDL receptors to bring in more cholesterol as a precursor for steroid hormones and to activate CYP11A1 enzymes for cholesterol side chain cleavage. ACH can function as a melanocortin 1 receptor expressed on melanocytes if too much ACTH is being produced. Can darken the skin. ACTH and cortisol are *pulsatile* throughout the day and follow circadian rhythm. Cortisol is *highest 6-8 hours after sleeping* and begins to decline after awakening. *Cortisol is lowest at midnight* Cortisol affects the liver, skeletal muscle, inflammatory and immune cells, bones, peripheral adipose tissue, heart, vascular smooth muscle and adrenal medulla *Cortisol Cortisone Shunt* = mineralocorticoid receptor has higher affinity for cortisol than aldosterone! Aldosterone sensitive tissues (like the kidney) have *11-beta HSD2* to shunt cortisol to cortisone (the most inactive form). This protects receptors from spill over effect. Licorice root prevents inactivation of cortisol in the kidney. MCR is activated by cortisol and this leads to hypertension and hypokalemia. Salt retention is hyper activated by cortisol (not aldosterone which normally regulates it) o *Androgens* are released in response to increased ACTH. Bind androgen receptor to regulate pubarche. Androgens includes DHEA, DHEAS and androstenedione. Increase in production with age. Main site of production women and minor site of androgen production for men. Andrenarche begins years before gonadarche and stimulates pubarche. Androstenedione is converted in peripheral tissues to testosterone and estrone. o *NE and Epi* are released in response to sympathetic nervous system activation and its synthesis is dependent on high local concentrations of cortisol. Bind adrenergic receptors to regulate CV effects and bronchial dilation The medulla receives input from the SNS through preganglionic fibers from thoracic spinal cord. Medulla is like a nerve ganglion but lacks synapses from postganglionic fibers and releases secretions directly into the blood. Tyrosine enters chromaffin cells and is converted by tyrosine hydroxylase to dopa, which is the rate limiting step in catecholamine synthesis. Cortisol also promotes epi synthesis in medulla by upregulating PNMT enzyme which converts NE to Epi Medulla secretes 20% NE and 80% Epi Catecholamines are converted to *metanephrines*, which are more clinically useful for measurements given the very short half live of catecholamines in the blood o Catecholamine receptors *alpha 1* = located in the arterial/venous vasculature. Second messenger is increased IP3. Causes vasoconstriction, increased peripheral resistance, increased BP, mydraisis and increased closure of internal sphincter of the bladder *alpha 2* = located in the arterial/venous vasculature and nerve terminals. Second messenger is decreased cAMP. Causes inhibition of NE release, inhibition of ACh release and inhibition of insulin release. Regulator receptor! *beta 1* = located in the heart and juxtaglomerular apparatus. Second messenger is increase in cAMP. Causes tachycardia, increased lipolysis, increased myocardial contractility and increased released of renin *beta 2* = located in the heart, skeletal muscle vasculature and bronchial smooth muscle. Second messenger is increased cAMP. Causes vasodilation, slightly decreased peripheral resistance, bronchodilation, increased muscle and liver glycogenolysis, increased release of glucagon and relaxed uterine smooth muscle. Tames down fight or flight response! Fight or flight = mobilization of fuel, redistribution of blood flow, decreased urinary output and digestive functions, increased HR and BP, increased activity of sweat glands (ACh mediated), increased ventilation and dilation of pupils.

Prolactin

o Stimulates lactation o HPA: The hypothalamus secretes a little of PRFs which stimulate pituitary prolactin release, this is stimulated by the mammary glands. But mostly, the hypothalamus secretes dopamine which negatively inhibits prolactin release. The pituitary releases prolactin which acts on the mammary gland to produce milk. Prolactin acts as a negative regulator on hypothalamus secretion of PRFs. Estrogen from the ovary also cause the pituitary lactotrophs to release prolactin o Negatively regulates LH and FSH via hypothalamus (suppresses pulsatile GnRH) o Stimulators = breast stimulation, stress, estrogen, sleep, dopamine antagonists, TRH o Inhibitors = dopamine and dopamine agonists

GH

o Stimulates secretion of IGF-1 from liver and other organs which mediates GH's anabolic effects. Stimulates lipid and CHO metabolism. o HPO: The hypothalamus secretes GHRH which stimulates pituitary somatotrophs to release GH. The hypothalamus also secretes somatostatin which acts as a negative regulator on the pituitary GH stimulates the liver to produce IGF-1. GH also acts as a negative regulator at the hypothalamus IGF-1 acts as a negative regulator at the pituitary and the hypothalamus o Stimulators = hypoglycemia, dietary protein, exercise o Inhibitors = IGF-1, GH, Somatostatin o Somatostatin = inhibits GH release (opposes GHRH). Somatostatin receptors are present in many tissues (hypothalamus, GI tract, pancreas). Also inhibits pituitary TSH and prolactin, pancreatic glucagon and insulin o GH declines from 150ug/kg at puberty to 25ug/kg at age 55. Release is pulsatile. Amplitude and frequency are regulated by age, gender, nutrition, sleep, body composition, stress and exercise. Half life is 6-20min. Random serum measurement can be misleading. Stimulates post-natal growth via indirect effects of IGF-1

TSH

o Thyroid stimulating hormone. Synthesis and secretion of T4 and T3. Regulates thyroid cell proliferation and survival o HPA: Hypothalamus secretes TRH which stimulates release of TSH and also stimulates prolactin release. TRH stimulates pituitary release of TSH TSH stimulates production of T4/T3, which inhibits TSH release from the pituitary and TRH release from the hypothalamus Somatostatin release from the hypothalamus is a negative regulator on the pituitary's release of TSH. o TSH is responsive to intracellular T3 levels. When T3 is high, TRH receptors in the pituitary decrease and thus response of thyrotrophs to TRH decreases leading to decreased TSH secretions