4-6

a GLP-1 analog given as a parenteral antidiabetic drug

Exenatide: side effects: hypoglycemia, diarrhea, vomiting, pancreatitis, renal failure give 1 hour after other meds adjunct therapy

most reliable test for AKI

FENa unless the patient is on diuretics

FGF-23 (fibroblast growth factor 23) is produced by what cell type? What can stimulate FGF-23 (fibroblast growth factor 23) secretion? What are its direct actions?

FGF-23 (fibroblast growth factor 23): produced by osteocytes FGF-23 secretion is stimulated by - 1,25(OH)2D - increase in serum PO4 FGF-23 direct actions: - decreases renal reabsorption of PO4 - inhibits formation of 1,25(OH)2D (calcitriol); results in decreased absorption of calcium and phosphate from the GIT and decreased release from bone. Thus, serum PO4 will decrease secondary to decreased 1,25(OH)2D.

T/F: Neurogenic (or Central) Diabetes insipidus occurs due to insufficient renal response to vasopressin.

False

T/F: Somatostatin is released from hypothalamus and acts on posterior pituitary to inhibit the synthesis of growth hormone.

False

T/F: Administration of GH antagonists results in decrease in GH and IGF-1 levels.

False Decreases IGF-1; GH remains high. This is because the hepatocytes that produce IGF-1 are stimulated by GH. GH remains high because its inefficacy at its location does not stimulate any feedback.

Gold Standard: Oral Glucose Tolerance Test (OGTT) - Interpretation 1. FBG = 100 mg/dL 2. FBG = 135 one week, 126 the following week 3. consistent FBG readings between 100 and 126 4. 2-hour post-prandial = 139 5. 2-hour post-prandial = 200 6. consistent 2- hour post-prandial readings between 140 and 200

Fasting Blood Glucose Normal: <100 mg/dl Diabetes: >126 mg/dl on 2 separate occasions Impaired Fasting Glucose (IFG): >100 but <126 2 hr post glucose load Normal <140 mg/dl Diabetes >200 mg/dl Impaired Glucose Tolerance (IGT) >140 but <200

PTHrP hypercalcemia level Severe - Decreased serum PTH Increased urinary Normal or Decreased 1,25 dihydroxyvitamin D cAMP

Humoral Hypercalcemia (HHM) Increased of Malignancy

Management Goals of CAH

Hydrocortisone: replaces glucocorticoid Suppresses androgen production & Allows for normal growth and sexual maturation Fludrocortisone: Replaces mineralocorticoid Suppresses renin production, Maintains electrolyte balance and blood pressure

Assessing for Hormone Function Stimulation tests Assess end organ functioning GH: LH & FSH: TSH: ACTH: ADH:

Stimulation tests Assess end organ functioning GH: growth chart, IGF1 and bone age (x-ray of left hand) LH & FSH: presence or absence of periods and sexual hair, estrogen and testosterone levels TSH: TSH level and T4 low ACTH: early morning cortisol levels low ADH: Na levels low

Therapeutic uses of GH preparations

Pituitary dwarfism (not Laron dwarfism): It occurs due to the deficiency of GH that results in short stature and adiposity. The net effect of treatment with GH is to increase linear growth and lean body mass. Treatment continues until either a satisfactory adult height is obtained, the epiphysis close or the patient stops responding. GH deficiency in adults: Adults with GH deficiency have generalized obesity, reduced muscle mass, weakness, and reduced cardiac output. GH treatment is helpful in reversing these clinical manifestations. Turner's syndrome: GH is administered to girls with Turner's syndrome to achieve a normal height. GH is approved for the treatment of wasting in patients with AIDS. It helps in increasing lean body mass, weight , and physical endurance in these patients

Manifests at 20-40 years, Females predominance Polygenic inheritance, HLA DR3 and HLA DR4 Addison disease, Primary hypothyroidism, Graves disease, Pernicious anemia, Primary hypogonadism, Type 1 diabetes mellitus Myasthenia gravis , vitiligo, Coeliac disease,

Polyglandular Autoimmune SyndromesType II

Patient with Impaired Fasting Glucose (IFG) >100 but <126 mg% Impaired Glucose Tolerance (IGT) >140 but <200 mg% Increased risk for developing DM about 7%/yr Increased risk of macrovascular complication even before they develop DM CVD (50% increased)

Prediabetes

During which trimester is thyroxine most important? During pregnancy, is T4 physiologically low or high? Why?

Pregnancy and hypothyroidism: During the first trimester, the fetus is dependent on maternal thyroxine for growth and development. Untreated maternal hypothyroidism is associated with spontaneous abortion, congenital defects and mental retardation. Due to an increase in circulating levels of thyroid-binding globulin, caused by its increased synthesis in liver under the effect of estrogens during pregnancy, a larger fraction of T4 will be present as protein-bound. This would leave plasma free T4 levels below therapeutic levels. Because of this, an increased dose of levothyroxine (about 30- 50% higher) is required for optimal hormone replacement in a pregnant woman who has hypothyroidism.

used in mild-moderate hyperthyroidism. Some drugs (beta-blockers, propylthiouracil, glucocorticoids) also inhibit the peripheral conversion of T4 to T3 by inhibiting 5'-deiodinase resulting in decreased T3 and increased rT3. They are useful in thyroid storm. Beta blockers (atenolol) can control cardiac symptoms associated with hyperthyroidism, and are beneficial especially during the window period between starting thioamides (antithyroid drugs) and onset of their action that usually takes 4-12 weeks.

Propylthiouracil, Methimazole

gene for GH and prolactin adenomas

Protein kinase A (PKA)* Germline inactivating mutations of PRKARIA (Carney complex), a negative regulator of PKA

Case 5 46 y/o woman c/o weakness and fatigue O/E 10 lb weight gain since last visit 6 months ago BP 160/100 mmHg Laboratory Na 155 mEq/L K 2.8 mEq/L ↓serum renin 2/5/2016 ICM 102

Provisional Diagnosis Primary Aldosteronism Conn Syndrome Named after Jerome W. Conn (1907-1994) American endocrinologist First described in 1955 University of Michigan

• Octreotide dosage

S/C, daily

49 y/o male Presents to ER with mild headache, vomiting, and confusion Wife states that he has not eaten or drunk anything since yesterday History of chronic cough Smoked 4 packs/day x35 years In ER suddenly has tonicclonic convulsions • On examination: Papilledema Urine osmolarity 300 Serum Na 103 Serum K 3 Serum BUN low Serum ADH levels high

SIADH

What is recombinant IGF-1 called? What is it used to treat? Why is it administered with rIGFBP-3? What is the mechanism of action and most important adverse effect?

In Laron dwarfism, short-stature is caused by IGF-1 deficiency despite high GH levels. This is due to the defect in GH hormone receptors that fail to respond to GH. Mecasermin is used for treatment in this condition. Mecasermin is a recombinant IGF-1. It is also available as a complex of recombinant human IGF-1 and recombinant human IGF-binding protein-3 (rIGFBP-3). rIGFBP-3 serves to prolong the action of IGF-1 in the human body. Mecasermin stimulates transmembrane receptors that activate tyrosine kinase activity at their intracellular domain. The most important adverse effect of mecasermin is hypoglycemia.

GH preparations: Adverse effects

In children • Increased Intracranial tension • Headache • Papilledema • Scoliosis • Diabetes mellitus In adults • Peripheral edema • Arthritis • Arthralgia • Myalgia • Carpal tunnel syndrome • Diabetes mellitus

Adverse drug effects of GH preparations:

In children: Increased Intracranial tension Headache Papilledema Scoliosis due to rapid growth Diabetes mellitus In adults: Peripheral edema Arthritis Arthralgia Myalgia Carpal tunnel syndrome Diabetes mellitus

Doctor: Now, I want review your medications. Patient: OK Doctor: Let's start with you telling me the names of your medications, the doses if you know them and when you take them. Patient: I take Metformin for my diabetes, two pills a day, one in the morning and one in the evening. I take Lotensin, a low dose, for my kidneys and blood pressure, just one in the morning. Doctor: How many doses have you missed since I last saw you? Patient: I took a long road trip to see my son in California and I forgot my pills twice during that trip because I was off my usual routine.

Information Intensive (Direct) Adherence Monitoring-Example

Characterized by the "Whipple triad" 1. Episodic hypoglycemia 2. Central nervous system (CNS) dysfunction (confusion, anxiety, stupor, convulsions, coma) 3. Dramatic reversal of CNS abnormalities by glucose administration

Insulinoma

A mother gives birth to a new baby. The nurse is not sure of the gender and contacts the doctor for evaluation. Pediatrician examined the baby and found an ambiguous genitalia as shown in the picture.

Investigations Abdominal Ultrasound showed a uterus and bilateral ovaries, possibly enlarged adrenals ↑17-OH progesterone ↓ Cortisol ↑ Testosterone Diagnosis: Congenital adrenal hyperplasia

The symptoms are primarily neurologic, and their severity depends on both the magnitude and speed of the decline of plasma sodium. Nausea and malaise can occur when the plasma sodium levels are ~125 mEq/L. With further decline in the sodium levels, patient can develop headache, lethargy, confusion, and obtundation. Most serious symptoms of severe and rapidly developing hyponatremia are seizures, coma, permanent brain damage, respiratory arrest, brain stem herniation, and death. Treatment depends on acute (<48hrs)/chronic, severity of symptoms and degree of hyponatremia.

SIADH Mild cases can be managed by water restriction initially. Drugs are required for moderate to severe hyponatremia and symptomatic patients. Too rapid normalization of hyponatremia can lead to the development of central pontine myelinolysis.

is an inhibitor of dipeptidyl peptidase-4 (DDP-4). DDP-4 degrades incretin and other GLP 1-like molecules. Inhibition of this enzyme increases circulating levels of GLP-1 and GIP. decreases postprandial glucose excursions by increasing glucose- mediated insulin secretion and decreasing glucagon levels. Oral administration; oral bioavailability >85%; t1/2 ~12 hrs. Dosage: 100 mg once-a-day; it can be given as monotherapy or combined with metformin or thiazolidinediones. Adverse drug effects: nasopharyngitis, upper respiratory infections, and headache

SITAGLIPTIN:

"wire loop" thickening of glomerular capillaries

SLE

More profound enzyme deficiency Ambiguous genitalia in females Aldosterone synthesis impaired Presents with hypoaldosteronemia Rapidly fatal if not treated Hyponatremia Hyperkalemia Dehydration Hypotension Hyperreninemia

Salt Wasting CAH (~2/3 patients)

- Short-term fat storage in adipose tissue - Protection from intermittent famines - Prevention of accumulation in non-adipose tissues during short- term obesity • Protects against: CAD, Insulin resistance, diabetes • Leptin injections appetite obesity in individuals with leptin deficiency - Rare condition - G deleted in codon 133frameshift mutationinactive leptin • In overfed rodents resistant to leptin, injection of leptin into CNS biological activity

LEPTIN

• A monomeric protein of 146 amino acids • Discovered in 1994 • Expressed mainly by fat cells • Reflects quantity of body fat - FatLeptinAppetite - Signal transduction • Leptin binds to Ob-R protein in hypothalamus • Controls energy expenditure ( metabolic rate) • In obesity, leptin but lack of expected in appetite - "Leptin resistance" - Saturation effect at blood-brain barrier

LEPTIN

• has peripheral effects as well as CNS effect - Peripheral OB receptors - Stimulates fatty acid oxidation in non-adipose tissue - Inhibits lipid accumulation in non-adipose tissue • Activation of AMPK and inactivation of acetyl-CoA carboxylase (by phosphorylation) • [Malonyl-CoA] • Inhibition of carnitine palmitoyl transferase I • Transport of fatty acyl-CoA into mitochondria - Does not prevent obesity though

LEPTIN

23 y/o male Occasional headaches, nausea and vomiting C/o joint pains & tingling in his feet and hands He remarked "I recently changed shoe size" On further questioning his class ring, which was always too big, now too tight What is his most likely diagnosis? • • • • • A. Gigantism B. Acromegaly C. A & B D. Obesity (weight gain) E. Cushing syndrome

Lab and radiologic investigations Glucose 180 mg/dl Hyperlipidemia T3 in high normal range Head CT: tumor in sella turcica region with bone destruction

A 50 year old woman has abnormal thyroid function tests. No positive history is present and routine physical exam is normal and not suggestive of any thyroid abnormality. She had normal free T3 and elevated TSH, which are confirmed on repeat measurements. Which of the following is most likely to explain her findings? A. Hyperthyroidism B. Non-thyroidal illness (sick euthyroidism) C. Estrogen therapy D. Subclinical hypothyroidism E. Familial (euthyroid) dysalbuminenic

Laboratory measurements of thyroid hormones and thyroid-stimulating hormone have proven invaluable in determining the true functional status of the thyroid gland. However, various medications and non-thyroidal illnesses can alter certain values, so usually a combination of values is used to make a diagnosis. TSH values tend to be the most reliable in the absence of hypothalamic or pituitary disease, and mild elevation is seen in hypothyroidism before free T4 declines.

Maturity Onset Diabetes of Young (MODY) Much less common than Type 1 or Type 2 DM Usually non-obese persons Monogenic mutations Glucokinase Hepatic Nuclear Factor 1 or 2 (HNF1 or 2) genes Disrupts insulin production Non-ketotic form of DM No islet cell antibodies Acts like very mild Type 1 DM Not type 2 in young person Associated with FHx DM over several generations

Maturity Onset Diabetes of Young (MODY) Much less common than Type 1 or Type 2 DM Usually non-obese persons Monogenic mutations Glucokinase, Hepatic Nuclear Factor 1 or 2 (HNF1 or 2) genes Disrupts insulin production Non-ketotic form of DM No islet cell antibodies Acts like very mild Type 1 DM Not type 2 in young person Associated with FHx DM over several generations

A 40 year old man presents with episodic flushing. On examination he is found to have a thyroid nodule. Biopsy of the nodule shows lakes of pinkish fibrillary material (amyloid) that stains with congo red. Blood tests show an elevated plasma calcitonin level. Which of the following thyroid malignancies is most consistent with these findings? A. Thyroid lymphoma B. Medullary thyroid carcinoma C. Papillary thyroid carcinoma D. Anaplastic thyroid carcinoma E. Follicular thyroid carcinoma

Medullary thyroid carcinomas secrete calcitonin, arise in the calcitonin-producing parafollicular cells, and account for about 5% of thyroid cancers. The flushing may be because of 5-HT that the tumor produces. Medullary carcinomas can be part of the MEN2 syndrome, that has the RET gene mutation. The patient should be investigated for the mutation and also investigated for other tumors (Review MEN2 syndrome). All blood relatives should be investgated if the RET gene mutation is present.

• Insulin Resistance • Hyperinsulinemia • Central adiposity (Excess waist fat) • Dyslipidemia • Glucose Intolerance • Hypertension • Pro-inflammatory status • Microalbuminemia

MetS

• Central obesity: waist circumference > ethnic and gender specific limit plus 2 of: -raised triglycerides> 150mg/dl (1.7 mmol/l) - reduced HDL cholesterol < 40mg/dl 91.3mM0 in males, 50mg/dl (1.9 mmol/l) in females - raised blood pressure: ≥ 130/85 mm Hg. -hyperglycemia: fasting blood glucose ≥ 100mg/dl (5.6mmol/l) (oral glucose tolerance test recommended but not required for diagnosis of metabolic syndrome) - previous diagnosis of diabetes

Metabolic Syndrome • Associated with: - Cardiovascular disease - Type II DM - Lipodystrophy - Non-alcoholic fatty liver disease - Hyperuricemia - Polycystic ovary syndrome - Obstructive sleep apnea

• Associated with: - Cardiovascular disease - Type II DM - Lipodystrophy - Non-alcoholic fatty liver disease - Hyperuricemia - Polycystic ovary syndrome - Obstructive sleep apnea

Metabolic Syndrome • Central obesity: waist circumference > ethnic and gender specific limit plus 2 of: -raised triglycerides> 150mg/dl (1.7 mmol/l) - reduced HDL cholesterol < 40mg/dl 91.3mM0 in males, 50mg/dl (1.9 mmol/l) in females - raised blood pressure: ≥ 130/85 mm Hg. -hyperglycemia: fasting blood glucose ≥ 100mg/dl (5.6mmol/l) (oral glucose tolerance test recommended but not required for diagnosis of metabolic syndrome) - previous diagnosis of diabetes

Hypothesis for Etiology of Craniopharyngioma Dual Theory Metaplastic Theory - -

Metaplasia of the formation of anterior pituitary Explains the leading to craniopharyngioma seen in adults adenohypophyseal cells in the tumor forming squamous cells Squamous papillary Embryogenetic Theory remnants of the craniopharyngeal duct and the Rathke's pouch Explains the Adamantinomatous tumor seen in children Neoplastic transformation of the epithelial 122

this drug is "anti-hyperglycemic" rather than hypoglycemic. It prevents postprandial hyperglycemia. it usually does not cause hypoglycemia by itself and does not cause weight gain. Favorable effect on lipid profile. It can reduce plasma triglycerides by 15- 20% which helps in decreasing macrovascular complications of diabetes. It has a half-life of 1.5-3 hrs, is not metabolized, and is excreted unchanged by the kidneys. In patients with renal impairment, accumulates and the risk of lactic acidosis is increased.

Metformin can be administered as monotherapy or in combination with sulfonylureas, thiazolinediones, and insulin.

What are the major differences between methimazole and PTU?

Methimazole is more potent, longer-acting than propylthiouracil. It is used as single daily dose and is a preferred thioamide for long-term treatment of hyperthyroidism. It inhibits synthesis of thyroid hormone. It is a teratogen. Propylthiouracil has short half-life of 1.5 hrs. It needs to be given 2-3 times a day. Its use is reserved for use during first trimester of pregnancy (considered to be relatively safer than methimazole), in thyroid storm, and in those experiencing adverse effects to methimazole. It is hepatotoxic. Adverse drug reactions of both: Common: Maculopapular rash, arthralgia Serious: Agranulocytosis, vasculitis

SIADH management

Mild cases can be managed by water restriction initially. Drugs are required for moderate to severe hyponatremia and symptomatic patients. Too rapid normalization of hyponatremia can lead to the development of central pontine myelinolysis.

Case 4 This 24 day old term- infant had an uncomplicated prenatal history. He presents with failure to thrive and seizures and possible sepsis He has an erythematous papular rash on the face, trunk and upper extremities. Ultrasonography shows enlarged heart and truncus arteriosus with a large ventricular septal defect..

Skin biopsy: Shows eosinophils in the papillary dermis and vessels. Hypocalcemia Tracheal aspirate: E. cloacae Urine culture: Candida species

Abdominal pain Vomiting, nausea Anorexia Polyuria Polydipsia Dehydration Altered consciousness Kussmaul breathing Ketones on breath

Symptoms and Signs (DKA)

They bind to nuclear peroxisome proliferator activated receptor gamma (PPAR). This receptor regulates the transcription of several insulin responsive genes. Overall effect is a reduction in insulin resistance and an enhancement of tissue sensitivity to insulin. Activation of PPAR in adipose tissue reduces the flux of fatty acids into muscles, resulting in decreased insulin resistance. Activation of adiponectin, which is one of the adipokines in the adipose tissue. Adiponectin is associated with increased insulin sensitivity by elevating AMP kinase. These drugs are "euglycemics" since they do not cause hypoglycemia. They are metabolized using the cytochrome P450 system in the liver. Maximal clinical effect is apparent only after 6-12 weeks

THIAZOLIDINEDIONES ("INSULIN SENSITIZERS - Rosiglitazone - Pioglitazone

Not any longer a preferred agent for treating type 2 diabetes mellitus. Short-acting; Hypoglycemic episodes are very rare; safe in the elderly.

TOLBUTAMIDE

T/F: Octreotide can be administered subcutaneously for acromegaly

True

T/F: Octreotide can be administered subcutaneously for esophageal varices ruptures

True

T/F: Somatostatin is released from hypothalamus and acts on anterior pituitary to inhibit the synthesis of growth hormone.

True

Which Polyglandular Autoimmune Syndrome is this? Manifests in Older Children and Adolescents, M=F Autosomal recessive mutation in APECED gene (AIRE Addison Disease, Hypoparathyroidism, Type 1 diabetes mellitus, Primary hypothyroidism Chronic Mucocutaneous Candidiasis, Nail dystrophy, Dental enamel, hypoplasia T, vitiligo

Type I Manifests in Older Children and Adolescents, M=F Autosomal recessive mutation in APECED gene (AIRE Addison Disease, Hypoparathyroidism, Type 1 diabetes mellitus, Primary hypothyroidism ,, Chronic Mucocutaneous Candidiasis, Nail dystrophy, Dental enamel, hypoplasia T, vitiligo Type II Manifests at 20-40 years, Females predominance Polygenic inheritance, HLA DR3 and HLA DR4 Addison disease, Primary hypothyroidism, Graves disease, Pernicious anemia, Primary hypogonadism, Type 1 diabetes mellitus Myasthenia gravis, vitiligo, Coeliac disease,

What are 2 classes of drug that stimulates insulin secretion by blocking ATP-sensitive potassium channels in the pancreatic beta-cells? What is the half life of repaglinide? When should it be taken in relation to mealtime? What drug is it often taken in combination with?

sulfonylureas & MEGLITINIDES (non-sulfa drugs): Repaglinide: Mechanism of action: Rapid onset and short duration of action. Peak effect in 1 hr; t1/2 ~ 1 hr. It is taken 10-15 minutes before a meal. Due to its rapid onset of action and short duration of action, it has gained acceptance as a fast-acting premeal therapy to limit postprandial hyperglycemia. Use cautiously in patients with hepatic impairment. Taken alone or in combination with metformin. Used in patients allergic to sulfonamides, or who develop tolerance to sulfonylureas. Common adverse effect is hypoglycemia that occurs due to delayed food intake or skipped meal while taking repaglinide.

What type of lupus nephritis is this? Focal proliferative GN focal, segmental, or global glomerulonephritis involving <50% of glomeruli, Subendothelial and mesangial immune deposits Active SLE, hematuria proteinuria Hypertension, edema, urinary sediment, worsening renal function, and nephrotic range proteinuria

type III

It is a 9 amino acid peptide (nonapeptide) synthesized mainly in the supra-optic nucleus of the hypothalamus (small amounts are synthesized in the paraventricular nucleus).

vasopressin

A 33-year old woman has had increased anxiety with headaches and diaphoresis over the past 2 months. On physical examina?on she is afebrile, with a heart rate of 90/minute and blood pressure 150/90 mm Hg. Laboratory studies show elevated urinary catecholamines, elevated plasma renin ac?vity, and normal TSH. Her plasma cor?sol level is normal. An abdominal CT scan is performed. The histopathology and gross tumor is shown. 98 At which of the following loca?ons is a mass lesion most likely to be found? • A Aor?c bifurca?on • B Hepa?c capsule • C Pancrea?c tail • D Medias?num • E Splenic hilum

• 10% of pheochromocytomas are extra- adrenal. Most common site is at the bifurcation of aorta. • They willproduce the same classical symptoms as adrenal pheochromocytoma. Remember only a subset of pheochromocytomas occur as part of the MEN syndrome. 100

A 7 week old infant develops severe dehydra?on , hypotension and expires. The kidneys and adrenal gland at autopsy are shown. Hypovolemic shock in this infant was most likely caused by inadequate secre?on of which of the following? 1. Renin 2. Atrial Natriure?c factor 3. An?diure?c hormone 4. Angiotensin 5. Aldosterone 6. Cor?sol

• Aldosterone deficiency causes hypovolemic shock in classic Congenital adrenal hyperplasia • This is a case of 21-hydroxylase deficiency leading to hypovolemic shock. Both cor?sol and Aldosterone will be deficient here. The pa?ent will have Hyponatremia (due to loss in urine), Hyperkalemia, Dehydra?on, Hypotension, High renin levels 15

Diseases More Common in Elderly

• Anemia • Atrial fibrillation • Hypertension • Coronary artery disease • CHF • Lung cancer • Breast cancer • Prostate cancer • Prostate disease • Sexual dysfunction • Stroke/CVA • COPD • Dementia • Diabetes (type 2) • Hypothyroidism • Osteoarthritis • Osteoporosis • Parkinson's Disease • Pneumonia • UTIs

Addison Disease: Causes

• Autoimmune (#1 non-iatrogenic cause in US) JFK !!! • Auto Abs against 21-hydroxylase • Antibody-dependent cell-mediated cytotoxicity • Destruction by infectious agent • Tuberculosis, Fungi (e.g. Histoplasmosis), AIDS • Iatrogenic • Chronic Corticosteroid treatment and withdrawal without tapering • Ketoconazole or Fluconazole antifungal drug therapy • Post-adrenalectomy:Impropermanagement • Genetic: Adrenal hypoplasia congenita and Adrenoleukodystrophy • Others • Amyloidosis, Hemochromatosis, Sarcoidosis and Metastatic cancer to adrenal glands e.g. bilateral adrenal metastases in 10% of lung cancer patients

Oxytocin : Adverse reactions & Contraindications

• Cardiac arrhythmia, CNS stimulation, excessive uterine contractions, and hyponatremia. • - Fetal distress - Abnormal fetal presentation - Prematurity - CPD (cephalo-pelvic disproportion)

Metabolic overload in Muscle

• Chronic exposure of muscle to elevated lipids • Results in induction of Beta-oxidation enzymes- leads to enhanced beta-oxidation • However TCA and ETC are not upregulated accordingly • Get incomplete metabolism of FA's • Lipid-derived metabolites accumulate in mitochondria eg long and medium chain acylcarnitines • These inhibit the kinases that phosphorylate IRS-1 and IRS-2

Epi-genetic Factors in Metabolic Syndrome

• Clear Correlation between poor nutritional status of mother during fetal development and potential risk of MetS for the Child in later life • Overfeeding during fetal development and pre-weaning period results in obesity, adipocyte hypertrophy, insulin resistance, elevated BP, endothelial cell dysfunction, altered CV and renal function in offspring and resistance to anorexic effects of Leptin • Manipulation of protein access leads to decreased beta- islet cell mass and changes to glucose homeostasis

A 30-year-old woman with thyrotoxicosis has a diffusely enlarged gland on palpation of the neck. Her thyroid scan and 24-h uptake show uniformity of uptake and an increased percentage of iodine uptake. Her blood test is positive for thyroid binding globulins. Which of the following is most likely in this patient? A. Graves disease B. Subacutethyroiditis C. Toxic multinodular goiter D. Hashimoto thyroiditis E. Toxicadenoma

• In Graves disease, the uptake tends to be increased and uniform. Uptake may be increased without thyrotoxicosis in conditions characterized by defects in organification of iodine, such as is found in some patients with Hashimoto thyroiditis, but the uptake tends to be patchy.

Obesity and Metabolic Syndrome

• Incidence of MetS increases with severity of obesity • Over 50% of obese adolescents go on to develop MetS • Insulin Resistance is 5-6 times more common in individuals with a BMI >30Kg/m2

Metabolic Disruptions in MetS

• Insulin Resistance is a top contributor to MetS • Adipose tissue secretes adipocytokines such as Tumor necrosis factor -alpha (TNF-alpha), IL-6, Leptin, adiponectin and Resistin. • Major role of insulin is to induce storage of fuel as fat (TAG's) in adipose tissue or CHO as Glycogen in liver and skeletal muscle. • Effect of Insulin resistance at level of fat is an increase in circulation TG's (Dyslipidemia) • Get increased delivery of fatty acids to liver which drives hepatic TG synthesis • These TG's are packaged into VLDL's

Why no ketosis?

• Insulin inhibits lipolysis • Type 2 patients do generate insulin in contrast to Type 1 patients • This is sufficient to suppress lipolysis • Hence ketone body synthesis is low

Which is the only diabetes medication that decreases cancer risk?

• Insulin is also a growth factor -> Increased risk of cancer • Sulfonylureas can increase risk of cancer • Metformin decreases the risk due to decreased circulating insulin

What Factors Are Likely to Affect Body Weight? Physiological feedback mechanisms

• Involving mouth, stomach, intestines, and brain increase or decrease hunger - Many hormones play role • Ghrelin - Produced in stomach - Increases hunger and appetite - Positive energy balance - Low in obese people as well as people with eating disorder • Leptin - In fat tissue signals brain to decrease hunger and food intake - Promote negative energy balance - May be deficient or defective in obese individuals, but very rare • Cholecystokinin - Released when stomach is distended, increasing feelings of satiation, decreasing hunger

Insulin resistance

• It is defined as a pathophysiological condition in which a normal insulin concentration does not adequately produce a normal insulin response in the peripheral target tissues such as adipose, muscle, and liver. • Under this condition, pancreatic beta cell secretes more insulin (i.e., hyperinsulinemia) to overcome the hyperglycemia among insulin-resistant individuals. • Although hyperinsulinemia may compensate for insulin resistance to some biological actions of insulin, that is, maintenance of normoglycemia, however, it may cause an overexpression of insulin activity in some normally sensitive tissues. • This accentuation of some insulin actions coupled with a resistance to other actions of insulin results in the clinical manifestations of MetS

A patient with a low TSH and high T3 will most likely have which of the following disorders? A. Hyperthyroidism B. Nonthyroidal illness (sick euthyroidism) C. Estrogen therapy D. Subclinical hypothyroidism E. Familial (euthyroid) dysalbuminenic hyperthyroxinemia

• Low TSH with high T4 and T3 or T3 alone (T3 toxicosis) reflects hyperthyroidism.

Management of HTN with evidence of HN: Joint AHA/ACC/CDC (JNC8) algorithm (2014)

• Main objective = again and maintain the BP goal. - Below 140/90 mmHg if no albuminuria - 130/80 mmHg if albuminuria present - Progression may conDnue despite BP control (NB if ApoL1 posiDve) • Important = Choice of an.-HTN medication: - ACEI and ARB = drugs of choice for renal protection in proteinuric CKD, benign HN (less benefit if non-proteinuric) - Age >18 years with CKD, regardless of race or diabetes status: initial (or add-on) antihypertensive treatment should include an ACEI or ARB to improve kidney outcomes (unless otherwise contraindicated).

What are the most important enzymes involved in Metabolic overload in the Liver?

• Malonyl-CoA levels increase ( FA synthesis) • This inhibits Carnitine palmitoyl transferase-1 (CPT-1) and thus less beta-oxidation of FA's • Insulin inhibits expression of beta-oxidation enzymes via the PPAR receptors • The above leads to hepatic steatosis • Leads to glucose intolerance • Get accumulation of TAG's, LC-Acyl CoA's, DAG and Ceramides

A 33-year-old woman has noted a weight gain of 6 kg over the past year. She has normal menstrual periods. On physical examina?on her blood pressure is 170/105 mm Hg. A serum electrolyte panel shows sodium 141 mmol/L, potassium 4.4 mmol/L, chloride 100 mmol/L, CO2 25 mmol/L, glucose 181 mg/ dL, and crea?nine 1.0 mg/dL. 131 Which of the following radiologic findings would you most expect to be present in this pa?ent? • A 2 cm right adrenal mass with abdominal CT scan • B4cmmassataor?c bifurca?on with MR imaging • C Mul?ple pulmonary nodules on chest radiograph • D 10 cm cys?c right ovarian lesion by abdominal ultrasound

• Of all the choices, A can produce Cushing syndrome, pheochromocytoma (B) will have hypertension but none of the other features, Lung tumors can cause Cushing's but are usually a solitary lesion(C), Struma ovarii can cause hypertension due to thyrotoxicosis but not the other features like weight gain (D) and same for the "hot"nodule.

A 32 year old woman presents with features of thyrotoxicosis with a low uptake of iodine in the thyroid bed but uptake in the pelvis can be seen. Which of the following disorders will have this presentation? A. Graves disease B. Iodine-induced hyperthyroidism C. Choriocarcinoma D. Strumaovarii E. Toxic multinodular goiter

• Ovarian teratomas can contain thyroid tissue (struma ovarii) and rarely cause thyrotoxicosis with excess thyroid hormone produced by the teratoma rather than the thyroid. • Next question

Mechanism of beta-cell failure in type II diabetes

• Overnutrition and increased lipid supply induce enzymes of beta- oxidation (CPT-1) • This increases AcetylCoA levels • Pyruvate carboxylase is activated • Leads to basal insulin hypersecretion • Loss of glucose-stimulated increment in pyruvate cycling • Blunting of glucose-stimulated insulin secretion • Increased demand for insulin synthesis places increased workload on the ER • Leads to ER stress and protein misfolding • Amylin is secreted leading to amyloid protein

- Binds to an inhibitory receptor on cells containing NPY/AgRP -> decreased secretion of NPY and AgRP - Net effect: decreased appetite

• PYY3-36 is a homologue of NPY

A 65-year-old man presents with signs and symptoms of thyrotoxicosis. His radioiodine scan and 24-h uptake show a patchy pattern but normal amount of radioiodine uptake. This presentation is most consistent with which of the following disorders? A. Graves disease B. Subacutethyroiditis C. Toxic multinodular goiter D. Hashimoto thyroiditis E. Toxicadenoma

• Patchy radioiodine uptake is common in multinodular goiter (euthyroid presentation) and is sometimes seen in Hashimoto's thyroiditis (hypothyroid presentation), but hyperthyroidism with normal or increased uptake typifies toxic multinodular goiter. Toxic adenoma will have a demarcated hot

GH antagonist - Decreases IGF-1; GH remains high - Also effective in those who do not/stop responding to octreotide

• Pegvisomant

A 50-year-old man has episodic headaches for 3 months. On physical examina?on his blood pressure is 185/110 mm Hg, with no other remarkable findings. Laboratory studies show sodium 145 mmol/L, potassium 4.3 mmol/L, chloride 103 mmol/L, C02 26 mmol/L, glucose 91 mg/dL, and crea?nine 1.3 mg/dL. An abdominal CT scan shows a 7 cm le] adrenal mass. During surgery, as the surgeon is removing the le] adrenal gland, the anesthesiologist notes a marked rise in blood pressure. Which of the following laboratory test findings most likely explains his findings? • A Decreased serum cor?sol • B Decreased urinary homovanillic acid • C Increased serum ACTH • D Increased urinary free catecholamines • E Elevated serum ANCA

• Pheochromocytomas have alpha- as well as beta adrenergic effects. Before surgery first and alpha and then abeta block is necessary otherwise the pa?ent can die on the table due to uncontrollable hypertension. • Pheochromocytoma is diagnosed by the increased urinary free catecholamines

Causes of Hypopituitarism

• Pituitary tumors Nonfunctioning tumors (~50%) • Congenital Isolated growth hormone deficiency (IGHD), Growth hormone insensitivity Laron Syndrome, Isolated gonadotropin deficiency Kallmann Syndrome Genetic mutations targeting pituitary during embryogenesis • Traumatic brain injury • Radiation Intracranial and bone tumor ALL • Suprasellar tumors Craniopharyngioma Rathke's cleft cyst Dermoid cysts and hamartoma Meningioma Metastatic tumors Suprasellar aneurysms • Sheehan syndrome • Infiltration Lymphocytic hypophysitis Sarcoidosis Tuberculosis Wegener's granulomatosis Langerhans cell histiocytosis Syphilis

Why is GERD increased in the elderly? Atrophic gastritis? Decreased drug metabolism? Increased constipation?

• Reduced lower esophageal sphincter tone -> increased GERD • Increased prevalence of achlorrhydia and reduced intrinsic factor -> atrophic gastritis • Decreased blood flow to liver -> decreased drug metabolism • Decreased intestinal transit time, increased resting rectal tone -> constipation

Contraindications of metformin

• Renal impairment • Hepatic disease • Alcoholism • Cardiac failure, myocardial infarction • Chronic hypoxic lung disease. These conditions all predispose to increased lactate production and hence to the potentially fatal complication of lactic acidosis.

Therapeutic uses of GH

• Short stature due to Congenital/acquired GH deficiency (Pituitary Dwarfism) • GH deficiency in adults - Age-related deficiency - Sheehan syndrome (as in the present case) • Turner's syndrome • AIDS related muscle wasting

Insulin as a Hormonal Signal in the Brain

• Stimulates POMC/CART cells, causes Satiety - Increases energy expenditure • Inhibits NPY/AgRP cells - Decreases appetite (Satiety) - Inhibits energy expenditure

- weakness of pelvic floor muscles - urine leaks when intra-abdominal pressure increases - females > than males over 65 - associated with estrogen deficiency - management is pelvic floor muscle training and surgery

• Stress incontinence

A 40-year-old patient with a recent viral infection presents with a significantly tender gland, low radioiodine uptake, and signs and symptoms of thyrotoxicosis. Which of the following disorders is most likely to be diagnosed in this patient? A. Graves disease B. Subacutethyroiditis C. Toxic multinodular goiter D. Hashimoto thyroiditis E. Toxicadenoma

• The pattern and amount of radioiodine uptake on 123I scan is fundamental to the correct diagnosis of thyrotoxicosis. Low-uptake thyrotoxicosis can occur when there is destruction of the thyroid follicles with release of thyroid hormone, such as in subacute thyroiditis, which usually presents as an exquisitely painful gland. Iodine-induced hyperthyroidism, factitious hyperthyroidism, and painless (silent) thyroiditis also cause low-uptake thyrotoxicosis.

A 42-year-old man has weight loss of 4 kg over the past 6 months, along with bruises on his skin with even minor trauma and back pain. He has smoked 2 packs a cigareTes per day for 35 years. On physical examina?on he has obesity in a truncal distribu?on, plethora, and a blood pressure of 160/110 mm Hg. A radiograph of the spine reveals a compressed fracture of T11. 113 Which of the following neoplasms is he most likely to have? • A Pheochromocytoma of bladder • B Follicular carcinoma of thyroid • C Osteosarcoma of femur • D Small cell anaplas?c carcinoma of lung • E Islet cell carcinoma of pancreas

• This is a case of Cushing syndrome due to the paraneoplas?c phenomenon of the lung tumor making the ACTH. • All the other tumors are capable of paraneoplas?c secre?ons but do not cause Cushing disease. The history of smoking in this pa?ents points to the lung tumor also. 115

A patient with chronic autoimmune (Hashimoto) thyroiditis develops a rapidly enlarging thyroid mass. This change is most likely to represent which of the following disorders? A. Thyroid lymphoma B. Medullary thyroid carcinoma C. Papillary thyroid carcinoma D. Anaplastic thyroid carcinoma E. Follicular thyroid carcinoma

• Thyroid lymphomas constitute about 5% of thyroid cancers and occur most often in patients with Hashimoto thyroiditis. Lymphomas and anaplastic carcinomas tend to grow rapidly.

A 25-year-old woman is seen in your office with complaints of nervousness, weight loss, tremors, and palpitations for a few months. You suspect hyperthyroidism. In a patient with iodine-deficiency goiter who moves from an iodine deficient area to an iodine-replete area, the occurrence of hyperthyroidism most likely represents which one of the following? A. Graves disease B. Iodine-induced hyperthyroidism C. Choriocarcinoma D. Struma ovarii E. Toxic multinodular goiter

• Thyrotoxicosis can have several etiologies. Iodine-induced hyperthyroidism is called the Jod- Basedow phenomenon and can occur in patients with endemic goiter who move to areas where iodine is plentiful.

- due to obstruction to bladder outlet (PBH). - due to urethral stricture

• Urethral obstruction incontinence

Hormones contributing to weight gain

• Weight loss (mean 13.5 ± 0.5 kg) led to: • ↓ leptin, peptide YY, cholecystokinin, insulin, amylin • ↑ ghrelin, gastric inhibitory polypeptide, pancreatic polypeptide • ↑ subjective appetite

What is the effect of PTH on the gut?

indirectly increases Ca+ and PO4 reabsorption

Diagnosis of Increased Prolactin - >10x normal

macroadenoma -men and older women

Physiologic role: Uterine muscle contraction (maximal effect at full term) Milk letdown response: increased contraction of myoepithelial cells of mammary ducts during lactation (suckling reflex) Slight antidiuretic and pressor activity

oxytocin

Posterior pituitary hormones

oxytocin, vasopressin

Vasopressin antagonist acting on the posterior pituitary

conivaptan

May cause pseudodementia in elderly

depression

ynthetic analog of vasopressin; long-acting (t1/2 =1.5-2.5 hours)

desmopressin

Neurogenic (or Central) Diabetes insipidus Drugs for treatment:

desmopressin : occurs due to decreased secretion of vasopressin Chlorpropamide (a sulfonylurea agent/oral hypoglycemic agent): Enhances the effects of ADH on V2 receptors Reduces urine output by 30-70% Adverse effects: hypoglycemia (after low calorie intake); disulfiram-like reaction to alcohol.

This is another long-acting insulin analog in which a fatty acid is bound to lysine amino acid at position B29. It is absorbed from subcutaneous (SC) site quickly and binds to serum albumin. As compared to insulin NPH, is associated with fewer chances of hypoglycemia and less weight gain.

detemir

What is the effect of Vit D on the gut?

directly increases Ca+ and PO4 reabsorption

7th leading cause of death in US (2007) 71,382 Heart disease and stroke (2004) HD noted on 68% and stroke on 16% of DM- related death certificates among people ≥65 years HD death rates and risk for stroke 2-4x higher than adults without DM

dm

Diagnosis of Increased Prolactin - 1-2x normal

drugs, stress

What causes proteinuria in Hypertensive Nephropathy?

due to compensatory hypertrophy of less affected glomeruli with higher intraglomerular pressure mild < 1 g/day (focal involvement) but may reach 10 g/day if superimposed renovascular disease or malignant Htn

Are these benign or malignant? seborrheic keratosis cutaneous horn basal cell carcinoma

seborrheic keratosis (benign) cutaneous horn (pre-malignant) basal cell carcinoma (malignant)

ergocalciferol

d2

cholecalciferol

d3

What is the effect of Calcitonin on Ca and PO4 reabsorption?

decreases both

What is the effect of Calcitonin on osteoclasts and bone resorption?

decreases both

It provides a better once daily 24 hour insulin coverage than ultra-lente or NPH insulin. Unlike insulin NPH, lente and ultralente, it has sustained "peak-less"absorption and so it resembles closely the release of insulin from a SC insulin pump. Use of insulin glargine as "basal insulin" has been associated with less hypoglycemia when compared to other basal insulins - intermediate and other long-acting insulins. It cannot be combined with rapid/short-acting insulins in the same syringe due to its acidic pH.

glargine

What are 4 signs of craniopharyngioma in adults?

headaches, hypothyroidism, hypotension, hypoglycemia -changes can vary depending on location of tumor: intrasellar = headache/endocrinopathy prechiasmal = loss of visual acuity, visual field constriction retrochiasmal = hydrocephalis, double vision, papilledema

Early finding: CKD in Hypertensive Nephropathy (HN) (Hypertensive Nephrosclerosis)

hyperuricemia (independent of diuretic therapy) -> due to reduction in renal blood flow through narrow vascular bed

obesity classes

i- 30-34.9 ii - 35-39.9 iii - 40+

Common causes of SIADH

include central nervous system disorders (meningitis, encephalitis, cerebrovascular disorder, head injury), pulmonary diseases (pneumonia, tuberculosis), some malignant tumors (small cell carcinoma of the lung), and can be drug induced Drug induced SIADH: Carbamazepine, vinca alkaloids, chlorpropamide.

What is the effect of Vit D on Ca and PO4 reabsorption?

increases both

What is the effect of Vit D on osteoclasts and bone resorption?

increases both

Mechanism of action: Thioamides

inhibit hormone synthesis by inhibiting thyroid peroxidase. They block iodine organification and coupling reactions Propylthiouracil also inhibits peripheral deiodination of T4 to T3.

drug of choice to treat DM in pregnancy

insulin

FENa>1 extrinsic or intrinsic?

intrinsic

What is the effect of PTH on Ca and PO4 reabsorption?

it increases Calcium reabsorption and decreases phosphate reabsorption by increasing synthesis of 1 alpha hydroxylase

insulin is slowly released from the Zn complexes.

lente

-Responsible for long-term weight problems -Weight-control in non-obese - Concentration without effect in obese -Responsible for long-term weight problems

leptin

Systemic diseases that cause chronic hypocalcemia

malabsorption Intestinal Malnutrition malabsorption Calcitonin producing tumor (Medullary carcinoma of thyroid) Rickets

recombinant IGF-1 acting on the anterior pituitary

mecasermin

pink‐ staining, thickened capillary loops

membranous nephropathy

Is Bence Jones proteinuria testable by urine dipstick?

no

What is the effect of calcitonin on the gut?

nothing

Foods with as little P, K and Na as possible.

nuts, soda, juice, tuna, milk, sardines, steak, chicken, eggs

Somatostatin analog acting on hypothalamus

octreotide

• Loss of elastic recoil • Increase in respiratory residual volume • Increase dead space (ventilating non-perfused lung) • Decrease in tidal volume, FEV1 and vital capacity • Decrease in arterial PO2 • Stiffer chest wall and weaker muscles

old people

• Major arteries thicker and stiffer. • Increased left atrial size • S4 common • Reduced left ventricular compliance and increased mass (infiltration with lipids, collagen, amyloid) • Decreased cardiac output and decreased maximum heart rate. • Increase in systolic hypertension and widening of pulse pressure • Orthostatic hypotension • Heart murmurs: aortic sclerosis common; diastolic murmurs are always pathological

old people

gene for Aggressive adenomas

overexpression of cyclin D

GH antagonist acting on the anterior pituitary

pegvisomant

What is the appropriate pituitary response to hypoglycemia?

production of ACTH and GH

most common pituitary adenomas

prolactin secreting

basal insulins when injected twice a day

protamine (NPH insulin) or with zinc ions (lente insulin) in an acetate buffer

Which 3 things cause papillary necrosis?

pyelonephritis w diabetes pyelonephritis w obstruction analgesic nephritis

Syndromes of Adrenocortical Hypofunction

Addison Disease Other causes of Adrenal insufficiency Waterhouse-Friderichsen Syndrome

Lypodystrophy from insulin use

Atrophy of subcutaneous fat tissue at the site of injection. Rare Hypertrophy of fat tissue can occur that can be corrected by liposuction.

Case 6 16 y/o girl c/o Sudden episodes of feeling anxious Sweating, palpitation and shortness of breath "Like I am about to die" Episodes last for about 30-60 min In between these episodes she is fine Hx: Panic attacks Laboratory TSH and free T4 normal Urine VMA increased 2/5/2016 ICM 118 Provisional Diagnosis

Pheochromocytoma

Sheehan Syndrome

("Postpartum Necrosis of the Anterior Pituitary") Rare now due to better obstetric care Ischemic necrosis due to post parturition hypotension •Pituitary vulnerable due to reduced blood supply and increased size (2x) during pregnancy Posterior pituitary not affected as it has a rich blood supply independent of portal vasculature

gene that accounts for African-Americans 8X higher risk of HPT-induced ESRD

(APOL1 gene on Ch22 associaDon)

Hypogonadism

(FSH/LH ↓)

Cretinism

(TSH ↓)

- Sandostatin-LAR

(a slow release preparation of octreotide) - once every 4 weeks

Symptoms of hypoglycemia - when are they first noticed & what are they?

(first noticed at blood glucose levels of 40-50 mg/dl; blood glucose <20 mg/dl can produce seizures and coma) Autonomic hyperactivity Tremulousness Sweating Anxiety Tachycardia Hunger and nausea Impaired CNS function: Headache Mental confusion Dizziness Blurred vision Bizarre behavior (poor judgment) If untreated, this can lead to convulsions and coma. Patients undergoing "tight glycemic control" are more at risk of hypoglycemic episodes.

Calcitriol (1, 25(OH)2D) • Therapeutic uses:

- Advanced renal disease when vitamin D therapy is inadequate (reduces PTH synthesis as well as increasing intestinal Ca absorption) - Normalization of serum Ca in hypoparathyroidism or other hypocalcemic states if vitamin D is inadequate Beware of hypercalcemia

Surgical therapy • Indications:

- BMI ≥ 40 kg/m2 or - BMI ≥ 35 kg/m2 plus obesity-related diseases • February 2011 FDA approved Lap-Band for BMI ≥ 30 kg/m2 plus obesity-related diseases • For details see separate lecture!

THIAZOLIDINEDIONES ("INSULIN SENSITIZERS")

- Rosiglitazone - Pioglitazone

What is the appropriate response to oral glucose in the test for acromegaly?

- a normal patients BG will increase less than a pt with acromegaly -serum GH in a patient with acromegaly will decrease for 1.5 hrs after administration of glucose, a normal patient will not be affected

Prevalence of obesity up in some minority populations

- highest rates: Native Americans, Hispanics, African Americans - Lowest rates in Asians - Highest in populations with less education and lower income levels

Metformin

-for DM2, PCOS -decreases gluconeogenesis, increases insulin sensitivity -side fx: GI distress, lactic acidosis do not give in pats w renal failure

It constricts splanchnic, hepatic and renal blood vessels. This effect is utilized for controlling bleeding from ruptured esophageal varices

somatostatin

recombinant human rh(GH) acting on the anterior pituitary

somatropin

After suffering a seizure, a 23 year old woman is found to have profound hypoglycemia. Determination of which of the following would aid in differentiating a suicide attempt from a disease process? 1. C-peptide 2. Gastrin 3. Glucagon 4. Pro-insulin 5. Vasoactive intestinal peptide

1

Maria comes to see you because she has very scanty irregular periods. She is 20 years old , 5ft 10ins and has severe acne with marked facial. She complains of no other obvious problems except that she has male pattern distribution of hair on her abdomen. She most likely has deficiency of: 1. 21 ά Hydroxylase 2. 11 β Hydroxylase 3. 3 β hydroxylase 4. 5 ά reductase

1

1) A 36-year-old woman with borderline personality disorder sees her physician on a regular basis for chronic pain that is resistant to treatment. She complains constantly, yet is reluctant to try any therapies other than prescribed medications, which also have not worked to date. Her physician comments on this to his nurse, saying "I think she is faking the pain just to get attention from all of us." Which of the following strategies would best be applied to address this potential conflict? A) Separating intention from impact B) Distinguishing feelings from emotions C) Discerning truth from perspective D) Reducing cognitive dissonance

1) Correct answer A Answer B does not apply to this vignette as there is no description here of emotions or feelings being incongruent. Answer C appears correct on the surface. However, we can rarely discern truth when we are considering the intentions of others. This patient's behavior is aggravating, but the reasons behind the behaviors are complex and we may never know all of them. Answer D is incorrect because there is no aspect of "being of two minds" about anything in this vignette. Answer A is correct because it is helpful to remind ourselves that we never can know a person's intentions unless they honestly tell us. We can, however, acknowledge the impact of a person's behaviors and work within ourselves to find ways to negotiate the conflict or to change our frames about the person.

Negotiating Differences: Using the ARTS Mnemonic

1. Ask first for the other's perspective • Beware of assumptions 2. Respond with empathy 3. Tell your perspective • Separate people from the problem • State your interests, not your positions • Focus on strengths • Provide specific feedback 4. Seek solutions • Brainstorm options for mutual gain • Look for mutual interests • Search for a measurable outcome - how will we know it works

Renal osteodystrophy and joint pain have several mechanisms:

1. Calcitriol (activated form of vitamin D) is not made. 2. Chronic acidosis mobilizes the "bone salt". 3. PTH is stimulated by high phosphate and low calcitriol, demineralizes bones. 4. Poor response to insulin and IGF1. 5. β2-microglobulin accumulates, causes amyloidosis of joints. 6. Treatment: Calcitriol, phosphate restriction, partial removal of parathyroid glands.

CHRONIC RENAL FAILURE: top 6 CAUSES

1. Diabetes 2. Hypertension 3. Infections: Pyelonephritis etc 4. Immunological: Systemic lupus erythematosus, poststreptococcal glomerulonephritis, Goodpasture syndrome 5. Genetic, e.g. Alport syndrome (mutations in type IV collagen), polycystic kidney disease 6. Toxins

COMPLICATIONS of CRF

1. Infections: - Increased susceptibility because of anemia etc. - Can be acquired during dialysis - Worsens uremia due to excessive protein breakdown 2. Hemorrhage: - Platelet dysfunction - Use of anticoagulants during hemodialysis 3. Uremic encephalopathy: - Can lead to psychiatric problems

UREMIA: ACCUMULATING PRODUCTS

1. Nitrogenous wastes: Urea, uric acid, creatinine 2. Electrolytes: Na+, K+, Cl-, HPO42-, Mg2+ 3. Protons (metabolic acidosis) 4. Small proteins, peptides 5. Exogenous products: - Drugs - Starfruit

How does FGF cause serum PO4 to decrease? (3 ways)

1. Reduces expression of sodium- phosphate co-transporters (NaPi-IIa, NaPi-IIc) in the renal tubules 2. Decreases levels of calcitriol, resulting in decreased Ca2+ & P absorption from GIT 3. FGF 23 decreases PTH synthesis and secretion: ↓ PTH results indirectly in decreased phosphate and calcium absorption from GIT

3. What is the most common cause of hyperpituitarism?

1. pituitary adenoma 2. hyperplasia/carcinoma of AP 3. ectopic hormone secretion from foregut tumors

differential for prolactinoma

1. primary hypothyroidism (increased TSH leads to increased prolactin) 2. stress 3. pregnancy 4. steroids Dopamine receptor antagonists Antidepressants H2 antagonists Chronic renal failure Idiopathic Stalk disconnection Acromegaly

Diagnosis of Increased Prolactin - 2-10x normal

tumor compressing stalk

10 A 42‐year‐old woman has a sudden onset of fever with headache, nausea, diaphoresis, and palpitations. On physical examination her temperature is 39.2° C; pulse, 115/min; irregular respiratory rate, 30/min; and blood pressure, 150/85 mm Hg. Deep tendon reflexes are 4+ bilaterally. Her outstretched hands exhibit a high frequency tremor. Which of the following drugs should she receive emergently? A Aspirin B Hydrocortisone C Insulin D Propranolol E Tetracycline

10 D Thyroid storm is a medical emergency. There is not enough time to wait for confirmatory laboratory thyroid testing. There are increased catecholamine levels, and the β‐blocker propranolol will help prevent emergent death from cardiac failure. Acetaminophen and ice packs are better choices to treat fever alone. Propylthiouracil (PTU) is the antithyroid medication with the fastest onset of action (hours), along with iodine to help reduce preformed thyroid hormone output. The fever and ancillary findings here go beyond what would be expected with an acute infection.

The most common cause of goiter before fortification of common salt was introduced by WHO recommendation was which of the following? A. Iodine deficiency B. Lithium C. Hashimoto thyroiditis D. Propylthiouracil E. Toxic multinodular goiter

11 Answer • Worldwide iodine deficiency (endemic) goiter was common in areas where soil was deficient in iodine, when common table salt was not supplemented with potassium iodide. It is not seen in the United States or other countries where salt is fortified with iodine.

5% of CAH Sephardic Jews Aldosterone & cortisol are blocked Aldosterone precursor - Deoxycorticosterone (DOC) accumulation Retention of sodium and hypertension Hypokalemia Virilization in females Ambiguous genitalia Late onset has signs of androgen excess in males Precocious puberty

11-β hydroxylase deficiency

The conversion of T4 to T3 is inhibited by which of the following? A. Iodine deficiency B. Lithium C. Hashimoto thyroiditis D. Propylthiouracil E. Toxic multinodular goiter

14 Answer • Propylthiouracil, propranolol, glucocorticoids, and iodine inhibit conversion of T4 to T3.

2. A 68-year-old obese man has recently been diagnosed with type 2 diabetes. His fasting blood sugar is 160 mg/dl, serum triglyceride 400 mg/dl, and Hb A1c is 9.2%. Which of the following drug would be most appropriate as a starting therapy in this patient? A) Miglitol B) Metformin C) Repaglinide D) Chlorpropamide E) Glyburide

2) Answer (B) Metformin decreases serum triglycerides by 15-20 %. It has almost equal in efficacy as compared to sulfonylureas to decrease the levels of Hb A1c. Metformin is best to be used in obese diabetic patient with raised serum triglyceride levels.

Your patient has features of Cushing's syndrome. He has a high urinary free cortisol and elevated ACTH after low dose dexamethasone suppression test. To determine whether he has ectopic ACTH secretion or Cushing's disease you would now do: 1. Cosyntropin stimulation test 2. High dose dexamethasone suppression test 3. 17 hydroxy pregnelonone level 4. Metyrapone test 5. Adrenal Biopsy

2. Ectopic ACTH secretion will not be affected by high dose dexamethasone

Delay deterioration of CRF

• ACE-Inhibitors/ARB • BP control (130/80-85) • Blood sugar control • Protein restricDon

Somatostatin analogs: Therapeutic uses

• Acromegaly • To prevent gigantism • Carcinoid syndrome • VIPoma,gastrinoma • Ruptured esophageal varices

Beta Islet Cell in Obesity

• Beta-Islet cell mass increases at onset of obesity • As body weight increase and insulin resistance worsens, Beta-Islet cell mass decreases • Chronic exposure to nutrients triggers beta-islet cell death • Glucolipotoxicity

Mechanism of insulin resistance

• Binding of insulin results in a tyrosine phosphorylation of downstream substrates and activation of two parallel pathways: the phosphoinositide 3-kinase (PI3K) pathway and the mitogen activated protein (MAP) kinase pathway. • In insulin resistance the PI3K-Akt pathway is affected, while, the MAP kinase pathway functions normally in insulin resistance. • This leads to a change in the balance between these two parallel pathways. • Inhibition of the PI3K-Akt pathway leads to a reduction in endothelial NO production, resulting in an endothelial dysfunction, and a reduction in GLUT4 translocation, leading to a decreased skeletal muscle fat and glucose uptake.

An 8 month old infant is being evaluated for growth and mental retardation. Physical examination reveals a small infant with dry rough skin, protuberant abdomen, periorbital edema, flattened broad nose and a large protuberant tongue. Which of the following disorders is most likely to be the cause of this patient's signs and symptoms? A. Graves disease B. Cretinism C. Multi-nodular goiter D. Toxicadenoma E. Strumaovarii

• Correct B Answer • In young children hypothyroidism produces cretinism, with marked physical and mental retardation (unlike adults and older children who get myxedema). Other features include decreased erythropoiesis leading to anemia, increased cholesterol leading to atherosclerosis and increased interstitial deposition of mucopolysccharides leading to coarsened skin and myxedema. Even subclinical hypothyroidism (or iodine deficiency) in mother during pregnancy may predispose the child to hypothyroidism • End of Quiz Answer • Wrong • Try again

Your patient is a 25 year old female who gave birth three months ago. She has not lactated and has no return of menses. She feels tired, nauseated and weak. CRF,LHRH are high, FSH, LH, TSH. Urinary free cortisol are exceedingly low. Her serum Na+ is 120 mmol/L. BP is 90/50 with a postural drop. This is an example of 1. Secondary pituitary dysfunction 2. Primary adrenal dysfunction 3. Primary ovarian dysfunction 4. Secondary adrenal dysfunction 5. Primary hypothalamic dysfunction

4

A 25-year-old female is expecting her first child. Results from routine prenatal testing indicate that the fetus is at high risk for congenital adrenal hyperplasia due to an abnormally low level of P450c21 (21β-hydroxylase). Which drug is the best choice to protect the fetus from genital abnormalities? 1. Fludrocortisone 2. Cortisone 3. Aminogluthethimide 4. Aldosterone 5. Dexamethasone 6. Androstenedione 0 0 0 0 0 0

5

56 A 5‐year‐boy has developed features that suggest puberty over the past 6 months. On physical examination, the boy has secondary sex characteristics, including pubic hair and enlargement of the penis. Which of the following morphologic features is most likely to be seen in his adrenal glands? A Cortical atrophy B Cortical hyperplasia C Cortical nodule D Medullary atrophy E Medullary hyperplasia F Medullary nodule

56 B Adrenogenital syndrome can lead to precocious puberty, which is most commonly associated with a deficiency of 21‐hydroxylase. The lack of this enzyme reduces cortisol production, driving corticotropin production, which leads to adrenal hyperplasia and production of sex steroid hormones. Bilateral adrenal cortical atrophy is typically seen in cases of Addison disease or after long‐term exogenous glucocorticoid therapy. A nodule in the adrenal cortex that has zona glomerulosa cells produces primary hyperaldosteronism; if it has zona fasciculata cells, it produces Cushing syndrome. Most adrenal nodules are nonfunctional and incidental findings. A nodule in the adrenal medulla, if functional, produces catecholamines, and older patients with such nodules have hypertension. Medullary atrophy is rare but might result from infections or toxins. Medullary hyperplasia is uncommon but could also produce catecholamines.

57 A female infant is born at term to a 41‐year‐old Yupik woman after an uncomplicated pregnancy. Soon after birth, the neonate develops hypotension. Physical examination shows ambiguous genitalia with a prominent clitoris. Laboratory studies show Na+, 131 mmol/L; K+, 5.1 mmol/L; Cl-, 93 mmol/L; CO2, 18 mmol/L; glucose, 65 mg/dL; creatinine, 0.4 mg/dL; testosterone, 50 mg/dL (normal A Aromatase B 11‐Hydroxylase C 21‐Hydroxylase D 17α‐Hydroxylase E Oxidase

57 C A complete deficiency of 21‐hydroxylase leads to the classic salt‐wasting form of adrenogenital syndrome because the enzyme deficiency blocks formation of aldosterone and cortisol. Mutations may be deletions or duplications, or involve recombination between the CYP21 gene and a pseudogene. These mutations may lead to severe deficiency with salt‐wasting and prenatal virilization or partial deficiency with postnatal virilization, with an apparent autosomal recessive pattern of inheritance. A deficiency of 11‐hydroxylase blocks cortisol and aldosterone production as well, although intermediate metabolites with some glucocorticoid activity also are synthesized. Aromatase is involved with conversion of androstenedione to estrone, a pathway of steroid synthesis that does not affect cortisol production. A deficiency of 17α‐ hydroxylase would lead to reduction of both cortisol and sex steroid synthesis. Oxidase is the final enzyme in the pathway to aldosterone production.

A 40-year-old woman notes increasing enlargement and discomfort in her neck over the past week. The nurse prac??oner palpates diffuse, symmetrical enlargement with tenderness in the region of the thyroid gland. Thyroid func?on tests show serum TSH of 0.8 mU/L and thyroxine of 11.9 micrograms/dL. She is referred to an endocrinologist, but the next available appointment is in 8 weeks. When the endocrinologist examines the pa?ent, the thyroid is no longer palpable and there is no pain. Repeat thyroid func?on tests reveal a serum TSH of 3.8 mU/L and thyroxine of 5.7 micrograms/dL. Which of the following thyroid diseases is most likely to produce these findings? • A Nodular goiter • B Non-Hodgkin lymphoma • C DeQuervain disease • D Hashimoto thyroidi?s • E Graves disease • F Riedel thyroidi?s

• Diffusely enlarged and tender thyroid with mild thyrotoxicosis and no iodine uptake is sugges?ve of thyroidi?s. • None of the other lesions will be tender.

A 38 year old woman presents with features of thyrotoxicosis and uniformly increased radioactive iodine uptake in the thyroid scan. Serum is negative for thyrotropin receptor antibodies or any thyroid autoimmunity. Which of the following disorders is most likely in this patient? A. Graves disease B. Iodine-induced hyperthyroidism C. Choriocarcinoma D. Strumaovarii E. Toxic multinodular goiter

• Diffusely increased radioiodine uptake in the thyroid accompanying thyrotoxicosis usually represents Graves disease, in which thyrotropin receptors are stimulated by antibodies. However in patients of choriocarcinoma high levels of human chorionic gonadotropin can also stimulate the thyrotropin receptor and produce the same findings in the absence of the stimulating antibody.

Contribute to increased fat mass and sarcopenia in aging

• Dysregulation of hypothalamic-pituitary systems • ↓ Growth hormone Prospective trials in older adults Replaced GH ↓ fat, ↑ lean tissue ↓ central fat • ↓ Testosterone levels in men • ↓ Estrogen levels in women • ↑ levels of cortisol in both sexes

Common Causes of Fall - Elderly

• Environmental (furniture, surfaces, lighting) • Vision (poor vision, cataracts, glaucoma) • Hearing and balance (impaired hearing, weakness, incoordination) • Medication (polypharmacy, psychoactive drugs, orthostatic hypotension) • High blood pressure treatment (postural hypotension)

A 32 year old woman presents with a nodular enlarged thyroid (goiter). She has recently immigrated from Tibet (China) to USA. Lab tests show a moderately high TSH, T3 and T4 are in the low normal range. Urine pregnancy test is posi?ve. What risk should be explained to the pa?ent? A. The baby is suscep?ble to cre?nism B. She may develop myxedema C. She has Graves disease D. She may have cancer of thyroid E. She has mul?nodular goiter and needs surgery

• Even subclinical hypothyroidism in pregnant women increases the fetal suscep?bility to congenital hypothyroidism!

Regulation of Phosphate homeostasis primarily involves* 3 hormones:

• FGF-23 • Parathyroid hormone (PTH) • 1,25-dihydroxycholecalciferol (1,25(OH)2D3)

Consequences of Diabetes

• Hyperglycemia and ketoacidosis • Hypoglycemic shock • Microvascular damage • Impaired wound healing • Retinopathy • Nephropathy • CV Disease • Glaucoma

Pseudohypoparathyroidism

• Hypocalcemia • High Parathyroid hormone levels • Positive Chvostek sign • Positive Trousseau sign • Occasionally: Cataracts or papilledema • Obesity • Brachydactyly is the most reliable sign Shortening of the fourth and fifth metacarpals causes shortening of the digits Dimpling over the knuckles of a clenched fist (Archibald sign) Shortening of the distal phalanx of the thumb (murderer's thumb or Potter's thumb) - • Short ulna, Bowed radius, deformed elbow

Differential Diagnosis FOR OBESITY

• Hypothyroidism • Hypercortisolemia: Cushing syndrome • Growthhormonedeficiency • Testosteronedeficiency • Drug side effect: - Long-term glucocorticoid treatment - Immunosuppression - Intensive insulin treatment of type 1 DM - HAART - Neuropsychotropic drugs

Adverse drug reactions of dopamine receptor agonists

: Nausea (stimulation of dopamine receptors in CTZ), headache, postural hypotension.

What urinalysis results are very senstive for ATN?

>10 muddy brown casts per field

Extreme Obesity

>40

5. A 30-year-old pregnant woman at term was started oxytocin to induce labor. It acts as uterine stimulant by which of the following mechanisms? A) activating IP3-DAG-Ca+2 pathway B) activating cAMP pathway C) activating cGMP-NO pathway D) activating Na+-K+ channels

A

Clinical Abnormalities associated with MetS

• Non-alcoholic fatty liver disease (NFLD) • Polycystic Ovary Syndrome ( PCOS) • Not all obese persons develop MetS • Not all persons with MetS are obese • Complex interactions between dietary habits, hormonal status and genetic background • Association between poor nutrition during fetal development and increased risk of adult CV disease

FREQUENTLY USED MEDICATIONS in patients with CRFFor hypertension:

ACE inhibitors or losartan (angiotensin receptor blocker) are first-line treatment; also nephrectomy. For bone problems: Calcium carbonate: For bone mineralization α-Calcidol (1-OH-cholecalciferol): Vitamin D For anemia: Epogen (erythropoietin): Stimulates erythropoiesis Folic acid: Supports erythropoiesis Fe-sulfate: Possible iron deficiency, given with epogen

Cushing Syndrome : Pathogenesis

ACTH Independent (Serum ACTH : Low) Exogenous glucocorticoids Atrophic adrenals Primary Adrenal Pathology Adrenocortical Adenoma(10%) Adrenal carcinoma (5%) Nodular Adrenal hyperplasia (<2%) ACTH Dependent (Serum ACTH : High) Pituitary Tumor - ACTH secreting (*Cushing Disease) (70%) Ectopic ACTH secreting tumor (e.g. Ca Lung) (10%) Bilateral Adrenal Hyperplasia 2/5/2016 Comprehensive Adrenal Lecture 90

Addison Disease: Why dark skin?

ACTH and melanocyte stimulating hormone (MSH) related prohormone When ACTH is cleaved from POMC, MSH also released - Both components of same (POMC) Increased MSH level results in characteristic bronze hyperpigmentation

May present with asymptomatic renal insufficiency, hematuria, pain or mass. Kidney failure by age 60 is common.

ADPKD

Clinical Symptoms similar to primary No hyperpigmentation ACTH is suppressed Mineralocorticoid secretion reduced Major regulator renin-angiotensin-aldosterone system No salt craving No ↑K with metabolic acidosis May have ↓Na due to ↑ ADH secretion Secondary stimulator of ACTH

Acute Adrenal Hypofunction Most commonly precipitated on discontinuing steroid treatment Exogenous glucocorticoid May become life threatening acute emergency Steroid therapy should be tapered slowly Recovery usually begins as ACTH level rises Leading to normalization of cortisol Complete recovery can take up to 1 year Stressors may also precipitate in patients on steroid therapy Even minor infections Patients need higher dose of corticosteroids during stress

- due to atony of bladder (over-distended detrusor muscle) - sometime from damage to pelvic floor nerves - more common in men due to prostatic enlargement

• Overflow incontinence

A 38 year old woman presents with episodic flushing and palpitation. On examination she has a solitary thyroid nodule. FNA of the nodule shows round balls of cells intermixed with a pinkish ground substance that stains with congo-red. An abdominal CT shows another tumor on the upper pole of right kidney. This is diagnosed as pheochromocytoma. Genetic studies show mutation of the RET gene. What is the diagnosis of the thyroid lesion? A. Medullary thyroid carcinoma B. Papillary thyroid carcinoma C. Follicular thyroid carcinoma D. Anaplastic carcinoma thyroid E. Thyroid lymphoma

Answer • Correct A • Episodic hypertension is highly suggestive for the presence of pheochromocytoma. RET gene mutation suggests that it is part of the MEN 2 Syndrome. Blood relatives of the patient should be screened for the mutation and presence of thyroid, parathyroid and adrenal (pheochromocytoma) tumors. • Next question Answer • Wrong • Try again

A 45 year old male presents with a solitary nodule in the neck. He admits to insomnia and being anxious. On examination he has fine tremors and hypertension. Laboratory tests show high T3 , high T4 and low TSH. 131I uptake is high in the nodule. Ultrasound shows a well demarcated lesion and an FNAC shows follicular pattern. Which of the following is the most likely diagnosis? A. Graves disease B. Medullary thyroid carcinoma C. Papillary thyroid carcinoma D. Follicular thyroid carcinoma E. Toxic adenoma thyroid

Answer • Correct E • Toxic adenoma is a solitary, well circumscribed lesion. Treatment is radio-iodine ablation and then thyroxine replacement for life. Follicular carcinoma will show the same FNAC pattern but will show invasion. • Next question Answer • Wrong • Try again

A 60-year-old man comes to your office with a 2-year history of fatigue, weight gain, cold intolerance, and increasing fullness in his anterior neck. You suspect hypothyroidism. Which of the following is the most common cause of spontaneous hypothyroidism in the U.S.? A. Iodine deliciency B. Lithium C. Hashimoto thyroiditis D. Propylthiouracil E. Toxic multinodular goiter

Answer • Hypothyroidism can result from several causes including congenital defects, chronic autoimmune thyroiditis (Hashimoto's thyroiditis), medications (thionamides, lithium, iodine), other iatrogenic causes, iodine deficiency, and hypothalamic or pituitary insufficiency. Chronic autoimmune thyroiditis is the most common cause of hypothyroidism in the U.S.

A 33 year old woman with diabetes states, "I know I shouldn't drink so much soda, but I just love the taste". What stage of change does her statement reflect? A) Pre-contemplation B) Contemplation C) Preparation D) Action E) Maintenance

B

Adverse effects of desmopressin:

Because of its V2 selectivity, V1 receptor- mediated adverse effects are less compared to vasopressin. Water intoxication can occur with both vasopressin and desmopressin due to antidiuretic effect via their V2 mediated actions.

23 y/old man presents with headache, nausea and vomiting. He also complains of joint pains and tingling in his feet and hands. On examination he is 7 ft tall, and has a prominent jaw and broad hand and feet disproportionate to his height. He admits to a change in his shoe size during the last year. Eye examination reveals proliferative retinopathy. Lab investigations show blood sugar 180 mg/dl. There is hyperlipidemia and T3 is in the high normal range. There is hypercalcemia Head CT scan shows a tumor in the sella turcica region What is the diagnosis? A. Gigantism B. Acromegaly C. Gigantism with acromegaly D. Obesity (weight gain) E. Cushing syndrome

C

54 y/o man presents with headaches and vomiting. He has recurring fever for the past month. He has polydipsia, polyphagia and polyuria and has gained 5 pounds in the last few months. He complains that he keeps bumping into things these days. On examination he does not have conjugate eye movement. Confrontation eye test reveals bitemporal hemianopsia. He has hypogonadism. Investigations reveal that Blood GH, LH and FSH levels are low. Which of the following is correct? A. Growth hormone is likely to be normal B. Adrenal function may be compromised C. Thyroid and reproductive function may be affected

C

A 54 y/o male presents with headaches and vomiting. He has recurring fever for the past month. No infection has been confirmed. He has gained 5 pounds in the last few months and has a ravenous appetite "I just cannot stop eating". He complains of vision problems also. On examination he does not have conjugate eye movement. Confrontation eye test reveals bitemporal hemianopsia . Investigations reveal endocrinopathies. What is the presumptive diagnosis? A. Meningitis B. Brain tumor C. Pituitary tumor D. Psychosis E. Malingering

C

65 A 26‐year‐old man developed sudden severe abdominal pain. On physical examination, he had marked abdominal tenderness and guarding. Laboratory studies showed serum glucose, 76 mg/dL; calcium, 12.2 mg/dL; phosphorus, 2.6 mg/dL; creatinine, 1.1 mg/dL; and parathyroid hormone, 62 pg/mL (normal range 9 to 60 pg/mL). During surgery, four enlarged parathyroid glands were found and excised, with reimplantation of one half of one gland. After the surgery, his serum calcium concentration returned to normal. Three years later, he had an episode of upper gastrointestinal hemorrhage. An endoscopy and biopsy specimen showed multiple benign gastric ulcerations. Abdominal MRI indicated multiple 1‐ to 2‐cm mass lesions in the pancreas. He underwent surgery, and multiple tumors were found. Which of the following additional neoplasm lesions is he most likely to have? A Adrenal pheochromocytoma B Endometrial carcinoma C Pituitary adenoma D Pulmonary small cell anaplastic carcinoma E Thyroid medullary carcinoma

C Multiple endocrine neoplasia (MEN) type 1 is also known as Wermer syndrome. (Remember the "three P's" in neoplasia or hyperplasia—pancreas, pituitary, and parathyroids.) Adrenal pheochromocytomas are associated with MEN 2B. Endometrial carcinomas can arise in patients who have unopposed estrogen secretion, which can occur in estrogen‐producing ovarian tumors. These are not part of MEN 1. Small cell carcinomas of the lung are known for various paraneoplastic syndromes, but not usually hypercalcemia. It also is doubtful that this patient would have lived 5 years with a small cell carcinoma. If her hypercalcemia had been a paraneoplastic syndrome, the parathyroid glands would not have been enlarged, and the serum calcium level would not have returned to normal after surgery. Medullary thyroid carcinomas are part of MEN 2A or 2B.

Drugs for the management/prevention of Renal Osteodystrophy

Calcitriol Paricalcitol Phosphate restriction Phosphate binders ( Cinacalcet sevelamer )

A 47-year-old woman feels a "lump" in her neck that she didn't no?ce 5 months before. Her physician palpates a firm nodule about 2 cm in size to the le] of midline in the region of the thyroid gland. By scin?graphic scanning this nodule appears "cold" with normal ac?vity in the surrounding normally sized thyroid gland. The thyroid ultrasound is shown. 125 Which of the following is the most likely diagnosis? • A Papillary carcinoma • B Follicular adenoma • C Thyroglossal duct cyst • D Toxic nodular goiter • E Granulomatous thyroidi?s • F Hashimoto thyroidi?s

Concept and Explana?on • A "cold" solid nodule is more likely to be a benign follicular adenoma • Papillary carcinomawillbe par?ally cys?c and solid, thyroglossal duct cyst will be cys?c, toxic nodular goiter will be a "hot" nodule, thyroidi?s will be diffusely tender and show no uptake, Hashimoto thyroidi?s will be diffuse enlargement with uniform low uptake of iodine. 127

A 57-year-old man is found comatose. On physical examina?on he has decreased skin turgor. Laboratory studies show a blood glucose of 780 mg/dl. Urinalysis reveals no ketosis or proteinuria, though there is 4+ glucosuria. Which of the following histopathology pictures is consistent with this pa?ent's diagnosis? 1. A 2. B 3. C 4. D

Concept and Explana?on • Hyperosmolar coma is more common in type 2 diabe?cs • Aistheisletofatype2DM,Bisfromatype1 DM, C is a normal pancrea?c islet and D is a picture of insulinoma. 106

A 47-year-old woman has felt a "lump" in her neck for the past 2 months. On physical examina?on there is a firm nodule in the right lobe of her thyroid. Following fine needle aspira?on and cytologic diagnosis of a neoplasm, a thyroidectomy is performed. Grossly, there is a 3 cm mass in the right lower pole that on sec?oning is cys?c and has papillary excrescences. 116 Which of the following sets of microscopic pathologic findings is most typical for this lesion? • A Giant cells • B Amyloid stroma • C Small thyroid follicles • D Clear nuclei • E Pleomorphic spindle cells

Concept and Explana?on • Solitary nodules of the thyroid are neoplas?c and solid-cys?c lesions are usually papillary carcinoma of the thyroid. • Characteris?c nuclear features are seen in the papillary carcinoma of the thyroid. Giant cells are seen in DeQuervain Thyroidi?s, amyloid in medullary carcinoma, thyroid follicles in follicular neoplasms, pleomorphic spindle cells in anaplas?c carcinoma

non-selective vasopressin receptor antagonist with high affinity for V1a and V2. Parenteral administration

Conivaptan

Progression to MetS is linked to:

• Poor dietary choices • Lack of physical activity • Epigenetic changes during fetal development and SNP's in defined genes • Disruption of the Hypothalamic-Pituitary Axis • Metabolic and Inflammatory dysregulation

A 55-year-old man comes to your office complaining of a non- tender nodule in the right anterior neck that has been getting larger over the few months since he first felt it. He admits to occupational radiation exposure in the past. He has no complaints or symptoms of hyperthyroidism or hypothyroidism. A biopsy is done which shows a tumor with clear nuclei ("orphan annie") nuclear grooves and papillary structures. A diagnosis of a papillary thyroid carcinoma is made. Which of the following is the most common variety of thyroid cancer? A. Thyroid lymphoma B. Medullary thyroid carcinoma C. Papillary thyroid carcinoma D. Anaplastic thyroid carcinoma E. Follicular thyroid carcinoma

• Thyroid cancers may arise from the thyroid follicular epithelium, the parafollicular C cells, or lymphoid cells in the thyroid. Papillary carcinomas, including tumors with mixed papillary elements, are most common and account for over 70% of thyroid cancers. Second most common thyroid cancers have purely follicular histology.

Why do plasma lipids increase in DM?

• We treat Insulin resistance to Carbohydrates • But remember that we have insulin resistance to fatty acids • Thus blood FFA levels rise • These end up in the liver and converted to cholesterol

Mrs Y is a diabetic patient who has developed persistent proteinuria and has a raised blood pressure. She is also known to have left ventricular hypertrophy from the high blood pressure. Which is the best antihypertensive drug that will offer benefits to most of her pathologies? a. Thiazidediuretic b. Beta blocker c. Calciumchannelblocker d. ACEInhibitor e. Alphablocker

Correct answer: d. ACEI will reduce proteinuria through a direct effect on the renal microcirculation and filtration process, control blood pressure, slow the progression of renal disease and has an effect on left ventricular remodelling. The other drugs have only antihypertensive effects and minimal antiproteinuric effects.

5-10% of childhood tumors • Locally aggressive, and may compress or destroy sella turcica and pituitary • If pituitary is affected it causes growth retardation First GH goes, then FSH/LH, then TSH and ACTH ("danger to life") Recurrence+ (NO metastasis)

Craniopharyngioma

Characterized by Hyperglycemia >250 mg/dl Ketosis Metabolic Acidosis pH <7.3 or HCO3 <15 Develops in hours or days Type 1 DM Very rarely type 2 Newly diagnosed Missing insulin doses Infections Stress

Diabetic Ketoacidosis (DKA)

What are the definitive lab results for dx of diabetic nephropathy?

Diabetic nephropathy - Affecting approx 44% of new patients entering dialysis in the United States • Typically defined by: - macroalbuminuria of more than 300 mg/day or - macroalbuminuria and abnormal renal function i.e. an abnormality in creatinine, creatinine clearance, or (GFR).

12 y/o male Parents are worried about his poor growth In the last 2 yrs he became shortest boy in class • On examination No pubertal signs of sexual development •Younger brother began at 9 yrs • ROS: occasional headache

Diagnosis Suggestive of craniopharyngioma with early signs of hypopituitarism

How can hypothyroidism cause Hyperprolactinemia?

Elevated TRH (thyrotropin-releasing hormone) levels can stimulate prolactin secretion to cause hyperprolactinemia.

T/F Anterior Pituitary is derived from Neuroectoderm "Neural" Posterior Pituitary is derived from Ectoderm "Epithelial"

False

T/F: Administration of somatostatin analogs decreases IGF-1; GH remains high.

False

T/F: Alzheimer's causes 50% of dementia.

False

T/F: Nephrogenic Diabetes insipidus occurs due to decreased secretion of vasopressin

False

T/F: Octreotide can be administered IV for acromegaly

False, it has a short half life and should be administered subcutaneously.

mutations causing Craniopharyngioma

GSK 3B binding domain of B-catenin

Case 4 61 y/o woman presents with Purple striae on abdomen Rounded facial appearance Weight gain Mostlyaroundabdomen Newly diagnosed with hypertension Smoked 2 packs/day of cigarette for past 40 yrs Chest x-ray: 4 cm, centrally located lung mass ↑Plasma cortisol ↑ACTH High-dose DXM does not suppress ACTH

ICM Final Diagnosis Cushing Syndrome due to paraneoplastic phenomenon (lung tumor) Treatment Lung tumor surgical removal Chemotherapy Radiation

Most of the anabolic actions of GH are mediated by

IGF-1 (somatomedins) - the peptides produced in the liver and cartilage.

Oxytocin Actions are meditated through which pathway? What are indications for oxytocin? Why would it be given intranasally?

IP3/DAG ↑ Ca+2 Therapeutic uses • To induce and augment labor after cervix has ripened • To control post-partum hemorrhage • To improve milk ejection - nasal oxytocin

Dwarfism contrasted with Achondroplasia

In children hypopituitarism can cause: Dwarfism (GH↓), Cretinism (TSH ↓), Hypogonadism (FSH/LH ↓) and Adrenocortical def. (ACTH ↓) syndrom

Doctor: How are you feeling? Patient: Pretty fair. I have good days and not so good days. Doctor: Well, are you taking your medication? Patient: Of course. Doctor: OK. Are you having any problems? Patient: Sometimes I get nauseated after I take it...and I've been getting gas, too. Doctor: Well, your blood sugars need to be better. Keep taking your medication and I'll increase the dose a bit and see you in 4 weeks.

Indirect Adherence Monitoring-Example

acts by tyrosine kinase system. It increases glucose uptake by muscles and fat, decreases hepatic glucose output, and controls postprandial hyperglycemia.

Insulin

Produced by recombinant technology. They are analogs of human insulin. One or the other amino acid is substituted in the beta chain to modify the pharmacokinetics. must be taken 5-15 minutes before a meal

Insulin lispro, aspart, and glulisine

rapidly dissociated into monomeric form when injected subcutaneously. This allows its rapid absorption into circulation, and rapid onset of action.

Insulin lispro, aspart, and glulisine

- Stimulate POMC/CART neurons -> increased CART and a-MSH - Inhibit NPY/AgRP neurons-> decreased NPY and AgRP - Net effects: Satietyte

Leptin and insulin

Hypopituitarism

Loss of ≥2 anterior pituitary hormones Most commonly destruction of pituitary by tumor Varied presentation Progressive loss of hormones LH/FSH, ACTH, TSH GH Prolactin may increase because of 'dissociation' - •

• Defined by WHO in 1998 as a constellation of metabolic abnormalities that confers increased risk of cardiovascular disease and diabetes mellitus. • Risk Factors: - Overweight/obesity - Sedentary lifestyle - Aging

Metabolic syndrome

Mechanism of action: Decreases hepatic gluconeogenesis Decreases peripheral resistance to insulin action; stimulates glucose uptake and utilization by peripheral tissues Decreases glucose absorption from the GIT Decreases plasma glucagon The hypoglycemic effect is not dependent on the presence of functioning β- cells. (acts mainly in the liver)

Metformin

Retinoblastoma (RB) protein How is this gene mutated and what kind of tumors does it cause?

Methylation of RB gene promoter Aggressive adenomas

PTH tumor

Mutations and Inversions CyclinD1 CASR (Familial) MEN1 (Even in Sporadic tumors) RET

Even with the treatment, mortality is high (>50%). Cardinal features are hypothermia, respiratory depression and unconsciousness. Other features are bradycardia, delayed reflexes, and dry and rough skin.

Myxedema coma: A medical emergency Treatment with IV levothyroxine or triiodothyronine + supportive treatment.

insulin is slowly released from the subcutaneous site as the protamine is enzymatically digested, and the released insulin enters the systemic circulation slowly

NPH

Main cause of anemia in CRF

No erythropoietin made. - Hemolysis during dialysis can also contribute to anemia. - Treatment:Recombinant erythropoietin (moderately expensive). - Blood transfusions are cheaper, but greater risks: infections, iron overload.

No symptoms or signs at birth Clinical manifestations later in childhood or early adulthood Childhood Precocious puberty Clitoromegaly Acne Earlyadulthood Hirsutism Acne Alopecia Infertility Oligomenorrhea/amenorrhea Clitoromegaly Polycystic ovaries May be misdiagnosed as PCOS Clinical manifestations overlap

Nonclassic CAH

Bone Complication of Hyperparathyroidism • - - • - -

Osteitis Fibrosa Cystica Thinned Cortex, Hemorrhage and Cysts in bone Seen mostly in phalanges and Skull Brown Tumors Intraosseous accumulation of Giant cells and osteoclasts Brown color due to hemorrhage

What is the effect of PTH on osteoclasts and bone resorption?

PTH has effects on osteoblasts, not osteoclasts.

Manifests in Older Children and Adolescents, M=F Autosomal recessive mutation in APECED gene (AIRE Addison Disease, Hypoparathyroidism, Type 1 diabetes mellitus, Primary hypothyroidism ,, Chronic Mucocutaneous Candidiasis, Nail dystrophy, Dental enamel, hypoplasia T, vitiligo

Polyglandular Autoimmune Syndromes Type I

• Highest levels of ghrelin ever measured in humans • Ghrelin levels in most obese people are lower than in non-obese

Prader-Willi syndrome

Reminder-Relationship Centered Care

RCC is founded upon 4 principles: • Relationships in health care ought to include the personhood of the participants • Affect and emotion are important components of these relationships • All health care relationships occur in the context of reciprocal influence • The formation and maintenance of genuine relationships in health care is morally valuable.

adenoma Treatment

Radiotherapy for macroadenoma Dopamine agonists - Bromocriptine Cabergoline Surgical resection Trans-sphenoidal

What is the effect of appropriate eyeglasses on diabetic eye disease?

Retinopathy Yearly eye exam by ophthalmologist 65% of adults with poor vision helped by appropriate eyeglasses Treat diabetic eye disease Improve BG control Laser therapy ↓ Severe vision loss by 50-60%

• Insulin has anti-inflammatory effects • Insulin resistance is pro-inflammatory

Role of Insulin

• Normally insulin leads to an increase in Endothelial NOS activity in platelets • This leads to a decrease in thrombin-induced platelet aggregation. • This limits the pro-coagulant effects • Disruption of insulin action thus has a pro- coagulant effect

Role of Insulin in Cardiac Pathology

• Non-absorbable polymer that binds intestinal PO43- preventing its absorption and decreases serum phosphate levels. • Primarily used in patients with renal failure on dialysis. • Adverse effects are mainly GI symptoms: nausea, vomiting, dyspepsia, diarrhea

Sevelamer

Sevelamer

Sevelamer is a phosphate binder used in treatment of renal osteodystrophy

a dipeptidyl peptidase-4 inhibitor given as an oral antidiabetic drug

Sitagliptin

Treatment of acromegaly -

Somatostatin analogues Surgical - Medical Trans • sphenoidal - • Growth hormone receptor antagonist Octreotide - • Radiotherapy Pegvisomant •

It has inhibitory effects on almost all GIT secretions including gastrin and hydrochloric acid. This effect is utilized clinically to suppress the secretion of mediators in carcinoid syndrome, VIPomas, gastrinomas, and other such hormone secreting tumors of GIT

Somatostatin is also released from pancreas and other parts of GIT.

Recombinant human GH

Somatotropin

recombinant human GH (rhGH) with191 amino acids peptide identical to human GH

Somatropin

7. A 5 year old girl is brought to the doctor by her mother, who states that the girl has been drinking a lot of water lately and even wetting her bed at night repeatedly. Physical examination reveals a young girl with slightly protruding eyeballs. An x-ray of her head reveals multiple lytic bone lesions involving the skull. Biopsy shows aggregates of langerhans cells and a diagnosis of Histiocytosis-X is made. Which of the following sets of laboratory values is most likely in this patient? A. Hypernatremia and low osmolarity with low specific gravity urine B. Hypernatremia and high osmolarity with high specific gravity urine C. Hyponatremia and low osmolarity with low specific gravity urine D. Hyponatremia and high osmolarity with high specific gravity urine E. Normal sodium and normal osmolarity with normal specific gravity urine

The diagnosis is diabetes insipidus (DI). This characterized by polydipsia and polyuria but not the polyphagia and hyperglycemia of diabetes mellitus. The hallmark findings are hypernatremia with low urine osmolarity. Causes of DI may be idiopathic, radiation and surgery, hypothalamic tumors, infections and Histiocytosis-X (Hand-Shuller- Christian Syndrome). Histiocytosis-X is characterized by a triad of bone lesions, diabetes insipidus and exophthalmos.

What is C-Peptide?

The full proinsulin protein is shown here. The yellow part called the C peptide is cleaved off in order to produce the functional insulin (red). One C peptide is produced foreach one of the functional Insulin molecules in the body

Functional Incontinence

The problem is getting to and using the toilet. - Occur without urinary tract pathology. - can be associated with poor mobility chronic/acute illness, poor cognition or medication e.g diuretics.

What causes Sheehan's Syndrome?

There is no direct arterial blood supply to the anterior hypophysis - only a low-pressure portal vein system Due to Hypotension the low pressure hypothalamo-hypophyseal portal system collapses This compromises the blood supply to the Anterior Pituitary Leading to necrosis

acts as storage form of thyroid hormones in the lumen of follicles. It is enough to maintain euthyroid state for 2-3 months

Thyroglobulin

ndocytosed by follicular cells where it undergoes proteolysis to release T3 and T4 into the blood.

Thyroglobulin

Therapeutic uses of oxytocin:

To induce and augment labor after cervix has ripened: administered IV To control post-partum hemorrhage: administered IM To improve milk ejection: nasal oxytocin is available

Selective V2-receptor antagonist Oral administration

Tolvaptan

Treatment of hyperprolactinemia

Treatment with dopamine receptor agonists is the preferred treatment. These drugs act on D2 receptors in anterior pituitary to inhibit prolactin secretion. Bromocriptine (synthetic ergot derivative) Cabergoline (long-acting) Bromocriptine is preferred over cabergoline in women who desire to conceive and are having unprotected sexual intercourse during the therapy.

T/F Posterior Pituitary is derived from Neuroectoderm "Neural" Anterior Pituitary is derived from Ectoderm "Epithelial"

True

T/F: Administration of GH antagonists decreases IGF-1; GH remains high.

True

T/F: Administration of somatostatin analogs result in decrease in GH and IGF-1 levels.

True

T/F: Alzheimer's causes 65% of dementia.

True

T/F: Nephrogenic Diabetes insipidus occurs due to insufficient renal response to vasopressin

True

T/F: Neurogenic (or Central) Diabetes insipidus occurs due to decreased secretion of vasopressin

True

The prevalence in the USA is highest in whites and lowest in African Americans and Hispanic Americans. The classic presentation is with polyuria, polydipsia and polyphagia. If it is not recognized at that stage then the patient goes into diabetic ketoacidosis

Type 1 Diabetes (Insulin-dependent)

It provides slow basal concentration of insulin throughout the day

Ultra-lente

- Due to detrussor muscle instability/overactivity - Symptoms: Urgency, frequency, can't make it to the toilet on time (bladder problem) - 17% of population over age 65 - Management: bladder training and medication

Urge incontinence

What are expected urinalysis results for CKD in Hypertensive Nephropathy? (cells/casts, protein)

Urine: - Few cells / casts - Proteinuria: • due to compensatory hypertrophy of less affected glomeruli with higher intraglomerular pressure mild < 1 g/day (focal involvement) but may reach 10 g/day if superimposed renovascular disease or malignant HPT

Management of Diabetes Insipidus

Vasopressin (arginine-vasopressin)

• Hemorrhage, fibrin thrombi, and necrosis in the adrenals • Patients develop purpura, and DIC, septic shock, and die in a few hours • Most common etiologic Infectious agents are • Neisseria meningitidis • Pseudomonas aeruginosa • Streptococcus pneumoniae • Staphylococcus aureus • Sudden withdrawal of high dose steroid therapy

Waterhouse-Friderichsen Syndrome (Acute "Adrenal Apoplexy")

• Lanreotide:

a long acting analog of somatostatin; once every 4 weeks

deposits of amorphous pink material within glomeruli, interstitium, and arteries

amyloidosis

maintains insulin levels in-between the meals

basal insulins

effects of GH & IGF-1 on Protein synthesis (muscle)

both increase

Dopamine (D2) agonists (ergot derivatives) acting on the hypothalamus

bromocriptine cabergoline

TSH action on thyroid gland is mediated by ____and leads to ______________

cAMP stimulation of iodide uptake and its concentration in the follicular cells ("iodide trapping").

Drug interactions of insulin

Beta-blockers: Counter-regulatory mechanisms such as activation of beta 2 adrenoceptors in the liver come into play in the setting of hypoglycemia to help normalize plasma glucose levels. Activation of beta 2 adrenoceptors in the liver mediates glycogenolysis that helps in regulating plasma glucose levels. Concomitant administration of beta-blockers would prolong hypoglycemia (caused by insulin) by inhibiting counter-regulatory mechanisms (glycogenolysis). Beta 1 selective adrenoceptor antagonists (such as atenolol) may be safer than non-selective beta-blockers (propranolol) in this respect. Beta-blockers mask the warning signs of hypoglycemia (palpitation, tremors, anxiety) in diabetic patients, delaying the recognition and treatment of hypoglycemia. Ethanol: precipitates hypoglycemia Salicylates: precipitate hypoglycemia Thiazides, loop diuretics, corticosteroids: raise the blood glucose and reduce effectiveness of insulin; concomitant use of diuretics with insulin (especially IV) can increase the chances of hypokalemia that can result in ventricular arrhythmia, respiratory paralysis and even death.

Mechanism of action of somatostatin

Binding of one GH molecule to the extracellular domain of two GH receptors induces their dimerization and activates intracellular domain. Activated domain associates with Jak2 tyrosine-protein kinase and phosphorylates relevant proteins that activate downstream signaling pathways, including signal transducer and activator of transcription (Stat), which ultimately modulate gene expression. Most of the anabolic actions of GH are mediated by somatomedins (Insulin- like growth factor, IGF-1) - the peptides produced mainly in the liver and cartilage in response to the action of GH. The somatomedins stimulate skeletal growth, amino acid transport, protein synthesis, nucleic acid synthesis and cell proliferation Direct effects: GH causes catabolic effects by its direct actions. Lipolysis Hyperglycemia by stimulating gluconeogenesis and by decreasing insulin sensitivity of tissues

Lab investigation (DKA) CBC BC

CBC Hct elevated Dehydration leading to hemoconcentration WBC increased Stressed state Increased adrenaline → demargination of white cells Infection CT scan if altered consciousness Rule out cerebral edema

Adverse oxytocin Reactions:

Cardiac arrhythmia, CNS stimulation Uterine hyperstimulation can cause fetal distress Oxytocin also has ADH-like actions that might cause edema and hyponatremia. Contraindications: Fetal distress Abnormal fetal presentation Prematurity CPD (cephalo-pelvic disproportion)

Treatment of hypoglycemia

Conscious patients: 10-20 g rapidly absorbed carbohydrate (juice, sugar, oral glucose) Unconscious patients: 20-50 mL of 50% glucose solution IV over a 2-3 minute period Unconscious patients with no IV facilities: 1 mg glucagon SC or IM to restore consciousness (mean response time 6.6 min), followed by IV injection.

Who Should You Screen?(ADA 2011)

Consider in all adults with BMI ≥25 kg/m2 and additional risk factors 10 relative with DM High-risk race/ethnicity African American, Latino, Native American, Asian American, Pacific Islander Women delivering a baby weighing >9 lb or diagnosed with GDM HTN (≥140/90 mmHg or on therapy for HTN) HDL cholesterol <35 mg/dl (0.90 mmol/l) and/or triglyceride >250 mg/dl (2.82 mmol/l) Women with PCOS A1C ≥5.7%, IGT, or IFG on previous testing Clinical conditions associated with insulin resistance Severe obesity, acanthosis nigricans HxCVD In absence of above criteria, testing should begin at age 45 years If results are normal, repeat testing at least at 3-year intervals

8-year-old presents with vomiting x2 days C/o abdominal pain Does not want to eat Passing urine frequently Today difficulty breathing, sleepy, and fussy Looks gaunt and dehydrated so Mom has brought him to clinic On examination BP 96/50mmHg RR 36/min PR 120/min Mucus membranes pink, anicteric, dry Deep sighing respiration with use of accessory muscles (Kussmaul breathing) Abdomen: soft, decreased bowel sounds, mild diffuse tenderness but no rebound or guarding boratory results CBC Hb 14.8 gm/dl WBC 13,000/ml Platelet 298,000/ml Chemistries BUN 38 mg/dl Creatinine 0.6 mg/dl K 3.2 mmol/l Na 138 mmol/l HCO3 10 mmol/l Blood glucose 260 mg/dl ABG pCO2 28 mmHg pO2 102 mmHg pH7.12 Urinanlysis Ketones: Positive

Diagnosis: Type 1 Diabetes Mellitus with ketoacidosis

Case 3 continued diabetic woman - - 15 years later.... Patient is found unresponsive in a confused state at home. She is brought to the hospital. She had been experiencing polyuria and poor fluid intake for the past week. Family notes that she was recently diagnosed with pneumonia and has generally been non- compliant with treatment. On examination mucus membranes are dry, skin turgor markedly decreased. RBS: 620 mg/dl. Na 145mEq/L. Creatinine moderately elevated, osmolarity 340mOsm/ml, NO ketones, Bicarbonate normal.

Diagnosis: Type 2 DM-Hyperglycemic hyperosmolar non-ketotic State (HHNS)

Case 3 15-year-old boy presents to ER with Fever Rigors Vomiting Headache Rosy, spotted rash for 1 days This morning developed focal seizure O/E Comatose patient BP 70/50 mm Hg and P 120/min Skin: cold, clammy with peripheral cyanosis, petechial & purpuric rash Nuchal rigidity + Given saline infusion BP does not improve

Provisional diagnosis Gram negative septicemia Presumed meningococcal infection Disseminated intravascular coagulation Shock- Septicemic Meningococci can be cultured from blood and sometimes from cutaneous lesions Acidosis and acute renal failure may also be seen

Standard of Care Every visit Weight management BP Review SMBG Foot exam

Quarterly HbA1c Semi-annually if <7 Yearly Urine microalbumin Creatinine Lipid panel Eye exam

TIRED mnemonic for hypoglycemia

Tachycardia Irritability Restlessness Excessive hunger Depression and diaphoresis

Pheochromocytoma : Treatment

Treatment is surgical Before surgery Fluid load Blockade with phenoxybenzamine β-adrenergic antagonist

Contraindications and cautions with the use of sulfonylureas:

Type 1 diabetes mellitus: no functioning beta cells, so no therapeutic effect. Pregnancy and lactation: because these agents can cross placenta and can be excreted in breast milk; changeover to insulin. (Currently, there are some clinicaltrials ongoing to assess efficacy and safety of certain oral antidiabetic agents (metformin and glyburide) to control hyperglycemia during pregnancy). Allergy to sulfa drugs. Stressful conditions during which glucose control can be difficult: Start insulin during stressful events (infections, trauma, surgery etc.). Significant hepatic and renal insufficiency: doses may need to be reduced. Special warning on the increased risk of cardiovascular mortality with sulfonylureas.

Why Screen? ADA Rationale

Type 2 DM frequently not diagnosed until complications appear Approximately 1⁄4 of all people in US with DM may be undiagnosed Prediabetes and DM meet established criteria for conditions in which early detection is appropriate Long presymptomatic phase before the diagnosis made Effective interventions exist to prevent progression of prediabetes to DM and to reduce risk of complications

Therapeutic uses of metformin:

Type 2 DM: Obese patients with "insulin resistance". o Usually the first drug to start for the management of type 2 DM o Often used in combination with sulfonylureas if metformin alone is not adequate. Metformin is also useful in polycystic ovary syndrome (PCOS).

Lab investigation (DKA) Urinalysis Blood gases

Urine Ketones Glucose cannot enter cells Substitutes energy source with ketone bodies Blood gases Metabolic acidosis Increased anaerobic respiration and ketosis Respiratory compensation may also be seen

Therapeutic uses of thiazolidinediones:

Used in combination with other oral anti-diabetic drugs in type 2 diabetic patients. In September 2010, US FDA put restrictions on rosiglitazone in response to the data that suggested an elevated risk of cardiovascular events, such as heart attack and stroke. This drug is now available under risk evaluation and mitigation strategy for the diabetic patients who are not able to achieve glucose control on other medications. Adverse effects: Fluid retention, edema, angina, myocardial infarction Contraindications: Congestive heart failure (Black Box Warning); liver disease.

Pheochromocytoma: Signs and Symptoms

Usually in paroxysms Symptom triad Headache Palpitation Sweating Other symptoms Flushing Anxiety Nausea Weightloss Fatigue Precipitated by Emotional stress Exercise Anesthesia Abdominal pressure Intake of tyramine- containing foods Wide fluctuations in BP

Pheochromocytoma : Investigation

VMA in urine Diet may affect it Plasma free metanephrines and normetanephrines CT scan 131I-MIBG Iodine 131-labelled metaiodobenzylguanidine scan

Drugs to manage SIADH

Vasopressin receptor antagonists: These are the preferred drugs today to manage hyponatremia (hypervolemic or euvolemic hyponatremia). o Conivaptan (vasopressin antagonist): non-selective vasopressin receptor antagonist with high affinity for V1a and V2. Parenteral administration o Tolvaptan: Selective V2-receptor antagonist Oral administration Demeclocycline (a tetracycline): inhibits the effect of ADH on the distal tubule (not a preferred drug now)

There can be excessive protein breakdown in end-stage renal disease, aggravated by infections and other stresses including:

- Stimulated by acidosis - Stimulated by cortisol and cytokines Excessive protein breakdown worsens uremia (more nitrogenous wastes formed), important during infections.

51 A 39‐year‐old man has had headache, weakness, and a 5‐kg weight gain over the past 3 months. He has experienced mental depression during the same period. On physical examination, his face is puffy. His temperature is 36.9° C and blood pressure is 160/75 mm Hg. He has cutaneous striae over the lower abdomen and ecchymoses scattered over the extremities. A radiograph of the spine shows a compressed fracture of T11. Laboratory findings show fasting plasma glucose level of 200 mg/dL, serum Na+ of 150 mmol/L, and serum K+ of 3.1 mmol/L. The plasma cortisol level is 38 μg/dL at 8:00 am and 37 μg/dL at 6:00 pm. Administration of low and high doses of dexamethasone fails to suppress the plasma cortisol level and excretion of urinary 17‐hydroxycorticosteroids. The plasma corticotropin level is 0.8 pg/mL. Which of the following lesions is most likely to be present in this man? A Adenohypophyseal adenoma B Adrenal cortical adenoma C Extra‐adrenal pheochromocytoma D Small cell carcinoma of the lung E Thyroid medullary carcinoma

...51 B The clinical and laboratory features of this case point to Cushing syndrome. The dexamethasone suppression test is used to localize the source of excess cortisol. When low‐dose and high‐dose dexamethasone trials fail to suppress cortisol secretion, a pituitary corticotropin‐secreting adenoma as the source of excess glucocorticoids is unlikely. The choice is an ectopic source of corticotropin, such as a lung cancer, or a tumor of the adrenal cortex that is secreting glucocorticoids. The plasma corticotropin level distinguishes between these two possibilities. Corticotropin levels are high if there is an ectopic source, whereas glucocorticoid secretion from an adrenal neoplasm suppresses corticotropin production by the pituitary, leading to atrophy of the contralateral adrenal cortex. A pheochromocytoma secretes catecholamines, accounting for hypertension, but not osteoporosis or the electrolyte changes noted. Medullary thyroid carcinomas have neuroendocrine cells, but are unlikely to produce corticosteroids.

A 58-year-old man with a history of diabetes mellitus has noted the presence of bone pain, especially of his hands, for the past 6 months. On physical examina?on there is no swelling or redness of his hands, no joint deformity, but the range of mo?on is slightly decreased. Laboratory studies show sodium 139 mmol/L, potassium 4.0 mmol/L, chloride 98 mmol/L, C02 22 mmol/L, glucose 153 mg/dL, crea?nine 7.8 mg/dL, calcium 7.8 mg/dL, phosphorus 5.7 mg/dL, total protein 6.2 g/dL, and albumin 4.0 g/dL. Which of the following condi?ons is this man most likely to have? A. Adrenal adenoma B. Medullarythyroid carcinoma C. Extra-adrenal pheochromocytoma D. Parathyroid hyperplasia E. Pituitaryadenoma

0% 0% 0% 0% 0% 15 25 Countdown Adrenal adenoma Medullary thyroid carc... Extra-adrenal pheochr... Parathyroid hyperplasia Pituitary adenoma Concept and Explana?on • The most important cause of secondary hyperparathyroidism is renal failure. The most common cause of renal failure are Diabetes mellitus and hypertension • Renal failure is diagnosed by the BUN and crea?nine levels. Low calcium and high phosphorus levels suggest that compensatory increase of PTH will be triggered. Pain in pa?ent's hands could be due to an arthri?c process (which is ruled out by absence of joint involvement and inflamma?on), the next logical step isto connect the suspected high PTH to this pain. Tunneling resorp?on of bone in the fingers is one of the first features of renal osteodystrophy. Therefore this pa?ent most likely has secondary hyperparathyroidism and there will be parathyroid hyperplasia. None of the other condi?ons can produce all of the symptoms and signs here. 26

A 35 year old woman with history of schizophrenia presents with nipple discharge and amenorrhea for 5 months. Physical examina?on reveals a milky discharge from both nipples. MRI shows enlargement of pituitary. What is the most likely cause of pituitary enlargement in this pa?ent? 1. Pituitary tumor 2. Loss of hypothalamic regula?on 3. GnRH excess 4. GHRH excess

0% 0% 0% 0% 15 Countdown 2 Pituitary tumo... Loss of hypoth... GnRH excess GHRH excess Concept and Explana?on • Prolac?n secre?on from the pituitary is nega?vely regulated by Dopamine. • Therefore loss of Dopamine (as in this case may have been due to Dopamine inhibitors used for trea?ng her condi?on) will lead to not only increased Prolac?n produc?on and secre?on but may also lead to an increased cell number of prolac?n secre?ng cells causing pituitary enlargement

A 23-year-old man wants to increase his muscle mass for playing physical contact sports. He aTempts to accomplish this by injec?ons of a substance obtained from a 'friend'. Over the next year he develops acne, icterus, and increased fa?gue. An infer?lity workup reveals hypospermia. Laboratory studies show Hgb 19.2 g/dL, Hct 58.1.4%, platelet count 330,300/microliter, and WBC count 7500/microliter. 101 Which of the following neoplasms is he at greatest risk for developing in the future? • A Hepatocellular carcinoma • B Papillary carcinoma • C Renal cell carcinoma • D Rhabdomyosarcoma • E Seminoma

0% 0% 0% 0% 0% 15 102 Countdown A Hepatocellular carcinoma B Papillary carcinoma C Renal cell carcinoma D Rhabdomyosarcoma E Seminoma Concept and Explana?on This is a case of "steroid abuse". One of the complica,ons is hepatocellular carcinoma. Other complica,ons of steroid abuse are: • Stunted growth • Hepa?c toxicityand tumors later • Increased infec?ons • Hair loss • Hypogonadism • Cardiomyopathy • Hypertension • Increased tendency to clot: pulmonary embolism and stroke 103

A 36 year old woman complains of swelling in the anterior por?on of her neck, which she first no?ced 6 months ago. She has some discomfort during swallowing. Physical findings are a symmetrically enlarged thyroid. A thyroid biopsy is shown. 10 Which of the following best describes the clinical symptoms expected in this pa?ent? 1. Dry skin, hyperfa?guability, hypogonadism 2. Nervousness, irritability, paresthesiae, tetany 3. Tremors, Tachycardia, weight loss 4. Pale complexion, cold intolerance, lethargy 5. Hyperpigmenta?on, weakness, hypotension

0% 0% 0% 0% 0% 15 11 Countdown Dry skin, hype... Nervousness, i... Tremors, Tachy... Pale complexio... Hyperpigmentat... Concept and Explana?on • Symmetrically enlarged thyroid usually points to a func?onal disorder rather than a tumor. • The biopsy is that of a hyperfunc?onal thyroid gland- tall columnar epithelial lining the follicles, bluish colora?on of the colloid and the scalloped, moth eaten edges of the colloid. The only answer that fits the hyperthyroid picture fully is C, B is ruled out due to the paresthesiae and tetany 12

A 41-year-old man has been drinking large quan??es of water--up to 20 liters per day--for the past week. Today he has altered conciousness. On physical examina?on he has diminished skin turgor and dry mucous membranes. Laboratory studies show sodium 162 mmol/L, potassium 4.1 mmol/L, chloride 121 mmol/L, and bicarbonate 27 mmol/L. His serum glucose is 75 mg/dL and crea?nine 1.0 mg/dL. His serum osmolality is 343 mOsm/kg. 110 A deficiency of which of the following hormones is most likely present in this man? • A An?diure?c hormone • B Oxytocin • C Insulin • D Growth hormone • E Prolac?n

0% 0% 0% 0% 0% 15 111 Countdown A Antidiuretic... B Oxytocin C Insulin D Growth hormo... E Prolactin Concept and Explana?on • Low ADH causes water loss without aTendant solute loss in diabetes insipidus • As long as the pa?ent keeps replacing the water they are loosing in urine, they are alright. The pa?ents will gointo dehydra?on and comaif they have altered conciousness and stop drinking water. • The other choices that can lead to polyuria and polydipsia are C and D due to hyperglycemia, but not of this propor?on. 112

A 55-year-old woman has had diffuse, dull, constant abdominal pain for the past 2 months. On physical examina?on no abnormal findings are noted. An abdominal CT scan shows a 3 cm right adrenal mass. The right adrenal is excised and on microscopic examina?on the mass is composed of cells resembling adrenal cortex. Which of the following features is the most reliable indicator that this mass is malignant? • A Cellular atypia • B Presence of mitoses • C Invasion • D Size of the mass • E Cellular necrosis

0% 0% 0% 0% 0% 15 123 Countdown A Cellular aty... B Presence of ... C Invasion D Size of the ... E Cellular nec... Concept and Explana?on • Absence of cellular atypia does not rule out malignancy in endocrine neoplasms. • Metastasis and or invasion determine the carcinoma or malignant status in most endocrine neoplasms. 124

A 56 year old man presents with episodic occasional fain?ng and nervousness for the past 5 months. He says that he feels panicky, weak and sweats profusely during these aTacks. The symptoms are relieved by drinking regular "mountain dew" or a smoothie. Which of the following tests will be the best test for diagnosis in this pa?ent? 1. Blood sugar for hypoglycemia 2. A test for insulin secre?on 3. HbA1c 4. Ultrasound for a suprarenal tumor 5. Spiral CT for Lung tumor

0% 0% 0% 0% 0% 15 123454 Countdown Concept and Explana?on • The pa?ent is showing "Whipple's triad"- Episodic hypoglycemia (symptoms and signs) and the hypoglycemia improves when he ingests glucose. He must have an insulinoma • The diagnos?c test is to look for the amount of insulin secreted by the pancreas. We will test for C-pep?des. It will also help us rule out any extraneous source of oral hypoglycemic agents

A female neonate develops neonatal sepsis and then develops convulsions and dies soon a]er birth. Her karyotyping was as follows and there is family history of a chromosome 22 abnormality in the family. 16 Which of the following is most likely to be the cause of convulsions in this pa?ent? 1. Acute hemorrhagic adrenali?s 2. Hyponatremia 3. Hypocalcemia 4. Hypoglycemia 5. Hypokalemia

0% 0% 0% 0% 0% 15 17 Countdown Acute hemorrha... Hyponatremia Hypocalcemia Hypoglycemia Hypokalemia Concept and Explana?on • DiGeorge's syndrome presents as immune deficiency and hypoparathyroidism, as there is aplasia of both thymus and parathyroids. • The repeated and severe infec?ons in these pa?ents are due to the immune deficiency and the hypocalcemia is due to lack of Parathyroid hormone. Hypocalcemia is the cause of convulsion as it increases neuromuscular irritability. Normally calcium controls the membrane poten?al. 18

A 12-year-old girl with Goodpasture syndrome progressed to chronic renal failure and was placed on chronic hemodialysis. She developed severe hypertension. However, parents had difficulty accep?ng the reality of her disease, and she missed dialysis appointments and did not take her an?hypertensive medica?on regularly. Laboratory studies now show her serum ionized calcium is 5.9 mg/dl with phosphorus 6.2 mg/dl and albumin 3.6 g/dl. Which of the following bone lesions is she most likely to have? 83 Which of the following bone lesions is she most likely to have? • A Ostei?s fibrosa cys?ca • B Fibrous dysplasia • C Osteosarcoma • D Giant cell tumor • E Osteomalacia

0% 0% 0% 0% 0% 15 84 Countdown A Osteitis fib... B Fibrous dysp... C Osteosarcoma... D Giant cell t... E Osteomalacia... Concept and Explana?on • Renal osteodystrophy due to secondary hyperparathyroidism in young children is ostei?s fibrosa cys?ca and renal rickets. • Osteomalacia (E) will be seen in adults. All the others are real tumors and have no connec?on to the secondary hyperthyroidism 85

Sclerotic bands along the superior and inferior vertebral body endplates give a striped appearance to the vertebral bodies

The Rugger Jersey spine sign is diagnostic of the osteodystrophy associated with secondary hyperparathyroidism of chronic renal failure

All are well absorbed orally. Administered ~ 30 minutes before meal. 90% or more bind to plasma proteins.

1st and 2nd generation sulfonylureas differ according to their pharmacokinetic properties. Chlorpropamide has the longest half-life (~30 hrs). 2nd generation agents are approximately 100 times more potent than 1st generation. Although their half-lives are short (3-5 hours), their hypoglycemic effect persist for 12-24 hours. They are often administered once daily. Sulfonylureas are primarily metabolized in the liver and excreted in the urine. Accordingly, they should be used cautiously in patients with liver or kidney dysfunction.

Differential diagnosis for hypoglycemia

Abnormal Insulin Sensitivity Diffuse Liver disease Inherited Glycogenoses (Glycogen Storage Diseases) Ectopic production of IGF-II e.g. Fibromas Abuse of hypoglycemic agents Insulinoma Further Lab tests Urine test substance abuse Blood alcohol level Insulin and C-peptide assay

Evidence that DM type 1 is an Autoimmune disorder

About 10% of these patients present as either part of the Polyglandular Autoimmune Syndromes or have at least one other organ- specific Autoimmune disease Hashimoto disease Graves disease Addison disease Myasthenia Gravis Pernicious anemia

Treatment of Waterhouse-Friderichsen Syndrome

Acute adrenal insufficiency crisis is a medical emergency Treatment should be given on suspicion Blood drawn for cortisol levels IV hydration with saline High-dose hydrocortisone IV Antibiotics for infection

Maintenance Treatment

After stabilization Lifelong replacement of glucocorticoid and mineralocorticoid Monitor treatment clinically Growth charts in young Weight ↑dose with stress of minor illness Fever, nausea, vomiting Give IM if vomiting or major stressful events Surgery, accident

Nephrogenic Diabetes insipidus Drugs for treatment:

Amiloride: used in lithium-induced diabetes insipidus. Thiazide diuretics

DIABETIC KETOACIDOSIS (DKA)

An absolute or relative insulin deficiency promotes lipolysis and metabolism of free fatty acids to ketones (β-hydroxybutyrate, acetoacetic acid, and acetone) in the liver. Excess glucagon enhances gluconeogenesis and impairs peripheral ketone utilization. Stress (infection, pregnancy, trauma, pancreatitis, hyperthyroidism and acute MI) can contribute to development of DKA by stimulating release of insulin counter- regulatory hormones such as glucagon, catecholamines, glucocorticoids, and growth hormone. Patient present with signs and symptoms of hyperglycemia (thirst, polyuria, fatigue, blurred vision, consistently elevated blood glucose concentrations), acidosis (fruity breath odor, deep and difficult breathing), dehydration (dry mouth; warm dry skin; fatigue) and may experience stomach pain, nausea, vomiting and loss of appetite Management: Fluid administration, insulin (continuous IV infusion of regular insulin), and correction of electrolyte imbalance (be careful of serum potassium levels).

A 27-year-old woman has had diarrhea with for the past 1 week. On physical examina?on her thyroid gland is diffusely enlarged and tender. Laboratory studies show TSH 0.3 mU/L, T4 15.8 microgram/dL, and free thyroxine 4.3 ng/ ml. The representa?ve microscopic appearance of her thyroid is shown here. 35 Based on these findings what will be seen on a thyroid scan of this pa?ent? 1. Diffuse and higher uptake 2. Hot nodule 3. Cold Nodule 4. Diffuse low uptake 5. No or very low uptake

0% 0% 0% 0% 0% 15 36 Countdown Diffuse and hi... Hot nodule Cold Nodule Diffuse low up... No or very low... Concept and Explana?on • Paradoxical "thyrotoxicosis" with no or very low iodine uptake on scan suggests ongoing destruc?on of thyroid gland • DeQuervain disease is a self limi?ng inflammatory condi?on-therefore the thyroid gland tenderness. During the acute phase there is destruc?on of thyroid follicles which releases the thyroxine causing transient thyrotoxicosis. There is no iodine uptake by the follicular cells due to the diffuse inflammatory process and loss of func?on (remember the cardinal signs of inflamma?on!) 37

A 60-year-old man with a long history of diabetes mellitus has noted pain in his right leg for the past 3 months. On physical examina?on there are no abnormal findings. Laboratory studies show his serum phosphorus is 4.8 mg/dL, calcium 8.9 mg/dL, urea nitrogen 48 mg/dL, and crea?nine 5.0 mg/dL. The appearance of the parathyroid glands removed at surgery and shown here. 41 which of the following complica?ons is he is most likely to have? • A Gout • B Polyneuri?s • C Chronic arthri?s • D Ostei?s fibrosa cys?ca • E Metasta?c renal cell carcinoma

0% 0% 0% 0% 0% 15 42 Countdown A Gout B Polyneuritis... C Chronic arth... D Osteitis fib... E Metastatic r... Concept and Explana?on • Hyperparathyroidism causes demineraliza?on of bones • This is a case of secondary hyperparathyroidism due to Diabe?c renal failure (BUN and Crea?nine). The bone pain suggests prolonged bone resorp?on (early cases have resorp?on of small bones of the hands and skull) and now large bones are involved. The pa?ent is at risk for developing os?e?s fibrosa cys?ca and osteomalacia (not a choice here). 43

A 39-year-old woman has noted discomfort with fullness to her neck over the past year. On physical examina?on she is afebrile and normotensive. There is irregular enlargement of her thyroid gland, but no tenderness on palpa?on. A scin?graphic scan shows normal uptake except for increased uptake in a 1 cm area in the le] lower lobe. Her an?-thyroid peroxidase an?body is nega?ve. 86 Which of the following complica?ons is she most likely to develop? • A Thyrotoxicosis • B Papillary carcinoma • C Graves disease • D Subacute thyroidi?s • E Hypothyroidism

0% 0% 0% 0% 0% 15 87 Countdown A Thyrotoxicos... B Papillary ca... C Graves disea... D Subacute thy... E Hypothyroidi... Concept and Explana?on • "Hot nodules" irrespec?ve of pathology can produce Thyrotoxicosis • The pa?ent had a hyper-func?oning nodule in the thyroid, papillary carcinoma normally presents as a cold nodule, Graves will have diffuse enlargement of thyroid with diffuse high iodine uptake, Subacute thyroidi?s wil lpresent with transient thyrotoxicosis but there will be no or very liTle uptake on scan, hypothyroidism will present with diffuse enlargement of thyroid and low iodine uptake on scan. 88

A clinical study is performed involving subjects who developed Addision disease. They were recorded to have laboratory studies with hyponatremia, hyperkalemia, hypoglycemia, and decreased plasma cor?sol. They became hypotensive. In some subjects, this disease had an acute onset over less than 2 days' ?me. 89 Which of the following diseases is most likely to produce this acute course? • A Waterhouse- Friderichsen syndrome • B Metasta?c small cell anaplas?c carcinoma • C Disseminated Mycobacterium tuberculosis infec2on • D Reac?ve systemic amyloidosis • E Blunt force abdominal trauma

0% 0% 0% 0% 0% 15 90 Countdown A Waterhouse-F... B Metastatic s... C Disseminated... D Reactive sys... E Blunt force ... Concept and Explana?on • Sudden, acute hypoadrenalism is caused by infec?on and destruc?on of adrenal gland. • This is defined as Waterhouse-Friederichsen syndrome. A classical presenta?on is given earlier. All other condi?ons will have a more insidious and chronic clinical picture leading to Addison disease. Blunt force abdominal trauma can damage the kidney but normally not affect adrenal func?on. 91

A 40-year-old woman has noted enlargement of her anterior neck region over the past 8 months. On physical examina?on her vital signs include T 36.8 C, P 64/minute, RR 15/minute, and BP 155/105 mm Hg. There is diffuse, symmetrical thyroid enlargement without tenderness. A chest radiograph is normal. Fine needle aspira?on of the thyroid yields cells consistent with a neoplasm. Biopsy is shown. Laboratory studies show that she is euthyroid, but her serum ionized calcium is mildly elevated. Which of the following is likely to be elevated in her blood? A. Calcitonin B. TSH C. Parathyroid Hormone D. PTHrP E. Vitamin D F. T3 and T4

0% 0% 0% 0% 0% 0% 10 66 Countdown Calcitonin TSH Parathyroid Ho... PTHrP Vitamin D T3 and T4 Concept and Explana?on • Medullary carcinoma produces high levels of calcitonin that has poor biologic ac?vity • The diagnosis is confirmed by the histology and the posi?ve orange stain with congo-red (right panel). High ionic calcium is due to poor biologic ac?vity of the calcitonin made by the tumor cells. TSH will be normal, PTHwill be suppressed or normal, PTHrP will be absent or normal, Vitamin D will be normal, as will be the T3 and T4. 67 71

A 50-year-old man has been diagnosed with a malignancy of the thyroid. The biopsy is shown. He undergoes a total thyroidectomy. Within a day following surgery, he is noted to have peri-oral ?ngling sensa?ons and neuromuscular irritability. 107 Which of the following serum laboratory tests should be ordered immediately to determine further therapy for this man? • A TSH • B Parathormone • C Total thyroxine • D Ionized calcium • E Calcitonin • F Iodine

0% 0% 0% 0% 0% 0% 15 108 Countdown A TSH B Parathormone... C Total thyrox... D Ionized calc... E Calcitonin F Iodine Concept and Explana?on • An important cause of hypoparathyroidism is surgical removal during thyroid surgery • This pa?ent has developed hypocalcemia due to the lack of PTH hormone. The earliest diagnosis of falling calcium levels can be made by assessing ionized calcium levels. The neuromuscular irritability is a result of that. The pa?ent may also have peri-oral paresthesiae. 109

A 2-year-old child is noted to have abdominal enlargement on a visit to the pediatrician. The physical examina?on is otherwise unremarkable. His abdominal MR image reveals a lesion above the le] kidney, shown here. 38 Which of the following laboratory test findings is most likely to be present in this child? 1. Elevated serum cor?sol 2. Decreased serum potassium 3. Increased urine homovanillic acid 4. High hemoglobin 5. Increased plasma renin 6. Elevated serum estrogen

0% 0% 0% 0% 0% 0% 15 39 Countdown Elevated serum... Decreased seru... Increased urin... High hemoglobi... Increased plas... Elevated serum... Concept and Explana?on • The most common adrenal tumor in childhood is Neuroblastoma • The diagnosis is made by imaging and detec?on of tumor metabolic products in urine- Homovanillic acid (HVA) and Vanillymandellic acid (VMA) ra?o. HVA is increased. Other poor prognos?c factors are age over 1 year at diagnosis, lack of differen?a?on to pseudo- roseTes, metastasis, N-myc amplifica,on and Neuron specific enolase posi?vity. 40

A 19-year-old previously healthy woman has had a mild pharyngi?s followed by a high fever over the past 24 hours. When seen in the emergency room, her skin now shows extensive areas of purpura. Vital signs include temperature 39 C, pulse rate 102/minute, respiratory rate 21/minute, and blood pressure 80/55 mm Hg. Laboratory studies show a serum sodium of 115 mmol/L, potassium 5.3 mmol/L, chloride 92 mmol/L, CO2 22 mmol/L, glucose 42 mg/dL, and crea?nine 1.1 mg/ dL. Autopsy of another pa?ent that had presented with similar findings had shown the adrenals as below. 47 Which of the following is the most likely diagnosis? • A Idiopathic adrenali?s • B Disseminated tuberculosis • C Reac?ve systemic amyloidosis • D Sheehan syndrome • E Meningococcemia • F Hemochromatosis

0% 0% 0% 0% 0% 0% 15 48 Countdown A Idiopathic a... B Disseminated... C Reactive sys... D Sheehan synd... E Meningococce... F Hemochromato... Concept and Explana?on • Acute adrenal failure can be caused by sep?cemia and Disseminated intravascular coagula?on • This is a pa?ent of Waterhouse-Friederikson syndrome as evidenced by hemorrhagic and necrosed adrenals and the history of Sepsis. 49

A 36 year old woman presents with swelling in her neck that she first no?ced 3 months ago. She also complains of intermiTent watery diarrhea. Physical examina?on reveals a nontender nodule in the le] lobe of the thyroid. The pa?ent's mother died of thyroid cancer 8 years ago. The thyroid nodule is found to be cold by radioiodine scan. Serum calcium and PTH levels are high. This pa?ent is at risk for which of the following neoplasms? 1. Craniopharyngioma 2. Pheochromocytoma 3. Pituitary adenoma 4. Neuroblastoma 5. Insulinoma

0%0%0%0%0% 15 Countdown 6 Craniopharyngi... Pheochromocyto... Pituitary aden... Neuroblastoma Insulinoma Concept and Explana?on • Mul?ple endocrine tumors can be seen in the MEN syndromes. Thyroid (medullary carcinoma)is associated with MEN 2.Other tumors in MEN 2 are parathyroid tumors and Pheochromocytoma. Neuromas are also seen. • The watery diarrhea is due to 5-HT made by the medullary carcinoma, serum calcium and PTH increase is due to Parathyroid tumor or Hyperplasia, the third tumor that fits here could be pheochromocytoma or neuromas (which isnot a choice) 7

A 30 year old woman complains of headache, visual disturbance, deepening of the voice and generalized weakness. She reports amenorrhea for the past year sta?ng that she recently required a large size shoe. She has also noted a milky nipple discharge. Laboratory studies show impaired glucose tolerance and hypercalcemia. Which of the following will be most useful in making the final diagnosis for this pa?ent? 1. CT scan of abdomen 2. Serum cor?sol level 3. Nuclear sestamibi neck scan 4. Serum HbA1c 5. Serum androstenedione 6. MRI of skull

0%0%0%0%0%0% 15 Countdown 8 CT scan of abd... Serum cortisol... Nuclear sestam... Serum HbA1c Serum androste... MRI of skull Concept and Explana?on • The most common func?onal pituitary tumor is prolac?noma followed by GH secre?ng tumor. Many pituitary tumors make more than one hormone. • This pa?ent has features of prolac?noma (galactorrhea) and GH tumor (Acromegaly along with hypercalcemia and hyperglycemia). The confirmatory diagnos?c test will be MRI of skull to establish a pituitary tumor fromamong the choices 9

DIETARY MANAGEMENT of CRF

1. Restrict sodium, potassium, chloride, magnesium, phosphate, but not calcium. 2. Ensure adequate vitamins. 3. Protein: 0.6 g/kg conservative, 1.2 g/kg on dialysis. 4. Sufficient carbohydrate, to limit protein breakdown.

11 A 47‐year‐old woman has had increasing fatigue with dyspnea and reduced exercise tolerance for the past year. On examination she has nonpitting edema of the lower extremities. Laboratory studies show a serum TSH level of 10 mU/L and T4 level of 2 μg/dL. She is most likely to have pathologic findings affecting which of the following cells? A Hypophyseal basophils B Hypophyseal pituicytes C Hypothalamic glial cells D Hypothalamic neurons E Thyroid C cells F Thyroid follicular cells

11 f The normal feedback loop of peripheral thyroid hormones (T3 and T4) onto the BASOPHILS OF THE ADENOHYPOPHYSIS (A) regulates TSH release (under tropic control of TRH from the hypothalamus). When patients with primary thyroid failure, the most common cause for hypothyroidism with myxedema in adults, do not have sufficient residual functioning thyroid follicular cells producing thyroid hormones, then the TSH will rise, as in this case, in conjunction with a low T4 level. The levels of TRH from the hypothalamus are much lower and harder to measure for correlation with thyroid gland function. The measurement of TSH is also the most useful screening test for hyperthyroidism. Neurohypophyseal axons release ADH and oxytocin produced in the hypothalamus, whereas modified glial cells called pituicytes do not release hormones. Thyroid parafollicular, or "C" cells, produce calcitonin.

12 A 2‐year‐old child has failure to thrive since infancy. Physical examination shows that the child is short and has coarse facial features, a protruding tongue, and an umbilical hernia. As the child matures, profound intellectual disability becomes apparent. A deficiency of which of the following hormones is most likely to explain these findings? A Cortisol B Insulin C Norepinephrine D Somatostatin E Thyroxine (T4)

12 E Cretinism is a condition that is uncommon whenever routine newborn screening is available for testing and treatment at birth for hypothyroidism. Hypothyroidism that develops in older children and adults is known as myxedema. A lack of cortisol from primary adrenal failure leads to Addison disease, or a 21‐ hydroxylase deficiency could produce congenital adrenal hyperplasia. An absolute deficiency of insulin leads to type 1 diabetes mellitus, but this is more likely to develop in childhood or later, and there would be weight loss. There is no deficiency state caused by a lack of norepinephrine or somatostatin.

High levels of thyroidal peroxidase antibody are found in which of the following conditions? A. Iodine deficiency B. Lithium C. Hashimoto's thyroiditis D. Propylthiouracil E. Toxic multinodular goiter

17 Answer • Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) is the most common cause of hypothyroidism in the U.S. and it is associated with high levels of thyroid autoantibodies.

18 A 40‐year‐old man notes weight loss, increased appetite, and double vision for 6 months. On physical examination, his temperature is 37.7° C, pulse is 106/min, respirations are 20/min, and blood pressure is 140/80 mm Hg. A fine tremor is observed in his outstretched hands. He has bilateral proptosis and corneal ulceration. Laboratory findings include a serum TSH level of 0.1 mU/L. A radioiodine scan indicates increased diffuse uptake throughout the thyroid. He receives propylthiouracil therapy, and his condition improves. Which of the following best describes the microscopic appearance of his thyroid gland before therapy? A Destruction of follicles, lymphoid aggregates, and Hürthle cell metaplasia B Enlarged thyroid follicles lined by flattened epithelial cells C Follicular destruction with inflammatory infiltrates containing giant cells D Nodules with nests of cells separated by hyaline stroma that stains with Congo red E Papillary projections in thyroid follicles and lymphoid aggregates in the stroma

18 E The clinical findings in this case point to hyperthyroidism, and the increased, diffuse uptake corroborates Graves disease as a probable cause because the thyroid‐stimulating hormone (TSH) level is quite low. The thyroid‐stimulating immunoglobulins that appear in this autoimmune condition result in diffuse thyroid enlargement and hyperfunction, and papillary projections lined by tall columnar epithelial cells. Destruction of thyroid follicles with lymphoid aggregates and Hürthle cell metaplasia is characteristic of Hashimoto

Underweight BMI

18.5

62 A 37‐year‐old woman states that, although most of the time she feels fine, she has had episodes of palpitations, tachycardia, tremor, diaphoresis, and headache over the past 3 months. When her symptoms are worse, her blood pressure is measured in the range of 155/90 mm Hg. She collapses suddenly one day and is brought to the hospital, where her ventricular fibrillation is converted successfully to sinus rhythm. On physical examination, there are no remarkable findings. Which of the following laboratory findings is most likely to be reported in this patient? A Decreased serum cortisol level B Decreased serum glucose level C Decreased serum potassium level D Increased serum free T4 level E Increased urinary free catecholamines F Increased urinary homovanillic acid (HVA) level

62 E These findings suggest a pheochromocytoma of the adrenal medulla. This is a rare neoplasm, but in cases of episodic hypertension, this diagnosis should be considered. Screening for urinary free catecholamines, metanephrine, and vanillylmandelic acid (VMA) can help to determine the diagnosis. Up to 25% of cases may be associated with an underlying tumor suppressor gene mutation, such as RET, NF1, or VHL. The level of HVA is more likely to be increased in a neuroblastoma, which is a tumor that occurs in children. The serum cortisol is increased with Addison disease, which is accompanied by hypotension. Hypoglycemia can also occur in Addison disease, as well as islet cell tumors. The serum potassium level can be decreased with aldosterone‐secreting adrenal adenomas. An increased T4 level occurs in patients with Graves disease; this disease can cause weight loss, heat intolerance, anxiety, tachycardia, tremors, and cardiac arrhythmia.

23 y/o med student presents with no periods for 3 months. She has a milky discharge from the breast. She is sexually active and is on OCPs. She had oligomenorrhea for 1 month and now has amenorrhea for 2 months. What is the presumptive diagnosis? 23% 23% A. Contraceptive failure B. Breast stimulation C. Stress D. Prolactinoma E. Mastitis with pus discharge

A

4) A 7-year old boy is presented to the physician. His parents express concern that he is constantly hungry and has gained a lot of weight for his age. Blood tests show that his Ghrelin levels are very high. What process is required for the activation of his ghrelin? A. Octanoylation B. Removal of a serine C. Glycosylation D. Dimerization E. Glycation

A

A 7-week-old infant develops severe dehydration and hypotension and expires. The adrenal glands at autopsy show massive hypertrophy. Hypovolemic shock in this infant was most likely caused by inadequate synthesis of which of the following hormones? (A) Aldosterone (B) Angiotensin (C) Antidiuretic hormone (D) Atrial natriuretic factor (E) Renin

A

Physical examination of a neonate shows virilization. Cytogenetic studies reveal a 46,XX karyotype. The infant described has an autosomal recessive genetic disorder. The infant is expected to manifest which of the following developmental anomalies (A) Adrenal hyperplasia (B) Bladder diverticulum (C) Cystic renal dysplasia (D) Empty sella turcica (E) Polycystic ovaries

A

A 24 year old woman presents with a diffuse thyroid enlargement and amenorrhea. On examination she has fine tremors, exophthalmos and pre-tibial myxedema. X-ray of her hands shows periosteal reaction and radial calcification in the metacarpals (acropachy). 131I uptake is diffuse and high. TSH is low and free T3 and T4 are high. Blood test is positive for thyroid stimulating antibodies. What is the most likely diagnosis in this patient? A. Graves disease B. Toxicadenoma C. Toxic multinodular goiter D. Secondary (pituitary) hyperthyroidism E. Estrogen therapy (Contraceptive pills)

Answer • Correct A • This patient has all the salient signs- exophthalmos, pre-tibial edema and acropachy that distinguish Graves disease from other causes of hyperthyroidism. Iodine scan for toxic adenoma will show a hot nodule, toxic multi-nodular goiter will have a patchy uptake. Pituitary hyperthyroidism will have high TSH along with high T3 and T4. Estrogen therapy increases total not free T3 and T4 due to an increase in the binding protein • Next question Answer • Wrong • Try again

8-year-old girl presented with abnormal secondary sexual development. The patient had no notable medical history and was taking no medication. On examination, breast development Tanner stage 1 and pubic hair development Tanner stage 3. She had an enlarged clitoris and mild facial acne. Ht 54 in (138 cm), wt 70.5 lb (32 kg). Laboratory studies: Basal 17-hydroxyprogesterone (17-OHP) 5,860 ng/dL (normal for prepubescent girls <110 ng/dL) Total testosterone 56 ng/dL (1.94 nmol/L) normal <32 ng/dL [1.11 nmol/L]) Dehydroepiandrosterone sulfate 87 mcg/dL (2.35 μmol/L) normal 3-85 mcg/dL (0.08-2.29 μmol/L). Based on the patient's history and physical examination, which one of the following is the most likely diagnosis? A. Adrenocortical carcinoma. B. Nonclassic congenital adrenal hyperplasia. C. Premature adrenarche. D. Sex cord-stromal tumor.

B

A 59 y/o woman admitted to the hospital with pneumonia and is being treated with antibiotics. On the third day she develops insatiable thirst. She is passing 4 litres of low osmolarity urine per day. Serum osmolarity is slightly high with hypernatremia. Urine is negative for glucose. She is asked to restrict water intake for a few hours, but still keeps passing large quantities of low osmolarity urine. She becomes listless and confused. Next she is given a vasopressin injection and two hours later she is still passing low osmolarity urine. What is the differential diagnosis? A. Diabetes mellitus B. Nephrogenic diabetes insipidus C. Urinary tract infection D. Central diabetes insipidus E. Psychological polydipsia

B

A 60-year-old woman with small cell carcinoma of the lung notes rounding of her face, upper truncal obesity, and muscle weakness. Physical examination reveals thin, wrinkled skin, abdominal striae, and multiple purpuric skin lesions. The patient's blood pressure is 175/95 mm Hg. Laboratory studies will likely show elevated serum levels of which of the following hormones? (A) Aldosterone (B) Corticotropin (C) Epinephrine (D) Prolactin (E) Thyrotropin

B

• 12 y/o is brought to pediatrician by his parents because they are worried about his poor growth. They say that in the last 2 yrs he has become the shortest boy in his class • On examination: - No pubertal signs of sexual development, although his brother who is 10 years old has begun his at 9 yrs • Further questioning reveals occasional headache • CT scan of Head shows suprasellar calcification What is the diagnosis? A. Pituitary tumor B. Brain tumor affecting pituitary function C. Poor nutrition D. Over anxious parents

B

In DKA, what is the body's potassium status? What other electrolytes may be problematic?

Blood glucose Elevated Insulin absent Facilitated transport of glucose into cells prevented Electrolytes Low, normal or high K In all cases, body is potassium depleted Occasionally ↓Ca, ↓ PO4

condiDon in which therapy to relieve congesDve symptoms of heart failure (HF) is limited by a decline in renal funcDon as manifested by a reducDon of GFR (2004, NaDonal Heart, Lung and Blood InsDtute) • IniDally thought that decrease in GFR = caused by reduc.on in blood flow, but the interacDon is in fact bidirec.onal

Cardiorenal syndrome (CRS)

condition in which therapy to relieve congestive symptoms of heart failure is limited by a decline in renal function (manifested by a reduction of GF) - 30-60% of patients with heart failure have renal impairment (eGFR< 60 ml/ min/1.73 m2) - Increases mortality - CKD -> increased risk of atherosclerosis and HF -> CV disease responsible for 1⁄2 deaths in patients with AKI - Systemic disorders may cause both cardiac and renal dysfunction

Cardiorenal syndrome (CRS)

A 22 year old college student is brought to the ER with sudden onset of symptoms. She was at a post-exam party when the symptoms developed. She appears confused and disoriented. On examination she is sweating profusely and has blurred vision and tachycardia. Her blood glucose level is 45 mg/dl Her friend says that she had similar attacks in the past but this one is the worst.

Case 2 continued: 5 Days later Now feeling better Sitting up in bed, smiling Good appetite Mom learns To administer insulin injections and check blood glucose About the signs of hypoglycemia and hyperglycemia Patient discharged on insulin therapy Long-acting (glargine) and rapid-acting (aspart) insulin

has the longest half-life (~30 hrs) of sulfonylureas

Chlorpropamide

Diagnosis of Hypoparathyroidism Clinical Exam Laboratory Findings

Chvostek sign (i.e. twitching of facial muscles after Trousseau sign tapping the facial nerve justin front of the ear) (i.e. carpal spasm after maintaining an arm blood pressure cuff at 20 mm Hg above the patient's systolic blood pressure for 3 min) Low or absent plasma PTH levels Hypocalcaemia Hyperphosphatemia

gigantism vs. acromegaly

Clinical syndrome depends on state of bone epiphysis Gigantism: in children and adolescents Crippled by nerve, muscle, and joint problems Acromegalic features develop post puberty Die young of complications of diabetes Acromegaly: in adults Joint deformities (arthritis) Secondary diabetes and complications

4. A 50-year-old man is being treated with repaglinide for type 2 diabetes mellitus. Which of the following actions best describe the therapeutic effect of the drug in this patient? A) Slowing of glucose absorption from the gastrointestinal tract B) Blockade of glucagon receptors C) Blockade of beta 2 receptors in the liver D) Stimulation of insulin release E) Stimulation of gluconeogenesis

D

A 36 y/o man is brought to the emergency department because of lethargy, weakness and confusion. His blood pressure is normal. Serum sodium and serum osmolarity is low Serum BUN is low. Urine osmolarity is increased. Urine is negative for glucose and ketone bodies. What is the differential diagnosis? A. Renal failure B. Diabetic coma C. Dehydration D. SIADH Which of the following is the most likely cause for this patient's disorders? A. Renal failure B. Diabetic coma C. Pituitary tumor D. Lung tumor

D

A 2-year-old child living in Stockholm is small for its age and exhibits profound mental retarda?on. On physical examina?on he has dry, coarse skin. 95 Which of the following pathologic features involving the thyroid gland is this child most likely to have? • A Papillary adenoma • B Diffuse hyperplasia • C Granulomatous inflamma?on • D Mul?nodular goiter • E Marked atrophy

E • Thyroid aplasia is an important cause of hypothyroidism in infancy • These children are born normal, as opposed to the congenital hypothyridism. They are normal because the mothers T3 and T4 is able to sustain normal development in utero. A]er birth as they do not have a func?oning thyroid the symptoms develop. In case of congenital hypothyroidism the development in utero is also affected because the mother has thyroid deficiency also. Thereby the children may have thyroid insufficiency and signs and symptoms at birth. 97

A 4-year-old girl is brought to the pediatric clinic by her mother who reports that her daughter has decreased appetite, lethargy, and an enlarging belly and now for the past two days has developed "raccoon eyes". Physical examination reveals a large, firm, irregular, nontender mass in the child's abdomen and peri-orbital ecchymoses. A CT-guided biopsy reveals neoplastic "small blue cells." The child's malignant neoplasm is removed and the surgical specimen is shown. Which of the following laboratory tests would be useful in monitoring this patient for recurrence of disease? (A) Serum acetylcholine (B) Serum α1-antitrypsin (C) Serum potassium (D) Urinary angiotensin (E) Urinary vanillylmandelic acid Genetic analysis of tumor cells taken from the patient described in Question above may reveal which of the following mutations? (A) k-ras amplification (B) Deletion of c-myc (C) Amplification of n-myc (D) 8;21 chromosomal translocation (E) 9;22 chromosomal translocation

E,C

3) A 56-year-old woman visits her physician for an annual examination and refill of her conjugated estrogen pills and the following dialog occurs: Doctor: Have you been having any problems? Patient: I still have some vaginal dryness and hot flashes. Doctor: How often have you missed your hormone pill in the last month? Patient: I forgot to bring them on a business trip and missed about four days' worth? Doctor: Any other doses missed? Patient: No, I'm really pretty careful about taking them regularly. Which of the following best describes this physician patient interaction? A) Direct adherence monitoring B) Eliciting the patient's perspective C) Shared decision-making D) Paternalistic model

3) Correct answer A B is incorrect because, though the physician specifically asks about the missed pills and the patient volunteers why she has missed them, the physician did not elicit this perspective. C is incorrect because there is no decision making demonstrated in the vignette. D is incorrect because it also refers to a decision making model and there is no decision making demonstrated in the vignette. A is correct because this is a detailed inquiry into the patient's medication usage and missed doses.

30 A 63‐year‐old woman had frequent headaches for 1 month. She now suddenly experiences a generalized seizure and becomes obtunded. She is taken to the emergency department, where a physical examination reveals an irregular heart rate. Laboratory findings include serum calcium of 15.4 mg/dL, serum phosphorus of 1.9 mg/dL, and albumin of 4.2 g/dL. A chest radiograph shows multiple lung masses and lytic lesions of the vertebral column. Which of the following conditions best accounts for these findings? A Chronic renal failure B Disseminated tuberculosis C Metastatic breast carcinoma D Parathyroid carcinoma E Vitamin D toxicity

30 C A common cause of clinically significant hypercalcemia in adults is a malignancy. When a patient presents with hypercalcemia, a disorder of the parathyroid glands or a malignancy at a visceral location must be considered. Hypercalcemia from malignancy can be caused by osteolytic metastases or a paraneoplastic syndrome from secretion of parathyroid hormone-related protein by the tumor. Metastatic disease from common primary sites, such as the breast, lung, and kidney, is much more common than parathyroid carcinoma, which tends to be local but aggressive. Chronic renal failure causes phosphate retention, which tends to depress the serum calcium level and leads to secondary hyperparathyroidism; the serum calcium level is maintained at near‐normal levels. Tuberculosis, a granulomatous disease, can be associated with hypercalcemia from up‐regulation of 1,25‐dihydrocholecalciferol in activated macrophages; lytic bone lesions from tuberculosis are uncommon. Parathyroid carcinomas are an uncommon cause of hyperparathyroidism, and bone metastases from parathyroid carcinomas are rare. Vitamin D toxicity theoretically can lead to hypercalcemia, but this condition is uncommon.

39 An infant is born following premature delivery. Multiple external congenital anomalies are noted. The infant exhibits a seizure soon after birth. The blood glucose is 19 mg/dL. Which of the following maternal diseases is the most likely cause for the observed findings in this infant? A Cystic fibrosis B Diabetes mellitus, type 2 C Gestational diabetes D Maturity onset diabetes of the young E Pancreatic neuroendocrine tumor

39 B The findings are complications of diabetes with pregnancy, and the malformations suggest that hyperglycemia preceded the pregnancy, and type 2 diabetes is quite common, even now in women of childbearing age. The neonatal hypoglycemia is a consequence of excessive islet beta‐cell function from having been in a hyperglycemic environment. Though cystic fibrosis is present from birth, the loss of pancreatic exocrine function takes years, and loss of islets is a late finding. Gestational diabetes refers to glucose intolerance in pregnancy, and newborns are likely to have hypoglycemia as a consequence of their own beta cell hyperfunction, but not anomalies. Maturity‐onset diabetes of the young (MODY; but not in infancy) resembles type 2 diabetes and can occur from a variety of genetic defects in pathways monitoring glucose levels, but is much less common. Pancreatic neuroendocrine tumors are uncommon but could secrete glucagon with secondary diabetes.

a synthetic version of exendin-4, an incretin mimetic isolated from the salivary glands of the lizard Heloderma suspectum (Gila monster). Effects: Increases insulin secretion when glucose levels are elevated (glucose-dependent insulin secretion; eliminating the risk of hypoglycemia) Suppresses glucagon secretion Slows gastric emptying (slows the rate of glucose entry into the circulation) Decreases appetite subcutaneous injection twice daily as an adjunctive therapy in type 2 diabetic patients who have not achieved adequate glycemic control by a sulfonylurea drug, metformin or a combination of metformin and a sulfonylurea Also approved for using as monotherapy. Adverse drug effects: Common: Nausea (~44%), vomiting, diarrhea. Rare and fatal: Necrotizing and hemorrhagic pancreatitis.

EXENATIDE:

CDKN1B (p27/KIP1)* How is this gene mutated and what kind of tumors does it cause?

Germline inactivating mutations of CDKN1B ("MEN-like"- syndrome) ACTH adenomas

Menin* How is this gene mutated and what kind of tumors does it cause?

Germline inactivating mutations of MEN1 (multiple endocrine neoplasia, type 1) GH, prolactin, and ACTH adenomas

How is this gene mutated and what kind of tumors does it cause? Aryl hydrocarbon receptor interacting protein (AIP)*

Germline mutations of AIP (pituitary adenoma predisposition [PAP] syndrome) GH adenomas

When should pregnant women be screened for DM? When in the pregnancy should the 75-gOGTT test be done is there are no signs of GDM? What should a pregnant woman's fasting glucose + her 1 & 2 hr post meal measurements be?

Gestational Diabetes Mellitus (GDM) Screening Strategy and New Criteria - Screen for undiagnosed type 2 DM at 1st prenatal visit if risk factors are present - Screen for persistent DM 6-12 weeks postpartum Women with GDM - Lifelong screening for DM or prediabetes at least every 3 years 75-gOGTT Plasma glucose measurement 24-28 weeks of gestation in women not previously diagnosed with overt DM Perform in morning after overnight fast ≥8 h Diagnosis of GDM Only one abnormal needed: Fasting ≥92 mg/dl (5.1 mmol/l) 1 h ≥180 mg/dl (10.0 mmol/l) 2 h ≥153 mg/dl (8.5 mmol/l)

- Stimulates NPY/AgRP -> increased NPY AND AgRP Secretion -Net effect: increased appetite

Ghrelin

How do glucocorticoids treat hyperparathyroidism?

Glucocorticoids: 1) Decreased calcitriol synthesis,resulting in decreased absorption of calcium from the GIT and decreased calcium output from bone into the circulation. 2) Inhibit reabsorption of calcium from the renal tubules, resulting in increased calcium excretion in urine. Both actions help in reducing serum calcium levels....

A 27 year old woman presents with fatigue irritability and amenorrhea. She also has hoarseness of voice. On examination she has coarse and cold skin. Thyroid is mildly enlarged. Muscle reflexes are slow and blood pressure is normal. Lab tests show TSH is high, T3 and T4 are low. FNAC of the thyroid shows sheets of lymphocytes mixed with follicular and hurthle cells. What is the diagnosis for this patient? A. Non functional adenoma of the pituitary B. Hashimoto thyroiditis C. Reidel's thyroiditis D. Multi-nodular goiter E. Depression

Answer • Correct B • Presence of sheets of lymphocytes and hurthle cells confirm the diagnosis. The patient has classical features of myxedema. Remember amenorrhea and hair loss can be seen in both hypo- and hyperthyroidism. Non-functioning pituitary adenoma will present with low TSH and multinodular goiter will have normal T3 and T4. Reidel's thyroiditis will present with a fibrosed thyroid. • Next question Answer • Wrong • Try again

A 35 year old woman presents with a lymph node on the left side of the neck. On examination in addition to the lymph node, her thyroid also has a small barely palpable nodule. Lab tests confirm a euthyroid status. Biopsy of the lymph node shows metastasis from a papillary tumor with clear nuclei, and calcification (psammoma bodies). A diagnosis of papillary thyroid carcinoma is made. Which of the following is true for this tumor? A. Radiation is not a factor in pathogenesis B. 5 year survival is 5% C. The prognosis is excellent even with metastasis D. The tumor is part of MEN 2 Syndrome

Answer • Correct C • Papillary thyroid carcinoma has the clear "orphan annie" nuclei with nuclear grooves. Generally a past history of radiation exposure is seen. Medullary carcinoma is usually part of the MEN 2 syndrome and is a rare tumor • Next question Answer • Wrong • Try again

Evidence for Genetic and Environmental factors Type 1 DM

Polygenic Inheritance Linkage shown to > 20 regions of human genome HLA locus IDDM1 VNTRs in the Insulin gene promoter Candidate gene search and association studies Polymorphism in CD-25 (IL-2R)-immune tolerance PTPN22 (-ve regulation of T cell function) IL-10 (immunoregilator)

22-year-old woman Up every night to urinate and drink water for weeks Last night she noticed that her bed was wet Complains of weight loss Tired all the time Has no energy to go shopping She says that she has been spending more time watching TV, and eating lots of junk food Complains of itchy, white vaginal discharge x2 days Family History: mother is diabetic x10yrs & is overweight On examination Weight 98 kg Height 1.63m BMI 35 - Class 2 obesity RR 18/min; PR 88/min; BP 128/80; T 36oC Mucous membranes pink, moist, anicteric, acyanotic Thickened dark skin in neck, axilla and belt-line (acanthosis nigricans) Pelvic exam White "cottage cheese" vaginal discharge Few furuncles in groin Lab results: Random blood glucose 484 mg/dl Insulin, C-peptide levels in normal range (What does this signify?) Urine Negative for ketones Positive for glucose Specific Gravity 1.030

Diagnosis: Type 2 Diabetes with vaginal candidiasis and furunculosis Case 3 continued- 15 years later.... Patient is found unresponsive in a confused state at home. She is brought to the hospital. She had been experiencing polyuria and poor fluid intake for the past week. Family notes that she was recently diagnosed with pneumonia and has generally been non- compliant with treatment.

causes of Nephrogenic Diabetes insipidus

Drug-induced nephrogenic diabetes insipidus: Lithium, demeclocycline, clozapine. Familial nephrogenic diabetes insipidus: due to mutations in V2 gene Drugs for treatment: Amiloride: used in lithium-induced diabetes insipidus. Thiazide diuretics

Evidence for Genetic and Environmental Factors Type 1 DM

Drugs and chemicals Nitrosamines Bovine Serum Albumin (BSA) Hygiene hypothesis Viral Infection (Mumps, Rubella, CMV, Coxsackie, B4, EBV) "Bystander damage", Molecular Mimicry "Predisposing virus"→"Precipitating virus"

Microprolactinomas - sex distribution

Female preponderance 20:1 Mostly silent in men In women even small tumors may produce symptoms In men cause decreased libido and impotence & are Usually detected later (Why?)

Contraindications: oxytocin

Fetal distress Abnormal fetal presentation Prematurity CPD (cephalo-pelvic disproportion)

Adverse drug effects of somatostatin analogs:

GIT problems: abdominal cramps, steatorrhea, diarrhea, malabsorption Gall stones Vitamin B12 deficiency Cardiovascular problems: Sinus bradycardia (25%), conduction disturbances(10%)

is an autoimmune disorder characterized by hyperthyroidism, diffuse goiter, and IgG antibodies that bind to and activate the TSH receptors to produce excessive amounts of thyroid hormones.

Graves' disease: Toxic uninodular goiter and thyroid tumors are other causes of hyperthyroidism. Thyroid storm: It is the most severe form of hyperthyroidism.

Common adverse effects of sulfonylureas:

Hypoglycemia: Sulfonylureas can cause hypoglycemia and the chances are more with agents having longer duration of action. It is more likely to occur when caloric intake is not sufficient, patient is taking other medications that can interact with sulfonylureas and potentiate hypoglycemic action, or after vigorous exercise. Hypoglycemia is particularly a problem in elderly patients who are taking longer acting sulfonylureas, and in patients with impaired hepatic or renal function. Weight gain: due the anabolic effect of insulin.

Management (DKA)

IV fluids Correct dehydration Correct osmolarity & acidosis "Flushes out"ketones Insulin ↓ketone formation (lipolysis) and correct acidosis Continue insulin until acidosis resolved Replace K (total body deficit) Correct electrolyte imbalance Repeated checks of conscious level If cerebral edema, elevate head of bed & give mannitol

Treatment CUSHING SYNDROME

In general, treat the cause Taper exogenous steroid Appropriate surgery Pituitary Cushing's syndrome Transphenodial surgery Small cell lung carcinoma Remove tumor Unilateral tumor Adrenalectomy Bilateral adrenalectomy leads to death Medical therapy Ketoconazole or metyrapone 2/5/2016 Blocks cortisol synthesis by inhibiting 11β-hydroxylase

Macroprolactinomas - sex distribution

Incidence equal in both sexes

Events requiring an increase in insulin dose in type 1 diabetic patients

Infections Trauma, surgery Serious psychological stress Pregnancy Myocardial infarction Hyperthyroidism Diabetic ketoacidosis High level of insulin antibodies Concomitant use of drugs that cause hyperglycemia

Pathogenesis of Type 2 DM

Insulin Resistance Genetic defects of the insulin receptor and signaling pathway OBESITY Role of free fatty acids Role of adipocytokine β-cell dysfunction Qualitativedefect:lossofnormalpulsatilefunction Decreased mass: Islet cell degeneration and deposition of Amyloid Type 2 Diabetes mellitus is a disease of "Insulin resistance and β cell dysfunction"

Pathogenesis of Type 1 DM

Islet β cell destruction primarily by T- lymphocytes infiltration results in deficiency of Insulin absolute • Hypotheses • Autoimmune Disease Circulating Abs (~70%) GAD-65, ICA512 and anti-insulin antibodies TH1 Response-TNF-α, IFN-γ and IL-1 Genetic and Environmental Factors • • • •

Adverse effects of metformin

Mainly gastrointestinal (nausea, vomiting, diarrhea) in ~ 20% patients. Lactic acidosis: This is a rare but fatal complication, the risk of which increases in the conditions mentioned under contraindications. Lactic acidosis, in the presence of metformin, could occur due to impaired hepatic uptake of lactic acid resulting from inhibition of certain enzymes involved in gluconeogenesis.

Cushing's Syndrome: Clinical Features

Moon facies Thin skin Hirsutism Excess hair in male distribution Acne Emotional lability Depression Euphoria Psychosis

desmopression Nasal spray is available for:

Neurogenic diabetes insipidus Enuresis

Factors for Increased Infection in Diabetes Suppresion of Immune response

PMNs and macrophage function is impaired T lymphocyte function depressed Antibody production normal Blood supply impaired due to vasculopathy Skin injuries → Neuropathy Needle injections predispose to infection, especially colonization of skin and nares with Staph aureus (rare) Renal failure, when present, predisposes to infection

A 6 month old girl with WiskoT-Aldrich syndrome is brought to the emergency room shortly a]er spiking a fever of 38.7 C (103 F). The infant has a history of chronic respiratory infec?ons, gastrointes?nal infec?ons, petechiae and eczema. Her serum calcium is normal. This infant is most likely to have which of the following associated birth defects? 1. Adrenal cor?cal hyperplasia 2. Meckels diver?culum 3. Cys?c renal dysplasia 4. Hypoplasia of thymus 5. Pituitary hypoplasia

0% 0% 0% 0% 0% 15 19 Countdown Adrenal cortic... Meckels divert... Cystic renal d... Hypoplasia of ... Pituitary hypo... Concept and Explana?on • WiskoT-Aldrich syndrome (WAS) is a condi?on with variable expression, but commonly includes immunoglobulin M (IgM) deficiency. WAS always causes persistent thrombocytopenia and, in its complete form, also causes small platelets, atopy, cellular and humoral immunodeficiency, and an increased risk of autoimmune disease and hematologic malignancy. Hypoplasia of thymus is one of the defects associated with this disease. Although the presenta?on may be similar to DiGeorge's syndrome these pa?ents will not have hypocalcemia, also the peripheral smear will show the typical neutrophils of WiskoT-Aldrich syndrome. In addi?on pa?ents will have eczema. 20

A 21 year old woman experiences abrup?o placentae, with severe bleeding during the delivery of a term fetus. Five months later she presents with profound lethargy, pallor, weakness and amenorrhea. Which of the following symptoms would help differen?ate this pa?ent's diagnosis from par?al pituitary stalk disconnec?on? 1. Atrophy of the endocrine pancreas 2. Failure to ovulate 3. Adrenal atrophy 4. Failure at lacta?on 5. Thyroid hypofunc?on

0% 0% 0% 0% 0% 15 21 Countdown Atrophy of the... Failure to ovu... Adrenal atrop... Failure at lac... Thyroid hypofu... Concept and Explana?on • Prolac?n secre?on from the pituitary is nega?vely regulated by Dopamine • This vigneTe describes a pa?ent of Sheehan's syndrome. The pituitary is necrosed so no produc?on of any pituitary hormone. In stalk par?al disconnec?on for anterior pituitary only, all other pituitary hormones will be suppressed except prolac?n which will increase. Infull stalk disconnec?on Oxytocin and ADH will also be lost 22

A 48-year-old woman has experienced constant back pain exacerbated by movement over the past month. She reports increasing weakness over the past 3 months. On physical examina?on her blood pressure is 165/110 mm Hg. She is overweight, with a BMI of 28. A radiograph of the spine reveals a compressed fracture at T10. Laboratory findings include a serum glucose of 155 mg/dL. Which of the following pathologic lesions is most likely to explain her findings? A. Adrenal cor?cal carcinoma B. Anaplas?c thyroid carcinoma C. Empty sella syndrome D. Pheochromocytoma E. Mul?nodulargoiter

0% 0% 0% 0% 0% 15 27 Countdown Adrenal cortical carcinoma Anaplastic thyroid carc... Empty sella syndrome Pheochromocytoma Multinodular goiter Concept and Explana?on • Hypercor?solemiacausesdemineraliza?onofbones. • Thepa?entisobeseandhashyperglycemia.Intheabsence of any other clues, the two most important diagnoses will be Diabetes and Cushing's. Back pain is explained by the T10 collapse but does not correlate with Diabetes mellitus. So we are le] with Cushing's disease. Chronic hypercor?solemia can causes demineraliza?on of bones. Among the answers the only thing that fits is the Adrenal cor?cal carcinoma. 50% of these are func?onal and cause Cushing's syndrome. The T10 collapse may also be due to bony metastasis. The only other condi?on that can cause metastasis is the anaplas?c thyroid cancer, but there are no features of a thyroid enlargement and also the pa?ent would have lost weight. Thyroid cancer also does not explain the hyperglycemia. 28

A 38-year-old woman has noted painless enlargement of her neck for the past month. On physical examina?on she has diffuse, symmetrical thyroid enlargement without tenderness on palpa?on. Laboratory studies show her serum TSH is 3.1 mU/L and thyroxine 1.4 ng/dL. The thyroid diminishes in size over the next 5 years. She now has a serum TSH of 8.7 mu/L. Based upon this representa?ve microscopic appearance of her thyroid gland early in the course of her disease, which of the following laboratory test findings is she most likely to have? 29 Based upon this representa?ve microscopic appearance of her thyroid gland early in the course of her disease, which of the following laboratory test findings is she most likely to have? 1. Increased serum calcitonin 2. High an?-thyroid peroxidase an?body ?ter 3. Increased serum parathormone 4. Posi?ve an?nuclear an?body test 5. Pancytopenia

0% 0% 0% 0% 0% 15 30 Countdown Increased seru... High anti-thyr... Increased seru... Positive antin... Pancytopenia Concept and Explana?on • Diffuse thyroid enlargement is sugges?ve of a hyperfunc?on or hypofunc?on disorder and not a tumor. • The histopathology shows Hashimoto thyroidi?s. This is supported by the insidious course of the disease and the high TSH levels. • The diagnos?c tests for Hashimoto disease are an?-thyroid peroxidase an?bodies and an?- microsomal an?bodies. 31

A 55-year-old man has had headaches for the past 2 months. On physical examina?on his blood pressure is 160/110 mm Hg. Laboratory studies show serum cor?sol at 8 am 15 microgram/dL, plasma renin ac?vity 1.2 ng/mL/hr, serum aldosterone 44 ng/dL, and serum potassium 2.9 mmol/L. The gross appearance of the lesion in the adrenal gland is depicted here. Which of the following is the most likely diagnosis? 32 Which of the following is the most likely diagnosis? 1. Cushing syndrome 2. Pheochromocytoma 3. Mul?ple endocrine neoplasia, type I 4. Metasta?c carcinoma 5. Conn syndrome

0% 0% 0% 0% 0% 15 33 Countdown Cushing syndro... Pheochromocyto... Multiple endoc... Metastatic car... Conn syndrome Concept and Explana?on • Intheabsenceofadiure?cuse,aldosteroneshouldbe considered as a reason for Hypokalemia • Theheadacheisexplainedbyhypertension.Hypertension associated with hypokalemia should point to the renin- angiotensin-aldosterone axis defect. The adrenal gland tumor explains source for aldosterone upregula?on. Cor?cal adenoma may also be seen in Cushing syndrome but there the Aldosterone axis is not affected as profoundly and the hypokalemia is not as profound. • Theprofileoflesionscausingaldosteronismhaschanged since the past 3 years and the most common cause of aldosteronism is hyperplasia of the adrenal cortex. 34

A 1-year-old male child has been irritable for the past day. On physical examina?on he has a right inguinal hernia with incarcera?on of a loop of small intes?ne. A laparotomy is performed and the defect is closed. The ?ssue from the hernia sac is excised. The surgical pathology report indicates the presence of a focus of adrenal cortex in the excised hernia sac. 80 Which of the following is the most likely diagnosis? • A Congenital adrenal hyperplasia • B Adrenal cor?cal carcinoma metastasis • C Incidental ectopia • D Risk for subsequent adrenocor?cal insufficiency • E Mul?ple endocrine neoplasia syndrome

0% 0% 0% 0% 0% 15 81 Countdown A Congenital a... B Adrenal cort... C Incidental e... D Risk for sub... E Multiple end... Concept and Explana?on • Incidental ectopia of many ?ssues can happen occasionally. Once diagnosed and removed, there are no long term consequences unless it affected the func?on of a vital organ. 82

A 39-year-old woman has noted a firm enlarging nodule on her neck for the past 6 months. On physical examina?on there is a firm, well-circumscribed, non-tender nodule to the right of midline in her neck. A]er fine needle aspira?on biopsy she undergoes thyroidectomy and the microscopic appearance of the lesion is shown here. 44 Which of the following statements regarding her disease is most appropriate? • A The serum thyroxine is increased • B She will survive for at least 10 years • C An?-microsomal and an?- thyroglobulin an?bodies are detectable • D A dietary iodine deficiency preceded its appearance • E The pa?ent has rela?ves with a similar condi?on

0% 0% 0% 0% 0% 15 45 Countdown A The serum th... B She will sur... C Anti-microso... D A dietary io... E The patient ... Concept and Explana?on • Solitary Nodular lesions of the thyroid suggest a tumor (benign or malignant). Among the malignant tumors Papillary carcinoma has excellent prognosis • There is a thyroid tumor in this pa?ent which the biopsy confirms as papillary carcinoma (psammoma body, papillary structure and the clear "orphan Annie" nuclei. Other choices are ruledout becauses the pa?ent will be euthyroid (A), there is no Hashimoto disease (C), Iodine deficiency has mul?nodular goiter (D), medullary not papillary carcinomais associated with familialand gene?c component (E). 46

A 16-year-old boy has had severe headaches for the past 2 months. On physical examina?on he has bilateral temporal hemianopsia. A head CT scan reveals a mass below the hypothalamus eroding bone at the base of the skull with calcifica?on. The mass is surgically excised and the microscopic appearance is shown here. 50 Which of the following statements regarding his condi?on is most appropriate? • A Recurrences are common • B Rela?ves may be similarly affected • C Acromegaly is a common manifesta?on • D An autoimmune disease is o]en present • E Similar lesions are found elsewhere in the body

0% 0% 0% 0% 0% 15 51 Countdown A Recurrences are common B Relatives may be similar.. C Acromegaly is a comm.. D An autoimmune diseas... E Similar lesions are fou.. Concept and Explana?on • Calcifica?on in asella turcica tumor is diagnos?c of Craniopharyngioma. In children the disease will present as growth retarda?on due to compromise of pituitary func?on. • The tumor is locally aggressive and recurrences are common. There is no familial component (B), GH is reduced in these pa?ents (C), it is a tumor and not an autoimmune disease (D), the tumor does not metastasize (E) 52

A 50-year-old man has had a non-healing ulcer on his le] foot for 4 months. On examina?on his BMI is 35. He has the microscopic appearance in islets of Langerhans seen here. 56 Which of the following metabolic complica?ons is he most likely to have? • A Hypoglycemic shock • B Ketoacidosis • C Cushing syndrome • D Pancrea??s • E Hyperosmolar coma

0% 0% 0% 0% 0% 15 57 Countdown A Hypoglycemic... B Ketoacidosis... C Cushing synd... D Pancreatitis... E Hyperosmolar... Concept and Explana?on • Type 2 Diabe?cs are more prone to Hyperosmolar coma, as opposed to Type 1 Diabe?cs who are more prone to Ketoacido?c coma. • Pa?ents on insulin therapy (Type 1 DM) are more prone to hypoglycemic shock if improperly used, Ketoacidosis isalsomore common in Type 1 DM, Cushing syndromeis due to Cor?sol or ACTH hypersecre?on and will not cause the changes seen in the pancrea?c islet, Pancrea??s destroys the exocrine pancreas, Hyperosmolar coma is seen in Type 2 DM that has the amyloid deposits seen in this pa?ents pancrea?c islets. 58

A 5-month-old female infant was the product of an uncomplicated pregnancy and was born at term. However, the baby has failure to thrive. On physical examina?on there is clitoral hypertrophy and poor skin turgor. The baby appears neurologically normal. Laboratory studies show serum sodium 116 mmol/L, potassium 3.2 mmol/L, chloride 83 mmol/L, and CO2 22 mmol/L. There is no history of diarrhea or vomi?ng. Which of the following inborn errors of metabolism is this infant most likely to have? Which of the following inborn errors of metabolism is this infant most likely to have? • A 21-hydroxylase deficiency • B Phenylalanine transferase deficiency • C Galactose-1-uridyl transferase deficiency • D Glucose-6- phosphatase deficiency • E Iodine peroxidase deficiency

0% 0% 0% 0% 0% 15 72 Countdown A 21-hydroxyla... B Phenylalanin... C Galactose-1-... D Glucose-6-ph... E Iodine perox... Concept and Explana?on • Hyperandrogenemia due to 21 hydroxylase causes ambiguous genitalia in a female and precocious puberty in males. There is also lack of Mineralocor?coids and Glucocor?coid produc?on • The vigneTe gives the classical features of 21 Hydroxylase deficiency. 73

A clinical study is performed of subjects from birth to age 80 years who were documented by laboratory tes?ng to have hypocalcemia. The medical records of these subjects are analyzed and the disease condi?ons documented in these subjects recorded. A subset of these pa?ents had hypocalcemia documented in infancy. Which of the following condi?ons is most likely to have been present in this subset of pa?ents? • A Parathyroid carcinoma • B Vitamin D deficiency • C Chronic renal failure • D DiGeorge syndrome • E Parathyroid adenoma

0% 0% 0% 0% 0% 15 75 Countdown A Parathyroid ... B Vitamin D de... C Chronic rena... D DiGeorge syn... E Parathyroid ... Concept and Explana?on • One of the most important causes of hypocalcemia in infancy is • DiGeorge's syndrome

A 14-year-old boy has felt a "bump" in his neck for the past year. On physical examina?on just anterior to the trachea in the midline is a palpable non-tender 2 cm mass. A fine needle aspirate of the mass yields only clear, mucoid fluid, Which of the following is the most likely diagnosis? • A Thyroglossal duct cyst • B Lymph node metastasis of papillary carcinoma • C Follicular adenoma • D Cys?c hygroma • E Branchial cyst • F Parathyroid cyst

0% 0% 0% 0% 0% 15 78 Countdown A Thyroglossal... B Lymph node m... C Follicular a... D Nodule of a ... E Parathyroid ... Concept and Explana?on • Single, well defined, midline neck cysts are thyroid remnants making the Thyroglossal duct cysts • Cys?c hygroma is lateral, some?mes bilateral, o]en mul?loculated and in the posterior triangle. Lymph node metastasis usually occurs to the deep neck nodes along the sternocleidomastoid, adenoma nodule will be within the thyroid, a parathyroid cyst is uncommon and will be posterior to thyroid, brancial cyst will be lateral and contains clear or hemorrhagic fluid. 79

A 48-year-old man has experienced abdominal pain for the past 3 months. On physical examina?on there are no abnormal findings. Upper GI endoscopy is performed and there is a 2 cm diameter sharply demarcated ulcera?on in the antrum. Laboratory studies show his serum calcium is 11.5 mg/dL, phosphorus 2.3 mg/dL, and albumin 5.9 g/dL. The microscopic appearance of the lesion removed at surgery is depicted here. 53 Which of the following addi?onal complica?ons of his disease is he most likely to have? • A Nephrolithiasis • B Hemoptysis • C Hepa??s • D Diarrhea • E Macrocy?c anemia • F Non-Hodgkin lymphoma

0% 0% 0% 0% 0% 0% 15 54 Countdown A Nephrolithia... B Hemoptysis C Hepatitis D Diarrhea E Macrocytic a... F Non-Hodgkin ... Concept and Explana?on • Antral ulcers and mul?ple ulcers in duodenum and jejunun (rare) are due to primarily acid hypersecre?on. Hypercalcemia is one of the reasons for increased acid secre?on. • This pa?ent has hypercalcemia with hypo- phosphatemia, sugges?ng primary hyper-parathyroidism. "Abdominal groans" (antral ulcers) is one of the features of this disease. The adenoma shown is a parathyroid adenoma (aTached thyroid ?ssue in the upper part) confirms thediagnosis. Among the choices "renal stones" is the only one that fits. Other condi?ons are not seen in Hyperparathyroidism. Hypercalcemia causes cons?pa?on not diarrhea. 55

A 28-year-old woman has had difficulty concentra?ng at work for the past month. She is constantly geong up and walking around to visit co-workers. She complains that the work area is too hot. She seems nervous and o]en spills her coffee. She has been ea?ng more but has lost 5 kg in the past 2 months. On physical examina?on her temperature is 37.5 C, pulse 101/ minute, respiratory rate 22/minute, and blood pressure 145/85 mm Hg. 62 Which of the following laboratory findings is most likely to be present in this woman? • A Decreased catecholamines • B Decreased iodine uptake • C Decreased plasma insulin • D Decreased TSH • E Increased ACTH • F Increased calcitonin

0% 0% 0% 0% 0% 0% 15 63 Countdown A Decreased ca... B Decreased io... C Decreased pl... D Decreased TS... E Increased AC... F Increased ca... Concept and Explana?on • Themostcommoncauseofhighbasalmetabolicrate (BMR) is thyroid hyperfunc?on. • Thispa?entdisplaysallthesignsandsymptomsofahigh BMR including the CNS. Increased catecholamines can cause similar pictures but the symptoms will be episodic (A), decreased iodine uptake will reduce BMR- hypothyroidism (B), although hyperglycemia can be seen in Thyrotoxicosis, decreased insulin is seen in DM and fa?gue will be present (C), high ACTH may cause hypertension but not the weight loss (E), medullary carcinoma may cause 5- HT related flushing etc but not sustained high BMR (F). Hyperthyroidism explains all the findings and will have TSH suppressed due to the high circula?ng levels of T 3 and T 4. 64

A 31-year-old woman, who has two healthy children, notes that she has had no menstrual periods for the past 6 months, but she is not pregnant and takes no medica?ons. Within the past week, she has noted some milk produc?on from her breasts. She has been bothered by headaches for the past 3 months. A]er nearly hiong a bus while changing lanes driving her vehicle, she is concerned with her vision. An optometrist's report of her visual fields is as below. On physical examina?on she is normotensive. 59 Which of the following laboratory test findings is most likely to be present in this woman? • A Increased serum cor?sol • B Lack of growth hormone suppression • C Increased serum alkaline phosphatase • D Hyperprolac?nemia • E Hyponatremia • F Abnormal glucose tolerance test • G Decreased serum TSH

0% 0% 0% 0% 0% 0% 0% 15 60 Countdown A Increased se... B Lack of grow... C Increased se... D Hyperprolact... E Hyponatremia... F Abnormal glu... G Decreased se... Concept and Explana?on • Bilateral hemianopsia is a sign of pituitary tumor unless proved otherwise • This pa?ent has classical signs of excess prolac?n secre?on. Prolac?noma is the most common func?onal pituitary tumor. As she is normotensive, GH secre?ng tumor and hyponatremia can be ruled out. 61

A 38-year-old man experiences abdominal pain, nausea, and cons?pa?on for the past 3 days. On physical examina?on he has no palpable abdominal masses and bowel sounds are present. His lungs are clear to ausculta?on. He has a heart rate of 80 with an irregular rhythm. An electrocardiogram demonstrates a shortened QT(corrected) interval and a prolonged PR interval. He has a stool posi?ve for occult blood. Upper GI barium study reveals mul?ple 1 cm diameter shallow ulcera?ons of the gastric antrum. Which of the following laboratory test findings is most likely to be present in this man? 68 Which of the following laboratory test findings is most likely to be present in this man? • A Thyroid peroxidase an,body of 4 IU/mL • B Serum calcium of 12.4 mg/dL • C Blood glucose of 225 mg/dL • D Total serum thyroxine of 21 ng/ mL • E Plasma cor,sol of 45 microgm/ dL at 8 am • F Urine normetanephrine of 692 microgm/gm of crea,nine • G Plasma renin ac,vity (upright) of 6.8 ng/mL/hr

0% 0% 0% 0% 0% 0% 0% 15 69 Countdown A Thyroid peroxidase an... B Serum calcium of 12.4... C Blood glucose of 225 ... D Total serum thyroxine .. E Plasma cortisol of 45 m... F Urine normetanephrin... G Plasma renin activity (... Concept and Explana?on • Features of Hyperparathyroidism are "Mental moans, abdominal groans, renal stones and demineralized bones", due to mostly hypercalcemia • This vigneTe has all the classical signs and symptoms of hypercalcemia. The antral ulcers are due to high gastrin caused by hypercalcemia. 70

A 55-year-old woman has had a 4 kg weight loss over the past 3 months. She exhibits decreased menta?on over the past 10 days. On physical examina?on she is afebrile and hypotensive. Bilateral papilledema is noted. A head CT scan shows marked diffuse cerebral edema with effacement of the lateral ventricles. Laboratory studies show a sodium of 108 mmol/L, potassium 4.0 mmol/L, chloride 83 mmol/L, CO2 14 mmol/L, glucose 82 mg/dL, and crea?nine 0.5 mg/dL. Which of the following is most likely to cause these findings? A. Small cell lung carcinoma B. Bluntheadtrauma C. Hypothalamicglioma D. Meningi?s E. Pituitarymacroadenoma

0%0%0%0%0% 15 23 Countdown Small cell lun... Blunt head tra... Hypothalamic g... Meningitis Pituitary macr... Concept and Explana?on • SIADH is almost always caused due to extra-pituitary factors. Paraneoplas?c syndrome is the more important one amongst others. • This pa?ent has hyponatremia, dehydra?on, hypotension as a result of this and cellular edema. These are the classic features of ADH hypersecre?on. The water retained is shunted to the intracellular spaces (because of low total body sodium). So the pa?ent presents as peripheral dehadra?on, but the cells are all bloated with water. The most pronounced clinical effect of this is seen as cerebral edema. 24

15 A 30‐year‐old woman has given birth to her second child. She develops heat intolerance and loses more weight than expected postpartum. On physical examination, her thyroid gland is enlarged but painless; there are no other remarkable findings. Laboratory studies show a serum T4 level of 12 μg/dL and a TSH level of 0.4 mU/L. A year later she is euthyroid. Which of the following is most indicative of the pathogenesis of this patient's disease? A Activational mutations in the RET proto‐oncogene B Anti-thyroid peroxidase antibodies C Irradiation of the neck during childhood D Prolonged iodine deficiency E Recent viral upper respiratory tract infection

15 B The presence of autoantibodies in the serum in this patient with transient hyperthyroidism would suggest Hashimoto thyroiditis ("hashitoxicosis"), but the variant called subacute lymphocytic painless thyroiditis may affect 1 in 20 postpartum women, and a minority progress to hypothyroidism. Mutations in the RET proto‐ oncogene are associated with papillary carcinoma and medullary carcinoma of the thyroid. Irradiation of the thyroid gland can give rise to hypothyroidism, but it is unlikely that irradiation in childhood would give rise to hypothyroidism at age 60 years. Irradiation also can predispose to the development of papillary carcinoma, but these tumors usually do not affect thyroid hormone secretion. An iodine deficiency can lead to hypothyroidism, but a goiter would be present. A history of a viral infection sometimes precedes subacute granulomatous thyroiditis, which is typically a self‐limited disease that lasts for weeks to 2 months.

19 A 45‐year‐old woman from Kathmandu, Nepal, reports a feeling of fullness in her neck, but has no other concerns. The enlargement has been gradual and painless for more than 1 year. Physical examination confirms diffuse enlargement of the thyroid gland without any apparent masses or lymphadenopathy. Laboratory studies of thyroid function show a normal free T4 level and a slightly increased TSH level. What is the most likely cause of these findings? A Diffuse nontoxic goiter B Follicular adenoma C Hashimoto thyroiditis D Papillary carcinoma E Subacute granulomatous thyroiditis F Toxic multinodular goiter

19 A Diffuse nontoxic goiter is most often caused by dietary iodine deficiency. This condition is endemic in regions of the world where there is a deficiency of iodine (e.g., inland mountainous areas); it also may occur sporadically. As in this case, patients are typically euthyroid. A follicular adenoma rarely functions to produce excess thyroid hormone; most are "cold," nonfunctioning nodules that do not involve the thyroid diffusely. A chronic lymphocytic thyroiditis, such as Hashimoto thyroiditis, initially can produce thyroid enlargement, but atrophy eventually occurs with resulting hypothyroidism. Papillary carcinomas most often produce a mass effect or metastases and do not affect thyroid function. Subacute granulomatous thyroiditis can lead to diffuse enlargement, and transient hyperthyroidism can occur, but the disease typically runs a course of no more than 6 to 8 weeks. Plummer disease, or toxic multinodular goiter, occurs when there is a hyperfunctioning nodule in a goiter.

Mechanism of action: Sulfonylureas block sulfonylurea receptors on ATP- sensitive K+ channels in the pancreatic beta cells. Inhibition of these channels changes resting potential, leading to opening of voltage-gated Ca+ channels, stimulating release of preformed insulin. Sulfonylureas reduce serum glucagon concentrations. This appears to involve indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit secretions from A type cells.

1st generation Tolbutamide (t1⁄2 4-5h) Chlorpropamide (t1⁄2 24-32h) 2nd generation Glyburide (t1⁄2 4-6h) Glipizide (t1⁄2 2-4h) Glimepiride (t1/2 5-7 h) Hypoglycemic effect of sulfonylureas and meglitinides require functioning beta- cells in the pancreatic islets of Langerhans.

2) A 52-year-old man with hypertension sees his physician for a follow up visit and the following dialog occurs: Doctor: high. Patient: Doctor: Patient: urinate. Doctor: Are you taking your medicine as prescribed? Your blood pressure is a little Yes. How are you feeling? I'm having some nightmares and I have to wake up a lot at night to OK, let's increase your medication and see you back in a month. Which of the following best describes this physician patient interaction? A) Indirect adherence monitoring B) Eliciting the patient's perspective C) Shared decision-making D) Patient-centered communication

2) Correct answer A Answer B is correct only for the part of the vignette where the physician asks "How are you feeling". This is not the best and most comprehensive answer for the question. Answer C is incorrect as there is no shared decision-making here. The doctor is making the decision to increase the patient's medication unilaterally. Answer D is also incorrect as this vignette describes very doctor-centered communication. When confronted by the patient's assertion that he might be having medication side effects, the doctor does not even follow up. Answer A is correct because the vignette describes adherence monitoring that is lacking in enough detail to determine if the patient is taking his medication as prescribed.

What is the preferred treatment for most patients with hyperthyroidism over 21 years of age? What are its adverse effects?

2. Radioactive Iodine ( 131I ) Administered as sodium 131 I orally. It is rapidly absorbed from the GIT, taken up and concentrated by the thyroid follicular cells. Mechanism of action: Emission of beta particles by 131I causes necrosis of follicular cells. Necrosis is evident in 6-12 weeks. Patient usually becomes euthyroid over a period of 2-6 months. Therapeutic uses: Severe hyperthyroidism (Graves' disease) Thyroid carcinoma Adverse effects: Hypothyroidism (80%) - managed with life-long thyroxine (T4) Contraindications: Pregnancy and lactation: Risk of fetal hypothyroidism, and cretinism

20 A 14‐year‐old girl noticed gradual neck enlargement during the past 8 months. On physical examination her thyroid gland is diffusely enlarged. Her serum TSH level is normal. A dietary history is most likely to reveal that she has begun eating more of which of the following foods? A Cabbage B Fava beans C Fish D Plantains E Rye bread

20 A She has developed a sporadic goiter. Vegetables of the Brassicaceae family, including cabbage, turnips, and Brussels sprouts, contain glucosinolate, which can decompose to release thiocyanate, a by product that interferes with thyroid hormone synthesis. Thus such substances are known as goitrogens. Young persons with increased demand for thyroid hormone are at increased risk. Fava beans contain oxidizing agents that incite hemolysis in persons with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency. In addition, beans contain long‐chain sugars that are indigestible with human intestinal enzymes, leaving them to be fermented by colonic bacteria that release gas (flatus). Fish have omega‐3 fatty acids that protect against atherogenesis. Plantains are starchy, as anyone mistaking them for sweet bananas soon discovers; rare food allergy develops to them. Fungus growing on moldy rye produces ergot poisoning.

21 A 70‐year‐old man has had greater difficulty swallowing for the past 2 years. Over the past 6 months, he has lost 3 kg. On physical examination, his temperature is 37.3° C, and pulse is 102/min. There is fullness to the anterior neck, with a 5 × 10 cm irregular mass on palpation. Laboratory studies show serum TSH of 0.2 mU/L. A thyroid scintigraphic scan shows a 1.5‐cm nodule with increased uptake in the right thyroid lobe, and decreased uptake into the remaining enlarged thyroid. What is the most likely diagnosis? A Follicular adenoma B Graves disease C Hashimoto thyroiditis D Papillary carcinoma E Toxic multinodular goiter

21 e A long‐standing diffuse goiter can evolve into a multinodular goiter, and one of the nodules can begin hyperfunctioning to cause so‐called Plummer disease. This "toxic" nodule has acquired growth and functional characteristics similar to a benign neoplasm, such as a follicular adenoma, but one that is functional. Rare toxic follicular adenomas can function and produce "hot" nodules, but the remaining gland is often atrophic, not enlarged. In Graves disease, the thyroid is enlarged, but usually diffusely, without pronounced nodularity, so that there is increased uptake into the entire gland. In addition, clinical features such as dermopathy and ophthalmopathy that are lacking with Plummer disease are associated with Graves disease. There may be initial diffuse thyroid enlargement with Hashimoto thyroiditis and transient hyperfunction, but over time the thyroid atrophies, and hypothyroidism ensues. It is extremely rare for a papillary carcinoma to function, and although this would be a hot nodule, the remaining thyroid would not be enlarged.

Impaired cortisol biosynthesis and androgen excess, with or without aldosterone deficiency Different degrees of enzyme function loss caused by CYP21 gene mutation 1 in 500 in Alaskan Inuit Simple Virilizing CAH (~1/3 patients) Enzyme marginally deficient Males: No genital defect, precocious puberty Females: Pseudohermaphroditism

21-Hydroxylase Deficiency

22 A 38‐year‐old woman felt a small bump on the right side of her neck 1 month ago, and it has not changed since then. Physical examination shows a 1‐cm painless nodule palpable in the right lower pole of the thyroid gland. There is no lymphadenopathy. Radionuclide scanning shows that the nodule does not absorb radioactive iodine, and no other nodules are present. A fine‐needle aspiration biopsy of the nodule is done, and the cytologic features are those of a follicular neoplasm. Which of the following laboratory findings is most likely to be present in this patient? A Anti-TSH receptor immunoglobulins B High free T4 C Low T3 D Normal TSH E Anti-thyroid peroxidase antibodies

22 D Solitary "cold" and solid (not cystic) thyroid nodules are likely to be neoplastic, and most are benign follicular adenomas that do not affect thyroid function. If the nodule was hyperfunctioning, and produced hyperthyroidism, it would appear "hot" on the scan, and suppress thyroid‐stimulating hormone (TSH). Anti‐TSH receptor immunoglobulins can be seen in Graves disease, as may high T4 and low TSH levels, but this is a diffuse disease of the thyroid. T3 levels are rarely measured. Antimicrosomal and antithyroglobulin antibodies are seen in Hashimoto thyroiditis (and Graves disease), but thyroiditis is a diffuse process and unlikely to produce a solitary nodule. As Hashimoto thyroiditis progresses, decreasing function of the thyroid can lead to decreasing T4 level and increasing TSH level, typical of primary thyroid failure.

24 A 44‐year‐old, otherwise healthy woman feels a small lump on the left side of her neck. A firm, painless, 1.5‐ cm cervical lymph node is palpable. The thyroid gland is not enlarged. A chest radiograph is unremarkable. Laboratory findings include serum glucose, 83 mg/dL; creatinine, 1.2 mg/dL; calcium, 9.1 mg/dL; phosphorus, 3.3 mg/dL; thyroxine, 8.7 μg/dL; and TSH, 2.3 mU/L. The hemoglobin is 14 g/dL, platelet count is 240,400/mm3, and WBC count is 5830/mm3. A fine‐needle aspiration biopsy of the thyroid gland is done. What is the most likely diagnosis? A Anaplastic carcinoma B Follicular carcinoma C Medullary carcinoma D Papillary carcinoma E Parathyroid carcinoma F Small lymphocytic lymphoma

24 D Papillary thyroid carcinomas may present initially with metastases, and local lymph nodes are the most common sites for metastases. The primary site may not be detectable as a palpable nodule. Papillary carcinoma is the most common thyroid malignancy. Metastases to the thyroid are uncommon. Anaplastic carcinomas are uncommon, but are very aggressive, locally invasive lesions. Follicular and medullary carcinomas tend to spread hematogenously. A parathyroid carcinoma is a locally infiltrative mass, and the serum calcium level is usually quite high in such patients. A small lymphocytic lymphoma, which is the tissue form of chronic lymphocytic leukemia, is uncommon at this patient's age, usually involves multiple nodes, and is accompanied by an elevated WBC count.

25 A 45‐year‐old man has felt a lump on the left side of his neck for 4 months. Physical examination shows a nontender nodule on the left lobe of the thyroid gland. An adjacent cervical lymph node is enlarged and nontender. Laboratory studies show no thyroid autoantibodies in his serum, and the T4 and TSH levels are normal. A thyroidectomy is performed; the figure shows the microscopic appearance of the nodule. Which of the following etiologic factors is most likely to be involved in the pathogenesis of the thyroid nodule in this patient? A Autoimmunity B Chronic dietary iodine deficiency C Consumption of goitrogens D RET gene mutation E Viral infection

25 D The papillary architecture in this nodule, with cells that have clear nuclei, is a pattern typical for papillary carcinoma. There is no such thing as a papillary adenoma. These nuclear changes, even if the pattern is follicular, confirm the diagnosis of papillary carcinoma. About 30% of all papillary thyroid carcinomas have mutational activation of RET or NTRK1 proto‐oncogenes, which belong to the family of receptor tyrosine kinases that transduce extracellular signals for cell growth and differentiation and exert many of their downstream effects through the ubiquitous MAP kinase signaling pathway. Iodine deficiency gives rise to uniform thyroid enlargement because the secretion of thyroid‐stimulating hormone (TSH) increases when there is reduced synthesis of T4. Autoimmunity plays a role in Hashimoto thyroiditis and Graves disease, and these do not progress to carcinoma, although non‐Hodgkin lymphoma may develop in the former. Goitrogens interfere with thyroid hormone synthesis and have an effect similar to that of iodine deficiency, with potential hypothyroidism, but not malignancy. Viral infections can cause a subacute thyroiditis, not carcinoma.

Overweight BMI

25-29.9

4 A 41‐year‐old woman notices that her gloves from the previous winter no longer fit her hands. Her facial features have become coarse in the past year, and her voice seems deeper. On physical examination, her blood pressure is 140/90 mm Hg. There is decreased sensation to pinprick over the palms in the distribution of her thumb and first two fingers. A radiograph of the foot shows an increased amount of soft tissue beneath the calcaneus. A chest radiograph shows cardiomegaly. Laboratory studies indicate a fasting serum glucose level of 138 mg/dL and hemoglobin A1c level of 8.6%. Which of the following additional test results is most likely to indicate the cause of her physical and laboratory findings? A Abnormal glucose tolerance test result B Failure of growth hormone suppression C Hyperprolactinemia D Increased serum TSH level E Loss of diurnal serum cortisol levels

4 B Failure to suppress growth hormone (GH) levels by glucose infusion suggests autonomous GH production. The patient's symptoms suggest acromegaly, and a GH‐secreting adenoma is most likely. Acromegaly causes an overall increase in soft tissue in adults because of the anabolic effects of the increase in GH. Because the epiphyses of the long bones are closed in adults, there is not the increase in height, or gigantism, that would be seen in children with a pituitary adenoma that is secreting excessive GH. Instead, the increase in soft tissue mass manifests as increasing shoe or glove size, carpal tunnel syndrome, and coarse facial features. This woman probably has an abnormal glucose tolerance test result, but this does not indicate the underlying cause of diabetes mellitus, which in this case is secondary to acromegaly. A prolactinoma would cause amenorrhea and galactorrhea in a woman. A thyroid‐stimulating hormone (TSH)−secreting adenoma of the pituitary can give rise to hyperthyroidism with an increased metabolic rate that would most likely to lead to weight loss, and glucose intolerance is not a feature of hyperthyroidism. Functional pituitary tumors can be detected clinically before they become large enough to cause pressure symptoms such as visual disturbances. Cushing syndrome from an adrenal cortical neoplasm producing cortisol could be accompanied by glucose intolerance, hypertension, and truncal obesity, but there is no overall increase in soft tissues.

27 A 44‐year‐old man with no previous illnesses has been bothered by progressive hoarseness, shortness of breath, and stridor for the past 3 weeks. On physical examination, he has a firm, large, tender mass involving the entire right thyroid lobe. CT scan shows extension of this mass posterior to the trachea and into the upper mediastinum. A fine‐needle aspiration biopsy of the mass is done, and microscopically shows pleomorphic spindle cells. The mass is noted at surgery to have infiltrated the adjacent skeletal muscle. Four of seven cervical lymph nodes have metastases. Pulmonary metastases also are identified on a chest radiograph. Which of the following neoplasms is most likely to be present in this man? A Anaplastic carcinoma B Follicular carcinoma C Medullary carcinoma D Non‐Hodgkin lymphoma E Papillary carcinoma

27 A The large size, histologic features, and aggressive nature of this neoplasm are consistent with anaplastic carcinoma. The prognosis is poor. Other thyroid malignancies tend to form solitary or multifocal (in papillary and medullary carcinomas) masses without spindle cells; they are less likely to be extensively invasive, although metastases can occur, particularly to local lymph nodes in the case of papillary carcinomas or lung in the case of follicular carcinomas. Malignant lymphomas do not have spindle cells and do not tend to be infiltrative.

An autopsy is performed on an 8 year old child with Diabetes mellitus of recent onset who had died en-route to the hospital following an automobile accident. Which of the following would favor a diagnosis of Type 1 DM as opposed to Type 2 DM? 1. Amylin deposition in islet of pancreas 2. Armani-Ebstein lesion 3. Insulitis 4. Kimmelstiel Wilson nodules 5. Proliferative retinopathy

3

49 A 33‐year‐old woman has had several "fainting spells" over the past 6 months. Each time, she has a prodrome of lightheadedness followed by a brief loss of consciousness. After each episode, she awakens and on examination has no loss of motor or sensory function. Physical examination after the current episode shows that she is afebrile, with a pulse of 72/min, respirations of 17/min, and blood pressure of 120/80 mm Hg. Imaging studies reveal a 0.5‐cm lesion in the head of the pancreas. The microscopic appearance of this lesion is shown in the figure. Which of the following pancreatic disorders is most likely to be present in this patient? A Acute necrotizing pancreatitis B Adenocarcinoma C Cystic fibrosis D Neuroendocrine tumor E Pseudocyst

49 D The figure shows a circumscribed cellular lesion in the pancreas, most suggestive of pancreatic neuroendocrine tumor (PanNET). Secretion of insulin by these lesions causes hypoglycemia and the described symptoms. Many of these tumors are less than 1 cm in diameter, making them difficult to detect. Most patients who have an insulin‐secreting PanNET have only mild insulin hypersecretion. The laboratory finding of an increased insulin‐to‐glucose ratio is helpful. Surgical excision is necessary in patients with marked symptoms. Acute pancreatitis is unlikely to increase islet cell release of insulin. Adenocarcinomas of the pancreas are derived from ductal epithelium and have no endocrine function. Fatty replacement of the pancreas can occur with cystic fibrosis, but the number of islets also gradually diminishes. Pseudocysts are complications of pancreatitis that are focal and do not produce insulin hypersecretion.

5 A 39‐year‐old G2, P2 woman, whose last pregnancy was 14 years ago, has had absent menstrual cycles for 6 months. She also reports expression of milk from her breasts. On physical examination, she is normotensive. She is 150 cm tall and weighs 63 kg (body mass index 28). Secondary sex characteristics are normal. Laboratory testing indicates that β‐human chorionic gonadotropin level is normal. She has a normal growth hormone stimulation test. CT scan of the head shows no abnormalities of bone and no hemorrhage. Brain MRI shows fluid density within a normal‐sized sella turcica. What is the most likely diagnosis? A Craniopharyngioma B Empty sella syndrome C Hereditary hemochromatosis D Prader‐Willi syndrome E Prolactinoma F Sheehan syndrome

5 B Empty sella syndrome is a rare condition, seen most frequently in obese women, and results from herniation of the arachnoid through the diaphragma sellae. Although the increased pressure can lead to reduction in pituitary tissue through compression atrophy, there is typically adequate functional anterior pituitary to prevent hypopituitarism. This herniation can cause a "stalk section" effect, however, with loss of prolactin inhibition and hyperprolactinemia. A craniopharyngioma is a destructive tumor mass that is usually seen at a younger age. Hemochromatosis can interfere with organ function, including hypopituitarism; onset usually occurs later in women than in men (in the 60s in women compared with the 40s in men), owing to differences in physiologic iron losses (e.g., menstrual blood loss). Prader‐Willi syndrome is an example of genomic imprinting with hypothalamic dysfunction seen in prepubertal boys. A prolactinoma could be a microadenoma, but MRI in this case rules this out because of the fluid density in the sella (seen with T2 weighting). If she had Sheehan syndrome after her pregnancy, she would have manifested hypopituitarism within months, not years.

50 A 43‐year‐old man from Stockholm, Sweden, has had low‐volume watery diarrhea for the past 3 months. He now has midepigastric pain. Over‐the‐counter antacid medications do not relieve the pain. On physical examination, he is afebrile; on palpation, there is no abdominal tenderness and no masses. An upper gastrointestinal endoscopy shows multiple 0.5‐ to 1.1‐cm, shallow, sharply demarcated ulcerations in the first and second portions of the duodenum. He is given omeprazole. Three months later, repeat endoscopy shows that the ulcerations are still present. Which of the following analytes is most likely to be increased in his in serum or plasma? A Gastrin B Glucagon C Insulin D Somatostatin E Vasoactive intestinal polypeptide (VIP)

50 A Zollinger‐Ellison syndrome can be caused by one or more pancreatic neuroendocrine tumors (PanNETs) secreting gastrin (gastrinoma). This secretion leads to intractable peptic ulcer disease, with multiple duodenal or gastric ulcerations. The incidence is 1 to 3 per million in Sweden. Proton pump inhibitors may help control the disease while evaluation for possible resection of tumors is undertaken. PanNETs may secrete various hormonally active compounds. Insulinomas may produce hypoglycemia. Glucagonomas and somatostatinomas may produce a syndrome characterized by mild diabetes mellitus. VIPomas may be associated with marked watery diarrhea, hypokalemia, and achlorhydria.

9 A 23‐year‐old man has experienced headaches, polyuria, and visual problems for the past 3 months. On physical examination, he has bilateral temporal visual field deficits. CT scan of the head shows a large, partially calcified, cystic mass occupying the sellar and suprasellar areas. Laboratory findings show a serum prolactin concentration of 60 ng/mL and serum sodium level of 152 mEq/L. Serum calcium, phosphate, and glucose levels are normal. The mass is excised, and histologic examination shows a mixture of squamous epithelial elements and lipid‐rich debris containing cholesterol crystals. Which of the following lesions is most consistent with the clinical and laboratory findings in this patient? A Craniopharyngioma B Metastases from a lung neoplasm C Multiple endocrine neoplasia type 1 D Multiple endocrine neoplasia type 2 E Prolactinoma

9 A Craniopharyngiomas are uncommon, usually suprasellar neoplasms; they are typically found in young individuals. They are thought to arise from embryologic remnants of the Rathke pouch in the region of the pituitary. These are aggressive neoplasms that infiltrate and destroy surrounding tissues, making complete excision difficult. Despite their aggressive behavior, they are composed of benign‐appearing squamoid or primitive tooth structures. The increase in prolactin occurs as a "stalk section" effect, and the hypernatremia results from diabetes insipidus caused by destruction of the hypothalamus, posterior pituitary, or both. A metastasis to this location in a young individual is highly unlikely. Multiple endocrine neoplasia (MEN) type 1 includes pituitary adenomas, but not craniopharyngiomas. MEN 2 does not involve the pituitary. Prolactinomas, similar to pituitary adenomas, can enlarge the sella when they are macroadenomas, but are not typically suprasellar or destructive of surrounding structures.

9. A 48-year-old man with type 2 diabetes diabetes and a history of alcoholism is not advised to be treated with metformin. Risk of which of the following conditions increases in such patients while on metformin? A) Severe allergic reactions B) Excessive weight gain C) Hypoglycemia D) Lactic acidosis E) Hepatotoxicity

9) Answer (D) Biguanides have been associated with lactic acidosis. Thus, metformin should be avoided in patients who are at increased risk of lactic acidosis, including alcoholism.

Normal serum calcium levels: phosphate levels:

9-11 mg/dl normal serum 2.5-4.5 mg/dl

Drugs inducing SIADH

: Carbamazepine, vinca alkaloids, chlorpropamide.

Adverse effects of vasopressin

: Most of the adverse effects of vasopressin are mediated through its action on the V1 receptor present on vascular and gastrointestinal smooth muscles. Vascular side effects: Myocardial ischemia, arrhythmias, peripheral vasoconstriction. GI side effects: Nausea, belching and cramps. Such effects are much less common and less severe with desmopressin that is more V2 selective.

Immunological problems with insulin

Allergic reactions: Immediate type hypersensitivity reaction (rare), urticaria and even anaphylaxis can occur. These reactions are mediated by IgE antibodies against the non-insulin protein components. Incidence is less with human insulins. Immune insulin resistance: Most patients develop a low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a small extent. In some patients a high titer of antibodies is present necessitating the administration of high daily doses of insulin. The complication is rare today due to the use of human insulin.

Case 2 6 yr old in for school physical History Frequent colds with missed days from school Favorite foods Potato chips and pickles O/E BP 96/64 PR 102/min RR 20/min Noted to have dark, tan skin Darker tan than his brother, mother, or other Caucasians in clinic Darkened palmar creases and gums

Addison Disease: Clinical features ↑pigmentation Due to increase melanin Stimulated by MSH from pro-opiomelanocortin (POMC) Initially in palmar creases On extensor surfaces Gum line May present emergently with patient in shock Hypotension Weight loss Fatigue Vomiting Diarrhea Anorexia Salt craving Abdominal pain Muscle or joint pain Postural dizziness

Somatostatin analogs:

Adverse drug reactions • GIT problems: abdominal cramps, diarrhea, malabsorption, steatorrhea • Gall stones • Vitamin B12 deficiency • Cardiovascular problems: Sinus bradycardia, conduction disturbances

1. Can cortisol interact with mineralocorticoid receptors? 2. Cortisol‐cortisone shunt? Any clinical significance? 3. Do we need normal liver function in a patient who is being prescribed prednisone? 4. Role of 11‐beta HSD? 5. Are corticosteroids bound to plasma proteins? What about the agents that are used for therapeutic purpose? 6. Which glucocorticoid agent to prefer when we need the drug to enter fetal circulation during pregnancy?

Aldosterone is the principal mineralocorticoid controlling sodium and potassium exchange in the distal nephron. Mineralocorticoid receptors in the kidney are responsible for this effect, and the sensitivities of both the glucocorticoid receptor and the mineralocorticoid receptor for cortisol in vitro are similar. Small changes in aldosterone affect sodium and potassium exchange in the kidney, whereas free and biologically active cortisol does not, yet cortisol circulates in much higher concentrations. This apparent paradox is explained by an intracellular enzyme—11‐ hydroxysteroid dehydrogenase type 2 (11‐HSD2)—that metabolizes cortisol to the inactive cortisone and protects the mineralocorticoid receptor from cortisol binding (above Figure). However, when circulating cortisol is extremely high (as in severe Cushing syndrome), this prereceptor metabolism of cortisol is overwhelmed and the mineralocorticoid receptor is activated by cortisol, resulting in volume expansion, hypertension, and hypokalemia (mineralocorticoid effects). Licorice‐induced hypertension: A component of licorice root prevents the oxidation of cortisol to cortisone and thus gives cortisol free access to the unprotected mineralocorticoid receptors in the kidney, causing hypokalemia and hypertension. In addition, some tissues can actually convert the inactive cortisone to cortisol with the isoform called 11‐hydroxysteroid dehydrogenase type 1 (11‐HSD1). The liver expresses 11‐ 6 HSD1 and can activate cortisone to cortisol, thereby completing the cortisol‐cortisone shunt such that the kidney inactivates cortisol to cortisone and the liver can reactivate cortisone to cortisol.

has - Two cell types: (Secrete neuropeptides) • NPY/AgRP (Neuropeptide Y/Agouti Related Peptide) • POMC/CART (Pro-Opiomelanocortin/Cocaine and amphetamine-regulated transcript)

Arcuate nucleus

the appetite control center in hypothalamus

Arcuate nucleus

Which drugs can induce SIADH? Which drugs can manage it?

Drug induced SIADH: SIADH - Carbamazepine, vinca alkaloids, chlorpropamide Drugs to manage SIADH - Demeclocycline - Conivaptan (non-selective vasopressin antagonist): affinity for V1a and V2; parenteral - Tolvaptan: more selective for V2 receptors; oral • Potential risk of liver injury (2013

Which drugs can cause hyperprolactinemia?

Drug induced hyperprolactinemia: Antipsychotics Metochlopramide

Not any longer preferred agent for treating type 2 diabetes mellitus. Long half-life (t1⁄2 24-32 hrs); long duration of action ~60 hrs. Metabolized in liver to active metabolites and majority is excreted unchanged in the urine. Contraindicated in patients with renal and hepatic insufficiency. Interacts with drugs which are oxidized in the liver. Hypoglycemia is more common due its long half-life. Disulfiram-like reaction with alcohol (occur in10-15% of pts. with a genetic disposition) It potentiates the effect of ADH in the collecting tubules of the nephron and can cause dilutional hyponatremia (in ~5% of patients) resulting in SIADH (Syndrome of inappropriate ADH secretion). 2nd line drug in the management of neurogenic diabetes insipidus. (Desmopressin is currently the preferred drug)

CHLORPROPAMIDE

Presenta.on: long history of HTN with LVH, mild proteinuria and slow progressive rise in BUN and crea.nine

CKD in Hypertensive Nephropathy (HN) (Hypertensive Nephrosclerosis)

What is the calcium phosphate product normal value?

Calciphylaxis occurs at a faster rate when the levels of calcium and phosphate are high. Chemically, they come out of solution as calcium phosphate. The likelihood of the chemical reaction occurring depends on the levels of calcium and phosphate, and can be predicted by multiplying the blood levels together. The calcium- phosphate product should be <4.5 in mmol/L and <55 in mg/dL

Acromegaly prognosis •

Skeletal changes do not regress Early identification and treatment may limit this condition Good prognosis with appropriate therapy

RANKL antagonist a synthetic fully humanized monoclonal antibody to RANKL that reduces osteoclast numbers and bone resorption. .

Denosumab:

How can glucocorticoids cause diabetes in patients at risk? What is the effect of cortisol on calcitriol, protein synthesis in the liver, muscle, and osteoblasts?

Diabetogenic effect: Glucocorticoids, by enhancing gluconeogenesis (by increasing the expression of phosphoenol pyruvate carboxykinase and glucose‐6‐ phosphatase) and reducing glucose uptake by cells, can cause diabetes mellitus in patients at risk Catabolic effects: Cortisol stimulates protein synthesis in the liver but has a catabolic effect on connective tissues, lymphoid tissue, muscle, fat and skin. Excessive amounts of glucocorticoids lead to decreased muscle mass, muscle weakness, and thinning of skin. Osteoporosis: 1) Glucocorticoids decrease calcium absorption from gastrointestinal tract by antagonizing the action of calcitriol, and increase calcium excretion in the urine by decreasing its reabsorption from the renal tubules. Decreased calcium absorption from GIT and increased calcium excretion in urine creates negative‐calcium balance that stimulates parathyroid hormone (PTH) release. PTH acts on bone to cause bone resorption; its continuous release contributes to cause osteoporosis. 2) Glucocorticoids also inhibit osteoblasts and increase bone resorption directly, leading to loss of calcium and osteoporosis.

• 54 y/o male Headache mostly in frontal region - Grade of pain 8 • Associated early morning vomiting • Recurring fever for past month 5 lb weight gain in last few monthsAttributed to ravenous appetite "I just cannot stop eating" " My eyes are giving me 'some trouble' as well " • O/E No infection detected No conjugate eye movement -Confrontation eye test • Bitemporal hemianopsia • Investigations reveal endocrinopathies

Differential Diagnosis Non functioning pituitary adenoma Functional pituitary adenoma Craniopharyngioma Meningioma • Others - Rathke's cleft cyst, dermoid cysts and hamartoma - Metastatictumors - Suprasellaraneurysms - Chordoma - Plasmacytoma - Pituitaryastrocytoma - Lymphocytichypophysitis - Langerhanscellhistiocytosis - Wegener's Pituitary enlargement may affect the central satiety center in hypothalamus Hyperphagia along with weight gain Bitemporal Hemianopsia, Loss of Peripheral vision"Patient may give history of repeated accidents or

What effect would an increase in dietary phosphate have on FGF-23? What is the effect of FGF on expression of renal sodium-phosphate cotransporters? Does FGF have an effect on calcitriol levels?

Fibroblast growth factor 23 (FGF-23) expression in bone is up-regulated by an increase in dietary phosphate (Pi) intake and by 1,25(OH)2D), and it is down-regulated, through unknown mechanisms, by PHEX (encoded by PHEX, or phosphate- regulating gene, DMP1 (dentin matrix protein 1), ENPP, and probably several additional proteins. Normal physiology: FGF-23 acts through one or more FGF receptors (e.g., FGFR1c): 1. to inhibit phosphate reabsorption (by reducing expression of renal sodium- phosphate cotransporters NaPi-lla and NaPi-llc in the proximal tubules), resulting in increased phosphate excretion in urine. 2. to decrease circulating 1,25(OH)2D levels. The decrease in calcitriol levels reduces active transport of phosphate and calcium across the intestines. Elevated FGF-23 possibly also decreases parathyroid hormone (PTH) synthesis and secretion by the parathyroid glands.

Pheochromocytoma Case continued Her father died suddenly 10 years ago at age 42 from unknown causes Hearing of Gina's illness her paternal aunt called After relaying the symptoms "This may be serious. Timmy had similar problems before his surgery" Tim is Gina's 43 yr old uncle who was diagnosed with thyroid cancer and pheochromocytoma Since his surgery he had genetic testing that diagnosed his condition 3 other family members were diagnosed with medullary thyroid cancer and one of the 3, an aunt had a pheochromocytoma

Final Diagnosis MEN 2 Syndrome

manifests clinically with nephrotic syndrome that does not respond to corticosteroid therapy. can result from many forms of glomerular injury; some may be linked to NPHS gene mutations.

Focal segmental glomerulosclerosis (FSGS)

effects of GH & IGF-1 on Glucose uptake (muscle)

GH decreases, IGF-1 increases

effects of GH & IGF-1 on Hepatic glycogenolysis

GH decreases, IGF-1 increases

effects of GH & IGF-1 on Hepatic gluconeogenesis

GH increases, IGF-1 decreases

effects of GH & IGF-1 on Insulin sensitivity

GH increases, IGF-1 decreases

effects of GH & IGF-1 on Lipolysis

GH increases, IGF-1 decreases

effects of GH & IGF-1 on plasma glucose levels

GH increases, IGF-1 decreases

• A peptide secreted by gastric mucosa on an empty stomach • 28 amino acids • Requires octanoylation of ser3 for activity • Also causes the release of growth hormone • Injections do the same things • In obesity, levels are decreased

GHRELIN

• Activates NPY/AgRP neurons in arcuate nucleus in hypothalamus - These are appetite-stimulating neurons • Short-termappetitecontrol • OverproductionObesity

GHRELIN

Anterior Pituitary Test

GHRH, CRH, GnRH and TRH given intravenously -Blood samples collected at 30, 0, 15, 30, 60, 90, and 120 min -GH, ACTH, cortisol, LH, FSH and TSH can be measured Failure to respond to stimulation indicates lack of pituitary function Nonsecretory adenoma

Half-life 5-7 hrs. More potent (dose 0.5-4 mg per day) Duration of action ~24 hrs. (single daily dose) Less chances of hypoglycemia (2-4% of patients)

GLIMEPIRIDE

t 1⁄2 2-4 hrs Duration of action ~14-16 hrs. Less chances of hypoglycemia Preferred in elderly

GLIPIZIDE

Incretins

GLP-1 and GIP

Adverse effects: Flatulence (due to the appearance of undigested carbohydrates in the colon where they are fermented and release gas), diarrhea, and abdominal pain Contraindications: Chronic inflammatory bowel disease, renal impairment, hepatic dysfunction When used with sulfonylureas, hypoglycemia that may occur should be treated with glucose rather than sucrose.

GLUCOSIDASE INHIBITORS: Miglitol and Acarbose

Mechanism of action: These drugs inhibit glucosidase, an enzyme attached to the brush border of intestinal cells and involved in the breakdown of starch and disaccharides into simple sugars. This action inhibits the postprandial digestion of starch and disaccharides in the GIT. Postprandial rise in plasma glucose is blunted, creating an insulin sparing effect. They are taken just prior to ingesting the first portion of each meal.

GLUCOSIDASE INHIBITORS: Miglitol and Acarbose

Therapeutic uses of a- glucosidase inhibitors:

GLUCOSIDASE INHIBITORS: Miglitol and Acarbose Management of type 2 diabetes as monotherapy or in combination with sulfonylureas. Suitable alternatives in patients with mild-moderate hyperglycemia and patients who are at risk for hypoglycemia and lactic acidosis. Useful as monotherapy in the elderly.

t1⁄2 4-6 hrs Duration of action 18-24 hrs. High plasma protein binding (99.8%); minimal transfer across placenta Hypoglycemia occurs in 20-30% of patients. Use with caution in patients with cardiovascular disease and in elderly patients in whom hypoglycemia would be dangerous.

GLYBURIDE

gene for Activating mutation GH adenomas

GSα

effect of high prolactin on GnRH

High Prolactin causes Lactation and suppresses GnRH

Drug interactions of sulfonylureas:

Hypoglycemic effect of sulfonylureas is potentiated by: Insulin Alcohol Beta adrenergic blockers Sulfonamides (antibiotic group) Salicylates Hypoglycemic effect of sulfonylureas is diminished by: Corticosteroids Thiazides, loop diuretics (furosemide) Phenytoin

Adult symptoms Hypo-function Reproductive system, Thyroid, Adrenal In children Mental or growth retardation "Symmetrical dwarfism" Delayed puberty Clinical effects vary and depend on Extent of loss of function Specific cell type and hormone involved Age of patient

Hypopituitarism

Presenting Signs and Symptoms of Craniopharyngioma in children and adults

Hypopituitarism - Delayed puberty May have Unlike adults, presents as growth retardation • - - - - Central diabetes insipidus Hyperphagia and obesity Loss of thirst sensation Loss of temperature regulation

• 77-year-old woman, seen in ER two hours after a fall at home • Developed fever 1 day before ER visit • Felt light headed and weak before she fell • Hit her head when she fell and may have lost consciousness briefly • 10 minutes after she got up, she vomited and complained of left chest tightness and SOB • T 38 degrees C • Pulse 120 bpm • BP 125/75 mmHg • No external evidence of injury • Bilateral pitting edema, feet and ankles • JVP not elevated • Scattered crackles on lung auscultation After Admission to Hospital • Noted to be confused • Tachypnea, but no wheezes • Mild tenderness over left abdomen • Rectal exam normal • Neurological exam normal (except for confusion) Admission Laboratory Data Urinalysis normal ECG showed sinus tachycardia Supine CXR - No obvious consolidation or pulmonary congestion Hb low BUN:creatinine = 7

Miss Jones was started on IV ampicillin for a probable chest infection, and was transfused 2 units of packed red cells. The following day she became restless and complained of abdominal pain. On examination her abdomen was distended, but soft. There was mild tenderness, but no guarding or rebound tenderness and the bowel sounds were sluggish. She continued to complain of abdominal pain and repeat examination revealed increasing abdominal distension and confusion. A diagnosis of intestinal obstruction was made. During laparotomy, a perforated gastric ulcer was found with soiling of the peritoneal cavity by fibrins and pus. The patient slowly recovered and was discharged home after 4 weeks.

inhibits the secretion of serotonin in carcinoid syndrome, VIP in VIPoma, and other mediators in GIT. It decreases all GIT secretions. This helps in controlling violent attacks of watery diarrhea and associated symptoms in these conditions.

Octreotide

drug to prevent gigantism

Octreotide GH excess in children can lead to gigantism if surgical measures are not taken/or are not possible to remove the GH secreting pituitary adenoma. Octreotide can reduce the synthesis of GH.

• Secreted by small intestines • increases in proportion to caloric intake • Actions in arcuate nucleus - Inhibits NPY/AgRP neurons - Stimulates POMC/CART cells • POMC release • POMC processing in hypothalamusrelease of a-MSH - a-MSH: inhibits food intake; increases energy use • CART: inhibit food intake; increases energy use

PYY3-36

• Hypoparathyroidism Signs and Symptoms:

Paraesthesiae Peri-oral & Neuromuscular irritability Tetany (Hyper excitability of the skeletal muscles) Psychiatric disturbances CVS: Conduction defect and prolonged QT interval Rarely, cataracts and brittle nails Calcification of Basal Ganglion and Parkinson like syndrome and Convulsions Associated conditions in Chronic disease Atopic eczema Impetigo Exfoliative Psoriasis dermatitis herpetiformis

acts as an antagonist of GH. It binds to GH receptors, but does not activate Jak-stat signaling or stimulate IGF-1 secretion. It is approved for the treatment of acromegaly when somatostatin analogs are not able to fully control the disease.

Pegvisomant

What is the mechanism of the pressor effect of vasopressin? The antidiuretic effects? The coagulation effects?

Pressor effect: Stimulation of V1 receptors on arteriolar smooth muscles mediate the pressor effect of vasopressin though IP3/DAG - calcium as second messenger system. V 2 receptor: Renal V2 receptors: Antidiuretic effects are mediated by increase in cAMP through stimulation of V2 receptors present on basolateral cells of the distal and collecting ducts of nephron. This causes an increase in cell surface expression of water channels, resulting in increased water permeability and water reabsorption. Extrarenal V2 receptors: mediate the release of coagulation factors - VIII & Von willebrand factor.

What is the pathogenesis of hypercalcemia in sarcoidosis?

Production of 1-alpha(OH)ase by macrophages in a lung granuloma can increase conversion of circulating 25(OH)D3 to 1,25(OH)2D3. This will increase gut Ca+2 absorption and bone Ca+2 resorption. The increased blood Ca+2 AND 1,25(OH)2D3 will inhibit PTH production by the parathyroid glands. The increased filtered load of Ca+2 through the kidney and suppressed PTH will contribute to hypercalciuria.

Final Diagnosis Metastatic Neuroblastoma

Prognostic Factors > 18 months, unfavorable Stage3,4 High mitotic Near Diploid Serum NSE + N < 18 months, favorable Stage 1, 2A, 2B & 4S - amplified karyrrhexis index - myc Mitotic index (<200/5000) Comprehensive Adrenal Lecture 150 - Hyperploidy karyrrhexis Schwannian

Treatment of malignancy hypercalcemia

Rehydration as necessary with saline - Restore renal function which is often impaired in hypercalcemia because of reduced GFR and dehydration • Bisphosphonates: Zoledronic acid, pamidronate • Calcitonin • Glucocorticoids (hypercalcemia in patients with multiple myeloma, lymphoma, sarcoidosis): 1) inhibit activity of 1- hydroxylase and prevents hydroxylation of 25(OH)D to calcitriol, 2) inhibit reabsorption of calcium from the renal tubules • Administration of Osteoprotegerin or Antibodies to RANK ligand

Case 7 3 y/o boy brought by his mother Concerned about lack of appetite, listlessness and avoidance of physical activity She says he complains of his legs aching. She has noticed that sometimes he gets unsteady on his feet and abruptly sits down. He also complains of tummy-ache She thinks his tummy may be swollen. He has constipation. 2/5/2016 Comprehensive Adrenal Lecture 136 Case 7 contd O/E The child is pale Bluish discoloration around the eyes blood pressure : high. The left flank region appears full and a mass is palpated in the left lumbar region Case 7: Investigations Full blood count - confirms anemia, Platelets are low, ESR is raised. Coagulation tests - Abnormal PT and APTT Urine shows: Homovanillic acid (HVA) and vanillylmandelic acid (VMA), with a low VMA-HVA ratio (poorly differentiated tumor): poor prognosis Neuron-specific enolase (NSE) - elevated levels ( 96% patients with metastases) : poor prognosis. Plain abdominal X-ray: Small flecks of calcification seen in the abdomen MRI scan: Retroperitoneal mass superior and attached to the left kidney

Scan in coronal view (following gadolinium enhancement) Reveals a large mass above the left kidney arising in the left adrenal gland. The spleen is lateral to the mass. The liver is seen on the right. Full blood count - confirms anemia, Platelets are low, ESR is raised. Coagulation tests - Abnormal PT and APTT Urine shows: Homovanillic acid (HVA) and vanillylmandelic acid (VMA), with a low VMA-HVA ratio (poorly differentiated tumor): poor prognosis Neuron-specific enolase (NSE) - elevated levels ( 96% patients with metastases) : poor prognosis. Plain abdominal X-ray: Small flecks of calcification seen in the abdomen MRI scan: Retroperitoneal mass superior and attached to the left kidney Histopathology of the mass reveals Neuroblastoma

Activation of the renin-angiotensin system due to Decreased renal perfusion arteriolarnephrosclerosis renalarterystenosis Arterial hypovolemia and edema congestiveheartfailure Cirrhosis nephrotic syndrome Pregnancy due to estrogen-induced increases in plasma renin substrate Lab findings Elevated aldosterone Elevated renin level

Secondary Hyperaldosteronism

Secretion of prolactin is under predominant inhibitory control of _________ secreted by _________. This acts on ___ receptors in the _____________ to inhibit prolactin secretion.

Secretion of prolactin is under predominant inhibitory control of dopamine secreted by hypothalamus. Dopamine (PRIH) acts on D2 receptors in the anterior pituitary to inhibit prolactin secretion.

a 9 year old male child is referred to the orthopedic clinic with a 4 month history of bilateral ankle pain and intermittent pain in the right knee. He also complains of lethargy for 4 weeks He was born by vaginal delivery at full term. He had been fully immunized. He is small for his age. - Anteroposterior and lateral radiographs of left ankle showing excessive widening of the growth plate:suggesting Rickets

Significant Lab Reports • • • • • - BUN and Serum Calcium: Phosphorus: PTH: : High Raised significantly Creatinine Low High Abdominal Ultrasound: Kidney: Spongiform Kidney 48

29 A 40‐year‐old man experiences weakness and easy fatigability of 2 months' duration. Physical examination yields no remarkable findings. Laboratory studies show serum calcium of 11.5 mg/dL, inorganic phosphorus of 2.1 mg/dL, and serum parathyroid hormone of 58 pg/mL, which is near the top of the reference range. A radionuclide bone scan fails to show any areas of increased uptake. What is the most likely cause of these findings? A Chronic renal failure B Hypervitaminosis D C Medullary thyroid carcinoma D Parathyroid adenoma E Parathyroid carcinoma F Parathyroid hyperplasia

The elevated parathyroid hormone (PTH) suggests primary hyperparathyroidism. The most common cause of primary hyperparathyroidism is a parathyroid adenoma. Secondary hyperparathyroidism, most commonly resulting from renal failure, is excluded when the serum inorganic phosphate level is low because phosphate is retained with chronic renal failure. Hypervitaminosis D can cause hypercalcemia because of increased calcium absorption, but in these cases, the PTH levels are expected to be near the low end of the reference range because of feedback suppression. Serum PTH levels near the high end of the reference range indicate autonomous PTH secretion unregulated by hypercalcemia. Although medullary carcinomas of the thyroid often have positive immunohistochemical staining for calcitonin, and plasma levels are sometimes increased, there is typically no major reduction in serum calcium as a result.

Therapeutic uses of vasopressin / analogs:

Vasopressin: Advanced cardiac life support Bleeding esophageal varices: V1 receptor-mediated vasoconstriction of splanchnic arterial vessels reduces portal blood flow and, thereby attenuates pressure and bleeding in esophageal varices. Desmopressin (Antidiuretic : vasopressor activity, 3000:1) Neurogenic (central) diabetes insipidus Von Willebrand disease (type 1) and hemophllia A Enuresis

Case 10 • A 58-year-old man with a 13-year history of type 2 diabetes mellitus visits a walk-in clinic because of increasing swelling in his lower extremiDes for 6 months - worsened over the past 6 weeks. No other complaints • Laboratory-blood: - HbA1c 11% - Autoimmune screen and serology negaDve. No serum cryoglobulins. • Urine: - Spot am urine protein:creaDnine raDo 3000 mg/g - Urinary protein excreDon: 4.35 g/24h - Albumin, 2.9 g/dL; urea 24 mg/dL, creaDnine 1.6 mg/dL, eGFR=40; K 5.5 mEq/L, Na 132 mEq/ History: • PMH: hypertension and type 2 diabetes mellitus. L, Total cholesterol 255 • Rx: Me|ormin 500 mg twice daily, glimepiride 2 mg daily, mg/dL, enalapril 10 mg twice daily, amlodipine 10 mg daily, and ibuprofen occasionally. • Does not abuse alcohol, tobacco, or illicit drugs, but he likes the occasional burger and Kentucky fried chicken. • No family history of kidney disease, although several of his family members have DMII and heart disease. Physical exam • Healthy-appearing man in no acute distress. • Vitals: apyrexial, BP: 152/93 mm Hg; HR 75; RR 14 • Pirng pre-Dbial and pedal edema; no rashes • Eyes: pre-proliferaDve diabeDc reDnopathy • CNS and R/S normal findings • CVS: S4 gallop.w s

What is the most important measure to prevent the progression of this pa.ent's condition? 1. Keep BP below 140/90 mmHg 2. Add insulin to bring the HbA1c to levels <7 % 3. A diet rich in proteins to address the low albumin which causes the edema 4. StaDns and low fat diet 5. Renal replacement therapy as soon as possible How would you treat this patient pharmacologically? 1. Decrease me|ormin 2. Stop glimepiride 3. Add insulin 4. Stop the NSAID 5. Add furosemide 6. All of the above

Loss of weight (GH) Loss of libido (hypogonadism) Oligomenorrhea/amenorrhea (Gynecomastia in males) Decreased need to shave (hypogonadism) (LH, FSH) Cold intolerance (TSH) pigmentation (ACTH)

What is the most likely diagnosis? Pan Hypopituitarism due to Sheehan Syndrome

Case 4 30 y/o woman Lethargy (always very tired) Feel like her legs about to 'give way' Hair loss, including pubic hair Muscle weakness • 3 pregnancies Last one about 2 months ago Complicated by severe postpartum hemorrhage and shock Irregular, very light periods (2d) Earlier menstruation was 5d, regular

What is the most likely diagnosis? Pan Hypopituitarism due to Sheehan Syndrome