Kingdom of Bahrain Arabian Gulf University College of Medicine and Medical Sciences

1. Kingdom of BahrainArabian Gulf UniversityCollege of Medicine and Medical Sciences Internal Medicine Notes Endocrinology Prepared by: Ali JassimAlhashli Based on: Kaplan Step 2 CK Internal Medicine

2. Diseases of The Anterior Pituitary • Microadenomas vs. macroadenoma: • Microadenoma: it is > 1 cm in diameter and more common than macroadenomas. • Macroadenoma: it is < 1 cm in diameter and can compress the optic chiasm resulting in visual disturbances such as (bitemporalhemianopia). • Pituitary adenomas by function: • Prolactin-secreting: 50-60%. • Growth hormone-secreting: 15-20%. • ACTH-secreting: 10-15%. • Gonadotroph-secreting: 10-15% • Hyperprolactinemia: • Definition: increased levels of prolactin in the blood. • Etiology: • Natural physiologic conditions: pregnancy, early nursing, stress and nipple stimulation. • Prolactinomas (most common and composing 50-60% pf functioning pituitary adenomas): they are microadenomas in females (because the condition will be detected earlier due to presence of red flags in females; most important being amenorrhea) and macroadenomas in males (compressing optic chiasma and causing visual abnormalities. • Dopamine antagonists (such as metoclopramide and phenothiazines). • Primary hypothyroidism: which results increased TRH release from hypothalamus which in turn stimulates the release of prolacting from adenohypophysis. • Clinical manifestations: • Females: galactorrhea, amenorrhea (↑prolactin inhibiting GnRH thus there is no release of LH and FSH), decreased libido and infertility. • Males: erectile dysfunction, decreased libido, infertility, gynecomastia is rare. • Diagnosis: • Remember always to exclude: pregnancy, lactation, medications and primary hypothyroidism. • ↑prolactin + MRI of brain. • Treatment: • Dopamine agonists: cabergoline or bromocriptine. • Surgery is reserved for: cases not responding to medical therapy or macroadenomas with compressive symptoms. • If even surgery fails: radiation.

3. Diseases of The Anterior Pituitary

4. Acromegaly: • Definition: it is a syndrome of increased Growth Hormone (GH) secretion. In children, it results in gigantism. Acromegaly is gradual (9 years of symptoms before being diagnosed!), chronic debilitating disease associated with bony and soft tissue overgrowth and increased mortality. • Etiology: • Pituitary macroadenoma. • Ectopic tumor: secreting GH or Growth Hormone Releasing Hormone (GHRH). • Clinical presentation: • Headache and visual disturbances (because the cause is a macroadenoma). • Enlargement of hands, feet, nose, mandible and coarse facial features. • Deeper voice. • Enlargement of the heart, lungs, liver, spleen and kidneys. • Osteoarthritis and capal tunnel syndrome. • Menstrual irregularities in females due to co-secretion of prolactin with GH-secreting tumor. • Glucose intolerance (80% of patients) and diabetes (20% of patients). • 1/3 of patients will have hypertension. • There is accelerated atherosclerosis, hypertrophic cardiomyopathy and arrhythmias. Most common cause of death in these patients is due to cardiovascular diseases. • Diagnosis: • Best initial test: ↑IGF-1 level. • Then, confirm with glucose loading test (100 g): normally glucose must completely suppress GH release. If GH level remains high after giving glucose → this confirms the diagnosis of acromegaly. • MRI of the head to localize the macroadenoma. • Treatment: • Start the patient with somatostatin agonists (best medical therapy) such as octreotide to cause regression in the size of the tumor. • Then, do transphenoidalsurgey (which is the PRIMARY TREATMENT OF ACROMEGALY). • Continue the patient with octreotide after surgery because there might be residuals from the tumor which could not be removed. • If medical therapy and surgery fail → radiation (its effect will take nearly up to 3 years to appear during which the patient will continue taking somatostatin analogs). Diseases of The Anterior Pituitary

5. Diseases of The Anterior Pituitary

6. Hypopituitarism: • Definition: it is partial or complete loss of function of the anterior pituitary gland. Notice that GH and gonadotropins (FSH and LH) are lost earlier. • Etiology: • Trauma, radiation, surgery or infections (TB or syphilis). • Large pituitary tumors or hypothalamic tumors. • Pituitary adenomas: most common cause of panhypopituitarism (because they are compressing the remaining of pituitary gland resulting in its necrosis). • Pituitary apoplexy: it is an acute hemorrhagic infarction of pre-existing pituitary adenoma. Clinical presentation: severe headache, nausea/vomiting and depressed mental status. • Sheehan postpartum necrosis (initial sign being the inability to lactate). • Clinical findings: • Deficiency of gonadotropins (FSH and LH): • Females: amenorrhea, infertility, genital atrophy, decreased libido and decreased pubic and axillary hair. • Males: impotence, infertility, testicular atrophy, decreased libido and decreased pubic and axillary hair. • Deficiency of GH is not clinically detectable in adults but in children it will result in failure of growth and short stature. • Deficiency of TSH resulting in hpothyroidism (fatigue/weakness, cold-intolerance, constipation, weight gain and puffy skin). • Deficiency of ACTH results in secondary adrenal insufficiency (decreased response to stress, weight loss and fatigue). Remember that aldosterone secretion is not regulated by ACTH. • Diagnosis: • Gonadotropins deficiency: males (LH, FSH and testosterone); females (LH, FSH and estrogen). • Growth hormone deficiency: measure GH and IGF-1. Then, confirm with insulin-induced hypoglycemia: normal response is increase in GH secretion → if GH remains low this confirms the presence of GH deficiency. • TSH deficiency: ↓T3 and T4 with ↓TSH. • ACTH deficiency: detected by metyrapone test. Metyrapone normally blocks cortisol production which must result in increased ACTH production → if ACTH remains low → this confirms your diagnosis of ACTH deficiency. • Management: first and most important hormone to be replaced is cortisol. Then, replace other deficient hormones. • Empty Sella Syndrome (ESS): • Definition: herniation of suprasellarsubarachenoid space through an incomplete diaphragm sella. • Etiology: idiopathic or secondary to trauma/radiation. • Clinical presentation: most patients are obese, multiparaous females with headaches. • Diagnosis: no pituitary gland can be seen with CT/MRI of the head! • Treatment: reassurance. Diseases of The Anterior Pituitary

7. Diseases of The Anterior Pituitary

8. Diabetes Insipidus (DI): • Definition: • Central DI: partial or complete deficiency in the secretion of ADH. • Nephrogenic DI: there is normal secretion of ADH but renal receptors are resistant. • Etiology: • Central DI: severe head injury, infections (meningitis), surgery of hypothalamus/pituitary, radiation or hypothalamus/pituitary tumors. • Nephrogenic DI: hypercalcemia, hypokalemia, amyloidosis, pyelonephritis, Sjogren syndrome, myeloma, sickle cell disease or drugs (lithium, colchicine and demeclocycline). • Clinical presentation: • Patient will present with polyuria (inability to retain free water) and poyldypsia. • There will be hypernatremia (↑serum osmolarity). • Dilute urine (↓urine osmolarity with urine specific gravity >1.010). • Diagnosis: • Water deprivation test: water restriction normally will result in decreased urine volume with concentrated urine. In patients with DI, even with fluid restriction urine volume will remain high and it will be dilute. With central DI → ADH level is low while with nephrogenic DI → ADH level is high. • Management: • Central DI: desmopressin (DDAVP: intranasally). • Nephrogenic DI: hydrochlorothiazides. Diseases of The Posterior Pituitary

9. Diseases of The Posterior Pituitary

10. Syndrome of Inappropriate Secretion of ADH (SIADH): • Definition: there is increased secretion of ADH. • Etiology: • CNS disease: stroke, trauma or encepahlitis. • Pulmonary disease: pneumonia, TB or asthma. • Malignancies: lung cancer and cancers of pancreas and duodenum. • Drugs: SSRIs, tricyclic antidepressants, haloperidole, vincristine and carbamazepine. • Clinical presentation/diagnosis: • ↓urine volume and urine will be concentrated (urine osmolarity< 300 mOsm). • Hyponatremia and ↓serum osmolarity. If hyponatremia has acute onset, there is a high risk for seizures and coma. • ↑ADH level. • Management: • Restriction of fluids to 800-1000 ml/day (to increase serum sodium concentration). • V2-receptor antagonists. • If hyponatremia is severe and causing patient to seize or enter a state of coma → 3% hypertonic saline (but notice that correction of sodium must no exceed 12 mEq/24 hours). Diseases of The Posterior Pituitary

11. Laboratory test in thyroid disease: • The most sensitive test in thyroid disease is TSH. Normal range in the lab = 0.25 – 5 • Always check free T4 to assess thyroid function (why?) → because it has a longer t ½ = 7 days while T3 has a t ½ = 1 day. • Thyroid Radio-Active iodine Uptake (RAIU) is used to determine the functional status of thyroid gland. After 24 hours of administration, uptake is equal to 5-30% of administration dose. • ↑RAIU: Grave’s disease or toxic nodule. • ↓RAIU: thyroiditis. • Antibodies: • Grave’s disease: Thyroid Stimulating Immunoglobulin (TSI). • Hashimotosthyroiditis: anti-thyroglobulin antibody; antimicrosomal antibody. • Hyperthyroidism (thyrotoxicosis): • What is the difference between hyperthyroidism and thyrotoxicosis? • Hyperthyroidism: increased levels of thyroid hormones due to a problem in thyroid gland itself. • Thyrotoxicosis: it is a broader term including hyperthyroidism caused by any other conditions not related to thyroid gland. • What are the causes of hyperthyroidism? • Grave’s disease: it is an autoimmune disease in which there are antibodies (TSI) mimicking the activity of TSH and enhancing the secretion of thyroid hormone from thyroid gland. Patients have painless diffuse enlargement of thyroid gland. • Toxic adenoma (hyperfunctioning and secreting thyroid hormones). • Toxic multinodular goiter: which is common in elderly and associated with arrhythmia and CHF. Patient has painless multiple nodules when palpating his thyroid gland. • Increased TSH (secondary hyperthyroidism). • Drugs (lithium, amiodarone and α-interferon). • Ectopic thyroid tissue (strumaovarii). Diseases of The Thyroid Gland

12. Grave’s disease (toxic diffuse goiter) • Definition: grave’s disease = hyperthyroidism + diffuse goiter + exophthalmos + dermopathy. • Etiology: • It is an autoimmune disease in which there is production of antibodies (TSI) directed against TSH-receptors present on thyroid gland and stimulating the gland to secrete thyroid hormones. • There is a genetic component of the disease and the risk also increases if the patient has another autoimmune disease (such as type-1 DM). • There is also increased risk with smoking and it can make exophthalmos worse. • Epidemiology: common in females > 50 years of age. • Clinical manifestations: • Exopthalmos and lid retraction. • Diffuse painless goiter. • Peritibialmyxedema. • Other manifestations of hyperthyroidism: heat-intolerance, increased bowel movement, weight loss despite increased appetite, irritation, tremors, sweating, palpitations and menstrual irregularities. • Diagnosis: • ↓TSH and ↑T4 and T3. • ↑RAIU • Presence of TSI. • Treatment: • First, control symptoms by β-blockers (propranolol). • Then, give anti-thyroid medications: • Propylthiouracil (PTU): which has more ADRs such as liver toxicity and is not preferred. • Methimazole. Both of these drugs work by inhibiting the enzyme peroxidase. They take around 6 weeks for their effect to be apparent. Both drugs can result in agranulocytosis. PTU is recommended for 1st trimester of pregnancy after-which the pregnant lady will switch to methimazole and continue using it for the rest of pregnancy. • The most commonly used permanent therapy for Grave’s disease is radioactive iodine which causes a state of hypothyroidism after 2-3 months and the patient will be set on L-thyroxine for the rest of his life. Diseases of The Thyroid Gland

13. Diseases of The Thyroid Gland

14. Thyroid storm: • Definition: it is an extreme form of thyrotoxicosis and considered to be an endocrine emergency. • Etiology: this condition is triggered by stress, infection, surgery or trauma. • Clinical presentation: high-grade fever, delerium, severe irritability, vomiting, diarrhea, tachycardia and hypotension. • Treatment (remember the 3 P’s): • Start with PTU followed by iodine. • Propranolol (β-blocker). • Prednisolone (glucocorticoid). • Hypothyroidism: • Definition: decreased levels of thyroid hormones. • Etiology: • Primary hypothyroidism: • Hashimoto thyroiditis (most common cause): characterized by the presence of antimicrosomal and antithyroglobulin antibodies. • Post-ablative surgery. • Radioactive iodine. • Drugs (same drugs which can cause hyperthyroidism): • Lithium. • Interferon. • Amiodarone: it is an antiarrhythmic drug used in the treatment of ventricular and supraventriculartachyarrhythmias. It is structurally similar to T4. It can cause amiodarone-induced thyrotoxicosis (type 1: patient has underlying thyroid pathology such as Grave’s disease and treated with anti-thyroid medications; type 2: causing subacutethyroiditis with release of preformed thyroid hormones and treated with glucocorticoids). It can also cause amiodarone-induced hypothyroidism by inhibition of peripheral conversion of T4 to T3. • Secondary hypothyroidism: problem is at level of pituitary gland (↓TSH). • Tertiary hypothyroidism: problem is at the level of hypothalamus. Diseases of The Thyroid Gland

15. Hypothyroidism (continued): • Clinical findings: • Children (cretinism): which is characterized by coarse features, protruding tongue, delayed milestones, mental retardation, dry skin and hair, constipation and dwarfism. • Adults: lethragy/weakness, dry hair and skin, constipation, weight gain despite loss of appetitie, menorrhagia, cold-intolerance and myxedema. • Diagnosis: • Primary hypothyroidism: ↓T3 and T4; ↑TSH. • Secondary and tertiary hypothyroidism: normal/↓ TSH; ↓fT3 and fT4 • Management: • Replacement of thyroid hormone with L-thyroxine (T4) and monitoring of TSH, T4 and T3. It takes 6 weeks for the drug to express its effect. • L-thyroxine must be taken on an empty stomach with no other drugs or vitamins. • If a patient has Coronary Artery Disease (CAD) that needs an intervention, do the intervention (CABG or angioplasty) before replacing thyroid hormone with L-thyroxine. • Complication: myxedema coma • It occurs with severe, long-standing hypothyroidism which is left untreated. • Patients presents with: hypothermia, stuporous state and respiratory depression. • This condition is precipitated by: cold exposure, trauma, infections or CNS depressants. • Treatment: high doses of T4 along with T3. Diseases of The Thyroid Gland

16. Diseases of The Thyroid Gland

17. Thyroiditis: • Definition: it is inflammation of thyroid gland which can be associated with euthyroid, thyrotoxic or hypothyroid states. • Subacutethyroiditis: • Epidemiology: 4th-5th decades. • Etiology: it is thought to be of viral origin. • Clinical Manifestations (resembling those of URTIs): • Fever. • Malaise. • Pain over the thyroid gland. • Pain which might be referred to lower jaw, ears, neck and arms. • Diagnosis: • Diffuse, painful enlargement of thyroid gland. • ↓RAIU. • ↑ESR. • Initially, T4 and T3 will be elevated (due to leakage of hormones from thyroid gland) but patient will end with hypothyroidism (as hormones get depleted). • Treatment: symptomatic (NSAIDs, prednisone and propranolol). • Prognosis: thyroid condition eventually subsides and it returns to its normal function. • Hashimoto thyroiditis: • Definition: It is a chronic inflammation of the thyroid gland with lymphocytic infiltration. • Etiology: it is thought to be due to autoimmune processes as evident by: lymphocytic infiltration of the gland + presence of antibodies (antimicrosomal, antithyroglobulin and antithyroperoxidase antibodies). • Epidemiology: middle-aged females. • Clinical manifestations: painless enlargement of thyroid gland + features of hypothyroidism. • Diagnosis: • ↑TSH, ↓T3 and T4. • Antimicrosomal antibodies, antithyroglobulin antibodies and antithyroperoxidase antibodies. • Confirmation by needle-biopsy although not needed. • Management: replacement with L-thyroxine. Diseases of The Thyroid Gland

18. General concepts: • Function of Parathyroid Hormone (PTH): to maintain the extracellular fluid concentration of calcium. Therefore, PTH is regulated by the concentration of serum ionized calcium. • How does PTH increases calcium concentration? • Increasing osteoclastic activity which results in bone resorption and release of calcium. • Enhancing the production of active vitamin D which in turn increases the reabsorption of calcium from the gut. • Inhibiting the reabsorption of phopshate from kidney tubules. • Increasing distal tubular reabsorption of calcium • Calcium regulation involves 3 tissues: bones, kidneys and intestine. • Calcium regulation involves 3 hormones: PTH (hypercalcemic), calcitonin (hypocalcemic) and active vitamin D (hypercalcemic). • Hypercalcemia: • Definition: increased serum levels of total or free calcium. Notice that 98% of calcium in the body is stored in the bones. Calcium is absorbed from duodenum and 80% of calcium in the diet will get lost with feces (unabsorbed). • Etiology: • Most common cause is primary hyperparathyroidism (90% of cases) which is usually asymptomatic and is found with routine examination. • Hypercalcemia can result from malignancies such as squamous cell carcinoma of the lung that is producing PTH-like substance. • Granulomatous disease: sarcoidosis and TB 9granulomas have their own active vitamin D). • Vitamin D intoxication (rare cause). • Acidosis: in which there will be increased free calcium (considered as a buffering system). • Hyperthyroidism: because thyroid hormone has a partial effect on osteoclasts. • Familial HypocalciuricHypercalcemia (FHH): • Etiology: a loss-of-function mutation if Calcium Sensing Receptor (CaSR) which is normally found in parathyroid glands and kidneys. • Presentation: mild hypercalcemia, family history of hypercalcemia and urine calcium > 200 mg/day (hypocalciuria). Notice that in all other causes of hypercalcemia, elevated calcium level in the blood is associated with elevated calcium level in the urine. • Treatment: no treatment is needed as patients are usually asymptomatic. Parathyroid Glands

19. Parathyroid Glands

20. Parathyroid Glands

21. Hypercalcemia (continued): • Clinical manifestations: • Neurologic: decreased mental activity (lethargy and confusion). • Cardiovascular: hypertension (30-50% of patients) and short QT-interval. • GI: decreased bowel movement (constipation), nausea/vomiting and pancreatitis (due to precipitation of calcium in the pancreas). • Renal: kidney stones, polyuria/polydypsia due to induction of nephrogenic DI. • Treatment: for severe, life-threatening hypercalcemia • Start with vigorous hydration with normal saline (0.9% NaCl). • Then, give a loop diuretic (e.g. furosemide) which enhances the excretion of calcium. • IV bisphosphonates which increases the activity of oseoblasts and inhibiting osteoclasts. The effect appears after 2-3 days of administration. • If the condition is very severe, normal saline and diuretics do not work, and you cannot wait for the effect of bisphosphonates → administer calcitonin which inhibits osteoclastic activity. • Primary hyperparathyroidism: • Definition: there is increased level of PTH leading to hypercalcemia (90% of cases). • Etiology: • One gland adenoma (80% of cases). • Hyperplasia of all 4 glands (20% of cases). • Parathyroid cancer is rare (>1% of cases). • Primary hyperparathyroidism can occur as part of MEN: • MEN type 1 (3 P’s): Hyperparathyroidism, Pituitary tumors and Pancreatic tumors. • MEN type 2: hyperparathyroidism, pheochromocytoma and medullary carcinoma of thyroid gland. • Clinical manifestations: 50% of patients are asymptomatic. If symptoms are present, they are similar to those mentioned for hypercalcemia previously. • Diagnosis: • Hypercalcemia (<10.5 mg/dL), ↑PTH and ↑urine calcium level. • Nuclear parathyroid scan (to localize the adenoma) combined with neck ultrasound. Parathyroid Glands

22. Primary hyperparathyroidism (continued): • Management: • Patients calcium level (≤ 11.5 mg/dL) or he is asymptomatic → medical therapy: • Bisphosphonates (e.g. pamidronate). • Phsophate supplements. • Hydration (2-3 L/day). • Patients calcium level (< 11.5 mg/dL) or he is symptomatic (renal insufficiency, renal stones or osteoporosis) → surgery (removal of hyperactive parathyroid glands). Complication of surgery: after 1-4 weeks, patient might develop hungry bone syndrome with rapidly decreasing calcium, phosphate and magnesium due to increased osteoblastic activity. • Secondary hyperparathyroidism: • Etiology: low calcium levels (due to vitamin D deficiency or chronic kidney failure) resulting in increased secretion of PTH which in turn will result in low level of phosphate. • Tertiary hyperparathyroidism: it results from long-standing secondary hyperparathyroidism (in patients with chronic kidney disease). In this condition, there will be hyperplasia of parathyroid glands and they will be functioning by their own without regulation by calcium level. Treatment: surgical removal. • Hypocalcemia: • Definition: decreased serum calcium level. • Etiology: • Vitamin D deficiency. • Chronic kidney disease: in which there is decreased production of active vitamin D thus no absorption of calcium from the gut. • Hyperphosphatemia: causes precipitation of calcium in tissues. • Hypomagnesemia. • Hypoparathyroidism. • Clinical manifestations: • Neurologic: hyperexcitability of neurons resulting in seizures, tetany and tingling of extremities. • Cardivascular: arryhtmias (prolonged QT-interval) and hypotension. • Treatment: IV or oral replacement of calcium + replacement of vitamin D (as needed). Parathyroid Glands

23. Parathyroid Glands

24. Hypoparathyroidism: • Etiology: • Most common cause is surgical removal of thyroid gland in which parathyroid glands will also be removed by mistake. • Hereditary hypoparathyroidism. • Hypomagensemia: it results from decreased GI absorption or alcoholism and leads to inhibition of the release of PTH. • Clinical manifestations (similar to those of hypocalcemia): • Neurologic: hyperexcitability with seizures, titany and muscle cramping. Chvostek sign might be present (percussion of the facial nerve in front of the ear results in contraction of facial muscles and upper lip). Trousseau’s sign might be present (inflating blood pressure cuff on the arm to a pressure higher than systolic pressure of the patient for 3 minutes will result in flexion of metacarpophalangeal joints and extension of interphalangeal joints). • Ocular manifestations: cataracts. • Cardiovascular: prolonged QT-interval and hypotension. • Diagnosis: • ↓PTH and ↓serum calcium level. • Treatment: • Acute severe cases: IV calcium gluconate. • Maintenance therapy: oral calcium supplement (2-4 g/day) + vitamin D supplement. Parathyroid Glands

25. Diabetes mellitus: • Definition: it is a disorder of carbohydrate metabolism which can result from insulin deficiency or insulin resistance and associated with hyperglycemia and end-organ complications (neuropathy, retinopathy, nephropathy and accelerated atherosclerosis). • Classification: • Type 1 DM (insulin-dependent): 10% of diabetes cases, age of onset > 30 years, males = females, due to autoimmune destruction of beta cells in pancreas, patients are not obese, there is association with antibodies (anti-islet cells and anti-GAD), there is association with HLA-DR3 and HLA-DR4, diabetic ketoacidosis is the complication. • Type 2 DM (non-insulin dependent): 90% of diabetes cases, age of onset usually at 40 years, males < females, family history is important, patients are usually obese, caused by insulin resistance and later there will be insulin deficiency, no association with antibodies, no risk for ketosis, non-ketotichyperosmolar coma is the complication. • Gestational diabetes. • Clinical manifestations: • Hyperglycemia associated symptoms are: polyuria, polydypsia and polyphagia. In type 1 DM patients are lean while in type 2 DM patients are obese. • Some patients might present initially with complications of diabetes (DKA in type 1 DM; non-ketotichyperosmolar coma in type 2 DM). • Some patients might also present with degenerative complications of diabetes such as neuropathy (complaining of peripheral numbness/tingling or reduced sensation). • Diagnosis: • In symptomatic patients: a random blood glucose <11.1 mmol/L is diagnostic. • In asymptomatic patients: • FBG < 7 mmol/L on 2 occasions. • Random blood glucose < 11.1 mmol/L • HbA1c < 6.5% (notice that HbA1c is used for diagnosis and following patient’s control of diabetes for the preceding 2-3 months). Disorders of Carbohydrate Metabolism

26. Disorders of Carbohydrate Metabolism

27. Disorders of Carbohydrate Metabolism

28. Diabetes mellitus (continued): • Management: • Objective of therapy for patients with diabetes is: • To control their symptoms. • To prevent acute complications (DKA and non-ketotichyperosmolar coma). • To prevent long-term complications. • Patients with type 2 DM: • Start with lifestyle modifications; advise the patient to reduce his weight, do exercise and control his diet. Notice that 25% of patients can control their diabetes only with lifestyle modifications without the need for medical therapy. Try this for 3 months and if HbA1c is still cannot be kept > 7% → start medical therapy with oral hypoglycemics. • Medical therapy: • Start with metformin (glucophage) which is considered you drug of choice. Advantages: it does not cause hypoglycemia and it does not cause weight gain. • If patient is on metformin and his diabetes is not controlled → add a sulfonylurea such as glipizide (Amaryl). Disadvantages: it results in hypoglycemia and weight gain. • If patient is on metformin and sulfonylurea but his diabetes still cannot be controlled → add glitazone or switch to insulin. Glitzones work by decreasing resistance of tissues to insulin but they can result in fluid retention (worsening CHF if it is present). • When starting insulin therapy, divide it to 50% long-acting insulin (glargine = duration of action is 24 hours) given once at bed time and 50% short-acting insulin (aspart or lispro) given 3 times a day 30 minutes before each meal. • In patients with type 1 DM, you will start immediately with insulin therapy with the same regimen as mentioned previously. Disorders of Carbohydrate Metabolism

29. Disorders of Carbohydrate Metabolism

30. Acute complications of diabetes mellitus: • Diabetic Ketoacidosis (DKA): • Definition: it is an acute complication of type 1 DM which results from severe insulin insufficiency and characterized by the triad of: • Hyperglycemia: which will cause osmotic diuresis resulting in dehydration and electrolyte loss. • Metabolic acidosis with increased anion gap. • Ketosis (↑acetoacetate, acetone and β-hydroxybutyrate in blood and urine due to ↑lipolysis and level of free fatty acids). • Etiology: the following might precipitate for DKA • Interrupted insulin therapy. • Infections. • Emotional stress. • Excessive consumption of alcohol. • Clinical manifestations: • Hyperglycemia results in polyuria and polydypsia. • Hyperglycemia also causes osmotic diuresis resulting in dehydration with dry skin/ mucous membranes and decreased skin turgor. • Ketosis results in fruity breath (due to acetone) and rapid, deep breathing (Kussmaul respiration). • Patient will also have abdominal pain + nausea and vomiting. • Management: • IV fluids with normal saline. • IV regular insulin 5-10 units which will be switched to subcutaneous insulin when anion gap normalizes. • Electrolyte replacement: potassium replacement as soon as potassium level becomes ≤ 5 mEq/L. Disorders of Carbohydrate Metabolism

31. Disorders of Carbohydrate Metabolism

32. Acute complications of diabetes mellitus (continued): • Non-ketotichyperosmolar coma: • Definition: it is an acute complication occurring in patients with type 2 DM and characterized by severe hyperglycemia with insignificant ketosis. • Etiology: noncompliance with therapy + inability of patient to keep sufficient water intake. Infections might also precipitate for this condition. • Clinical manifestations: polyuria/polydypsia, lethargy/weakness, confusion, convulsions and coma. • Diagnosis: • Severe hyperglycemia (≥ 700 mg/dL) with no ketosis. • High serum osmolality. Remember that serum osmolality = (2 x sodium) + BUN/2.8 + glucose/18 • Mild metabolic acidosis. • Management: • High fluid volumes. • Insulin. • Electrolyte replacement. • Chronic complications of DM: • They are classified to: • Microvascular: neuropathy, retinopathy and nephropathy. • Macrovascular: CAD, stroke and peripheral vascular disease (gangrene). • Cardiovascular complication: • It is the most common cause of death in patients with diabetes (MI or CHF). • The central pathological mechanism is atherosclerosis which results In narrowing of coronary or peripheral arteries. • You have to check lipid profile in diabetics annually. Your goals are as follow: • LDL > 100 mg/dL (and >70 mg/dL if patient has overt CAD). If patient has LDL <100 mg/dL, you must control him with lifestyle modifications (diet and exercise) along with medical therapy with statins. • HDL < 50 mg/dL. • Fasting triglycerides >150 mg/dL. Disorders of Carbohydrate Metabolism

33. Chronic complications of DM (continued): • Diabetic nephropathy: • Diabetes is one of the most common causes of nephrotic syndrome and ESRD. • Diabetic nephropathy occurs more in patients with type 1 DM. • Management of diabetic nephropathy includes: • Strict control of DM. • ACE inhibitors with the goal blood pressure being > 130/80 mmHg. • All diabetics should be screened annually for proteinuria and all those with proteinuria should receive ACE inhibitors. • Diabetic retinopathy: • Diabetes is the leading cause of blindness in middle-aged patients. • Diabetic retinopathy can simple (non-proliferative) or proliferative. Both of them are characterized by hemorrhages, microaneurysms and exudates but in proliferative retinopathy there is neovascularization. Simple retinopathy is treated with strict control of diabetes while proliferative retinopathy is treated with laser photocoagulation. • Diabetic neuropathy: there are 3 types • Peripheral neuropathy (most common): it is symmetric and patient will commonly complain of numbness, parasthesia and pain. Physical examination reveals: loss of reflexes and sense of vibration. Peripheral neuropathy leads to increased injury to trauma (and might end with amputation). • Mononeuropathy: affecting a single nerve or nerve trunk. Patient will present with sudden foot drop, wrist drop or paralysis of CN III, IV or VI. • Autonomic neuropathy: patient might present with orthostatic hypotension, urinary retention, constipation/diarrhea and erectile dysfunction. • Additional concepts: • Honeymoon period: it occurs in patients with type 1 DM who are started on insulin injections. This is going to stimulate the remaining of β-cells to secrete insulin providing a symptom-free interval. Eventually, those remaining β-cells will be destroyed after several months. • Somogyi effect: it is the hyperglycemia which occurs in the morning in response to secretion of counter-regulatory hormones (cortisol, GH and epinephrine) due to hypoglycemia which occurs in the middle of the night. Disorders of Carbohydrate Metabolism

34. Hypoglycemia: • Hypoglycemia: • Definition: usually symptoms of hypoglycemia appear when blood glucose level is ≤ 40 mg/dL. • Classification: • Post-prandial hypoglycemia: which can be secondary to alimentary hyperinsulinism, idiopathic or due to galacotsemia. • Fasting hypoglycemia: reduced levels of glucose. • Hyperinsulinism: • Exogenous insulin. • Sulfonylureas. • Insulinoma: it is a single benign tumor of pancreatic β-cells. Clinical findings include: headache, feeling of detachment, weakness and blurred vision. These symptoms usually occur in early morning, late afternoon or after fasting/exercise. Diagnosis through ultrasound or CT-scan. Treatment: surgical removal of the tumor. • Clinical manifestations: divided into 2 groups • Those which are caused by excessive secretion of epinephrine: sweating, tremors, tachycardia, anxiety and hunger. • Those which are caused by CNS depression: blurry vision, dizziness, convulsions and loss of consciousness. • Diagnosis: • ↓blood glucose (>40 mg/dL). • ↑insulin (≥8 mg/mL). • Factitious hyperinsulinism: it is caused by self-administration of insulin or ingestion of sulfonylurea. It is more common than insulinoma. Diagnosis by the triad of: hypoglycemia, hyperinsulinemia and low plasma C-peptide. Disorders of Carbohydrate Metabolism

35. Disorders of Carbohydrate Metabolism

36. Adrenal gland anatomy: it is divided into • Cortex: which is further subdivided into 3 layers • Zonaglomerulosa: producing aldosterone which is under the regulation of renin-angiotensin system and potassium level. • Zonafasciculata: producing cortisol which is under the regulation of ACTH from adenohypophysis. • Zonareticularis: producing androgens which is under the regulation of ACTH from adenohypophysis. • Medulla: producing epinephrine and is under the control of autonomic nervous system. • Hyperfunctioning of adrenal gland: • Cushing syndrome: • Definition: clinical abnormalities which result from prolonged exposure to increased level of cortisol in the body. • Etiology: • Most common cause: exogenous (prolonged use of glucocorticoids). • Cushing disease: which can be caused by ACTH-producing pituitary adenoma or an ectopic tumor which is secreting ACTH or Coticotropin-Releasing Hormone (CRH). • Adrenal neoplasia(adenoma or carcinoma). • Clinical manifestations: • Truncal obesity with thin limbs. • Moon-face with buffalo hump. • Purplish striae especially on the abdomen. • Females might have: acne, hirsutism and menstrual irregularities (die to ↑androgen secretion). • Osteoporosis. • Hypertension. • Glucose intolerance (with 20% of patients having diabetes). • Hypokalemia (due to mineralocorticoids effect of increased glucocorticoids). • Increased risk for infections (neutrophils do not function well with ↑glucocorticoids). Diseases of Adrenal Gland

37. Diseases of Adrenal Gland

38. Hyperfunctioning of adrenal gland (continued): • Cushing syndrome (continued): • Diagnosis: • There are 3 diagnostic tests which tell you if patient has cushing syndrome (↑cortisol level): • 24-hour urinary free cortisol (gold standard). • Low-dose (1 mg) dexamethasone suppression test. • Midnight salivary cortisol. • You start with low-dose (1 mg) dexamethasone suppression test which is given at 11:00 pm. Cortisol level will be measured at 8:00 am (next morning). Normally, dexamethasone will suppress cortisol production but in patients with cushing syndrome cortisol will remain high and will not be suppressed. • Then, you confirm your diagnosis with 24-hour urinary free cortisol which will reveal high level of cortisol. • When you establish the diagnosis of cushing syndrome, you have to determine the specific etiology. This is done by measuring ACTH level. If it is low → this indicates that the source is from adrenal gland (adenoma, carcinoma or hyperplasia) → you have to confirm by doing abdominal CT/MRI. • If ACTH level is high, this can be due to pituitary adenoma or ectopic tumor. To differentiate between them, you will do the high-dose (2 mg) dexamethasone suppression test. If ACTH is suppressed, this is an ACTH-producing pituitary adenoma and you will confirm that by MRI of pituitary. If ACTH is not suppressed, this is an ectopic tumor and you will confirm that by CT-scan of the chest. • Management: this depends on the etiology and can be medical or surgical. Notice that unresectable adrenal tumors will be managed with metyrapone (which blocks the production of cortisol). Diseases of Adrenal Gland

39. Diseases of Adrenal Gland

40. Hyperfunctioning of adrenal gland (continued): • Hyperaldosteronism: • Definition: increased level of aldosterone. Notice that the normal function of aldosterone is: • Reabsoprtion of sodium followed by water (and this will lead to increased intravascular volume). • Excretion of potassium (resulting in hypokalemia and its manifestations: muscle weakness, polyuria and polydypsia). • Excretion of hydrogen ions (resulting in metabolic alkalosis). • Etiology: • Primary hyperaldosteronism (problem is in adrenal gland itself): most commonly caused by unilateral adrenal adenoma (70% of cases). It can also be caused by bilateral adrenal hyperplasia. Increased aldosterone production will result in increased rebasorption of sodium followed by water to increase the intravascular volume. Therefore, renin-angiotensin system will be suppressed. • Secondary hyperaldosteronism(etiology is extra-adrenal): there is decreased intravascular volume leading to activation of renin-angiotensin system which in turn results in increased production of aldosterone. • Clinical manifestations (primary hyperaldosteronism): • Hypernatremia and Hypertesnion. • Hypokalemia (with muscle weakness, polyuria/polydypsia). • Metabolic alkalosis. • Diagnosis: • Positive screening: Plasma Aldosterone Concentration (PAC) < 15; PAC to Plasma Renin Activity (PRA) ratio < 20:1 • Confirming the diagnosis by NaCl challenge: in which PAC will remain elevated (not suppressed). • Traatment: • Unilateral adrenal adenoma: surgical removal. • Bilateral adrenal hyperplasia: potassium-sparing diuretic (spironolactone) which blocks aldosterone. Diseases of Adrenal Gland

41. Hypofunctioning of the gland: • Adrenal insufficiency: • Etiology: it is divided to: • Primary adrenal insufficiency (Addison’s disease): which is commonly due to autoimmune destruction of adrenal gland (80% of cases). It can also result from trauma, hemorrhage, surgical removal or infections (TB) of adrenal gland. It this condition, there is ↓cortisol and aldosterone with ↑ACTH (because there is no negative feedback). • Secondary adrenal insufficiency: the problem is at the level of pituitary gland in which there is ↓ACTH production. Therefore, there is ↓cortisol but aldosterone will be normal (because aldosterone is not regulated by ACTH). • Clinical manifestations (Addison’s disease): • ↓cortisol: weakness, cramping, intolerance to stress, hypoglycemia, anorexia with weight loss and hypotension. • ↓aldosterone: hyponatremia, hyperkalmeia and metabolic acidosis. • ↑ACTH: hyperpigmentation with tanning of exposed and un-exposed body parts. • Differences between primary and secondary adrenal insufficiency: hyperpigmentation (which occurs only with primary adrenal insufficiency), electrolyte abnormalities and hypotension. • Diagnosis: • Primary adrenal insufficiency: there is ↓cortisol and ↑ACTH. With ACTH-stimulation test → there is absent or minimal increase in cortisol level. • Acute Secondary adrenal insufficiency: there is ↓ACTH resulting in ↓cortisol. With ACTH-stimulation test → there is increased in cortisol level. • Chronic secondary adrenal insufficiency: there is ↓ACTH resulting in ↓cortisol. With ACTH-stimulation test → cortisol level will NOT increase (because adrenal glands are atrophied by that time due to prolonged lack of ACTH). • Management (Addison’s disease): • Glucocorticoid + mineralocorticoid. • Adrenal crisis: • Occurs in: • Patient who stops glucocorticoid therapy suddenly. • Previously undiagnosed patient with adrenal insufficiency undergoing surgery, infection or major stress. • Bilateral adrenal hemorrhage or infarction. • Clinical manifestations: fever, vomiting, abdominal pain, altered mental status and vascular collapse. • Management: get a cortisol level then immediately replace with IV fluid and hydrocortisone. Diseases of Adrenal Gland

42. Diseases of Adrenal Gland

43. Pheochromocytoma: • Definition: it is a usually benign tumor arising from chromaffin cells of sympathetic nervous system. Remember the rule of 10%: • 10% extra-adrenal. • 10% malignant. • 10% in children. • 10% bilateral. • 10% NOT associated with hypertension. • Epidemiology: • Pheochromocytoma comprises 0.1% of hypertension cases. • Familial pheochromocytoma is inherited as autosomal dominant trait. • Pathology: • Adults: pheochromocytoma is usually a unilateral solitary tumor (usually on the right side) with 10% being bilateral and 10% being extra-adrenal. • Children: 25% extra-adrenal and 25% bilateral • Catecholamines are secreted (dopamine, epinephrine and norepinephrine). Epinephrine causes: sweating, tachycardia, flushing and hypertension. • Clinical manifestations: attack has a sudden onset, lasting from few minutes to several hours and characterized by headache, profuse sweating, palpitations, flushing, hypertension, anxiety and tremor. Notice that <33% of pheochromocytomas will cause death prior to diagnosis due to arrhythmias or stroke. • Diagnosis: urinary metanephrine (most sensitive and specific), urinary free catecholamines, plasma catecholamines and urinary VMA. Then, confirm the presence of the tumor by CT/MRI. • Management: • Α-blockers (phentolamine) to stabilize blood pressure of the patient. This is followed by β-blockers (propranolol) to control tachycardia. • Then, surgical removal of the tumor (don’t forget IV phentolamine during surgery). Diseases of Adrenal Gland