Endocrine Emergencies

1. Endocrine Emergencies

2. Adrenal Insufficiency

3. Cortisol functions at target tissues to maintain vascular resistance, cardiac output, hepatic glucose production and free water excretion Cortisol concentration normally demonstrates diurnal variation and increases during times of medical stress Adrenal physiology

4. The hypothalamus secretes CRH which in turn stimulates ACTH production from the pituitary ACTH stimlates cortisol production from the adrenal glands The hypothalamus and pituitary are influenced by negative feedback from cortisol Adrenal physiology

5. Aldosterone is controlled primarily by angiotensin II and circulating potassium levels; ACTH stimulates aldosterone secretion only transiently Aldosterone stimulates sodium exchange for potassium in the distal nephron Adrenal physiology

6. The most common cause of adrenal insufficiency in industrialized countries May occur alone or associated with other autoimmune disorders Schmidt’s syndrome or type II autoimmune polyglandular syndrome. Type I diabetes and autoimmune thyroid disease Type I autoimmune polyglandular syndrome or APECED (autoimmune polyendocrinopathy-candidiasis-ectomdermal dystrophy) with chronic mucocutaneous candidiasis and hypoparathyroidism. Autoimmune Adrenal Insufficiency

7. Increasingly recognized as a cause of adrenal insufficiency Meningococcemia (Waterhouse-Friderichsen syndrome) and other forms of sepsis Anticoagulation therapy and coagulation disorders including antiphospholipid antibody syndrome Severe illness and stress; ACTH-induced increases in adrenal blood flow that exceeds the capacity for venous drainage Adrenal Hemorrhage

8. Tuberculosis Histoplasmosis Cryptococcus Blastomycosis Paracocciciomycosis Cytomegalovirus associated with HIV Infections

9. X-linked peroxisomal disorders of imparied very long chain fatty acid oxidation In adrenoleukodystropy the neurological features begin in childhood and progress to coma and death Adrenomyeloneuropathy neurological features (central demyelination, cortical blindness, neuropathies) begin in adolescence or young adulthood, progress more slowly and involve peripheral nerves Diagnosis made by measuring high concentrations of VLCFA Young men with adrenal insufficiency should be screened for this disorder Adrenoleukodystrophy and Adrenomyeloneuropathy

10. A family of autosomal recessive disorders caused by deficiency of one of the multiple enzymes in the cortisol synthesis pathway The enzyme deficiency causes inadequate cortisol production and a compensatory increase in ACTH ACTH stimulates adrenal hyperplasia and increased production of precursors proximal to the block in cortisol synthesis Congenital Adrenal Hyperplasia

11. Metastases to the adrenal are common Breast 54% Bronchogenic 44% Renal 31% Adrenal insufficiency from metastases is very rare Bilateral Adrenal Metastases

12. Accelerate metabolism of cortisol Thyroid hormone Rifampin Phenytoin Phenobarbital Mitotane Inhibit cortisol synthesis Ketoconazole (but not fluconazole or itraconazole) Etomidate Metyrapone Mitotane Aminoglutethimide Medications

13. Pituitary tumors due to mass or treatment of tumor Metastases to pituitary Craniopharyngioma Meningioma Infiltrative disorders (histiocytosis X, lymphocytic hypophysitis,sarcoidosis, hemochromatosis) Postpartum pituitary necrosis (Sheehan’s syndrome) Iatrogenic from exogenous steroids High doses of megestrol acetate Secondary Adrenal Insufficiency

14. Clinical Presentation

15. Dehydration, hypotenstion, shock out of proportion to severity of current illness, nausea, vomiting with anorexia, weight loss, unexplained fever, hyponatremia, hyperkalemia, azotemia, hypercalcemia, eosinophilia, and hypoglycemia Often precipitated by intercurrent illness in patient with unrecognized adrenal insufficiency or in a patient with known disease who did not increase cortisol replacement appropriately or patient who recently had glucocorticoid therapy withdrawn, or in patient with bilateral adrenal hemorrhage Adrenal Crisis

16. In acute emergencies “treat first, test later” In the acutely ill patient draw serum cortisol and ACTH then treat with dexamethasone 2-4 mg IV q12 hours or hydrocortisone 100 mg q6 hours then switch to dexamethasone for testing Laboratory Testing

17. Static testing not very useful If cortisol between 8-9 am if less than or equal to 3 ug/dl adrenal insufficiency likely If cortisol greater than 19 adrenal insufficiency ruled out Laboratory Testing

18. A serum cortisol of 20 ug/dl or more 1 hour following 250 ug of cortrosyn IM or IV excludes primary adrenal insufficiency Some have suggested a value of 18 is an adequate respone Difference between baseline and stimulated cortisol no longer used Does not exclude the presence of secondary adrenal insufficiency Dynamic Testing: Cortrosyn

19. Low dose cortrosyn 1 ug IV followed by cortisol measurement in one half hour. There is evidence for and against the utility of this test Dynamic Testing: Cortrosyn

20. In untreated primary adrenal insufficiency ACTH is greater than 100 pg/ml Not useful for judging adequacy of therapy ACTH Measurements

21. Performed fasting in morning IV administration of 0.1-0.15 units regular insulin/kg Cortisol >18 to 20 during hypoglycemia is normal Contraindicated in patients with severe illness, coronary artery disease, seizures, psychiatric disease In patients with pituitary disease growth hormone is measured simultaneously Insulin Tolerance Test

22. Metyrapone activates the HPA axis by blocking cortiosl production at the 11-hydroxylase step, the last step in cortisol synthesis This leads to cortisol deficiency which should activate ACTH production and production of precursors proximal to the block Metyrapone is given at midnight with a light snack Cortisol and 11-deoxycortisol are measured at 8 am. The test is considered normal if cortisol is less than 5 and 11-deoxycortisol is at least 7 ung/dl. Metyrapone Test

23. Once the diagnosis is made a search for the underlying cause is indicated if not immediately obviousFor primary adrenal insufficiency adrenal imaging is indicatedFor secondary disease MRI imaging of pituitary/hypothalamus may be needed.

24. For primary adrenal crisis: hydrocortisone 100 mg q6 hours if diagnosis established or dexamethasone 2-4 mg q12 hours if diagnostic testing needed For secondary adrenal crisis: dexamethasone may be preferred to avoid fluid retention and hypokalemia Intravenous saline to support volume and treat hyperkalemia Specific mineralocorticoid is usually not necessary while using high dose hydrocortisone Treatment

25. Hydrocortisone 10-20 mg in am, 5-10 mg in early pm Prednisone 5 mg in am, 0-2.5 mg in pm Florinef 0-0.1 mg per day Adequacy of glucocorticoid judged by patient well-being, decrease in pigmentation, electrolytes, blood pressure Adequacy of mineralocorticoid judged by blood pressure, edema, potassium and plasma renin activity All patients with adrenal insufficiency should have MedicAlert bracelet or carry documentation of this disorder Maintenance Therapy

26. Mild to moderate illness: double or triple usual glucocorticoid dosage Severe illness or vomiting: dexamethasone or solucortef IM self-administered by patient then seek prompt medical help Moderately stressful procedures such as endoscopy: hydrocortisone 100 mg one hour before procedure Major surgery: hydrocortisone 100 mg IV before induction of anesthesia and repeated q6 hours. Dose then tapered depending on patient’s rate of recovery, usually 50% decrease per day until maintenance dose achieved Acute Illness Coverage

27. Thyroid Storm

28. Severe and life-threatening thyrotoxicosis Exaggeration of the typical symptoms of hyperthyroidism Tachycardia with rate often>140 CHF Fever Change in mental status: delirium, psychosis, stupor, coma Nausea, vomiting, diarrhea, abdominal pain Hepatic failure, jaundice, abnormal liver function tests Thyroid Storm

29. Usually precipitated by an acute event in a patient with untreated hyperthyroidism Thyroid or nonthyroidal surgery Trauma Infection Acute iodine load or radioactive iodine Poor compliance with specific therapy Low socioeconomic status Preoperative preparation of patients undergoing thyroidectomy for hyperthyroidism has led to dramatic reduction in prevalence of surgically-induced thyroid storm Precipitants

30. IV Fluid Acetominophen Beta blockade to control adrenergic symptoms Thionamide - methimazole or PTU Iodine solution to block release of thyroid hormone Iodinated contrast agent to inhibit the peripheral conversion of T4 to T3 Glucocorticoids to reduce T4 to T3 conversion and to treat potential coexistent adrenal insufficiency Treatment

31. Use with caution in patients with CHF or other contraindication Propranolol is frequently selected as it can be given intravenously and reduces the conversion of T4 to T3 Esmolol - loading dose of 250-500 ug/kg IV followed by infusion of 50-100 ug/kg/min. This permits rapid titration of drug and minimizes adverse reactions Beta Blockers

32. Block de novo thyroid hormone synthesis within 1-2 hours of administration but have no effect on preformed thyroid hormone stored in the gland PTU blocks conversion of T4 to T3 but since other drugs given in storm are usually coadministered it is okay to use methimazole which has a longer duration of action High doses needed: Methimazole 30 mg q6 or PTU 200 mg q4 hours Both drugs can be suspected in liquid for rectal administration Thionamides

33. Iodine blocks release of T4 and T3 from the gland SSKI 5 drops every 6 hours or Lugol’s solution 10 drops tid Delay administration of at least one hour after thionamide administration to prevent iodine being used as a substrate for new hormone synthesis If iodine allergic, lithium has been used for the same purpose Iodine

34. Iopanoic acid used for oral cholecystography Potent inhibitors of T4 to T3 conversion Dose 0.5 to 1 gm qd Give at least one hour after thionamide to prevent iodine from being used as a substrate for new hormone synthesis Iodinated Radiocontrast Agents

35. Reduce T4 to T3 conversion May have a direct effect on underlying autoimmune process if storm is due to Graves disease Use of glucocorticoids has improved outcome in one series Hydrocortisone 100 mg IV q8 hours Glucocorticoids

36. Myxedema Coma

37. Severe hypothyroidism due to severe long-standing untreated hypothyroidism Precipitating acute event almost always present: infection, myocardial infarction, cold exposure, sedative drugs Older women affected most frequently May result from any of the usual causes of hypothyroidism Important clues in a poorly responsive patient include presence of thyroidectomy scar or history of radioiodine treatment or known hypothyroidism Mortality rate is high 30-40% Myxedema Coma

38. Hypothermia Decreased mental status Hypotension Bradycardia Hyponatremia Hypoglycemia Hypoventilation Clinical Presentation

39. History, physical exam, and exclusion of other causes of coma Treat before waiting for lab confirmation but draw TSH, free T4, cortisol before treatment Most patients will have primary hypothyroidism with high TSH and low free T4; rare patients have low free T4 and low TSH consistent with secondary hypothyroidism due to hypothalamic or pituitary disease Cortisol measurement will help exclude coexistent adrenal insufficiency Diagnosis

40. Optimal mode of thyroid hormone therapy is controversial Increasing serum thyroid hormones rapidly carries some risk of precipitating MI or atrial arrhythmia but this risk must be accepted given high mortality rate of myxedema coma Levothyroxine 0.2-0.4 mg IV initial dose .05 to 0.1 mg IV qd thereafter Switch to oral when feasible T3 can be given 5-20 ug initially, then 2.5-10 ug q8 hours Stop T3 when clinical improvement occurs Treatment: Thyroid Hormone

41. Avoid dilute fluids Severe hypotension that does not respond to fluids should be treated with vasopressors until T4 has had time to act Passive rewarming with heating blanket (active rewarming carries risk of vasodilatation) Empiric antibiotics until appropriate cultures are proven negative Supportive Measures

42. Pheochromocytoma

43. Arise from chromaffin cells of adrenal medulla and sympathetic ganglia Rare: incidence 2-8 cases per million; prevalence estimates 0.01% to 0.1% of hypertensive population Occurs equally in men and women, primarily in 3rd through 5th decades Curable with surgical removal of tumor Potential for lethal paroxysm Catecholamine -Secreting Tumors: Pheochromocytoma and Paragangliomas

44. Usually present and are due to pharmacologic effects of excess circulating catecholamines The five P’s: Pressure- sudden major increase in BP Pain- abrupt onset of throbbing headache, chest and/or abdominal pain Perspiration- profuse generalized diaphoresis Palpitations Pallor Symptoms

45. Extremely variable in presentation Spontaneous Precipitated by diagnostic procedures, postural changes, anxiety, exercise, or maneuvers that increase intra-abdominal pressure Duration 10-60 minutes and may occur daily to monthly Additional symptoms: constipation, attacks of hypotension and shock, tremor, anxiety, epigastric and chest pain Spells

46. Hypertension - paroxysmal in half, may be severe and resistant to conventional therapy Orthostatic hypotension Pallor Grade II-IV retinopathy Tremor Weight loss Fever Café au lait spots in neurofibromatosis Painless hematuria and paroxysmal attacks induced by micturition in pheo of bladder Hyperglycemia Hypercalcemia Erythrocytosis Clinical Signs

47. 10% are extradrenal 10% occur in children 10% are multiple or bilateral 10% recur after surgical removal 10% are malignant 10% are familial Rule of 10

48. Endocrine Thyrotoxicosis Menopausal syndrome Hypoglycemia Mastocytosis Cardiac Essential hypertension Cardiovascular deconditioning Paroxysmal arrhythmia Withdrawal of adrenergic inhibiting medications (clonidine) MAO-inhibitor treatment and ingestion of tyramine or decongestant Angina Differential Diagnosis

49. Psychoneurologic Anxiety and panic attacks Hyperventilation Migraine headaches Amphetamine, phenylpropanolamine, or cocaine use Diencephalic epilepsy Factitious Sympathomimetic ingestion Differential Diagnosis

50. Familial pheochromocytoma MENII a Pheochromocytoma Medullary thyroid carcinoma Hyperparathyroidism MENII b Pheochromocytoma (bilateral in >70%) Medullary thyroid carcinoma Mucosal neuromas Thickened corneal nerves Intestinal ganglioneuromatosis Marfanoid body habitus Familial Syndromes