Endocrine Emergencies Adrenal Insufficiency Adrenal physiology Cortisol functions

Endocrine Emergencies

Adrenal Insufficiency

Adrenal physiology · 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 · 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 · 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

Autoimmune Adrenal Insufficiency · · 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.

Adrenal Hemorrhage · 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

Infections · Tuberculosis · Histoplasmosis · Cryptococcus · Blastomycosis · Paracocciciomycosis · Cytomegalovirus associated with HIV

Adrenoleukodystrophy and Adrenomyeloneuropathy · · · 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

Congenital Adrenal Hyperplasia · · · 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 stimulates adrenal hyperplasia and increased production of precursors proximal to the block in cortisol synthesis

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

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

Secondary Adrenal Insufficiency · · · · 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

Clinical Presentation Finding Primary Secondary Anorexia and weight loss Yes (100%) Fatigue and weakness Yes (100%) Nausea/diarrhea Yes (50%) Muscle, joint, abdominal pain Yes (10%) Orthostatic hypotension Yes Hyponatremia Yes (80%) Yes (60%) Hyperkalemia Yes (60%) No Hyperpigmentation yes No Secondary deficiencies of testosterone, GH, thyroid, ADH No Yes Associated autoimmune diseases Yes No

Adrenal Crisis · · 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

Laboratory Testing · In acute emergencies “treat first, test later” · In the acutely ill patient draw serum cortisol and ACTH then treat with dexamethasone 24 mg IV q 12 hours or hydrocortisone 100 mg q 6 hours then switch to dexamethasone for testing

Laboratory Testing · 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

Dynamic Testing: Cortrosyn · · 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 · 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

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

Insulin Tolerance Test · · · 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

Metyrapone Test · · 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.

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

Treatment · For primary adrenal crisis: · · · hydrocortisone 100 mg q 6 hours if diagnosis established or dexamethasone 2 -4 mg q 12 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

Maintenance Therapy · · · 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 Medic. Alert bracelet or carry documentation of this disorder

Acute Illness Coverage · · 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 q 6 hours. Dose then tapered depending on patient’s rate of recovery, usually 50% decrease per day until maintenance dose achieved

Thyroid Storm

Thyroid Storm · · · · 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

Precipitants 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

Treatment · 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 T 4 to T 3 Glucocorticoids to reduce T 4 to T 3 conversion and to treat potential coexistent adrenal insufficiency

Beta Blockers · 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 T 4 to T 3 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

Thionamides · · 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 T 4 to T 3 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 q 6 or PTU 200 mg q 4 hours Both drugs can be suspected in liquid for rectal administration

Iodine · Iodine blocks release of T 4 and T 3 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

Iodinated Radiocontrast Agents · Iopanoic acid used for oral cholecystography · Potent inhibitors of T 4 to T 3 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

Glucocorticoids · Reduce T 4 to T 3 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 q 8 hours

Myxedema Coma

Myxedema Coma · · · 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%

Clinical Presentation · Hypothermia · Decreased mental status · Hypotension · Bradycardia · Hyponatremia · Hypoglycemia · Hypoventilation

Diagnosis · · History, physical exam, and exclusion of other causes of coma Treat before waiting for lab confirmation but draw TSH, free T 4, cortisol before treatment Most patients will have primary hypothyroidism with high TSH and low free T 4; rare patients have low free T 4 and low TSH consistent with secondary hypothyroidism due to hypothalamic or pituitary disease Cortisol measurement will help exclude coexistent adrenal insufficiency

Treatment: Thyroid Hormone · · · · 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 T 3 can be given 5 -20 ug initially, then 2. 5 -10 ug q 8 hours Stop T 3 when clinical improvement occurs

Supportive Measures · Avoid dilute fluids · Severe hypotension that does not respond to fluids · · should be treated with vasopressors until T 4 has had time to act Passive rewarming with heating blanket (active rewarming carries risk of vasodilatation) Empiric antibiotics until appropriate cultures are proven negative

Pheochromocytoma

Catecholamine -Secreting Tumors: Pheochromocytoma and Paragangliomas · 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 3 rd through 5 th decades Curable with surgical removal of tumor Potential for lethal paroxysm

Symptoms · 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

Spells · 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

Clinical Signs · · · 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

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

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

Familial Syndromes · 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 · Neurofibromatosis (von Recklinghausen’s disease) · Von Hippel-Lindau (retinal angiomatosis and cerebellar hemangioblastoma) · Additional pheochromocytoma-related neurocutaneous syndromes: · · Other known associations without familial basis Carney’s triad · · 1% develop pheochromocytoma Ataxia telangiectasia Tuberous sclerosis Sturge-Weber Gastric leiomyosarcoma Pulmonary chondroma Extra-adrenal pheochromocytoma Cholelithiasis Renal artery stenosis

Paragangliomas · Para-aortic sympathetic chain · Organs of Zuckerkandl at origin of inferior · · mesenteric artery Wall of urinary bladder Sympathetic chain in the neck or mediastinum

Other Endocrine Manifestations of Pheochromocytoma · GHRH- acromegaly · ACTH/CRH - Cushing’s syndrome · VIP- watery diarrhea · PTH-RP- hypercalcemia

Diagnostic Evaluation · · · Biochemical documentation should precede any imaging studies 24 hour urine collection for catecholamines, metanephrine and VMA 24 hour urine collection should start with the onset of a spell in pateints with episodic hypertension Usually more than 2 fold increase above the upper normal limit No role for provocative testing with histamine or glucagon

Medications Interfering with Assessment Increase values · · · · · Tricyclic antidepressants Labetolol Levodopa Decongestants Amphetamines, busipirone and most psychoactive medications Sotalol Methyldopa Ethanol Benzodiazepines · · Metyrosine Methylglucamine Decrease values

Plasma Catecholamines Plasma catecholamines · must be obtained from fasting supine patient with indwelling catheter in place for 20 minutes · affected by diuretics, smoking, renal insufficiency Plasma metanephrines · Recent report shows accuracy for diagnosis Chromogranin A · Costored and secreted with catecholamines and increased in 80 -90% of patients with catecholamine secreting tumors Neuropeptide Y increased in 87% Measurements of urinary catecholamines and metabolites, chromogranin A, plasma norepi and dopamine are invalid In advanced renal insufficiency. Plasma epi levels more reliable

Localization Studies · · 90% of tumors are found in the adrenal and 98% are in the abdomen Pheo’s have a characteristic T 2 -weighted appearance on MRI Common locations of extradrenal paragangliomas are superior para-aortic region in 46%, inferior para-aortic in 29%, urinary bladder in 10%, thorax in 10%, head and neck 3%, pelvis 2% If results of imaging studies are negative an MIBG scan be performed. Sensitivity 88%, specificity 99%

Treatment of Pheochromocytoma · Surgical resection after careful pre-op alpha and · · · beta adrenergic blockade Controls blood pressure and prevents intraoperative hypertensive crisis Alpha blockade started at least 10 days preop to allow for contracted blood volume Encourage high salt intake during this time

Alpha blockade · Phenoxybenzamine 10 mg bid and increased 10 -20 · · mg every 2 days until BP and spells controlled Average dosage 0. 5 -1. 0 mg/kg daily Orthostatic hypotension increased, tachycardia, miosis, nasal congestion, diarrhea, fatigue

Beta blockade · · Administer only after alpha inhibition is effective because beta blockade alone may result in more severe hypertension due to unopposed alpha adrenergic stimulation Indicated to control tachycardia associated with high circulating catecholamines and alpha blockade Use cautiously and at low dose as chronic circulating catecholamines may cause a cardiomyopathy and beta blockers can result in pulmonary edema Labetolol is a combined beta blocker and alpha blocker but instances of paradoxic hypertensive crisis (due to incomplete alpha blockade) have been reported; safety as primary agent is controversial

Catecholamine Synthesis Inhibitor: Metyrosine · Useful in patients with persistent catecholamine · · producing tumors that cannot be treated with combined alpha and beta blockade Inhibits tyrosine hydroxylase Side effects: diarrhea, sedation, anxiety, nightmares, urolithiasis, galactorrhea, extrapyramidal manifestations

Acute Hypertensive Crises · Phentolamine test dose of 1 mg followed by repeat · · 5 mg IV boluses Response maximal in 2 -3 minutes and lasts 10 -15 minutes 100 mg/500 cc 5% dextrose can be infused IV and titrated to BP control

Postoperative Course · · · Hypotension may occur after surgery: treat with fluids and colloid Less frequent in patients who have had adequate alpha blockade preoperatively Hypoglycemia BP usually normal prior to discharge Some patients remain hypertensive for up to 4 -8 weeks 2 weeks after surgery 24 hour urine obtained to insure cure then every 5 years