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Endocrine

Soe Naing, MD, MRCP(UK), FACE Endocrinologist Associate Clinical Professor of Medicine Director of Division of Medical Director of Community Diabetes Care Center UCSF-Fresno Medical Education Program

Version: SN/2-10-2016

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SUMMARY AND RECOMMENDATIONS:

Evaluation: From “Endocrine HTN” available at http://www.endotext.org/

Endocrine Hypertension accounts for about 3% of the secondary forms of hypertension and is a term assigned to states in which hormonal derangements result in clinically significant hypertension. The most common causes of endocrine hypertension are

1. primary , 2. pheochromocytoma, and 3. Cushing’s syndrome.

Hypertension in young patients and refractory hypertension should alert the physician to screen for secondary causes. The first step when evaluating a patient with suspected endocrine-related hypertension is to exclude other causes of .

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1. Primary Hyperaldosteronism

• (hyperaldosteronism) causes hypertension by an inappropriately high secretion that does not suppress adequately with loading. Primary aldosteronism is believed to account for 8% of all cases of hypertension and 20% of cases of resistant hypertension. It should also be suspected with early-onset hypertension or before age 50 years (or both). It may be difficult to distinguish primary aldosteronism from cases of low essential hypertension, with which it may overlap. Patients of all ages may be affected, but the peak incidence is between 30 years and 60 years. Excessive aldosterone production increases sodium retention and suppresses plasma renin. It increases renal excretion, which can lead to . Cardiovascular events are more prevalent in patients with aldosteronism (35%) than in those with essential hypertension (11%). Primary aldosteronism may be caused by an aldosterone-producing adrenal (Conn syndrome), 40% of which have been found to have somatic mutations in a gene involved with the potassium channel. Primary aldosteronism is also commonly caused by unilateral or bilateral adrenal . (from Current Medical Diagnosis & Treatment 2016)

• This should be suspected in any patient with the triad of: 1. HTN 2. unexplained hypokalemia and 3. metabolic .

• The most common subtypes are: 1. Aldosterone-producing adenoma (Conn’s) (APA) 2. idiopathic hyperaldosteronism (IHA)/Bilateral adrenal hyperplasia/ Bilateral micronodular hyperplasia

• The screening test of choice is “plasma aldosterone to renin ratio or PAC/PRA ratio”.

• Protocol: (please refer to “up-to-date” under the session of "Approach to the patient with hypertension and hypokalemia" for detail)

The test is performed by measuring a morning (preferably 8 AM), ambulatory, paired, random plasma aldosterone concentration (PAC) and plasma renin activity (PRA) or plasma renin concentration (PRC). In general, PRA and PRC are undetectable in patients with primary aldosteronism. In most patients with primary aldosteronism, the PAC is >15 ng/dL; the net effect is a PAC/PRA ratio greater than 20.(Some use a cutoff criteria of 30). Most antihypertensive medications can be continued and posture stimulation is not required.

Spironolactone and should not be initiated until the evaluation is completed since these can cause an elevation in PRA. The patients already receiving , therapy should be discontinued for at least six weeks. Other potassium-sparing diuretics, such as amiloride and triamterene, usually do not interfere with testing unless the patient is on high doses.

Angiotensin-converting enzyme (ACE) inhibitors, receptor blockers (ARBs), and direct renin inhibitors can falsely lower PAC/PRA ratio, and therefore the test should be repeated at least 4 weeks after stopping these medications if there is a strong clinical suspicion of hyperaldosteronism.

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Table: Effects of Antihypertensive Drugs on the Aldosterone-Renin-Ratio (ARR)

Drug Effect on Renin Effect on Aldosterone Net Effect on ARR β Blockers ↓ ↑ ↑

α1 Blockers → → →

α2 Sympathomimetics → → → ACE inhibitors ↑ ↓ ↓ AT1R blockers ↑ ↓ ↓ Calcium antagonists → → → Diuretics (↑) (↑) →/(↓)

Abbreviations: ACE, angiotensin-converting enzyme; AT1R, angiotensin II receptor type 1.

From Harrison's Principles of Internal Medicine, 19e

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Treatment Conn syndrome (unilateral aldosterone-secreting adrenal adenoma) is usually treated by laparoscopic adrenalectomy, although long-term medical therapy is an option. Bilateral adrenal hyperplasia is best treated with medical therapy. Medical treatment must include a potassium-sparing diuretic, particularly spironolactone, eplerenone, or amiloride. Spironolactone also has activity and men frequently experience breast tenderness, , or reduced libido; it is given at initial doses of 12.5–25 mg orally once daily; the dose may be titrated upward to 200 mg daily. Spironolactone is contraindicated in pregnancy and reproductive-age women are cautioned to use contraception during therapy. Eplerenone is becoming favored for men, since it does not have antiandrogen effects; however, it has a short half-life and must be taken orally twice daily in doses of 25–50 mg. Another option is amiloride, which is effective in doses of 10–20 mg/day and is the preferred medication for hyperaldosteronism during pregnancy. pressure must be monitored daily when beginning these anti- medications; significant drops in have occurred when these drugs are added to other antihypertensives. Other antihypertensive drugs may be required, particularly amlodipine, and ACE inhibitors or ARBs. (from Current Medical Diagnosis & Treatment 2016)

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Overview of management of patients with suspected mineralocorticoid excess.

From Harrison's Principles of Internal Medicine, 19e

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2. Pheochromocytoma

Pheochromocytomas and paragangliomas are catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system. These tumors may arise sporadically or be inherited as features of multiple endocrine neoplasia type 2, von Hippel–Lindau , or several other pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas identifies a potentially correctable cause of hypertension, and their removal can prevent hypertensive crises that can be lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to a hypertensive crisis with associated cerebrovascular or cardiac complications.

Pheochromocytoma is estimated to occur in 2–8 of 1 million persons per year, and ∼0.1% of hypertensive patients harbor a pheochromocytoma. The mean age at diagnosis is ∼40 years, although the tumors can occur from early childhood until late in life. The classic “rule of tens” for pheochromocytomas states that ∼10% are bilateral, 10% are extra-adrenal, and 10% are malignant.

Its clinical presentation is so variable that pheochromocytoma has been termed “the great masquerader”.

Table: Clinical Features Associated with Pheochromocytoma, Listed by Frequency of Occurrence

1. 10. Weight loss 2. Profuse sweating 11. Paradoxical response to antihypertensive drugs 3. Palpitations and tachycardia 12. and 4. Hypertension, sustained or paroxysmal 13. Constipation 5. Anxiety and panic attacks 14. Orthostatic hypotension 6. Pallor 15. Dilated cardiomyopathy 7. Nausea 16. Erythrocytosis 8. Abdominal pain 17. Elevated blood sugar 9. Weakness 18. Hypercalcemia From Harrison's Principles of Internal Medicine, 19e

 This should be suspected in any patient with the triad of: 1. , 2. sweating and 3. tachycardia

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Diagnosis of Pheochromocytoma and Paraganglioma

 The screening test of choice is “24-hour fractionated catecholamines and metanephrines and/or plasma fractionated metanephrines”.

Table: Biochemical and Imaging Methods Used for Diagnosis of Pheochromocytoma and Paraganglioma

Diagnostic Method Sensitivity Specificity 24-h urinary tests Catecholamines +++ +++ Fractionated metanephrines ++++ ++ Total metanephrines +++ ++++ Plasma tests Catecholamines +++ ++ Free metanephrines ++++ +++ Imaging CT ++++ +++ MRI ++++ +++ MIBG scintigraphy +++ ++++ Somatostatin receptor scintigraphya ++ ++ 18Fluoro-DOPA PET/CT +++ ++++ aValues are particularly high in head and neck paragangliomas.

Abbreviations: MIBG, metaiodobenzylguanidine; PET/CT, positron emission tomography plus CT. For the biochemical tests, the ratings correspond globally to sensitivity and specificity rates as follows: ++, <85%; +++, 85– 95%; and ++++, >95%.

From Harrison's Principles of Internal Medicine, 19e: Pheochromocytoma

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PHEOCHROMOCYTOMA-ASSOCIATED SYNDROMES From Harrison's Principles of Internal Medicine, 19e: Pheochromocytoma

About 25–33% of patients with a pheochromocytoma or paraganglioma have an inherited syndrome. At diagnosis, patients with inherited syndromes are a mean of ∼15 years younger than patients with sporadic tumors.

Neurofibromatosis type 1 (NF1) was the first described pheochromocytoma-associated syndrome. The NF1 gene functions as a tumor suppressor by regulating the Ras signaling cascade. Classic features of neurofibromatosis include multiple neurofibromas, café au lait spots, axillary freckling of the skin, and Lisch nodules of the iris. Pheochromocytomas occur in only ∼1% of these patients and are located predominantly in the adrenals. Malignant pheochromocytoma is not uncommon.

Neurofibromatosis. A. MRI of bilateral adrenal pheochromocytoma. B. Cutaneous neurofibromas. C. Lisch nodules of the iris. D. Axillary freckling.

The best-known pheochromocytoma-associated syndrome is the autosomal dominant disorder multiple endocrine neoplasia type 2 (MEN2) . Both types of MEN2 (2A and 2B) are caused by mutations in RET (rearranged during transfection), which encodes a tyrosine kinase. The locations of RET mutations correlate with the severity of disease and the type of MEN2. MEN2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism; MEN2B also includes MTC and pheochromocytoma as well as multiple mucosal neuromas, marfanoid habitus, and other developmental disorders, though it typically lacks hyperparathyroidism. MTC is found in virtually all patients with MEN2, but pheochromocytoma occurs in only ∼50% of these patients. Nearly all pheochromocytomas in MEN2 are benign and located in the adrenals, often bilaterally. Pheochromocytoma may be symptomatic before MTC. Prophylactic thyroidectomy is being performed in many carriers of RET mutations; pheochromocytomas should be excluded before any surgery in these patients.

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Von Hippel–Lindau syndrome (VHL) is an autosomal dominant disorder that predisposes to retinal and cerebellar hemangioblastomas, which also occur in the brainstem and spinal cord. Other important features of VHL are clear cell renal carcinomas, pancreatic neuroendocrine tumors, endolymphatic sac tumors of the inner ear, cystadenomas of the epididymis and broad ligament, and multiple pancreatic or renal cysts. Other syndromes are the paraganglioma syndromes (PGLs) and familial pheochromocytoma (FP).

Von Hippel–Lindau disease. A. Retinal angioma. All subsequent panels show findings on MRI: B– D. Hemangioblastomas of the cerebellum (B) in brainstem (C) and spinal cord (D). E. Bilateral pheochromocytomas and bilateral renal clear cell carcinomas F. Multiple pancreatic cysts.

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3. Cushing’s syndrome From up-to-date and Harrison's Principles of Internal Medicine, 19e

Cushing’s syndrome reflects a constellation of clinical features that result from chronic exposure to excess glucocorticoids of any etiology. The disorder can be ACTH-dependent (e.g., pituitary corticotrope adenoma) or ACTH-independent (e.g., ), as well as iatrogenic (e.g., administration of exogenous glucocorticoids). The term Cushing’s disease refers specifically to Cushing’s syndrome caused by a pituitary corticotrope adenoma.

Cushing’s syndrome is generally considered a rare disease. It occurs with an incidence of 1–2 per 100,000 population per year. In the overwhelming majority of patients, Cushing’s syndrome is caused by an ACTH-producing corticotrope adenoma of the pituitary.

 This should be suspected in any patient with 1. supraclavicular fat pads, 2. easy bruising/ skin atrophy, 3. wide purplish abdominal striae, and 4. proximal .

 The 3 screening tests to establish the diagnosis of Cushing's syndrome or hypercortisolism: 1. 24-hour urinary , 2. late night salivary cortisol, and 3. low-dose suppression tests.

 The tests to establish the cause of Cushing's syndrome: 1. Plasma ACTH concentrations 2. High-dose dexamethasone suppression tests 3. CRH (corticotropin-releasing ) stimulation test 4. Petrosal venous sinus catheterization.

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Typical findings in Cushing syndrome. (from Current Medical Diagnosis & Treatment 2016)

Clinical features of Cushing’s syndrome. (From Harrison's Principles of Internal Medicine, 19e) A. Note central obesity and broad, purple stretch marks (B. close-up). C. Note thin and brittle skin in an elderly patient with Cushing’s syndrome. D. Hyperpigmentation of the knuckles in a patient with ectopic adrenocorticotropic hormone (ACTH) excess.

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>1.8 mcg/dL

>1.8 mcg/dL

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