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Authors: Arthur S. Tischler, M.D., Anastassios G. Pittas, M.D.
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1. Case 1 Answers – Adrenal Insufficiency due to autoimmune adrenalitis

  1. The differential diagnosis is extensive and includes sepsis (widespread infection), stroke, myocardial infarction, and adrenal insufficiency. Teaching Aim: Adrenal insufficiency is under appreciated and it should be suspected in acutely and severely ill patients. The diagnosis of adrenal insufficiency was entertained.
  2. Answer D. When adrenal insufficiency (AI) is suspected, treatment with "stress dose" steroids should not be withheld while waiting for the diagnosis to be made. When the diagnosis of AI has not been established, dexamethasone is the preferred steroid as it does not interfere with testing for AI. The most commonly used test for the diagnosis of AI is the Cortrosyn (synthetic ACTH) stimulation test. A blood sample for cortisol (and ACTH) is drawn [time 0'], then 0.25 mg of synthetic ACTH is injected intravenously and the cortisol level is measured 30 and 60 minutes later [time 30' and time 60']. A normal test is defined as a cortisol level over 20 at any time point.
  3. Answer A. The patient had an abnormally low (given her severe medical stress) baseline cortisol level that did not increase after stimulation with synthetic ACTH. She, therefore, has adrenal insufficiency. Another way to make the diagnosis is to check a cortisol level while the patient is under significant stress, like the patient in this case. A cortisol level under 13 is considered inappropriate during severe stress and the diagnosis of AI can be made. A cortrosyn stimulation test (or a cortisol level under severe stress) identifies adrenal insufficiency only; it cannot differentiate between primary and secondary.
  4. Answer A. Adrenal insufficiency refers to the absence of glucocorticoid and/or mineralocorticoid depending whether the deficiency is primary (adrenal gland dysfunction - both glucocorticoid and mineralocorticoid are missing) or secondary (hypothalamic/pituitary dysfunction - only glucocorticoid is missing secondary to ACTH loss). Labs are suggestive of primary adrenal insufficiency probably due to autoimmune adrenalitis given her history of autoimmune thyroid disease.
  5. She may or may not need basal supplementation depending on her adrenal reserve. She does need glucocorticoid supplementation when she is ill. High dose "stress dose" steroids should be given to any patient who may be adrenally insufficient based on history and clinical suspicion during severe illness including perioperatively.

    PATH ANSWERS
  6. B, C and E.
  7. D
  8. C
  9. A. True
  10. B. False

Autoimmune adrenalitis is characterized by lymphoplasmacytic inflammation, atrophy and fibrosis of the cortex, with sparing of the medulla. The condition may be sporadic or familial. Because it is immunologically mediated, the disease affects both adrenals and would also likely be seen in ectopic adrenal. Autoimmune adrenalitis is seen in ~60% of patients with Polyglandular Autoimmune syndrome type l (PGA l) and 100% of those with PGA 2. PGA1 (hypoparathyroidism, chronic mucocutaneous Candidiasis and adrenal insufficiency) is a rare disease inherited as an autosomal recessive trait. Typically, the disease presents with Candidiasis early in childhood and adrenal insufficiency develops ~ age 12 years. In contrast, PGA 2 is more common, typically presents between the ages of 20-40 years and the mode of inheritance is unclear. PGA2 is typically diagnosed when any two of the following are present: Adrenal insufficiency, autoimmune thyroiditis, type 1 diabetes mellitus. Hypoparathyroidism is usually NOT present in PGA2. Although up to ~ 50% of patients with autoimmune adrenal insufficiency have one or more other manifestations of autoimmune endocrinopathy, patients with common autoimmune endocrine diseases, (e.g., Hashimoto’s or Graves’ disease, or Type l diabetes) very seldom develop adrenal insufficiency.

In addition to the primary components of PGA1 and 2, primary hypogonadism is also a frequent component. Other endocrine or non-endocrine tissues may also be involved.

2. Case 2 Answers – Hypertension/Hyperaldosteronism

  1. Answer C. This could be essential hypertension, but the young age suggests secondary causes of hypertension such as pheochromocytoma, hyperaldosteronism, renal artery stenosis etc. The history of hypokalemia is highly suggestive of hyperaldosteronism. Teaching Aim: to recognize when it is appropriate to think of secondary causes for hypertension and initiate further evaluation prior to treatment.
  2. Answer D. A work-up for secondary causes of hypertension is needed. The history, physical examination and "routine" blood work will guide further diagnostic work-up. Given her hypertension and hypokalemia, an evaluation for hyperaldosteronism is justified. The initial evaluation includes measuring plasma aldosterone concentration (PAC) and plasma renin activity and calculating the ratio PAC/PRA. A high PAC/RRA ratio suggests autonomous production of aldosterone. Hypertension and hypokalemia suggest hyperaldosteronism.
  3. Answer B. After the diagnosis of hyperaldosteronism has been confirmed with biochemical testing (elevated aldosterone in a 24 hour urine measurement), imaging comes next, usually with a CT or MRI of the adrenals. Diagnostic order in endocrinology: biochemical confirmation first, then imaging. Answer D is reasonable but infrequently the correct answer in the Boards!
  4. Normal adrenal anatomy on CT scan is not uncommon. This patient may have Idiopathic Hyperaldosteronism (bilateral hyperplasia) or a small adenoma which is not large enough to be detected by conventional imaging. If imaging does not reveal pathology, one should look further with other imaging modalities including functional imaging that makes use of the pathophysiology of the disease. A 131-Iodocholesterol scan may be of use to help decide if one or both of the adrenals are overproducing aldosterone in this case. Where available, adrenal venous sampling, as was done in this case, is often felt to be the "gold standard" for determining if hyperaldosteronism is unilateral or bilateral.
  5. Answer A. Adrenalectomy is the standard therapy for a solitary adenoma or hyperaldosteronism that lateralizes on adrenal venous sampling. If there is bilateral hyperplasia, medical therapy is indicated. Spironolactone, an aldosterone antagonist and weak diuretic, is the treatment of choice in women. In men it can be used though it may lead to gynecomastia as it also blocks androgen action. Eplerenone, a new inhibitor of the mineralocorticoid receptor with fewer side effects, became available in 2004. Know when to use surgical vs. medical therapy for hyperaldosteronism.

    PATH ANSWERS
  6. B
  7. C
  8. C
  9. B. False

Hyperaldosteronism is attributable to adrenal cortical adenoma or hyperplasia in almost equal numbers of patients and is rare as the sole manifestation of carcinoma. In a patient with an aldosterone-producing adenoma, the opposite adrenal is likely to appear normal because the aldosterone producing zona glomerulosa cells normally do0 not participate in feedback loops involving ACTH. In patients treated with the aldosterone antagonist spironolactone, whorled intracytoplasmic inclusions known as “spironolactone bodies” may be seen in the normal zona glomerulosa cells and sometimes also in adenoma cells. Ultrastructurally, these are myelin-like figures that may be derived from smooth endoplasmic reticulum. Aldosterone-producing adenomas are not histologically distinguishable from other cortical adenomas.

3. Case 3 Answers – Neuroblastoma

  1. PATH - The major differential diagnoses include Wilms’ tumor, periadrenal sarcomas, and lymphomas.
  2. PATH - Generally, neuroblastomas are not associated with evidence of catecholamine hypersecretion sufficient to cause significant hypertension. Some neuroblastomas, particularly those with evidence of ganglionic maturation, may produce vasoactive intestinal peptide (VIP) and may be associated with a syndrome of watery diarrhea and hypokalemia.
  3. PATH - This lesion is best classified as a neuroblastoma.
  4. PATH – B. False

    The prognosis of neuroblastomas depends on a large number of variables, including age at diagnosis, stage, site of primary involvement, histological grade, and sex. Amplification of the N-myc oncogene represents a poor prognostic sign. Young age at presentation is an especially favorable prognostic sign.

4. Case 4 Answers – Pheochromocytoma

  1. Answer A. It may be present in 0.1% or fewer of hypertensive patients. Teaching Aim: Pheochromocytoma is an extremely uncommon cause of hypertension but it is a life-threatening condition and it is therefore important not to miss.
  2. Answer E. The rule of P's 3.
  3. Answer B. The work-up includes 24-hour measurement for urine catecholamines, metanephrines and VMA. Plasma catecholamines and metanephrines may also be measured. Biochemical evaluation always first. Urine measurement is the traditional test given the short half-life and variability of circulating catecholamines. However, plasma measurements, especially of metanephrines, may also be done for diagnosis of pheochromocytoma.
  4. Answer D. Unlike hyperaldosteronism, medical treatment of pheochromocytoma is initiated as soon as the diagnosis is made biochemically. A beta blocker should not be used without a concurrent alpha blocker. Epinephrine is an agonist at beta-2 adrenergic receptors which leads to vasodilatation and an alpha-adrenergic receptor agonist which cause vasoconstriction. If this vasodilatory effect of the beta-2 receptor activity is blocked, unopposed vasoconstriction occurs due to the alpha effect and blood pressure may worsen. Phentolamine is an alpha adrenergic antagonist which can be administered intravenously. It may be given when a hypertensive crisis occurs in a person with a pheochromocytoma and should lead to rapid improvement in blood pressure and symptoms by blocking the alpha adrenergic effects of the catecholamines.
  5. Answer B. Pheochromocytoma may occur by itself or as part of a familial syndrome such as multiple endocrine neoplasia (MEN) type 2a or 2b and Von Hippel Lindau syndrome. In MEN 2a, hyperparathyroidism and medullary carcinoma of the thyroid (MTC) may co-exist or be part of the family history. MEN 2b is associated with MTC, mucosal neuromas, marfanoid body habitus and other abnormalities. Neurofibromatosis may be associated with pheochromocytoma. Classic Von Hippel Lindau disease includes retinal angiomatosis, cerebellar hemangioblastoma and renal cell carcinoma. However, variants of VHL disease may cause pheochromocytoma alone (VHL type 2C) or may not cause renal cell carcinoma (type 2A).
  6. Answer C. Imaging follows biochemical demonstration of endocrine disease. Pheochromocytoma is usually localized by conventional imaging with CT or MRI with the tumor appearing bright on T2 in the latter. If these tests do not show a tumor, a functional test using either MIBG or labeled Octreotide (somatostatin receptor imaging) may help to find the tumor especially if it is outside of the adrenal gland. Vena caval sampling for catecholamines may be done if all imaging is negative. Treatment is by surgical removal after careful medical management with alpha and beta-blockers and possibly depleting the tumor of catecholamines with á methyl tyrosine (an inhibitor of catecholamine synthesis).
  7. PATH - Most pheochromocytomas are benign while virtually all neuroblastomas are malignant. Most pheochromocytomas are associated with catecholamine hypersecretion and evidence of hypertension. Although neuroblastomas can synthesize catecholamines, they are rarely associated with hypertension. Neuroblastomas are primarily tumors of childhood while pheochromocytomas occur primarily in adults.
  8. PATH - Medullary tumors contain catecholamines while those of the cortex contain steroid hormones. The demonstration of chromogranin proteins serves to distinguish pheochromocytomas (positive) from cortical neoplasms which are negative.
  9. PATH - Most pheochromocytomas are benign tumors. Nevertheless, the excess production of catecholamines may lead to fatal arrhythmias and hypertensive crisis. A small percentage of the tumors are malignant and metastasize. However, at present the only agreed-upon criterion for diagnosing malignancy is the presence of metastases.
  10. PATH – The presence of multiple tumors or of diffuse and nodular hyperplasia is strongly suggestive of familial disease. These findings are most often present in MEN2, but even in MEN2 they are not always present and patients with apparently sporadic tumors sometimes prove to harbor occult germline mutations of syndrome-associated genes. Biochemical (and perhaps morphological) findings may suggest the presence of VHL mutations. Most notably, pheochromocytomas arising in VHL disease typically produce norepinephrine but not epinephrine.