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[Endoc.] Adrenocortical Adenoma & Hypercholesterolism

[Endoc.] Adrenocortical Adenoma & Hypercholesterolism

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Published by: api-3769252 on Oct 16, 2008
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A 48-year-old woman went to the local emergency room because of an abrupt onset of lower back pain. X-ray examination showed a compression fracture of the third lumbar vertebra along with evidence of osteoporosis in the spine. Further history revealed a 50-pound weight gain over the preceding 3 years, muscle weakness, and a tendency to bruise easily. She also complained of increasing emotional lability, including bouts of euphoria and depression. Sleep was also disturbed. Her previously regular menses were now only occurring every 4 to 6 months. Physical examination showed an obese woman with excess adipose tissue largely in the face, above the clavicles, and about the trunk. The extremities were thin and exhibited muscle atrophy. Skin was thin and had bruises that could not be accounted for by trauma. There were large purple marks over the abdomen. Excess hair growth was present on the upper lip and skin. Neurologic examination showed weakness of proximal muscle groups but normal deep tendon reflexes. Blood pressure was 164/102 and pulse was 76 beats/min. Laboratory findings showed fasting plasma glucose to be 180 mg/dl. Serum electrolytes showed a slight increase in the bicarbonate level and a slight decrease in the potassium level. White blood cell count was 16,000 with 92% neutrophils and 8% lymphocytes.

1. What is the most likely endocrine cause of this patient's clinical picture? 2. How would this hormonal disturbance produce the various symptoms and signs noted? 3. Why is the fasting plasma glucose level elevated? What would you expect the concurrent plasma insulin level to be? 4. What is responsible for the hypertension and slight abnormalities in the plasma levels of bicarbonate and potassium? 5. Why is there an excess of neutrophils and a deficit of lymphocytes in the patient's blood? 6. How would you establish the presence of the suspected hormonal hypersecretion? 7. What is the possible etiology of such hypersecretion? 8. How could you use the principle of negative feedback control to discriminate among the etiologic possibilities? 9. What other hormones are likely to be present in excess in this patient? 10. The primary locus of this patient's disease was eventually determined to be the gland from which the hormonal disturbance originated and surgical removal was carried out. Postoperatively, she noted satisfactory weight loss and the return of a normal emotional state. However, she also developed generalized weakness, lethargy, and loss of appetite. Blood pressure fell to 98/62. What is now wrong with the patient, and how has this come about?

[ANSWER] 1. The constellation of signs and symptoms in this patient is a classic picture of the effects of excess cortisol or of any exogenously administered glucocorticoid.

2. Cortisol creates an antianabolic (i.e., catabolic) metabolic state. The muscle mass shows increased proteolysis with a resulting decrease in the size and number of muscle fibers and consequently by weakness and atrophy. In bone, collagen synthesis is inhibited and the rate of bone resorption is increased, which leads to osteopenia and to fractures. Calcium absorption from the gastrointestinal tract is diminished because of inhibition of the action of 1,25-(OH)2-vitamin D. This adds to the difficulty in maintaining bone mass. Inhibition of collagen synthesis in skin and blood vessel walls leads to thinning of these tissues and to fragility of capillaries; this causes bruising and purple bands in the skin. Appetite is stimulated centrally by cortisol, but the excess of ingested calories is selectively deposited in certain depots for reasons currently unexplained. Cortisol decreases REM sleep and increases the amount of time awake. All of the above effects stem from the binding of cortisol to its nuclear glucocorticoid receptor (type II). This modulates the transcription of numerous genes. 3. Cortisol inhibits the insulin-stimulated uptake of glucose by muscle and augments gluconeogenesis in the liver. These effects combine to raise fasting plasma glucose. Plasma insulin increases in response to the rise in plasma glucose. 4. Cortisol also binds to the mineralocorticoid receptor (type I glucocorticoid receptor), and an excess of cortisol can therefore mimic aldosterone actions on the kidney to produce sodium retention, edema, hypertension, hypokalemia, and metabolic alkalosis. 5. Cortisol has marked effects on the hematopoietic system. Recruitment of neutrophils from the bone marrow is stimulated, but their margination and transfer to tissue are inhibited so that the circulating number rises. Lymphocyte numbers decrease. 6. Hypersecretion of cortisol would be established by one or more of the following findings. The plasma cortisol level would be elevated in the morning but especially in the evening (a time of day when plasma cortisol normally is low because of diurnal variation). A 24hour urinary excretion of free cortisol would be elevated. A 24-hour urinary excretion of metabolites of cortisol (17-hydroxy corticoids) would also be elevated when corrected for body mass or when expressed per gram of creatinine. 7. Hypersecretion of cortisol could result from abnormalities at various points in the hypothalamic-pituitary adrenal axis. a. A benign or malignant adrenal neoplasm may secrete excess cortisol. b. Increased secretion of ACTH by a pituitary neoplasm or in response to an excess of corticotropinreleasing hormone may stimulate excess secretion of cortisol by both adrenal glands (adrenal hyperplasia). ACTH may also be secreted by nonpituitary neoplasms that express the propiomelanocortin gene. 8. a. Autonomous hypersecretion of cortisol by an adrenal neoplasm should suppress ACTH secretion by negative feedback. Hence plasma ACTH level will be low. b. If hypersecretion of cortisol is caused by a pituitary lesion, plasma ACTH will be elevated or at least inappropriately normal in the face of elevated cortisol levels. This resetting of the normal relationship between cortisol and ACTH can be demonstrated by administering an appropriate dose of a synthetic glucocorticoid, such as dexamethasone. In a normal individual, this will markedly decrease both plasma ACTH and plasma cortisol levels, but in an individual with abnormally functioning pituitary corticotrophs, plasma ACTH and cortisol will decrease little, if any. However, if a very large dose of dexamethasone is given, even the abnormal corticotrophs will be shut off, and plasma ACTH and cortisol will decrease significantly. c. Abnormal expression of the ACTH precursor gene by a nonendocrine tumor will be manifest by a very high plasma level of ACTH, with no suppression when dexamethasone is given. In addition, such high levels of ACTH may cause hyperpigmentation of the skin because of the melanocyte-stimulating hormone sequence within ACTH.

9. The loss of regular menses and the increasing facial hair suggest an excess of adrenal androgen secretion. Plasma levels of dehydroepiandrosterone and androstenedione will likely be elevated. These weak androgens may then be converted to the potent androgen, testosterone, in peripheral tissues. 10. This patient's hypercortisolism was found to be caused by an adrenal adenoma. Therefore her plasma ACTH level was very low because of negative feedback. As a result, the remaining normal adrenal cortical tissue was atrophic and nonfunctioning. Immediately after removal of the adrenal adenoma, the plasma cortisol fell to low levels, which produced her postoperative symptoms and low blood pressure. This situation can persist for many months until, first, her adrenocorticotrophs recover from prolonged suppression and, second, her remaining adrenal cortical cells increase in size and number and recover their ability to secrete normal amounts of cortisol.

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