Articles on Medical Diseases and Conditions

Tag: ACTH

  • Secondary Adrenal Insufficiency

    Secondary adrenal insufficiency is due to deficient production of ACTH by the pituitary. This usually results from pituitary disease but is occasionally due to hypothalamic disorders. In general, primary adrenocortical insufficiency (Addison’s disease) is associated with inability of the adrenal to produce either cortisol or aldosterone. In addition, there may be cutaneous hyperpigmentation due to pituitary hypersecretion of melanocytic-stimulating hormone (MSH). In secondary adrenal insufficiency, aldosterone secretion is usually sufficient to prevent hyperkalemia, and hyponatremia tends to be less severe. Cutaneous pigmentation does not occur because the pituitary does not produce excess MSH. The major abnormality is lack of cortisol due to deficiency of ACTH. The laboratory picture may simulate inappropriate ADH syndrome.

    Differentiation of primary from secondary adrenal insufficiency includes plasma ACTH assay (typically increased levels in primary Addison’s disease and normal or low in pituitary or hypothalamic etiology disease) and in some cases, the prolonged ACTH test. Other tests for pituitary function (metapirone test or CRH test) may be useful in some patients.

  • Addison’s Disease

    Addison’s disease is primary adrenocortical insufficiency from bilateral adrenal cortex destruction. Tuberculosis used to be the most frequent etiology but now is second to autoimmune disease atrophy. Long-term steroid therapy causes adrenal cortex atrophy from disuse, and if steroids are abruptly withdrawn, symptoms of adrenal failure may develop rapidly. This is now the most common cause of addisonian-type crisis. Less common etiologies of Addison’s disease are infection, idiopathic hemorrhage, and replacement by metastatic carcinoma. The most frequent metastatic tumor is from the lung, and it is interesting that there often can be nearly complete replacement without any symptoms.

    The salt-wasting forms of congenital adrenal hyperplasia—due to congenital deficiency of certain enzymes necessary for adrenal cortex hormone synthesis—might also be included as a variant of Addison’s disease.

    Weakness and fatigability are early manifestations of Addison’s disease, often preceded by infection or stress. Other signs and symptoms of the classic syndrome are hypotension of varying degree, weight loss, a small heart, and sometimes skin pigmentation. Anorexia, nausea, and vomiting occur frequently in adrenal crisis. The most common symptoms of adrenal crisis are hypotension and nausea.

    General laboratory tests

    Serum sodium is decreased in 50%-88% of patients with primary Addison’s disease, and serum potassium is mildly elevated in 50%-64% of cases (due to concurrent aldosterone deficiency). One investigator reported hypercalcemia in 6% of patients. There occasionally may be a mild hypoglycemia, although hypoglycemia is more common in secondary adrenal insufficiency. Serum thyroxine is low normal or mildly decreased and TSH is upper normal or mildly increased. Plasma aldosterone is usually decreased and plasma renin is elevated. There often is a normochromic-normocytic mild anemia and relative lymphocytosis with a decreased neutrophil count. Total eosinophil count is usually (although not always) close to normal.

    In primary adrenal insufficiency, a morning serum cortisol value is typically decreased and the plasma ACTH value is increased. Arginine vasopressin (AVP or ADH) is usually elevated.

    Diagnostic tests in Addison’s disease

    Screening tests. A single random serum cortisol specimen has been used as a screening procedure, since theoretically the value should be very low in Addison’s disease and normal in other conditions. Unfortunately, there are sufficient interfering factors so that its usefulness is very limited. Because serum cortisol normally has a circadian rhythm with its peak about 6-8 A.M., the specimen must be drawn about 6-8 A.M. in order not to misinterpret a lower value drawn later in the day. Stress increases plasma cortisol levels, although the increase is proportionately much less in Addison’s disease than in normal persons. The classic patient with Addison’s disease in crisis has an early morning cortisol level of less than 5 µg 100 ml (138 nmol/L), and a level of 5-10 µg/100 ml (138-276 nmol/L) is suspicious for Addison’s disease, especially if the patient is under stress. Patients with milder degrees of illness or borderline deficiency of cortisol may have a morning cortisol value of more than 10 µg/100 ml. It is often difficult to determine whether mild elevation of more than 10 µg/100 ml is due to stress or is a normal level. An early morning cortisol level of more than 20 µg/100 ml (550 mmol/L) is substantial evidence against Addison’s disease. Many endocrinologists do not consider a single random cortisol level to be reliable in screening for Addison’s disease. In spite of this it is usually worthwhile to obtain a serum specimen early for cortisol assay for diagnostic purposes (if it excludes Addison’s disease) or as a baseline (if it does not). A plasma sample should be obtained at the same time (EDTH anticoagulant) and frozen in case ACTH assay is needed later. As noted previously, serum sodium (and also chloride) is often low in classic cases, and if so would be suggestive of Addison’s disease if it were associated with a normal or elevated urine sodium and chloride level. However, as noted previously, serum sodium can be within population reference range in 12%-50% of patients.

    Rapid ACTH screening (“Cortrosyn”). Most investigators now prefer a rapid ACTH stimulation test rather than the single cortisol assay, since the rapid test can serve as a screening test unless the patient is extremely ill and in some patients may provide the same information as a confirmatory test. After a baseline serum cortisol specimen is obtained, 25 units of ACTH or 0.25 mg of corsyntropin (Cortrosyn or Synacthen, a synthetic ACTH preparation) is administered. There is variation in technique among the descriptions in the literature. Most measure plasma cortisol response after administration of corsyntropin but a few assay urinary 17-OHCS. Some inject corsyntropin intramuscularly and others intravenously. Intravenous (IV) administration is preferred but not required under ordinary circumstances. If the patient is severely ill or is hypotensive, IV is recommended to avoid problems in corsyntropin absorption. Some obtain a serum cortisol specimen 30 minutes after giving corsyntropin, whereas others do so at 60 or 120 minutes. Some obtain samples at two intervals instead of one. The majority appear to obtain one sample at 60 minutes. Some also obtain a sample at 30 minutes; this helps confirm the 60-minute value and avoids technical problems. However, the 30-minute specimen is not considered to be as reliable as the 60-minute specimen, especially if intramuscular (IM) injection was used. Theoretically, patients with primary adrenal insufficiency should demonstrate little response, whereas patients with pituitary insufficiency or normal persons should have stimulated cortisol levels that exceed 20 µg/100 ml (550 mmol/L). Some endocrinologists require an increment of at least 7 µg above baseline in addition to a peak value of 20 µg or more, especially when baseline cortisol is over 10µg/100 ml (225 mmol/L). However, increments less than or greater than 7µg are not as reproducible (on repeat corsyntropin tests) as the 20-µg peak cutoff value. Some patients with pituitary insufficiency demonstrate normal response to corsyntropin and some have a subnormal response. Because corsyntropin test results are not uniform in patients with pituitary insufficiency, it has been suggested that aldosterone should be measured as well as cortisol. Aldosterone levels should increase in pituitary hypofunction but should not rise significantly in primary adrenal failure. The metyrapone test is also useful to diagnose pituitary insufficiency.

    Some patients may have equivocal rapid test results, and others may have been treated with substantial doses of steroids for considerable periods of time before definitive tests for etiology of Addison’s disease are attempted. Under long-term steroid suppression, a normal adrenal cortex may be unable to respond immediately to stimulation. A definitive diagnosis of Addison’s disease is possible using prolonged ACTH stimulation. The classic procedure is the 8-hour infusion test. If biologic rather than synthetic ACTH is used, many recommend giving 0.5 mg of dexamethasone orally before starting the test to prevent allergic reactions. A 24-hour urine specimen is taken the day before the test. Twenty-five units of ACTH in 500 ml of saline is given intravenously during an 8-hour period while another 24-hour urine specimen is obtained. In normal persons, there will be at least a twofold to fourfold increase in cortisol or 17-OHCS levels. In Addison’s disease, there is practically no response. If pituitary deficiency is suspected, the test should be repeated the next day, in which case there will be a gradual, although relatively small, response. If exogenous steroids have been given over long periods, especially in large doses, the test period the classic approach is to repeat the 8-hour ACTH infusion procedure daily for 5-7 days. Patients with primary Addison’s disease should display little daily increment in cortisol values; those with secondary Addison’s disease should eventually produce a stepwise increase in cortisol values. Some have used a continuous ACTH infusion for 48 hours or depot IM synthetic ACTH preparations once daily instead of IV infusions or standard IM injections twice daily. If the patient has symptoms of adrenal insufficiency, both the rapid ACTH test and the prolonged ACTH test can be performed while the patient is taking 0.5-1.0 mg of dexamethasone per day, as long as therapy has not extended more than 5-6 days before starting the tests. Dexamethasone can be used because at these low doses it will not be a significant part of either serum or urine cortisol assays. Long periods of glucocorticoid therapy will interfere with the pituitary-adrenal feedback response necessary for rapid cortisol response to ACTH and will require longer periods of ACTH stimulation in the prolonged ACTH stimulation test.

    Thorn Test. If steroid measurements are not available, the Thorn test could be substituted, although it is not as accurate. First, a count of total circulating eosinophils is done. Then the patient is given 25 units of ACTH, either intravenously in the same way as in the ACTH test just described or intramuscularly in the form of long-acting ACTH gel. Eight hours after ACTH administration is started, another total circulating eosinophil count is made. Normally, cortisone causes depression of eosinophil production. Therefore a normal cortisol response to ACTH stimulation would be a drop of total circulating eosinophils to less than 50% of baseline values. A drop of less than 50% is considered suspicious for adrenal insufficiency. False positive responses (less than a 50% drop) may occur in any condition that itself produces eosinophilia (e.g., acute episodes of allergy).

    Adrenocorticotropic hormone (ACTH) assay. Plasma ACTH measurement has been used to help confirm the diagnosis of Addison’s disease and to differentiate primary from secondary adrenal failure. In primary adrenal failure, the ACTH value should be high and cortisol levels should be low. In hypothalamic or pituitary insufficiency, both ACTH and cortisol values theoretically should be low. Unfortunately, a considerable number of patients have cortisol or ACTH values within reference range. A specimen for plasma ACTH determination can be drawn at the same time as the specimen for baseline cortisol before stimulation tests and can be frozen for availability if needed.

    Antiadrenal antibodies. In primary Addison’s disease, antiadrenal antibodies have been detected in 60%-70% of patients. This test would have to be performed in large reference laboratories or certain university medical centers. Currently, this test is not being used as a primary diagnostic procedure.

  • Cushing’s Syndrome. Part 2

    48-hour dexamethasone suppression test.

    The 48-hour DST is the most widely used confirmatory procedure. Dexamethasone (Decadron) is a synthetic steroid with cortisone-like actions but is approximately 30 times more potent than cortisone, so that amounts too small for laboratory measurement may be given to suppress pituitary ACTH production. The test is preceded by two consecutive 24-hour urine collections as a baseline. If low doses (2 mg/day) are used, patients with normal adrenal function usually have at least a 50% decrease (suppression) in their 24-hour urine 17-OHCS values compared to baseline, whereas those with Cushing’s syndrome from any etiology have little if any change. This test result is usually normal in those patients whose low-dose overnight DST is abnormal (nonsuppressed) only because of obesity. If larger doses (8 mg/day) are used, about 85% (range, 42%-98%) of those with adrenal cortex hyperplasia due to pituitary oversecretion of ACTH have at least a 50% decrease (suppression) of their 24-hour urine 17-OHCS values. Adrenal cortisol-producing adenomas or carcinoma rarely decrease their urine 17-OHCS levels. Patients with the ectopic ACTH syndrome due to bronchial or thymus carcinoids have been reported to produce false positive test results (decrease in urine 17-OHCS levels) in up to 40% of patients. Patients with the ectopic ACTH syndrome from lung small cell carcinoma or other tumors rarely change urine 17-OHCS levels. Since the test takes a total of 4 days (48 hours at baseline and 48 hours of test duration) and requires 24-hour urine collections, and since there are a significant number of exceptions to the general rules, plasma ACTH assay is supplementing or replacing the high-dose DST for differentiation of the various etiologies of Cushing’s syndrome. Some investigators report that the metyrapone test (discussed later) is better than the 48-hour high-dose DST in differentiating pituitary oversecretion of ACTH from adrenal tumor.

    A single-dose overnight version of the high-dose DST has been reported, similar to the low-dose overnight test. A baseline serum cortisol specimen is drawn fasting at 8 A.M.; 8 mg of dexamethasone is given at 11 P.M.; and a second serum cortisol specimen is drawn fasting at 8 A.M. the next day. Normal persons and patients with pituitary ACTH syndrome have 50% or more cortisol decrease from baseline. Cortisol-producing adrenal tumors and ectopic ACTH patients have little change. Limited evaluation of this test reported similar results to the standard high-dose dexamethasone procedure.

    Metyrapone test. Metyrapone (Metopirone) blocks conversion of compound S to cortisol. This normally induces the pituitary to secrete more ACTH to increase cortisol production. Although production of cortisol is decreased, the compound S level is increased as it accumulates proximal to the metyrapone block, and 17-OHCS or radioassay CPB methods for cortisol in either serum or urine demonstrate sharply increased apparent cortisol values (due to compound S) in normal persons and those with pituitary-induced adrenal cortex hyperplasia. Fluorescent assay or RIA for cortisol do not include compound S and therefore yield decreased cortisol values. Adrenal tumors are not significantly affected by metyrapone. Some authorities recommend measuring both cortisol and compound S. An increase in compound S verifies that lowering of the plasma cortisol level was accompanied by an increase in ACTH secretion. This maneuver also improves the ability of the test to indicate the status of pituitary reserve capacity, and the test is sometimes used for that purpose rather than investigation of Cushing’s disease. To obtain both measurements, one must select a test method for cortisol that does not also measure compound S. Compound S can be measured by a specific RIA method. Phenytoin or estrogen administration interferes with the metyrapone test.

    Adrenocorticotropic hormone stimulation test. Injection of ACTH directly stimulates the adrenal cortex. Patients with cortex hyperplasia and some adenomas display increased plasma cortisol and 17-OHCS levels. If urine collection is used, a 24-hour specimen taken the day of ACTH administration should demonstrate a considerable increase from preinfusion baseline values, which persists in a 24-hour specimen collected the day after ACTH injection. Normal persons should have increased hormone excretion the day ACTH is given but should return to normal in the next 24 hours. Carcinoma is not affected. The ACTH stimulation test at present does not seem to be used very frequently.

    Serum adrenocorticotropic hormone. Serum ACTH measurement by immunoassay is available in many reference laboratories. At present, the assay techniques are too difficult for the average laboratory to perform in a reliable fashion, and even reference laboratories still have problems with accuracy.

    There is a diurnal variation in serum ACTH levels corresponding to cortisol secretion, with highest values at 8-10 A.M. and lowest values near midnight. Stress and other factors that affect cortisol diurnal variation may blunt or eliminate the ACTH diurnal variation. Serum ACTH data in adrenal disease are summarized in Table 30-1.

    Plasma adrenocorticotropic hormone in adrenal diseases

    Table 30-1 Plasma adrenocorticotropic hormone in adrenal diseases

    In Cushing’s syndrome due to adrenal tumor or micronodular hyperplasia, pituitary activity is suppressed by adrenal-produced cortisol, so the serum ACTH level is very low. In ectopic ACTH syndrome, the serum ACTH level is typically very high (4-5 times the upper preference limit) due to production of cross-reacting ACTH-like material by the tumor. However, some patients with the ectopic ACTH syndrome have serum levels that are not this high. In bilateral adrenal hyperplasia due to pituitary overactivity, serum ACTH levels can either be normal or mildly to moderately elevated (typically less than the degree of elevation associated with the ectopic ACTH syndrome). However, there is a substantial degree of overlap between pituitary tumor ACTH values and ectopic ACTH syndrome values. It has been suggested that ACTH specimens obtained at 10-12 P.M. provide better separation of normal from pituitary hypersecretion than do specimens drawn in the morning. Another study found that specimens drawn between 9:00 and 9:30 A.M. provided much better separation of normal from pituitary hypersecretion than specimens drawn at any other time in the morning. In summary, adrenal tumor (low ACTH levels) can usually be separated from pituitary-induced adrenal cortex hyperplasia (normal or increased ACTH levels) and from ectopic ACTH (increased ACTH levels). Pituitary-induced adrenal cortex hyperplasia has ACTH values that overlap with the upper range of normal persons and with the lower range of the ectopic ACTH syndrome. The time of day that the specimen is drawn may improve separation of normal persons from those with Cushing’s disease.

    Corticotropin-releasing hormone test. About 85% of Cushing’s disease is due to pituitary hyperplasia or tumor, and about 15% is due to ectopic ACTH from a nonpituitary tumor. Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the pituitary to release ACTH (corticotropin). Ovine CRH is now available, and investigators have administered this hormone in attempts to differentiate adrenal tumor and the ectopic ACTH syndrome from pituitary overproduction of ACTH. Initial studies reported that after CRH administration, pituitary ACTH-producing tumors increased plasma cortisol levels at least 20% over baseline and increased their ACTH level at least 50% over baseline. Normal persons also increase their ACTH and plasma cortisol levels in response to CRH, and there is substantial overlap between normal response and pituitary tumor response. Primary adrenal tumors and the ectopic ACTH syndrome either did not increase cortisol levels or increased ACTH less than 50% and plasma cortisol levels less than 20%. However, several studies found that about 10% of pituitary ACTH-producing tumors failed to increase plasma ACTH or cortisol to expected levels. This is similar to the rate that pituitary tumors fail to suppress cortisol production as much as expected in the high-dose 48-hour DST. About 15% of patients with the ectopic ACTH syndrome overlap with pituitary ACTH tumors using the ACTH criteria already mentioned, and about 10% overlap using the plasma cortisol criteria. Therefore, differentiation of the etiologies of Cushing’s syndrome by the CRH test alone is not as clear-cut as theoretically would be expected. To prevent false results, the patients should not be under therapy for Cushing’s syndrome when the test is administered.

    The CRH test has also been advocated to evaluate the status of pituitary function in patients on long-term, relatively high-dose corticosteroid therapy.

    To summarize, the expected results from the CRH test after injection of CRH are (1) for a diagnosis of Cushing’s disease, an exaggerated response from adenoma of pituitary; (2) for Cushing’s syndrome of adrenal origin or ectopic ACTH syndrome, no significant increase in ACTH; (3) for the differential diagnosis of increased ACTH from pituitary microadenoma versus ectopic ACTH syndrome, inconsistent results. The CRH test is not completely reliable in differentiating primary pituitary disease from hypothalamic deficiency disease.

    Cushing’s disease versus ectopic ACTH syndrome. The intracerebral inferior venous petrosal sinuses receive the venous blood from the pituitary containing pituitary-produced hormones; the right inferior petrosal sinus mostly from the right half of the pituitary and the left sinus from the left half. Several studies have suggested that catheterization of both inferior petrosal sinuses can differentiate ectopic ACTH production from the pituitary ACTH overproduction of Cushing’s disease in patients who do not show a pituitary tumor on computerized tomography (CT) scan or when the diagnosis is in question for other reasons. The most commonly used method is comparison of the ACTH level in the inferior petrosal sinuses with peripheral venous blood (IPS/P ratio) 3 minutes after pituitary stimulation by ovine CRH. Although several criteria have been proposed, it appears that an IPS/P ratio greater than 2.0 without CRH stimulation or a ratio of 3.3 or more in one of the inferior petrosal sinuses 3 minutes after CRH stimulation is over 95% sensitive and specific for Cushing’s disease versus ectopic ACTH syndrome (if technical problems are avoided). However, apparently this procedure is not as good in differentiating Cushing’s disease from pseudo-Cushing’s disease, since there is about 20% overlap with results from patients with some clinical or laboratory findings suggestive of Cushing’s disease (such as some patients with psychiatric depression) but without proof of pituitary hyperplasia or adenoma. In one study the same overlap was seen with clinically normal persons.

    Computerized tomography

    CT can frequently differentiate between unilateral adrenal enlargement (adrenal adenoma or carcinoma) and bilateral enlargement (pituitary hyperactivity or ectopic ACTH syndrome). However, it has been reported that nonfunctioning adrenal cortex nodules may occur in 1%-8% of normal persons, and one of these nodules could be present coincidentally with pituitary Cushing’s syndrome or ectopic ACTH. CT is very useful, better than pituitary sella x-ray films, in verifying the presence of a pituitary adenoma. Even so, third- and fourth-generation CT detects only about 45% (range, 30%-60%) of pituitary adenomas. In addition, it has been reported that 10%-25% of normal persons have a pituitary microadenoma, and some of these nonfunctioning nodules may be seen on CT and lead to a misdiagnosis of Cushing’s disease.

    Summary of tests in Cushing’s syndrome

    Currently, the most frequently utilized tests to screen for Cushing’s syndrome are the overnight low-dose DST and the test to detect abolishment of serum cortisol diurnal variation. Urine free-cortisol determination would provide more accurate information than the diurnal variation test. Confirmatory tests (if necessary) and tests to differentiate adrenal from nonadrenal etiology that are most often used are the 48-hour DST or the metyrapone test, serum ACTH assay, and CT visualization of the adrenals.

    Conditions that affect the screening and confirmatory tests should be kept in mind. In particular, alcoholism (especially with recent drinking) and psychiatric depression can closely mimic the test results that suggest Cushing’s syndrome. Finally, there are some patients in each category of Cushing’s syndrome etiology who do not produce the theoretically expected response to screening or confirmatory tests.