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http://www.pulmonaryreviews.com/jan03/pr_jan03_adrenal.html
ADRENAL INSUFFICIENCY: UNDERDIAGNOSED IN THE CRITICALLY ILL
SAN DIEGOThe overall incidence of adrenal insufficiency (AI) in critically ill patients is about 30% to 40% and may be as high as 60% in those with septic shock, although statistics vary with the severity of illness and the diagnostic criteria used. The condition remains underrecognized largely because current diagnostic approaches are not sensitive enough to detect it, according to Paul Marik, MD, who gave a presentation on the subject at the American College of Chest Physicians recent annual meeting.[1]
The gold standard for testing for AI in critically ill patients should be a random serum cortisol, and that level should be above 25 g/dL, asserted Dr. Marik, Professor of Critical Care Medicine at the University of Pittsburgh. In his presentation, Dr. Marik reviewed much of the controversy surrounding the definition of and appropriate tests for AI, as well as symptoms of the condition and glucocorticoid treatment.
SERUM CORTISOL: HOW LOW IS TOO LOW?
When the hypothalamic-pituitary-adrenal (HPA) axis is activated by a stressor, such as hypotension, fever, or pain, cortisol is released as part of the fight or flight stress response, which also serves to limit host-mediated tissue damage. Precisely what constitutes a sufficient stress cortisol level is, however, controversial at present.
Many published sources list a serum cortisol level above 18 to 20 g/dL as a normal response to stress.[2] According to Dr. Marik, though, a cutoff value of 18 is too low for an accurate diagnosis of AI. Studies show that during the stress of surgery, he argued, patients consistently increase serum cortisol to above 25 and often above the 30 g/dL threshold. In major surgery, levels peak between 30 and 45 g/dL.[2]
He continued by pointing out that in patients with severe illness, such as sepsis, serum cortisol concentrations tend to be higher than those [in] patients undergoing major surgery. In severe sepsis, cortisol levels often remain elevated for the duration of the illness, instead of declining over the course of a few days as they do after surgery.
Circulating cortisol levels therefore reflect the severity of the stressor, and hypotension and severe sepsis as seen in critical illness are two of the most intense stressors. Thus, Dr. Marik urged using a random cortisol stress level of 25 g/dL for the diagnosis of AI. Stress cortisol is the gold standard for assessing adrenal function, he said.
DEBUNKING THE 18 G/DL CUTOFF
Many traditional methods of testing for AI are either inappropriate or not sensitive enough to detect the condition. Historically, the cutoff of 18 g/dL for diagnosis was based on patients responses to the exogenous high-dose adrenal corticotropic hormone (HD-ACTH) stimulation test, which requires administration of 250 g of synthetic corticotropin. Cortisol levels below 18 g/dL or a change in cortisol levels of less than 9 g/dL were considered indicative of AI.
Several problems exist with this test, Dr. Marik contended. First, these criteria were originally established in nonstressed patients, most of whom had tuberculosis.
Most notably, the high dose of synthetic corticotropin does not reflect any pathophysiologic conditionthe amount exceeds the maximum possible ACTH levels achieved during stress by 1,000 times. It is akin to giving a patient 20,000 units of insulin, Dr. Marik stipulated.
Because of these extremely high levels of corticotropin, ACTH resistance may be masked by a cortisol response to the megadose given in the test. Patients may be able to respond to these extreme levels but still may have an insufficient response to normal stress levels.
In addition, measurement of a change in cortisol levels of less than 9 g/dL is clinically meaningless, according to Dr. Marik. Cortisol measurements need to be evaluated in a situational context depending on the baseline level. In a severely stressed patient, for example, if the initial cortisol reading is 45 g/dL and that level increases following HD-ACTH testing to 48 g/dL, the patient does not have AI but rather is responding appropriately. A stressed patient may not be able to increase those levels further, he said.
On the other hand, misdiagnosis can also occur when the requisite change in cortisol level of 9 is met. For example, a patients cortisol levels increase from 9 to 18 g/dL. According to the classic definition, a change in cortisol of 9 or more indicates that the patient was responding appropriately. However, in this case, the baseline level itself would be insufficient for a critically ill patient.
In all, the ACTH test is a physiologically meaningless test to perform in critically ill patients, stated Dr. Marik. He added, Hopefully, after this lecture, none of you will do this test anymore. If you do, then Ive failed in my mission.
HPA AXIS FAILURE, NOT SINGLE GLAND FAILURE
Perhaps the most important limitation of the HD-ACTH test is that it bypasses the hypothalamus and pituitary to test the adrenal gland directly. In patients with sepsis, the entire axis fails, not just the adrenal gland, Dr. Marik explained.
He outlined three distinct patterns of adrenal failure, denoting different types of HPA axis malfunction. In primary adrenal failure, patients with low cortisol levels dont respond to either the HD-ACTH or the low-dose (LD) ACTH test. (In the LD-ACTH test, 1 g of corticotropin is given instead of 250 g.) This indicates a problem with the adrenal gland.
In the second group, patients with low baseline serum cortisol levels do respond to both the HD- and LD-ACTH tests, which suggests a failure of the HPA axis. Finally, ACTH resistance is characterized by low initial cortisol levels and a patient response only to the HD-ACTH test. Adrenal insufficiency is a heterogeneous disease, Dr. Marik summarized.
SYMPTOMS AND TREATMENT
It is essential to recognize the signs of AI as even slight impairment of the adrenal response to severe illness can increase morbidity and mortality.[2] Because sepsis is one of the most common causes of AI, those patients are at high risk and should be closely monitored.
Hypotension is the key indicator of adrenal failure, stressed Dr. Marik. Other clinical features include hypoxia, unexplained fever, altered mental state, and eosinophilia. This condition is often reversible with treatment of the underlying disease.
Glucocorticoids have proven to be beneficial in reversing the effects of AI and in decreasing mortality. In one study, hydrocortisone administration resulted in faster weaning from vasopressors and improved survival (79% vs 55% in nontreated patients).[3] In another study, 40 patients in septic shock received either hydrocortisone or placebo. Hydrocortisone administration was associated with reversal of shock, fewer days on vasopressor support, earlier resolution of organ dysfunction, and shorter time spent on mechanical ventilation and in the ICU.[4]
Thus, when critically ill patients are hypotensive or display other symptoms of AI, Dr. Marik advised obtaining a baseline serum cortisol level and administering hydrocortisone pending the results of the test. The dose can be tapered as the patients condition improves and symptoms resolve. But he stressed that recognition is the key to successful treatment, The index of suspicion for adrenal insufficiency should always be high in critically ill patients.
Lisa Pallatroni
References
1. Marik PE. Adrenal insufficiency in critical illness. Presented at: American College of Chest Physicians Conference; November 6, 2002; San Diego, Calif.
2. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002;122:1784-1796.
3. Rivers EP, Gaspari M, Abi Saad G, et al. Adrenal insufficiency in high-risk surgical ICU patients. Chest. 2001;119:889-896.
4. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27:723-732.
ADRENAL INSUFFICIENCY: UNDERDIAGNOSED IN THE CRITICALLY ILL
SAN DIEGOThe overall incidence of adrenal insufficiency (AI) in critically ill patients is about 30% to 40% and may be as high as 60% in those with septic shock, although statistics vary with the severity of illness and the diagnostic criteria used. The condition remains underrecognized largely because current diagnostic approaches are not sensitive enough to detect it, according to Paul Marik, MD, who gave a presentation on the subject at the American College of Chest Physicians recent annual meeting.[1]
The gold standard for testing for AI in critically ill patients should be a random serum cortisol, and that level should be above 25 g/dL, asserted Dr. Marik, Professor of Critical Care Medicine at the University of Pittsburgh. In his presentation, Dr. Marik reviewed much of the controversy surrounding the definition of and appropriate tests for AI, as well as symptoms of the condition and glucocorticoid treatment.
SERUM CORTISOL: HOW LOW IS TOO LOW?
When the hypothalamic-pituitary-adrenal (HPA) axis is activated by a stressor, such as hypotension, fever, or pain, cortisol is released as part of the fight or flight stress response, which also serves to limit host-mediated tissue damage. Precisely what constitutes a sufficient stress cortisol level is, however, controversial at present.
Many published sources list a serum cortisol level above 18 to 20 g/dL as a normal response to stress.[2] According to Dr. Marik, though, a cutoff value of 18 is too low for an accurate diagnosis of AI. Studies show that during the stress of surgery, he argued, patients consistently increase serum cortisol to above 25 and often above the 30 g/dL threshold. In major surgery, levels peak between 30 and 45 g/dL.[2]
He continued by pointing out that in patients with severe illness, such as sepsis, serum cortisol concentrations tend to be higher than those [in] patients undergoing major surgery. In severe sepsis, cortisol levels often remain elevated for the duration of the illness, instead of declining over the course of a few days as they do after surgery.
Circulating cortisol levels therefore reflect the severity of the stressor, and hypotension and severe sepsis as seen in critical illness are two of the most intense stressors. Thus, Dr. Marik urged using a random cortisol stress level of 25 g/dL for the diagnosis of AI. Stress cortisol is the gold standard for assessing adrenal function, he said.
DEBUNKING THE 18 G/DL CUTOFF
Many traditional methods of testing for AI are either inappropriate or not sensitive enough to detect the condition. Historically, the cutoff of 18 g/dL for diagnosis was based on patients responses to the exogenous high-dose adrenal corticotropic hormone (HD-ACTH) stimulation test, which requires administration of 250 g of synthetic corticotropin. Cortisol levels below 18 g/dL or a change in cortisol levels of less than 9 g/dL were considered indicative of AI.
Several problems exist with this test, Dr. Marik contended. First, these criteria were originally established in nonstressed patients, most of whom had tuberculosis.
Most notably, the high dose of synthetic corticotropin does not reflect any pathophysiologic conditionthe amount exceeds the maximum possible ACTH levels achieved during stress by 1,000 times. It is akin to giving a patient 20,000 units of insulin, Dr. Marik stipulated.
Because of these extremely high levels of corticotropin, ACTH resistance may be masked by a cortisol response to the megadose given in the test. Patients may be able to respond to these extreme levels but still may have an insufficient response to normal stress levels.
In addition, measurement of a change in cortisol levels of less than 9 g/dL is clinically meaningless, according to Dr. Marik. Cortisol measurements need to be evaluated in a situational context depending on the baseline level. In a severely stressed patient, for example, if the initial cortisol reading is 45 g/dL and that level increases following HD-ACTH testing to 48 g/dL, the patient does not have AI but rather is responding appropriately. A stressed patient may not be able to increase those levels further, he said.
On the other hand, misdiagnosis can also occur when the requisite change in cortisol level of 9 is met. For example, a patients cortisol levels increase from 9 to 18 g/dL. According to the classic definition, a change in cortisol of 9 or more indicates that the patient was responding appropriately. However, in this case, the baseline level itself would be insufficient for a critically ill patient.
In all, the ACTH test is a physiologically meaningless test to perform in critically ill patients, stated Dr. Marik. He added, Hopefully, after this lecture, none of you will do this test anymore. If you do, then Ive failed in my mission.
HPA AXIS FAILURE, NOT SINGLE GLAND FAILURE
Perhaps the most important limitation of the HD-ACTH test is that it bypasses the hypothalamus and pituitary to test the adrenal gland directly. In patients with sepsis, the entire axis fails, not just the adrenal gland, Dr. Marik explained.
He outlined three distinct patterns of adrenal failure, denoting different types of HPA axis malfunction. In primary adrenal failure, patients with low cortisol levels dont respond to either the HD-ACTH or the low-dose (LD) ACTH test. (In the LD-ACTH test, 1 g of corticotropin is given instead of 250 g.) This indicates a problem with the adrenal gland.
In the second group, patients with low baseline serum cortisol levels do respond to both the HD- and LD-ACTH tests, which suggests a failure of the HPA axis. Finally, ACTH resistance is characterized by low initial cortisol levels and a patient response only to the HD-ACTH test. Adrenal insufficiency is a heterogeneous disease, Dr. Marik summarized.
SYMPTOMS AND TREATMENT
It is essential to recognize the signs of AI as even slight impairment of the adrenal response to severe illness can increase morbidity and mortality.[2] Because sepsis is one of the most common causes of AI, those patients are at high risk and should be closely monitored.
Hypotension is the key indicator of adrenal failure, stressed Dr. Marik. Other clinical features include hypoxia, unexplained fever, altered mental state, and eosinophilia. This condition is often reversible with treatment of the underlying disease.
Glucocorticoids have proven to be beneficial in reversing the effects of AI and in decreasing mortality. In one study, hydrocortisone administration resulted in faster weaning from vasopressors and improved survival (79% vs 55% in nontreated patients).[3] In another study, 40 patients in septic shock received either hydrocortisone or placebo. Hydrocortisone administration was associated with reversal of shock, fewer days on vasopressor support, earlier resolution of organ dysfunction, and shorter time spent on mechanical ventilation and in the ICU.[4]
Thus, when critically ill patients are hypotensive or display other symptoms of AI, Dr. Marik advised obtaining a baseline serum cortisol level and administering hydrocortisone pending the results of the test. The dose can be tapered as the patients condition improves and symptoms resolve. But he stressed that recognition is the key to successful treatment, The index of suspicion for adrenal insufficiency should always be high in critically ill patients.
Lisa Pallatroni
References
1. Marik PE. Adrenal insufficiency in critical illness. Presented at: American College of Chest Physicians Conference; November 6, 2002; San Diego, Calif.
2. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002;122:1784-1796.
3. Rivers EP, Gaspari M, Abi Saad G, et al. Adrenal insufficiency in high-risk surgical ICU patients. Chest. 2001;119:889-896.
4. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27:723-732.
http://www.postgradmed.com/issues/1998/07_98/hasinski.htm
Assessment of adrenal glucocorticoid function
Which tests are appropriate for screening?
Stefan Hasinski, MD
VOL 104 / NO 7 / JULY 1998 / POSTGRADUATE MEDICINE
This is the second of three articles on on endocrine disorders
Preview: Overproduction or underproduction of adrenal hormones raises sticky diagnostic problems for primary care physicians. Fortunately, assessment of hypoadrenalism has been greatly simplified. On the other hand, evaluation of patients with suspected hyperadrenalism (Cushing's syndrome) can be difficult, confusing, and frustrating. Dr Hasinski reviews the options for testing these critical adrenal functions and provides up-to-date information on interpreting test outcomes and pursuing a diagnosis.
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The adrenal glands, the two small pyramidal structures on the superior pole of the kidneys that weigh just 4 g each, can raise diagnostic havoc when their functions go awry. A quick review of these glands seems appropriate in explaining how to assess whether or not they are responsible for a number of symptoms.
Adrenal function
About 90% of the adrenal gland tissue consists of adrenal cortex, which has three distinct zones: the glomerulosa, or outer layer, which produces aldosterone; the fasciculata, or middle layer, which makes glucocorticoid precursors and cortisol; and the reticularis, or inner layer, which synthesizes adrenal androgens (1,2).
Cortisol synthesis originates with cholesterol, about 80% of which is delivered to the adrenal glands by low-density lipoprotein (LDL) cholesterol. The number of LDL receptors is increased when the adrenal glands are stimulated by corticotropin (ACTH). The remaining cholesterol is made through hydroxymethylglutaryl coenzyme A reductase activity, which is not controlled by corticotropin. Cholesterol is modified by a series of enzymes of the P-450 system to produce cortisol.
The production of cortisol is regulated tightly by the hypothalamus and the pituitary gland, with classic feedback inhibition. Corticotropin-releasing hormone is released from the parvicellular division of the hypothalamic paraventricular nucleus. Binding of corticotropin-releasing hormone induces production of pro-opiomelanocortin, which is then cleaved into various fragments, including melanocyte-stimulating hormones, beta-lipotropins, beta-endorphins, and corticotropin.
Corticotropin, a 39-amino-acid hormone, is released from the anterior pituitary and enters the systemic circulation. Once bound to the adrenal cortex, corticotropin induces cortisol synthesis and secretion. Cortisol binds to receptors in the hypothalamus and pituitary to inhibit the release of corticotropin-releasing hormone and corticotropin, respectively.
Cortisol secreted by the adrenal cortex is transported mainly bound to plasma proteins, specifically corticosteroid-binding globulin (transcortin), but also albumin and sex hormone-binding globulin (1,2). Between 90% and 97% of cortisol is bound to proteins (1). It is only the "free fraction," or nonprotein-bound hormone, that is available to bind to specific tissue receptors. Cortisol metabolism occurs mainly in the liver, and products of cortisol metabolism can be detected in the urine as 17-hydroxycorticosteroids (17-OHCS) (2).
Adrenal insufficiency
The diagnosis of adrenal insufficiency is relatively straightforward. The chief difficulties are recognizing the constellation of symptoms and maintaining a high index of suspicion.
Adrenal insufficiency can be primary, secondary, or tertiary, depending on the location of the lesion. Primary adrenal insufficiency, or Addison's disease, is due to adrenal gland failure. In the past, the most common cause was tuberculosis (2), but now it is autoimmune adrenalitis, which may be isolated or part of a generalized autoimmune disorder. Other causes include metastatic disease (most commonly from lung and breast carcinomas), hemorrhage, infection, rare familial disorders (eg, adrenoleukodystrophy, adrenomyeloneuropathy), and HIV-related disease (1-3).
Symptoms of primary adrenal insufficiency include weakness, abdominal pain, nausea, weight loss, hypotension or shock, lack of libido, loss of body hair in women, hyperpigmentation, and psychiatric changes. Laboratory findings may include hyponatremia, hyperkalemia, mild acidosis, hypoglycemia, and hypercalcemia.
In secondary adrenal insufficiency, release of corticotropin from the pituitary is impaired. In tertiary adrenal insufficiency, release of corticotropin-releasing hormone from the hypothalamus is insufficient. Symptoms of secondary and tertiary adrenal insufficiency may be identical to those of primary disease, except that hyperpigmentation does not occur in the secondary or tertiary form because of insufficient production of corticotropin and other products of pro-opiomelanocortin metabolism (ie, melanocyte-stimulating hormones). Aldosterone, the potent adrenal mineralocorticoid hormone, is controlled mainly by potassium and the renin-angiotensin system and is therefore only minimally affected by a lack of corticotropin.
Screening tests
The best screening test for evaluating adrenal glucocorticoid function involves rapid stimulation with cosyntropin (Cortrosyn), a synthetic analogue of corticotropin. After baseline plasma cortisol and aldosterone levels are measured, 250 micrograms of cosyntropin is given as an intravenous bolus or an intramuscular injection. Plasma cortisol and aldosterone levels are measured again 30 to 60 minutes later. The blood samples for aldosterone can be held until the results of the cortisol response are known. If the cortisol response is insufficient, the aldosterone levels can help localize the deficiency.
A baseline cortisol level of greater than 18 micrograms/dL is consistent with normal adrenal function (2). However, opinions differ as to how to interpret test results (1-3). I prefer to use a cortisol level that increases twofold over baseline and rises above 20 micrograms/dL as an indication of normal adrenal function. This standard considers both baseline and reserve adrenal function. The baseline corticotropin level can help differentiate primary from secondary or tertiary hypoadrenalism but must be interpreted cautiously because corticotropin release from the pituitary varies throughout the day. A newer and possibly more sensitive test uses 1 microgram of cosyntropin to evaluate the cortisol response, which should be the same as with the cosyntropin 250 micrograms test (4). The aldosterone response in a cosyntropin test is blunted or absent in patients with primary adrenal insufficiency. In secondary or tertiary adrenal insufficiency, aldosterone response is normal (an increase of two times baseline) because the renin-angiotensin axis is not affected by decreased corticotropin.
A corticotropin-releasing hormone stimulation test can be used to differentiate secondary (pituitary) from tertiary (hypothalamic) disease, although this test is seldom necessary. In the past, the central axis was assessed with a metyrapone (Metopirone) test. Metyrapone inhibits cortisol synthesis, which results in release of corticotropin-releasing hormone and corticotropin. However, in patients with suspected adrenal insufficiency, this test can be dangerous because it may precipitate an addisonian crisis. The rapid cosyntropin stimulation test has generally replaced the metyrapone test.
Another test for differentiating primary from secondary or tertiary adrenal insufficiency is a prolonged cosyntropin-stimulation (Rose) test. After baseline plasma cortisol and 24-hour urinary 17-OHCS levels are established, 250 micrograms of cosyntropin is infused continuously over 48 hours. Plasma cortisol and 24-hour urinary 17-OHCS are then remeasured on the second day of the infusion, and a final plasma cortisol level is determined as the infusion is completed (5). In primary adrenal insufficiency, no change is seen in cortisol or 17-OHCS concentrations. In secondary or tertiary adrenal insufficiency, an incremental increase occurs over the course of the infusion. This implies that the cortex has undergone atrophy because of insufficient corticotropin stimulation. However, with longer stimulation, the cortex is capable of functioning.
Once a decision has been made as to whether adrenal insufficiency is primary, secondary, or tertiary, the appropriate imaging study should be used to rule out other treatable causes. Computed tomography (CT) scanning is preferred for study of the adrenal glands for primary disease, and magnetic resonance imaging (MRI) is best for studies of the hypothalamus and pituitary glands for secondary and tertiary disease.
Hypercortisolism
Cushing's syndrome is defined as any chronic increase in glucocorticoid activity. By far the most common cause is prolonged use of glucocorticoid agents for treatment of chronic inflammatory diseases (eg, rheumatoid arthritis) or after organ transplantation. Other possible causes include pituitary adenomas (Cushing's disease), adrenal adenomas or carcinomas, and ectopic production of corticotropin-releasing hormone or corticotropin. Use of corticosteroids or chronic use of inhaled corticosteroids or corticosteroid creams must also be considered.
As with adrenal insufficiency, Cushing's syndrome may be elusive, and a high level of suspicion is needed. Symptoms can include worsening obesity, new-onset hypertension, skin changes (eg, easy bruising, striae), poor wound healing, facial plethora, hirsutism, acne, muscle weakness and wasting, peripheral edema, and neuropsychiatric changes (eg, depression, mania).
Cushing's syndrome can be classified as corticotropin-dependent or corticotropin-independent (table 1). Corticotropin-dependent Cushing's syndrome is further classified as caused by pituitary adenoma (Cushing's disease) or by ectopic production of corticotropin or corticotropin-releasing hormone. Corticotropin may be produced ectopically by malignancy (ie, lung carcinoma, renal-cell carcinoma), as is the case in about 80% of patients, or by other tumors, such as carcinoid tumors in the lung, pancreas, or thymus (1,6).
Table 1. Causes of Cushing's syndrome
Corticotropin-dependent
Pituitary adenoma (Cushing's disease)
Ectopic corticotropin production from carcinoma (eg, lung, breast, renal-cell)
Ectopic corticotropin-releasing hormone production from carcinoid tumors (eg, chest, thymus)
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Corticotropin-independent
Adrenal adenoma
Adrenal carcinoma
Micronodular dysplasia
Macronodular hyperplasia
Iatrogenic causes
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Corticotropin-independent Cushing's syndrome is caused by autonomous production of cortisol. Possible sources include adrenal adenomas, adrenal carcinomas, primary pigmented nodular adrenal dysplasia (micronodular dysplasia), macronodular hyperplasia, and other, relatively rare, disorders.
Screening tests
The first step in evaluating Cushing's syndrome is to determine whether hypercortisolism is present. The most convenient screening procedure is the overnight dexamethasone suppression test, in which 1 mg of dexamethasone is given orally at bedtime (usually between 10 and 11 pm). A fasting blood sample is drawn when the patient arises the next morning (preferably by 8 am), and cortisol is measured. The fasting plasma cortisol level should be less than 5 micrograms/dL, although some authorities believe that a level of less than 3 micrograms/dL is more sensitive and specific (7). A level greater than 5 micrograms/dL warrants further testing.
A 24-hour urine collection for urinary free cortisol is also an excellent screening test. High-performance liquid chromatography enhances conventional protein-binding assays and also increases sensitivity and specificity (7). False-negative results may occur because of inadequate collection, daily fluctuations in cortisol levels, or abnormalities caused by other medications the patient may be using. Therefore, at least three samples should be obtained. If all three samples show normal cortisol levels, Cushing's syndrome can be ruled out. If any of the three values is abnormal, further testing is warranted (6,8).
If either the overnight dexamethasone suppression test or any of the 24-hour urine evaluations are abnormal, false-positive results and pseudo-Cushing's syndrome need to be considered. Traditionally, a low-dose (2 mg/day) dexamethasone test has been used. High-dose (8 mg/day) dexamethasone suppression is used to distinguish Cushing's disease (pituitary) from other causes of Cushing's syndrome (table 2).
Table 2. Low-dose followed by high-dose dexamethasone suppression test
Day 1
Obtain baseline plasma cortisol and corticotropin values
Begin baseline 24-hr urine collection for free cortisol and 17-OHCS
Day 2 (low-dose dexamethasone suppression)
Complete baseline 24-hr urine collection
Start dexamethasone, 0.5 mg orally every 6 hr
Day 3
Continue dexamethasone, 0.5 mg orally every 6 hr
Begin second 24-hr urine collection for free cortisol and 17-OHCS
Day 4 (high-dose dexamethasone suppression)
Measure plasma cortisol
Complete second 24-hr urine collection
Begin dexamethasone, 2 mg orally every 6 hr
Day 5
Continue with dexamethasone, 2 mg orally every 6 hr
Begin third 24-hr urine collection for free cortisol and 17-OHCS
Day 6
Complete third 24-hr urine collection
Measure plasma cortisol and corticotropin
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17-OHCS, 17-hydroxycorticosteroids.
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For the low-dose dexamethasone suppression test, baseline plasma cortisol and corticotropin levels are measured and a 24-hour urine collection is made on day 1 to establish free cortisol and 17-OHCS levels. Beginning on day 2, after the urine collection is completed, 0.5 mg of dexamethasone is given orally every 6 hours for 8 doses (2 days). On day 3, a second 24-hour urine sample is collected, and free cortisol and 17-OHCS values are measured again. The high-dose dexamethasone suppression test starts on day 4. After the second 24-hour urine collection is completed, the dexamethasone dose is increased to 2 mg orally every 6 hours for 8 doses (2 days). On day 5, dexamethasone is continued and a third 24-hour urine collection is begun. Finally, on day 6, plasma cortisol and corticotropin are measured again. The third 24-hour urine sample can be held, pending the results of the second 24-hour sample, and urine cortisol and 17-OHCS levels can be determined if results of the second 24-hour urine study were abnormal.
In patients who have normal cortisol metabolism and those with pseudo-Cushing's syndrome, the second 24-hour urine collection (low-dose dexamethasone suppression) shows urinary free cortisol levels of less than 4 mg per 24 hours, and the plasma cortisol level is less than 3 micrograms/dL. The high-dose dexamethasone test is then used to distinguish Cushing's disease from other causes of Cushing's syndrome. In Cushing's disease, the third 24-hour urine collection shows a 90% decrease in cortisol from baseline and a 64% decrease in 17-OHCS (8-10). Lesser degrees of suppression indicate nonpituitary-dependent Cushing's syndrome (eg, adrenal adenoma or carcinoma, ectopic corticotropin production).
Administration of low- and high-dose dexamethasone to suppress cortisol production is cumbersome and may be difficult to complete properly. A high-dose overnight dexamethasone suppression test is simpler and may prove equally effective. With this test, baseline plasma cortisol and corticotropin levels are obtained from the fasting patient (by 8 am), 8 mg of dexamethasone is given orally at bedtime, and cortisol levels are remeasured the next morning. In patients with Cushing's disease, the follow-up cortisol values usually decrease by 50% from the baseline (8). The high-dose overnight test has been favorably compared with the standard high-dose dexamethasone suppression test (9). Some tumors (ie, carcinoids) cause some degree of suppression on dexamethasone testing.
Another test using synthetic corticotropin-releasing hormone may be able to differentiate Cushing's disease from other causes of Cushing's syndrome. In Cushing's disease, there is a paradoxical increase in the level of corticotropin after administration of corticotropin-releasing hormone. However, considerable overlap is seen among patients with normal levels and those with Cushing's syndrome. Therefore, this test should not be used routinely. Corticotropin levels should be measured by immunoradiometric assay, which has greater specificity and sensitivity, although this assay cannot detect an unusual type of corticotropin (ie, "big" corticotropin), which may also have biologic activity (8).
Scanning techniques
Appropriate radiologic and nuclear medicine studies should be used as directed by the biochemical studies. MRI of the pituitary, with and without gadolinium, is superior to CT scanning. Nonetheless, between 40% and 50% of pituitary tumors are missed by MRI in patients with Cushing's disease (6,8). CT scanning is preferred for viewing the adrenal glands and chest. However, adrenal CT scans must be interpreted cautiously, since 2% to 15% of patients have nonfunctioning adenomas (incidentalomas) (6,11). Iodo-seleno-cholesterol scans are used to evaluate synthetic function within the adrenal gland. Octreotide scans are used to localize ectopic corticotropin-producing tumors (carcinoids), many of which have somatostatin receptors (6).
When Cushing's disease is confirmed, inferior petrosal sinus sampling may help localize the cause. The inferior petrosal sinuses are selectively and simultaneously catheterized, and baseline blood samples for corticotropin are simultaneously obtained from both sinuses as well as peripherally. Corticotropin-releasing hormone (100 micrograms or 1 microgram/kg of body weight) is injected, and blood samples for corticotropin are drawn from the sinuses and peripherally at 2, 3, 5, and 10 minutes. Ratios are established between inferior petrosal sinus levels and peripheral corticotropin levels. A ratio greater than 2.0 is consistent with Cushing's disease. An interpetrosal gradient (eg, right versus left) greater than 1.2 after corticotropin-releasing hormone injection predicts the location of a lesion in 70% to 80% of patients (6,8,9). However, the procedure may be complicated by cavernous sinus thrombosis, infection, hemorrhage, and brainstem ischemia (8,9,12). Because of its complexity and risk for complications, inferior petrosal sinus sampling should be performed only in centers with considerable expertise.
Summary
The rapid cosyntropin stimulation test offers a simple means for detecting adrenal insufficiency. In contrast, assessment of suspected hypercortisolism (Cushing's syndrome) is difficult because cortisol levels fluctuate with intermittent release of corticotropin from the pituitary or from tumors. Also, a number of medications affect cortisol levels, leading to false-positive or false-negative results. The classic low-dose followed by high-dose dexamethasone test is cumbersome, and other, simpler studies, such as the overnight high-dose dexamethasone suppression test, may prove more practical and cost-effective. With both high and low levels of adrenal glucocorticoids, awareness and early recognition of the symptoms are important. An endocrinologist should be consulted when the overnight dexamethasone suppression test or the 24-hour urine cortisol collection is abnormal or if clinical suspicion is high despite normal results on screening tests.
References
Orth DN, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW, et al, eds. Williams textbook of endocrinology. 8th ed. Philadelphia: Saunders, 1992:489-619
Federman DD. The adrenal. In: Dale DC, Federman DD. Scientific American medicine. New York: Scientific American, 1995:1-18
Davenport J, Kellerman C, Reiss D, et al. Addison's disease. Am Fam Physician 1991;43(4):1338-42
Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72(4):773-8
Rose LI, Williams GH, Jagger PI, et al. The 48-hour adrenocorticotrophin infusion test for adrenocortical insufficiency. Ann Intern Med 1970;73(1):49-54
Hough FS. Diagnosis of Cushing's syndrome. S Afr Med J 1996;86(8 Suppl):1022-5
Lin CL, Wu TJ, Machacek DA, et al. Urinary free cortisol and cortisone determined by high performance liquid chromatography in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1997;82(1):151-5
Findling JW, Doppman JL. Biochemical and radiologic diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am 1994;23(3):511-37
Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med 1990;112(6):434-44
Flack MR, Oldfield EH, Cutler GB Jr, et al. Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann Intern Med 1992;116(3):211-7
Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990;323(20):1401-5
Oliverio PJ, Monsein LH, Wand GS, et al. Bilateral simultaneous cavernous sinus sampling using corticotropin-releasing hormone in the evaluation of Cushing disease. Am J Neuroradiol 1996;17(9):1669-74
--------------------------------------------------------------------------------
Dr Hasinski is assistant professor of medicine, division of endocrinology and metabolism, Allegheny University of the Health Sciences, Hahnemann Division, Philadelphia. Correspondence: Stefan Hasinski, MD, Division of Endocrinology and Metabolism, Allegheny University/Hahnemann Division, 230 N Broad St, Mail Stop 426, Philadelphia, PA 19102.
Assessment of adrenal glucocorticoid function
Which tests are appropriate for screening?
Stefan Hasinski, MD
VOL 104 / NO 7 / JULY 1998 / POSTGRADUATE MEDICINE
This is the second of three articles on on endocrine disorders
Preview: Overproduction or underproduction of adrenal hormones raises sticky diagnostic problems for primary care physicians. Fortunately, assessment of hypoadrenalism has been greatly simplified. On the other hand, evaluation of patients with suspected hyperadrenalism (Cushing's syndrome) can be difficult, confusing, and frustrating. Dr Hasinski reviews the options for testing these critical adrenal functions and provides up-to-date information on interpreting test outcomes and pursuing a diagnosis.
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The adrenal glands, the two small pyramidal structures on the superior pole of the kidneys that weigh just 4 g each, can raise diagnostic havoc when their functions go awry. A quick review of these glands seems appropriate in explaining how to assess whether or not they are responsible for a number of symptoms.
Adrenal function
About 90% of the adrenal gland tissue consists of adrenal cortex, which has three distinct zones: the glomerulosa, or outer layer, which produces aldosterone; the fasciculata, or middle layer, which makes glucocorticoid precursors and cortisol; and the reticularis, or inner layer, which synthesizes adrenal androgens (1,2).
Cortisol synthesis originates with cholesterol, about 80% of which is delivered to the adrenal glands by low-density lipoprotein (LDL) cholesterol. The number of LDL receptors is increased when the adrenal glands are stimulated by corticotropin (ACTH). The remaining cholesterol is made through hydroxymethylglutaryl coenzyme A reductase activity, which is not controlled by corticotropin. Cholesterol is modified by a series of enzymes of the P-450 system to produce cortisol.
The production of cortisol is regulated tightly by the hypothalamus and the pituitary gland, with classic feedback inhibition. Corticotropin-releasing hormone is released from the parvicellular division of the hypothalamic paraventricular nucleus. Binding of corticotropin-releasing hormone induces production of pro-opiomelanocortin, which is then cleaved into various fragments, including melanocyte-stimulating hormones, beta-lipotropins, beta-endorphins, and corticotropin.
Corticotropin, a 39-amino-acid hormone, is released from the anterior pituitary and enters the systemic circulation. Once bound to the adrenal cortex, corticotropin induces cortisol synthesis and secretion. Cortisol binds to receptors in the hypothalamus and pituitary to inhibit the release of corticotropin-releasing hormone and corticotropin, respectively.
Cortisol secreted by the adrenal cortex is transported mainly bound to plasma proteins, specifically corticosteroid-binding globulin (transcortin), but also albumin and sex hormone-binding globulin (1,2). Between 90% and 97% of cortisol is bound to proteins (1). It is only the "free fraction," or nonprotein-bound hormone, that is available to bind to specific tissue receptors. Cortisol metabolism occurs mainly in the liver, and products of cortisol metabolism can be detected in the urine as 17-hydroxycorticosteroids (17-OHCS) (2).
Adrenal insufficiency
The diagnosis of adrenal insufficiency is relatively straightforward. The chief difficulties are recognizing the constellation of symptoms and maintaining a high index of suspicion.
Adrenal insufficiency can be primary, secondary, or tertiary, depending on the location of the lesion. Primary adrenal insufficiency, or Addison's disease, is due to adrenal gland failure. In the past, the most common cause was tuberculosis (2), but now it is autoimmune adrenalitis, which may be isolated or part of a generalized autoimmune disorder. Other causes include metastatic disease (most commonly from lung and breast carcinomas), hemorrhage, infection, rare familial disorders (eg, adrenoleukodystrophy, adrenomyeloneuropathy), and HIV-related disease (1-3).
Symptoms of primary adrenal insufficiency include weakness, abdominal pain, nausea, weight loss, hypotension or shock, lack of libido, loss of body hair in women, hyperpigmentation, and psychiatric changes. Laboratory findings may include hyponatremia, hyperkalemia, mild acidosis, hypoglycemia, and hypercalcemia.
In secondary adrenal insufficiency, release of corticotropin from the pituitary is impaired. In tertiary adrenal insufficiency, release of corticotropin-releasing hormone from the hypothalamus is insufficient. Symptoms of secondary and tertiary adrenal insufficiency may be identical to those of primary disease, except that hyperpigmentation does not occur in the secondary or tertiary form because of insufficient production of corticotropin and other products of pro-opiomelanocortin metabolism (ie, melanocyte-stimulating hormones). Aldosterone, the potent adrenal mineralocorticoid hormone, is controlled mainly by potassium and the renin-angiotensin system and is therefore only minimally affected by a lack of corticotropin.
Screening tests
The best screening test for evaluating adrenal glucocorticoid function involves rapid stimulation with cosyntropin (Cortrosyn), a synthetic analogue of corticotropin. After baseline plasma cortisol and aldosterone levels are measured, 250 micrograms of cosyntropin is given as an intravenous bolus or an intramuscular injection. Plasma cortisol and aldosterone levels are measured again 30 to 60 minutes later. The blood samples for aldosterone can be held until the results of the cortisol response are known. If the cortisol response is insufficient, the aldosterone levels can help localize the deficiency.
A baseline cortisol level of greater than 18 micrograms/dL is consistent with normal adrenal function (2). However, opinions differ as to how to interpret test results (1-3). I prefer to use a cortisol level that increases twofold over baseline and rises above 20 micrograms/dL as an indication of normal adrenal function. This standard considers both baseline and reserve adrenal function. The baseline corticotropin level can help differentiate primary from secondary or tertiary hypoadrenalism but must be interpreted cautiously because corticotropin release from the pituitary varies throughout the day. A newer and possibly more sensitive test uses 1 microgram of cosyntropin to evaluate the cortisol response, which should be the same as with the cosyntropin 250 micrograms test (4). The aldosterone response in a cosyntropin test is blunted or absent in patients with primary adrenal insufficiency. In secondary or tertiary adrenal insufficiency, aldosterone response is normal (an increase of two times baseline) because the renin-angiotensin axis is not affected by decreased corticotropin.
A corticotropin-releasing hormone stimulation test can be used to differentiate secondary (pituitary) from tertiary (hypothalamic) disease, although this test is seldom necessary. In the past, the central axis was assessed with a metyrapone (Metopirone) test. Metyrapone inhibits cortisol synthesis, which results in release of corticotropin-releasing hormone and corticotropin. However, in patients with suspected adrenal insufficiency, this test can be dangerous because it may precipitate an addisonian crisis. The rapid cosyntropin stimulation test has generally replaced the metyrapone test.
Another test for differentiating primary from secondary or tertiary adrenal insufficiency is a prolonged cosyntropin-stimulation (Rose) test. After baseline plasma cortisol and 24-hour urinary 17-OHCS levels are established, 250 micrograms of cosyntropin is infused continuously over 48 hours. Plasma cortisol and 24-hour urinary 17-OHCS are then remeasured on the second day of the infusion, and a final plasma cortisol level is determined as the infusion is completed (5). In primary adrenal insufficiency, no change is seen in cortisol or 17-OHCS concentrations. In secondary or tertiary adrenal insufficiency, an incremental increase occurs over the course of the infusion. This implies that the cortex has undergone atrophy because of insufficient corticotropin stimulation. However, with longer stimulation, the cortex is capable of functioning.
Once a decision has been made as to whether adrenal insufficiency is primary, secondary, or tertiary, the appropriate imaging study should be used to rule out other treatable causes. Computed tomography (CT) scanning is preferred for study of the adrenal glands for primary disease, and magnetic resonance imaging (MRI) is best for studies of the hypothalamus and pituitary glands for secondary and tertiary disease.
Hypercortisolism
Cushing's syndrome is defined as any chronic increase in glucocorticoid activity. By far the most common cause is prolonged use of glucocorticoid agents for treatment of chronic inflammatory diseases (eg, rheumatoid arthritis) or after organ transplantation. Other possible causes include pituitary adenomas (Cushing's disease), adrenal adenomas or carcinomas, and ectopic production of corticotropin-releasing hormone or corticotropin. Use of corticosteroids or chronic use of inhaled corticosteroids or corticosteroid creams must also be considered.
As with adrenal insufficiency, Cushing's syndrome may be elusive, and a high level of suspicion is needed. Symptoms can include worsening obesity, new-onset hypertension, skin changes (eg, easy bruising, striae), poor wound healing, facial plethora, hirsutism, acne, muscle weakness and wasting, peripheral edema, and neuropsychiatric changes (eg, depression, mania).
Cushing's syndrome can be classified as corticotropin-dependent or corticotropin-independent (table 1). Corticotropin-dependent Cushing's syndrome is further classified as caused by pituitary adenoma (Cushing's disease) or by ectopic production of corticotropin or corticotropin-releasing hormone. Corticotropin may be produced ectopically by malignancy (ie, lung carcinoma, renal-cell carcinoma), as is the case in about 80% of patients, or by other tumors, such as carcinoid tumors in the lung, pancreas, or thymus (1,6).
Table 1. Causes of Cushing's syndrome
Corticotropin-dependent
Pituitary adenoma (Cushing's disease)
Ectopic corticotropin production from carcinoma (eg, lung, breast, renal-cell)
Ectopic corticotropin-releasing hormone production from carcinoid tumors (eg, chest, thymus)
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Corticotropin-independent
Adrenal adenoma
Adrenal carcinoma
Micronodular dysplasia
Macronodular hyperplasia
Iatrogenic causes
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Corticotropin-independent Cushing's syndrome is caused by autonomous production of cortisol. Possible sources include adrenal adenomas, adrenal carcinomas, primary pigmented nodular adrenal dysplasia (micronodular dysplasia), macronodular hyperplasia, and other, relatively rare, disorders.
Screening tests
The first step in evaluating Cushing's syndrome is to determine whether hypercortisolism is present. The most convenient screening procedure is the overnight dexamethasone suppression test, in which 1 mg of dexamethasone is given orally at bedtime (usually between 10 and 11 pm). A fasting blood sample is drawn when the patient arises the next morning (preferably by 8 am), and cortisol is measured. The fasting plasma cortisol level should be less than 5 micrograms/dL, although some authorities believe that a level of less than 3 micrograms/dL is more sensitive and specific (7). A level greater than 5 micrograms/dL warrants further testing.
A 24-hour urine collection for urinary free cortisol is also an excellent screening test. High-performance liquid chromatography enhances conventional protein-binding assays and also increases sensitivity and specificity (7). False-negative results may occur because of inadequate collection, daily fluctuations in cortisol levels, or abnormalities caused by other medications the patient may be using. Therefore, at least three samples should be obtained. If all three samples show normal cortisol levels, Cushing's syndrome can be ruled out. If any of the three values is abnormal, further testing is warranted (6,8).
If either the overnight dexamethasone suppression test or any of the 24-hour urine evaluations are abnormal, false-positive results and pseudo-Cushing's syndrome need to be considered. Traditionally, a low-dose (2 mg/day) dexamethasone test has been used. High-dose (8 mg/day) dexamethasone suppression is used to distinguish Cushing's disease (pituitary) from other causes of Cushing's syndrome (table 2).
Table 2. Low-dose followed by high-dose dexamethasone suppression test
Day 1
Obtain baseline plasma cortisol and corticotropin values
Begin baseline 24-hr urine collection for free cortisol and 17-OHCS
Day 2 (low-dose dexamethasone suppression)
Complete baseline 24-hr urine collection
Start dexamethasone, 0.5 mg orally every 6 hr
Day 3
Continue dexamethasone, 0.5 mg orally every 6 hr
Begin second 24-hr urine collection for free cortisol and 17-OHCS
Day 4 (high-dose dexamethasone suppression)
Measure plasma cortisol
Complete second 24-hr urine collection
Begin dexamethasone, 2 mg orally every 6 hr
Day 5
Continue with dexamethasone, 2 mg orally every 6 hr
Begin third 24-hr urine collection for free cortisol and 17-OHCS
Day 6
Complete third 24-hr urine collection
Measure plasma cortisol and corticotropin
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17-OHCS, 17-hydroxycorticosteroids.
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For the low-dose dexamethasone suppression test, baseline plasma cortisol and corticotropin levels are measured and a 24-hour urine collection is made on day 1 to establish free cortisol and 17-OHCS levels. Beginning on day 2, after the urine collection is completed, 0.5 mg of dexamethasone is given orally every 6 hours for 8 doses (2 days). On day 3, a second 24-hour urine sample is collected, and free cortisol and 17-OHCS values are measured again. The high-dose dexamethasone suppression test starts on day 4. After the second 24-hour urine collection is completed, the dexamethasone dose is increased to 2 mg orally every 6 hours for 8 doses (2 days). On day 5, dexamethasone is continued and a third 24-hour urine collection is begun. Finally, on day 6, plasma cortisol and corticotropin are measured again. The third 24-hour urine sample can be held, pending the results of the second 24-hour sample, and urine cortisol and 17-OHCS levels can be determined if results of the second 24-hour urine study were abnormal.
In patients who have normal cortisol metabolism and those with pseudo-Cushing's syndrome, the second 24-hour urine collection (low-dose dexamethasone suppression) shows urinary free cortisol levels of less than 4 mg per 24 hours, and the plasma cortisol level is less than 3 micrograms/dL. The high-dose dexamethasone test is then used to distinguish Cushing's disease from other causes of Cushing's syndrome. In Cushing's disease, the third 24-hour urine collection shows a 90% decrease in cortisol from baseline and a 64% decrease in 17-OHCS (8-10). Lesser degrees of suppression indicate nonpituitary-dependent Cushing's syndrome (eg, adrenal adenoma or carcinoma, ectopic corticotropin production).
Administration of low- and high-dose dexamethasone to suppress cortisol production is cumbersome and may be difficult to complete properly. A high-dose overnight dexamethasone suppression test is simpler and may prove equally effective. With this test, baseline plasma cortisol and corticotropin levels are obtained from the fasting patient (by 8 am), 8 mg of dexamethasone is given orally at bedtime, and cortisol levels are remeasured the next morning. In patients with Cushing's disease, the follow-up cortisol values usually decrease by 50% from the baseline (8). The high-dose overnight test has been favorably compared with the standard high-dose dexamethasone suppression test (9). Some tumors (ie, carcinoids) cause some degree of suppression on dexamethasone testing.
Another test using synthetic corticotropin-releasing hormone may be able to differentiate Cushing's disease from other causes of Cushing's syndrome. In Cushing's disease, there is a paradoxical increase in the level of corticotropin after administration of corticotropin-releasing hormone. However, considerable overlap is seen among patients with normal levels and those with Cushing's syndrome. Therefore, this test should not be used routinely. Corticotropin levels should be measured by immunoradiometric assay, which has greater specificity and sensitivity, although this assay cannot detect an unusual type of corticotropin (ie, "big" corticotropin), which may also have biologic activity (8).
Scanning techniques
Appropriate radiologic and nuclear medicine studies should be used as directed by the biochemical studies. MRI of the pituitary, with and without gadolinium, is superior to CT scanning. Nonetheless, between 40% and 50% of pituitary tumors are missed by MRI in patients with Cushing's disease (6,8). CT scanning is preferred for viewing the adrenal glands and chest. However, adrenal CT scans must be interpreted cautiously, since 2% to 15% of patients have nonfunctioning adenomas (incidentalomas) (6,11). Iodo-seleno-cholesterol scans are used to evaluate synthetic function within the adrenal gland. Octreotide scans are used to localize ectopic corticotropin-producing tumors (carcinoids), many of which have somatostatin receptors (6).
When Cushing's disease is confirmed, inferior petrosal sinus sampling may help localize the cause. The inferior petrosal sinuses are selectively and simultaneously catheterized, and baseline blood samples for corticotropin are simultaneously obtained from both sinuses as well as peripherally. Corticotropin-releasing hormone (100 micrograms or 1 microgram/kg of body weight) is injected, and blood samples for corticotropin are drawn from the sinuses and peripherally at 2, 3, 5, and 10 minutes. Ratios are established between inferior petrosal sinus levels and peripheral corticotropin levels. A ratio greater than 2.0 is consistent with Cushing's disease. An interpetrosal gradient (eg, right versus left) greater than 1.2 after corticotropin-releasing hormone injection predicts the location of a lesion in 70% to 80% of patients (6,8,9). However, the procedure may be complicated by cavernous sinus thrombosis, infection, hemorrhage, and brainstem ischemia (8,9,12). Because of its complexity and risk for complications, inferior petrosal sinus sampling should be performed only in centers with considerable expertise.
Summary
The rapid cosyntropin stimulation test offers a simple means for detecting adrenal insufficiency. In contrast, assessment of suspected hypercortisolism (Cushing's syndrome) is difficult because cortisol levels fluctuate with intermittent release of corticotropin from the pituitary or from tumors. Also, a number of medications affect cortisol levels, leading to false-positive or false-negative results. The classic low-dose followed by high-dose dexamethasone test is cumbersome, and other, simpler studies, such as the overnight high-dose dexamethasone suppression test, may prove more practical and cost-effective. With both high and low levels of adrenal glucocorticoids, awareness and early recognition of the symptoms are important. An endocrinologist should be consulted when the overnight dexamethasone suppression test or the 24-hour urine cortisol collection is abnormal or if clinical suspicion is high despite normal results on screening tests.
References
Orth DN, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW, et al, eds. Williams textbook of endocrinology. 8th ed. Philadelphia: Saunders, 1992:489-619
Federman DD. The adrenal. In: Dale DC, Federman DD. Scientific American medicine. New York: Scientific American, 1995:1-18
Davenport J, Kellerman C, Reiss D, et al. Addison's disease. Am Fam Physician 1991;43(4):1338-42
Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72(4):773-8
Rose LI, Williams GH, Jagger PI, et al. The 48-hour adrenocorticotrophin infusion test for adrenocortical insufficiency. Ann Intern Med 1970;73(1):49-54
Hough FS. Diagnosis of Cushing's syndrome. S Afr Med J 1996;86(8 Suppl):1022-5
Lin CL, Wu TJ, Machacek DA, et al. Urinary free cortisol and cortisone determined by high performance liquid chromatography in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1997;82(1):151-5
Findling JW, Doppman JL. Biochemical and radiologic diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am 1994;23(3):511-37
Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med 1990;112(6):434-44
Flack MR, Oldfield EH, Cutler GB Jr, et al. Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann Intern Med 1992;116(3):211-7
Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990;323(20):1401-5
Oliverio PJ, Monsein LH, Wand GS, et al. Bilateral simultaneous cavernous sinus sampling using corticotropin-releasing hormone in the evaluation of Cushing disease. Am J Neuroradiol 1996;17(9):1669-74
--------------------------------------------------------------------------------
Dr Hasinski is assistant professor of medicine, division of endocrinology and metabolism, Allegheny University of the Health Sciences, Hahnemann Division, Philadelphia. Correspondence: Stefan Hasinski, MD, Division of Endocrinology and Metabolism, Allegheny University/Hahnemann Division, 230 N Broad St, Mail Stop 426, Philadelphia, PA 19102.
Legenden1999
New Member
SPE, thanks for the articles!
JH
JH
Another good reference is "Safe Uses of Cortisol". Written by William McK. Jefferies, this is the reference used by progressive practitioners in the treatment of non Addison's adrenal insufficiency. His work is the source of that AM cortisol value being near or over 30 and the cortisol doubling after ACTH stimulation. He also treated many patients with low dose hydrocortisone.
Testing labs have no credibility with me. I have no idea who they are using for their sample population and the state of health of same. Those so-called healthy subjects may well be declared healthy, yet they have the same issues we discuss here. For example, I have yet to see that perfectly vital and virile man with the total T of 190ng/dl.
Testing labs have no credibility with me. I have no idea who they are using for their sample population and the state of health of same. Those so-called healthy subjects may well be declared healthy, yet they have the same issues we discuss here. For example, I have yet to see that perfectly vital and virile man with the total T of 190ng/dl.
Another good reference is "Safe Uses of Cortisol". Written by William McK. Jefferies, this is the reference used by progressive practitioners in the treatment of non Addison's adrenal insufficiency. His work is the source of that AM cortisol value being near or over 30 and the cortisol doubling after ACTH stimulation. He also treated many patients with low dose hydrocortisone.
Testing labs have no credibility with me. I have no idea who they are using for their sample population and the state of health of same. Those so-called healthy subjects may well be declared healthy, yet they have the same issues we discuss here. For example, I have yet to see that perfectly vital and virile man with the total T of 190ng/dl.
Testing labs have no credibility with me. I have no idea who they are using for their sample population and the state of health of same. Those so-called healthy subjects may well be declared healthy, yet they have the same issues we discuss here. For example, I have yet to see that perfectly vital and virile man with the total T of 190ng/dl.
marianco
Doctor of Medicine
love_en said:
I agree. Jefferies' book is the bible for the use of Cortisol.
marianco said:
I am curious to know, why is this not required reading for doctors of internal medicine and endocrinologists? The knowledge presented in this book is important to anyone interested in optimal function of the body. It has been said by many that cortisol is the hormone of life and death.
marianco
Doctor of Medicine
Adrenal Glands
The problem of adrenal dysfunction is that is mimics so many other illnesses. Each specialist then looks at the symptoms from their point of view - completely missing the underlying dysfunction of the adrenal glands - attributing the symptoms to an illness they understand instead in their field. For example, when a person complains about joint pain, an internist may think about arthritis. When a person complains about sexual dysfunction, the primary care physician may think about hypogonadism at best, Viagra at most, not about adrenal fatigue (look at how many people on this board post their testosterone and estrogen levels but have no progesterone, DHEA, or cortisol levels done). When a person has anxiety, mood swings, depressed mood, insomnia, irritability, lack of energy, impaired concentration, the usual psychiatrist sees an anxiety or depressive disorder, completely missing adrenal fatigue. The endocrine tests, except for thyroid hormone, are rarely if at all routinely done by psychiatrists (amazingly since textbooks always talk about how depression and anxiety are linked to hypothalamic-pituitary-adrenal axis dysfunction). Often, when a person has chronic fatigue, internists do not think about adrenal fatigue - given how it is not recognized as an illness by endocrinologists.
Endocrinologists haven't helped because they have limited their specialty to only the extremes of endocrine illnesses (e.g. Adrenal dysfunction = Addison's Disease and Cushing's Disorder). I think the problem for Endocrinologists is that they do not link hormonal dysfunction to the function of other systems. For example, they have no idea how hormones affect the brain since their knowledge about the brain stops at the hypothalamus.
Only by practicing integrative medicine - where the physician practices a fusion of specialties - does the physician see the forest before the trees - i.e. see how everything is hooked together in function.
In a way, the problem of conventional medicine is that too many practitioners stay within the box of their own specialty - never linking with ideas from other specialties to form a whole or global concept of functioning and illness. For example, psychiatrists often cannot accept an endocrine or immune system explanation of mental illness because it is thought to be "outside" the brain and is thus a physical rather than mental illness. To me, mental illnesses always have a physical component. This is a very different point of view of what mental illness is.
Another problem is that "Integrative Medicine" practitioners do not integrate knowledge of system functioning. Rather, they integrate conventional medicine with alternative medicine treatments - herbal medicines, various forms of meditation/physical therapy, etc.
From my point of view, I integrate sociology, psychology, psychiatry, neurology, endocrinology, and immunology because the nervous system, endocrine system, and immune system are really one integrated information processing system who's function is to adapt to external and internal stresses in order to promote survival of the organism (i.e. one's individual identity and functioning - where identity can even extend to the notion of family and societal group).
In order to see the forest before the trees, one also has to have both depth and breadth of knowledge. That is actually difficult to achieve. One has to understand things from the atomic, organic chemistry, biochemistry level to organ system functioning, to the functioning of the individual in society. That is a huge area to cover. One of my friends, who is an assistant professor of psychiatry at a major medical school told me that if what I do is taught to medical residents, it would extend psychiatry residency by several years.
Remember that Jeffries only has depth of knowledge in cortisol and adrenal function. How much knowledge does he have about pancreatic, thyroid, gonadal hormone function? How does he tie it in together with brain function? As one of my attending physicians told me - "If you only talk about what you know, you will look like a genius."
Family practice has a chance to do integrative medicine that recognizes endocrine relationships such as adrenal fatigue. The problem is that manage care has warped the field by allowing only 6 minutes per patient visit in order to break even.
The field which has the best chance of doing integrative medicine is the Anti-Aging medicine field. An Anti-Aging doctor recognizes hormone imbalances easily because it is built-in in the field. Unfortunately, because some of its prominent practitioners use questionable science, I don't think it will become an officially sanctioned board-certified specialty. This is too bad because conventional medicine practitioners will only look at the field as "voodoo medicine", with suspicion. In this way, the anti-aging doctors have only hurt their field. The anti-aging doctors also tend to advertise the anti-aging way as a way to make a lot of money - rather than trying to spread the knowledge into conventional medicine.
Conventional medicine is slowly realizing hormone relationships - slowly. I see the growth in knowledge in practitioners. It is excruciatingly slow in coming however. This is why I think it won't become part of normal practice for at least 15-20 years. As an example of how psychiatry is slowly recognizing adrenal dysfunction in mental illness: the abortion pill, RU486, is in phase 3 trials as a treatment of psychotic depression. RU486 is a cortisol-receptor blocker and progesterone-receptor blocker. By blocking cortisol, it can reduce an overactive adrenal gland as a cause of psychotic depression. The adrenal gland is hardly mentioned, however. Just the blocked cortisol. Adrenal fatigue will still be missed in diagnosis since RU486 will actually make depression due to adrenal fatigue worse. Oh, well. At least it is a step in the right direction.
love_en said:
The problem of adrenal dysfunction is that is mimics so many other illnesses. Each specialist then looks at the symptoms from their point of view - completely missing the underlying dysfunction of the adrenal glands - attributing the symptoms to an illness they understand instead in their field. For example, when a person complains about joint pain, an internist may think about arthritis. When a person complains about sexual dysfunction, the primary care physician may think about hypogonadism at best, Viagra at most, not about adrenal fatigue (look at how many people on this board post their testosterone and estrogen levels but have no progesterone, DHEA, or cortisol levels done). When a person has anxiety, mood swings, depressed mood, insomnia, irritability, lack of energy, impaired concentration, the usual psychiatrist sees an anxiety or depressive disorder, completely missing adrenal fatigue. The endocrine tests, except for thyroid hormone, are rarely if at all routinely done by psychiatrists (amazingly since textbooks always talk about how depression and anxiety are linked to hypothalamic-pituitary-adrenal axis dysfunction). Often, when a person has chronic fatigue, internists do not think about adrenal fatigue - given how it is not recognized as an illness by endocrinologists.
Endocrinologists haven't helped because they have limited their specialty to only the extremes of endocrine illnesses (e.g. Adrenal dysfunction = Addison's Disease and Cushing's Disorder). I think the problem for Endocrinologists is that they do not link hormonal dysfunction to the function of other systems. For example, they have no idea how hormones affect the brain since their knowledge about the brain stops at the hypothalamus.
Only by practicing integrative medicine - where the physician practices a fusion of specialties - does the physician see the forest before the trees - i.e. see how everything is hooked together in function.
In a way, the problem of conventional medicine is that too many practitioners stay within the box of their own specialty - never linking with ideas from other specialties to form a whole or global concept of functioning and illness. For example, psychiatrists often cannot accept an endocrine or immune system explanation of mental illness because it is thought to be "outside" the brain and is thus a physical rather than mental illness. To me, mental illnesses always have a physical component. This is a very different point of view of what mental illness is.
Another problem is that "Integrative Medicine" practitioners do not integrate knowledge of system functioning. Rather, they integrate conventional medicine with alternative medicine treatments - herbal medicines, various forms of meditation/physical therapy, etc.
From my point of view, I integrate sociology, psychology, psychiatry, neurology, endocrinology, and immunology because the nervous system, endocrine system, and immune system are really one integrated information processing system who's function is to adapt to external and internal stresses in order to promote survival of the organism (i.e. one's individual identity and functioning - where identity can even extend to the notion of family and societal group).
In order to see the forest before the trees, one also has to have both depth and breadth of knowledge. That is actually difficult to achieve. One has to understand things from the atomic, organic chemistry, biochemistry level to organ system functioning, to the functioning of the individual in society. That is a huge area to cover. One of my friends, who is an assistant professor of psychiatry at a major medical school told me that if what I do is taught to medical residents, it would extend psychiatry residency by several years.
Remember that Jeffries only has depth of knowledge in cortisol and adrenal function. How much knowledge does he have about pancreatic, thyroid, gonadal hormone function? How does he tie it in together with brain function? As one of my attending physicians told me - "If you only talk about what you know, you will look like a genius."
Family practice has a chance to do integrative medicine that recognizes endocrine relationships such as adrenal fatigue. The problem is that manage care has warped the field by allowing only 6 minutes per patient visit in order to break even.
The field which has the best chance of doing integrative medicine is the Anti-Aging medicine field. An Anti-Aging doctor recognizes hormone imbalances easily because it is built-in in the field. Unfortunately, because some of its prominent practitioners use questionable science, I don't think it will become an officially sanctioned board-certified specialty. This is too bad because conventional medicine practitioners will only look at the field as "voodoo medicine", with suspicion. In this way, the anti-aging doctors have only hurt their field. The anti-aging doctors also tend to advertise the anti-aging way as a way to make a lot of money - rather than trying to spread the knowledge into conventional medicine.
Conventional medicine is slowly realizing hormone relationships - slowly. I see the growth in knowledge in practitioners. It is excruciatingly slow in coming however. This is why I think it won't become part of normal practice for at least 15-20 years. As an example of how psychiatry is slowly recognizing adrenal dysfunction in mental illness: the abortion pill, RU486, is in phase 3 trials as a treatment of psychotic depression. RU486 is a cortisol-receptor blocker and progesterone-receptor blocker. By blocking cortisol, it can reduce an overactive adrenal gland as a cause of psychotic depression. The adrenal gland is hardly mentioned, however. Just the blocked cortisol. Adrenal fatigue will still be missed in diagnosis since RU486 will actually make depression due to adrenal fatigue worse. Oh, well. At least it is a step in the right direction.
I agree with everything you have said. For the very reasons you pointed out, I am extreemly skeptical of ANYONE with the letters of MD or ND after their name. I have said it many times: those integrated and alternative practitioners have zero credibility with me because they do not get to the point. When I walk into a doctor or practitioner's office, my intelligence will be gravely insulted by being offerred strange diets, unproven supplements, drugs to treat symptoms and lastly, unproven diagnostic procedures. What I do expect, is for a doctor to see that my LH, FSH, testosterone and cortisol are low. I am amazed, that given the number of conventional and alternative doctors I have seen since age 7, all of them missed it. My adrenal issues started way before I became hypogonadal. Your list of symptoms for adrenal fatigue described what I have lived with since age 7. The icing on the cake was not going through the lightning bolt of testosterone that most young men get to experience.
marianco
Doctor of Medicine
Re: Adrenal Thread and over-the-counter treatments.
What is interesting is that almost everything needed to treat adrenal fatigue can be obtained over-the-counter, even Cortisol (Hydrocortisone) as a 10 mg per gram (approximately a flat 1/4 teaspoon) skin cream (1% cream for use on rashes and hemorrhoids), and progesterone (as a menopausal skin cream).
love_en said:
What is interesting is that almost everything needed to treat adrenal fatigue can be obtained over-the-counter, even Cortisol (Hydrocortisone) as a 10 mg per gram (approximately a flat 1/4 teaspoon) skin cream (1% cream for use on rashes and hemorrhoids), and progesterone (as a menopausal skin cream).
marianco
Doctor of Medicine
Progesterone, Adrenal Fatigue, etc.
Estradiol and Estrone are made from Testosterone by the Aromatase enzyme. Low estrogen levels in the face of normal testosterone levels may mean low aromatase enzyme activity - e.g. from lack of body fat.
Low brain dopamine activity in the pituitary leads to the release of prolactin from the pituitary. There are many causes of low dopamine activity including low testosterone, antipsychotic medications, medications which increase serotonin, Parkinsonism, ADHD caused by dopamine resistance, etc.
The primary rate limiting step in the production of steroid hormones is the first step - the conversion of cholesterol to pregnenolone by the cytochrome P450scc enzyme. Luteinizing Hormone from the Pituitary increases the activity of cytochrome P450scc enzyme. Insulin increases Luteinizing Hormone's effect on increasing the activity of cytochrome P450scc enzyme.
Even when testosterone level is optimized, when adrenal fatigue exists, one does not feel "right". Libido is impaired. Anxiety, irritability, difficulty dealing with stress, feelings of desperation occur. Difficulty in falling asleep and excessive sleepiness occurs. Lethargy occurs.
Signs of adrenal fatigue include: low normal cortisol, low to low-normal DHEA-s, low to low normal progesterone, low sodium or low potassium, low blood pressure, etc.
Progesterone has important actions including: improving concentration, stabilizing mood, reducing depression and anxiety, increasing energy, increasing serotonin, dopamine, norepinephrine activity, improving thyroid hormone activity, acting as a precursor to cortisol and testosterone, increasing potency of estrogen, increasing bone density, improving blood flow, blocking the production of estrogen from testosterone, blocking the production of dihydrotestosterone (DHT) from testosterone, etc. I think it also plays a role in libido.
It is important to not have excessive progesterone. Excessive progesterone can strengthen estrogen's actions to the point of negating the benefits of progesterone.
Estrogen increases serotonin, norepinephrine, and dopamine in the brain by acting as a monoamine oxidase inhibitor. It increases serotonin primarily. Low estrogen and high estrogen both result symptoms including low libido, depressive and anxiety symptoms, insomnia, etc.
Unless cortisol and DHEA-s are checked with saliva tests, progesterone level is an important clue to the presence of adrenal fatigue. I would check for it.
In regard to libido, mood and wellness problems, adrenal fatigue is a very common cause. Just today, every patient I saw had adrenal fatigue as a primary contributing factor for anxiety, depression, alcoholism, lethargy, obesity, loss of libido, concentration problems, irritability, insomnia, and even a miscarriage.
magic8989 said:
Estradiol and Estrone are made from Testosterone by the Aromatase enzyme. Low estrogen levels in the face of normal testosterone levels may mean low aromatase enzyme activity - e.g. from lack of body fat.
Low brain dopamine activity in the pituitary leads to the release of prolactin from the pituitary. There are many causes of low dopamine activity including low testosterone, antipsychotic medications, medications which increase serotonin, Parkinsonism, ADHD caused by dopamine resistance, etc.
The primary rate limiting step in the production of steroid hormones is the first step - the conversion of cholesterol to pregnenolone by the cytochrome P450scc enzyme. Luteinizing Hormone from the Pituitary increases the activity of cytochrome P450scc enzyme. Insulin increases Luteinizing Hormone's effect on increasing the activity of cytochrome P450scc enzyme.
Even when testosterone level is optimized, when adrenal fatigue exists, one does not feel "right". Libido is impaired. Anxiety, irritability, difficulty dealing with stress, feelings of desperation occur. Difficulty in falling asleep and excessive sleepiness occurs. Lethargy occurs.
Signs of adrenal fatigue include: low normal cortisol, low to low-normal DHEA-s, low to low normal progesterone, low sodium or low potassium, low blood pressure, etc.
Progesterone has important actions including: improving concentration, stabilizing mood, reducing depression and anxiety, increasing energy, increasing serotonin, dopamine, norepinephrine activity, improving thyroid hormone activity, acting as a precursor to cortisol and testosterone, increasing potency of estrogen, increasing bone density, improving blood flow, blocking the production of estrogen from testosterone, blocking the production of dihydrotestosterone (DHT) from testosterone, etc. I think it also plays a role in libido.
It is important to not have excessive progesterone. Excessive progesterone can strengthen estrogen's actions to the point of negating the benefits of progesterone.
Estrogen increases serotonin, norepinephrine, and dopamine in the brain by acting as a monoamine oxidase inhibitor. It increases serotonin primarily. Low estrogen and high estrogen both result symptoms including low libido, depressive and anxiety symptoms, insomnia, etc.
Unless cortisol and DHEA-s are checked with saliva tests, progesterone level is an important clue to the presence of adrenal fatigue. I would check for it.
In regard to libido, mood and wellness problems, adrenal fatigue is a very common cause. Just today, every patient I saw had adrenal fatigue as a primary contributing factor for anxiety, depression, alcoholism, lethargy, obesity, loss of libido, concentration problems, irritability, insomnia, and even a miscarriage.
Re: Adrenal Thread and over-the-counter treatments.
I have read that putting corticosteroids on the skin is not good. Something about it deteriorating the skin. I have tried the 1% hydrocortisone creams. I don't think I am absorbing enough for it to work. Then again, if this were a good method, we would be seeing the equivalent to Androgel to treat Addison's.
marianco said:
I have read that putting corticosteroids on the skin is not good. Something about it deteriorating the skin. I have tried the 1% hydrocortisone creams. I don't think I am absorbing enough for it to work. Then again, if this were a good method, we would be seeing the equivalent to Androgel to treat Addison's.
Re: Progesterone, Adrenal Fatigue, etc.
Marianco, I am curious how much progesterone cream that you prescribe your adrenal fatigue patients that have low progesterone, and what you actually consider low, and what you actually consider to be a good level for 40 year old man. Last I checked my progesterone was 0.6 (0.3-1.2 range). My DHEA is around the top of the range since starting supplementation, and I also take 2-3 Adrenal Extract capsules per day.
marianco said:
Marianco, I am curious how much progesterone cream that you prescribe your adrenal fatigue patients that have low progesterone, and what you actually consider low, and what you actually consider to be a good level for 40 year old man. Last I checked my progesterone was 0.6 (0.3-1.2 range). My DHEA is around the top of the range since starting supplementation, and I also take 2-3 Adrenal Extract capsules per day.
Legenden1999
New Member
Re: Progesterone, Adrenal Fatigue, etc.
Sometimes I see you write DHEA, and sometime I see DHEA-s, what if someone has high DHEA and low-normal DHEA-s ?
Reading http://www.drlam.com/A3R_brief_in_doc_format/adrenal_fatigue.cfm I can see DHEA tells you in what stage you are, but can a high DHEA rule out adrenal fatigue 100% ?
JH
marianco said:
Sometimes I see you write DHEA, and sometime I see DHEA-s, what if someone has high DHEA and low-normal DHEA-s ?
Reading http://www.drlam.com/A3R_brief_in_doc_format/adrenal_fatigue.cfm I can see DHEA tells you in what stage you are, but can a high DHEA rule out adrenal fatigue 100% ?
JH
Dr. Lam is another example of the naturopathic doctor that has a diet and some vitamins to sell you. I cannot imagine living on 2.5 oz of meat per day. I also have a hard time believing that you can get 600 calories from raw vegetables. This is the same semi-vegetarian bullshit that damaged my health in the past. Eat bulky foods that are nutrient and calorie poor, then make up the difference with supplements, no thanks. Dr get to the point! If cortisol and DHEA production are inadequate, replace it. Those testimonials from what appears to be mostly overweight women, are what can happen to anyone when they stop eating processed foods and too much carbohydrates. Hardly a miracle to me.
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