Cushings

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ACTH levels

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ACTH Levels
The first step in distinguishing the type of Cushing's syndrome is the measurement of ACTH. Patients with ACTH-secreting tumors will either have a normal or elevated level of ACTH. In contrast, patients with adrenal Cushing's will have a subnormal level.

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Late-Night Salivary Cortisol

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Late-night salivary cortisol is emerging as the most sensitive diagnostic test for Cushing's syndrome. Elevated cortisol between 11:00 p.m. and midnight appears to be the earliest detectable abnormality in patients with this disorder. Cortisol secretion is usually very low at this time of the day, but in patients with Cushing's syndrome, the value is virtually always elevated.

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Urine Free Cortisol

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24 hour urine free cortisol has, until recently, been considered the gold standard for the diagnosis of cortisol excess. A 24 hour urine free cortisol level does reflect the cortisol secretion throughout an entire day. Although the majority of patients with Cushing's have elevated levels of urine free cortisol, it is becoming increasingly evident that many patients with mild Cushing's syndrome will actually have normal levels of urine free cortisol. In other words, a normal 24 hour urine free cortisol does not exclude the diagnosis of Cushing's syndrome and additional testing is always needed. In addition, there are many conditions which may increase urine free cortisol that are not Cushing's syndrome, specifically depression, chronic alcoholism, and eating disorders.

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Low-Dose Dexamethasone Suppression Testing

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The low-dose dexamethasone suppression testing has been used for four decades as a diagnostic tool in the evaluation of patients with suspected Cushing's syndrome. Dexamethasone is a synthetic steroid that should suppress the cortisol production in normal subjects to a very low level. Currently, the most widely used test is the administration of a small dose of dexamethasone (1 mg) at 11:00 p.m. followed by a measurement of serum cortisol early the following morning. It is now clear that normal subjects should suppress their cortisol level to a very low level (<1.8 mg/dl). This test using this strict criterion will provide approximately 95-97% sensitivity in the diagnosis of Cushing's syndrome; however, some patients with mild Cushing's syndrome will suppress their serum cortisol to levels even lower than this. This test is still widely employed and certainly can be useful in combination with the other tests previously mentioned.

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Diagnostic tests

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The most appropriate diagnostic approach to patients with suspected Cushing's syndrome is somewhat controversial; however, four diagnostic studies are currently used: late-night salivary cortisol, 24 hour urine free cortisol, low-dose dexamethasone suppression, and the dexamethasone-CRH test. These are summarized in Figure 1. (Print Figure 1 and bring to your doctor.)

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Utah doctor

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Dr. Jack Wahlen
McKay-Dee Hospital
Ogden UT

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Cyclical Cushings

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Yy

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The following are the most common symptoms of Cushing's syndrome. However, each individual may experience symptoms differently. Symptoms may include:

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Upper body obesity

Round face

Increased fat around neck or a fatty hump between the shoulders

Thinning arms and legs

Fragile and thin skin

Stretch marks on abdomen, thighs, buttocks, arms, and breasts

Bone and muscle weakness

Severe fatigue

High blood pressure

High blood sugar

Irritability and anxiety

Excess facial and body hair growth in women

Reduced sex drive and fertility in men

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Surgery for Cushings patients without tumors

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DALLAS — Dec. 11, 2007 — Researchers at UT Southwestern Medical Center have found that patients with a mild form of Cushing syndrome, a metabolic disorder caused by adrenal tumors, demonstrate substantial clinical improvement after adrenalectomy.

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Sub clinical Cushings

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It is more difficult to diagnose subclinical Cushing syndrome because patients’ symptoms are non-specific, such as fatigue, obesity and hypertension. Using the traditional diagnostic tests, patients with subclinical Cushing syndrome rarely have enough cortisol in their urine to raise concern

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Mild Cushings might not show up in urine tests

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They noted that current research has shown that many patients with mild Cushing’s syndrome do not have elevations of urine-free cortisol, “making it a poor screening test for this condition.”

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dexamethasone suppression test

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The low-dose dexamethasone suppression test relies on the concept that the correct dose of dexamethasone will suppress ACTH, and cortisol will release in normal patients while patients with corticotroph adenomas will not suppress below a specified cut off. Raff and Findling noted that because of the significant variability of the biological behavior of corticotroph adenomas, research has shown that neither the overnight 1-mg dexamethasone suppression test nor the two-day low-dose dexamethasone suppression test appears to be reliable using the standard cutoffs for serum cortisol.

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Best test is three tests

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According to Raff and Findling, there is no diagnostic test used in the evaluation of Cushing’s syndrome that performs better than the late night/midnight salivary cortisol method. The concept is based on the fact that patients with mild Cushing’s syndrome fail to decrease cortisol secretion to its nadir at night. However, they still acknowledged that many factors, such as stress, sleep disturbances and psycho-neuroendocrine may falsely elevate nocturnal cortisol secretion.

“Because each of these tests has associated false positives and negatives, a combination of these tests is often necessary for a valid diagnosis,” Katznelson said. “In the end, these tests need to be considered in the context of a history and physical examination that favors this diagnosis.”

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MRIs not conclusive

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A woman with mild hypercortisolism, a normal or slightly elevated plasma ACTH and normokalemia has an approximately 95% likelihood of having Cushing’s disease before any differential diagnostic testing is performed, according to Raff and Findling. In contrast, a male patient with prodigious hypercortisolism of rapid onset, hypokalemia and marked elevations of plasma ACTH may be more likely to have an occult ectopic ACTH-secreting tumor.

About half of patients with ACTH-secreting microadenomas are estimated to have a normal pituitary MRI. In such situations, it is important to perform further testing, particularly an inferior petrosal sinus catheterization, to discern the presence of an ectopic ACTH-producing lesion, according to Katznelson.

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transsphenoidal surgery

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Currently, transsphenoidal surgery is the primary treatment of Cushing’s disease associated with an ACTH-secreting pituitary tumor. According to recent studies, remission rates after transsphenoidal pituitary microsurgery range from 42% to 86%.

Raff told Endocrine Today that the most important treatment recommendation that an endocrinologist makes to a patient with Cushing’s disease is referral to a neurosurgeon with extensive experience.

“Referral to a neurosurgeon who is highly experienced in this procedure is critical,” Katznelson agreed. He noted that there have been studies demonstrating that both the degree of tumor bulk resection and rates of biochemical remission are increased for all types of pituitary tumors when the surgery is performed by a neurosurgeon with extensive experience in endonasal pituitary surgery. “In Cushing’s disease, this is especially true,” Katznelson said. “Because the tumors in this disorder are often small, if not microscopic, the surgical strategy may require dissection through the gland. In inexperienced hands, this may result in higher rates of hypopituitarism and lower rates of biochemical cure,” Katznelson said

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Wilson’s syndrome

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a persistent failure of conversion from T4 to T3

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The causes of clinical hypothyroidism can thus occur at 3 different levels:

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1) the pituitary, 2) the thyroid gland, and 3) the tissues which respond to the glandular hormones. A problem at any level will produce the same end result: low thyroid system activity, and the typical hypothyroid symptoms.

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Reverse T3 and why T4 doesn't convert to T3

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High levels of cortisol prevent the conversion of T4 to T3, and cause the body to produce Reverse T3