MD Consult Case of the Week

[Guest Rose Marie]

Hey, this was in MD Consult this week as the Case of the Week! Woo Hoo!

 

Case of the Week

November 21, 2002

 

The patient is a 39-year-old woman who presents with complaints of depression, weakness, and weight gain. She has noted feeling depressed for the last several months and reports increased emotional lability. She has also felt tired and weak, and describes increased difficulty in climbing stairs. She feels that because of her depression she has been eating more and has gained 10 lbs. On closer questioning she notes easier bruising and development of "stretch marks" on her abdomen. There is no history of balding, menstrual irregularities, acne, skin pigmentation changes, headaches, visual field changes, polyuria, or known hypertension. She has never been treated with corticosteroids. She currently takes no medications.

 

On physical examination she is an emotionally labile woman, crying frequently.

 

BP 154/88 mm Hg, P 90.

 

Weight 185 lbs, obesity mainly central, with small buffalo hump and supraclavicular fat pads.

 

Skin: thin, many bruises, wide, deep red striae on lower abdomen. Full facies with plethora.

 

Chest: normal.

 

Heart: normal.

 

Abdomen: obese, no palpable masses.

 

Rectal: stool heme negative.

 

Extremities: thin arms and legs.

 

Neurological: visual fields fully intact, proximal muscle weakness noted in legs.

 

Question

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Based on this presentation, a diagnosis of hypercortisolism was suspected. What aspects of the history and physical examination are supportive of this diagnosis?

 

Features of this presentation that support a diagnosis of hypercortisolism include weight gain. Fat often accumulates in the abdomen, the dorsocervical areas, and the face. This leads to the classical "moon facies" and "buffalo hump." This patient also manifests fragile skin with easy bruisability. This also leads to the development of abdominal striae. Muscle wasting is evident leading to proximal muscle weakness and thin extremities. Furthermore, she complains of depression and emotional lability. Additional signs and symptoms of corticosteroid excess can be found by following the link below. These are often quite variable, and clinical presentation by itself is not adequate to diagnose Cushing's syndrome.

 

MANIFESTATIONS OF CUSHING'S SYNDROME

 

INCREASED WEIGHT

 

Obesity - not always present

Central weight distribution

Buffalo hump (dorsocervical fat pad)

Supraclavicular fat pads

Full (moon) facies

SKIN

Thin

Easy bruising

Striae - abdominal, thigh

Hyperpigmentation (with excessive ACTH secretion only)

Facial plethora

MUSCLE WASTING

Proximal muscle weakness

Thin extremities

POOR WOUND HEALING

 

PSYCHIATRIC

Emotional lability

Depression

Psychosis

INCREASED OPPORTUNISTIC INFECTIONS

 

GLUCOSE INTOLERANCE

 

OSTEOPOROSIS

 

CATARACTS

 

RENAL STONES

 

ABDOMINAL MASS - ADRENAL TUMOR ONLY

 

HEADACHE, VISUAL FIELD DEFECTS - PITUITARY MASS ONLY

 

LAB ABNORMALITIES

Hyperglycemia

Granulocytosis, lymphopenia

Eosinopenia

Hypercalcemia

Hypercalciuria

Mineralocorticoid excess (if present)

Hypertension

Hypokalemia

ANDROGEN EXCESS (IF PRESENT)

Acne

Oligo/amenorrhea

Male-pattern baldness

Hirsutism

Virilization

 

Question 2

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Initial laboratory evaluation of this patient included: Na 138 mEq/L, K 3.6 mEq/L, fasting glucose 118 mg/dl, calcium 9.4 mEq/L, albumin 3.2 g/dl, WBC 9,000 with 85% granulocytes and 10% lymphocytes. An 8 AM serum cortisol following an 11 PM dose of 1 mg of dexamethasone was 8 ?g/dl (normal <5), and a 24-hour urine collection contained 320 ?g (normal 5 to 90) of free cortisol (creatinine 1.4 g/24 hr), confirming the diagnosis of hypercortisolism. A baseline 8 AM serum cortisol was 24 ?g/dl (normal 5 to 25), with an adrenocorticotropic hormone (ACTH) level of 34 pg/ml (normal 9 to 52). The morning after the 11 PM administration of 8 mg of dexamethasone, the cortisol fell to 4 ?g/dl. A pituitary MRI was obtained that did not show an obvious adenoma. Computed tomography (CT) scan of the chest and abdomen revealed only diffuse bilateral hyperplasia of the adrenal glands. Because of the initial concern regarding hypercortisolism, the above labs were drawn initially. How do you interpret the laboratory evaluation and radiographic data collected to this point?

 

There are two phases involved in the diagnosis of Cushing's syndrome. The first is to demonstrate the presence of an excess of corticosteroids, and the second is to determine the etiology of the Cushing's syndrome in order to decide on therapy. Diagnosis is often complicated and may involve protracted testing.

 

For the diagnosis of hypercortisolism, random cortisol or ACTH levels are of little use in the diagnosis of hypercortisolism because of the pulsatile nature of their secretion. The simplest test to perform is the low-dose overnight dexamethasone suppression test, where 1 mg of dexamethasone is taken orally at 11 PM and the serum cortisol is checked at 8 AM the next morning. A value of less than 5 ?g/dl suggests normal adrenal function with approximately 98% accuracy, but up to 15% of normals may not suppress adequately. Non-suppression suggests the presence of Cushing's syndrome. A 24-hour collection of urine for free cortisol is more specific, although undercollection of urine may critically affect the results. (A 24-hour urine creatinine should also be performed to help exclude this.) A normal value is 5 to 90 ?g/dl for an adult, while most patients with Cushing's will be greater than 250. Patients with values between 90 and 250 can be further screened by looking for the loss of diurnal rhythm in cortisol secretion that occurs in Cushing's. Four blood samples are taken every half hour between 7 and 8:30 AM and then again between 4 and 5:30 PM. The mean of the afternoon samples should be approximately half of the morning value.

 

Once hypercortisolism has been established, it is useful to draw a morning serum ACTH to divide the Cushing's into ACTH-independent (undetectable to low) or ACTH-dependent (normal to elevated). A normal value is from 9 to 52 pg/ml. A useful classification of Cushing's syndrome breaks down the causes into ACTH-dependent and ACTH-independent [Table 1]. The classic dexamethasone suppression test is also a useful way of initially evaluating Cushing's syndrome; however, to be done correctly requires patient hospitalization for at least 3 days. Recent data indicate that the high-dose overnight suppression test provides equivalent information in a simpler manner. A baseline 8 am serum cortisol is obtained, the patient takes 8 mg of dexamethasone at 11 pm, and another serum cortisol is obtained the following morning at 8 am. Patients with pituitary adenomas should suppress to less than 50% of their baseline values, while those with adrenal tumors or ectopic ACTH secretion should not suppress.

 

Table 1. Differential Diagnosis of Cushing's Syndrome and Frequency

(Frequency Excludes Iatrogenic Patients)

 

ACTH-dependent Frequency ? ACTH-independent Frequency

Pituitary adenoma 60% Adrenal carcinoma 15%

Ectopic secretion of ACTH 15% Adrenal adenoma 10%

Ectopic secretion of CRH Very rare Micronodular adrenal disease Very rare

?Iatrogenic Common

?Factitious Rare ?

 

 

Performing both the high-dose overnight dexamethasone suppression test and obtaining an ACTH level once hypercortisolism is demonstrated is recommended. Patients with adrenal tumors or nodular disease should have low to undetectable levels of ACTH and not suppress to high-dose dexamethasone. An abdominal CT scan should be obtained next in this group. Patients with Cushing's disease should have normal to elevated levels of ACTH and should suppress. A pituitary MRI scan should be performed to document an adenoma. Patients with ectopic ACTH secretion should have normal to very elevated levels of ACTH and should not suppress to the dexamethasone. A chest and abdominal CT scan should be done next to attempt to document the source of the ACTH.

 

Link not available. Laboratory and Radiographic Evaluation Link was to these Journal Articles and textbooks

 

Textbook

Tests of Adrenocortical Function

Goldman: Cecil Textbook of Medicine, 21st ed.

Copyright ? 2000 W. B. Saunders Company ?

 

Journal Articles

Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome.

Papanicolaou DA - J Clin Endocrinol Metab - 01-Oct-2002; 87(10): 4515-21

From NIH/NLM MEDLINE ?

 

Diagnosis and differential diagnosis of Cushing's syndrome.

Findling JW - Endocrinol Metab Clin North Am - 01-Sep-2001; 30(3): 729-47

From NIH/NLM MEDLINE ?

 

The desmopressin test in the differential diagnosis between Cushing's disease and pseudo-Cushing states.

Moro M - J Clin Endocrinol Metab - 01-Oct-2000; 85(10): 3569-74

From NIH/NLM MEDLINE ?

 

Computed tomography appearance of the thymus and anterior mediastinum in active Cushing's syndrome.

Hanson JA - J Clin Endocrinol Metab - 01-Feb-1999; 84(2): 602-5

From NIH/NLM MEDLINE ?

I have these articles. If you would like a copy, msg me -rm

 

Question 3

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Lack of suppression of cortisol production with the 1 mg dexamethasone test and suppression of cortisol production with the 8 mg dexamethasone test suggest Cushing's disease as the etiology of the hypercortisolism. What is the difference between Cushing's disease and Cushing's syndrome and what is the differential diagnosis of hypercortisolism?

 

This case illustrates a classic presentation of Cushing's disease and underlines the frequent complexity involved in determining the etiology of hypercortisolism. The syndrome of hypercortisolism is named after Harvey Cushing who first published a description of "the consequences of hyperadrenalism" in 1910. Cushing's disease refers specifically to those patients with ACTH-producing pituitary tumors, while Cushing's syndrome includes all patients showing the effects of elevated corticosteroids. Patients with Cushing's syndrome may also overexpress other adrenal steroids such as aldosterone or androgens. ACTH-secreting pituitary adenomas are the most common form of Cushing's syndrome (if the very common iatrogenic cause is excluded). These are typically microadenomas that occur predominantly (80% to 90%) in women. Macroadenomas may occur and cause mass effects (headache, optic nerve compression, pituitary stalk compression, and hypopituitarism). On the opposite end of the spectrum, there are cases in which excessive ACTH can be shown to be coming from the pituitary gland. Pituitary surgery apparently cures the problem, yet no adenoma can be documented by pathology. These cases are postulated to be secondary to ectopic CRH secretion, primary corticotroph hyperplasia, or intermediate lobe tumors.

 

Excessive ACTH may be secreted from different types of tumors, causing ectopic ACTH-dependent Cushing's syndrome. These are most commonly small-cell lung carcinomas but also include thymic carcinomas, pancreatic carcinomas, pheochromocytomas, and bronchial carcinoids. The ACTH in these cases may be abnormally large ("big" ACTH) or small.

 

Adrenal carcinomas are malignant tumors that are frequently large enough at presentation to be externally palpable. They are also frequently associated with secretion of androgens. Adrenal adenomas are typically smaller than 3 cm at diagnosis and rarely secrete other hormones than corticosteroids. Adrenal incidentalomas (apparently nonfunctioning adrenal adenomas) may occasionally be associated with subtle glucocorticoid excess, which is defined as normal basal levels but failure to suppress after administration of low-dose dexamethasone.

 

Bilateral, apparently ACTH-independent adrenal hypertrophy may also rarely occur. Micronodular adrenal disease typically occurs in younger patients, with the glands often hyperpigmented from accumulation of lipofuscin. This condition may be familial and can occur as part of the Carney complex (with associated cardiac mxyomas, blue nevi, pigmented lentigines, Schwannomas, and testicular tumors). Bilateral macronodular disease also occurs. It is not clear if this condition is truly an ACTH-independent subtype, or whether prolonged ACTH stimulation causes adrenal hypertrophy, which then develops into an autonomous condition where the high levels of corticosteroids suppress further ACTH secretion.

 

Pseudo-Cushing's is a condition found in ethanol abusers, in which clinical manifestations suggestive of Cushing's syndrome are found in association with elevated cortisol levels and abnormal dexamethasone suppression of cortisol. The laboratory abnormalities will resolve, however, with withdrawal from alcohol. Other conditions that may be associated with increased serum cortisol levels are obesity, anorexia nervosa, anxiety, and acute stress. These elevations are transient or mild and without pathologic significance.

 

Follow this link to review the differential diagnosis of hypercortisolism and learn more about the difference between Cushing's disease and Cushing's syndrome.

 

Link not avaliable Follow this link to review the differential diagnosis of hypercortisolism and learn more about the difference between Cushing's disease and Cushing's syndrome. Goldman: Cecil Textbook of Medicine, 21st ed.

 

Question 4

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What is the underlying physiology of the hypothalamic-pituitary-adrenal axis?

 

In the normal state, the hypothalamus and pituitary regulate the secretion of corticosteroids by the adrenals. Hypothalamic release of CRH (which is increased by stress) causes the anterior pituitary to release ACTH, which in turn stimulates the adrenals to synthesize and secrete corticosteroids of which cortisol is the most important. The effects of cortisol are diverse and complex, and are primarily catabolic and insulin-antagonistic. Cortisol functions through binding to nuclear receptors regulating gene expression. Excessive levels of corticosteroids will normally inhibit CRH and ACTH release by negative feedback. Normal release of ACTH and cortisol is both pulsatile and diurnal, with the highest cortisol levels occurring in the early morning. Pathologic hypersecretion of corticosteroids may be induced by excessive ACTH secretion with resultant bilateral adrenal hyperplasia, or autonomous adrenal secretion, in which case ACTH levels will be suppressed.

?

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Link not available to: Wilson: Williams Textbook of Endocrinology, 9th ed. Review the functions of the hypothalamus and pituitary gland.

 

Question 5

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Unfortunately, imaging studies do not always confirm the results of the laboratory evaluation. When equivocal, what are additional tests used to provide further diagnostic information?

 

The patient was then sent for inferior petrosal sinus sampling, where simultaneous sinus and peripheral blood ACTH levels were obtained before and after administration of corticotropin releasing hormone (CRH). Generally, the most problematic cases will be in differentiating pituitary from ectopic ACTH sources, especially from bronchial carcinoids that may suppress to high-dose dexamethasone. Sampling of blood from the bilateral inferior petrosal sinuses should reveal an increased sinus:peripheral ratio of ACTH in Cushing's disease (>1.7). This test is more accurate if CRH stimulation is performed simultaneously, although CRH is only available experimentally at this time. Inferior petrosal sinus sampling may also help to lateralize a pituitary adenoma.

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Link not availableWhat additional tests would you order for this patient?

Reference was to these Journal Articles

 

Bilateral inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome: a comparison with other diagnostic tests.

Wiggam MI - J Clin Endocrinol Metab - 01-Apr-2000; 85(4): 1525-32

From NIH/NLM MEDLINE ?

 

Newer diagnostic techniques and problems in Cushing's disease.

Findling JW - Endocrinol Metab Clin North Am - 01-Mar-1999; 28(1): 191-210

From NIH/NLM MEDLINE ?

 

The hypoplastic inferior petrosal sinus: a potential source of false-negative results in petrosal sampling for Cushing's disease.

Doppman JL - J Clin Endocrinol Metab - 01-Feb-1999; 84(2): 533-40

From NIH/NLM MEDLINE ?

I have these articles, if you would like a copy, msg me - rm

 

Question 6

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What is the appropriate treatment for this patient?

 

Treatment of choice of Cushing's disease is a transsphenoidal adenectomy, leaving the remainder of the pituitary intact and functional postoperatively. Remission rates approach 90% if the adenoma can be localized. Complications include cerebrospinal fluid (CSF) leakage, meningitis, damage to optic or extraocular nerves, diabetes insipidus, and hypopituitarism. Radiation therapy (either internal or external) may be used for macroadenomas or recurrent disease. Full effects of the radiation therapy may take up to 9 months to occur, and the patient will need to be managed medically initially. Hypopituitarism is common following radiation. Bilateral adrenalectomy will cure the hypercortisolism but results in symptomatic growth of the pituitary adenoma (Nelson's syndrome) in up to 40% of cases, and for that reason has been largely supplanted by pituitary surgery. Ectopic ACTH secretion should be treated by excision of the primary tumor. If the tumor is unresectable or cannot be localized, medical management will be required. Adrenal adenomas should be curable by unilateral adrenalectomy. Adrenal carcinomas are frequently impossible to completely resect, and mean survival is only 10 to 14 months following diagnosis. If residual disease is present, the adrenolytic agent O,P-DDD is usually given, although side effects are significant, and there is debate whether survival or quality of life is improved.

 

All forms of Cushing's syndrome will result in suppression of the hypothalamic-pituitary-adrenal axis. Even if this is left intact following curative surgical therapy, full recovery often will not occur for 9 to 15 months, and patients will require temporary corticosteroid replacement therapy. Recovery may be monitored by measuring an early morning cortisol level before the morning replacement dose is taken.

 

Medical management of Cushing's is often only partially successful, although there have been reports of spontaneous remission of Cushing's disease with only medical therapy. There are several agents that inhibit various enzymes in the adrenal synthetic pathway including ketoconazole, metyrapone, trilostane, and aminoglutethamide. The adrenolytic agent O,P-DDD has already been mentioned. Octreotide may be of benefit in Cushing's disease and ectopic ACTH secretion. Valproate and cyproheptadine may occasionally be useful in Cushing's disease.

 

Links not available Learn more about the treatment of Cushing's disease.

Reference was to these Journal Articles

Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome.

Vella A - J Clin Endocrinol Metab - 01-Apr-2001; 86(4): 1596-9

From NIH/NLM MEDLINE ?

 

The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing's disease.

Estrada J - J Clin Endocrinol Metab - 01-Dec-2001; 86(12): 5695-9

From NIH/NLM MEDLINE ?

?

Apparently complete restoration of normal daily adrenocorticotropin, cortisol, growth hormone, and prolactin secretory dynamics in adults with Cushing's disease after clinically successful transsphenoidal adenomectomy.

Veldman RG - J Clin Endocrinol Metab - 01-Nov-2000; 85(11): 4039-46

From NIH/NLM MEDLINE ?

 

Medical therapy for Cushing's disease.

Sonino N - Endocrinol Metab Clin North Am - 01-Mar-1999; 28(1): 211-22

From NIH/NLM MEDLINE ?

I have these articles, just msg me -rm

 

Case Summary

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An increased sinus:peripheral ACTH ratio supported the pituitary as the source of the ACTH. A transsphenoidal exploration of the pituitary was performed, where a 3-mm adenoma was found and removed. Following surgery, the patient's cortisol levels dropped quickly, and she was placed on replacement hydrocortisone that was gradually tapered off over 9 months. There was no recurrence of hypercortisolism, and pituitary function remained intact.

 

Bibliography

Please note that these are all Journal Articles. I can obtain them - just msg me -rm

?

Atkinson AB. The treatment of Cushing's syndrome. Clin Endocrinol 1991;34:507.

Flack MR, Oldfield EH, Cutler GB, et al. Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann Intern Med 1992;116:211.

Grua JR, Nelson DH. ACTH-producing pituitary tumors. Endocrinol Metab Clin North Am 1991;20:319.

Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med 1990;112:434.

Limper AH, Carpenter PC, Scheithauer B, et al. The Cushing syndrome induced by bronchial carcinoid tumors. Ann Intern Med 1992;117:209.

Loriaux DL. Cushing's syndrome. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. Philadelphia, PA: JB Lippincott; 1990.

Stewart PM, Penn R, Gibson R, et al. Hypothalamic abnormalities in patients with pituitary-dependent Cushing's syndrome. Clin Endocrinol 1992;36:453.

 

This Case History is from Diagnostic Strategies for Internal Medicine: A Case-Based Approach

Charles J. Grodzin, Stephen C. Schwartz and Roger C. Bone.

Copyright ? 1996 by Mosby-Yearbook, Inc. ?

 

Wow - We got a case study on MD Consult

:exclaim: ?:exclaim: ?:exclaim: ?:exclaim: ?:exclaim: ?:exclaim:

[Guest Rose Marie]

Here is a link to Up To Date from the Endocrine Society regarding Cushings. This document has hyperlinks to pictures:

 

Clinical manifestations of Cushing's syndrome

http://www.cushings-support.com/cgi-bin....rd.cgi?

[Guest cushiecookie]

Rose Marie,  Thank You for this wonderful article. I think it would be great in the notebook. Then all members would have a copy. It is so wonderful how everyone is doing so much for this organization. Again I "THANK YOU"        

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