A Patient Presenting With Features Of Cushing Syndrome - Case Study

A 36-year-old white woman comes to you complaining of fatigue, irritability, depression, and a 30-lb (13.5-kg) weight gain over the last 2 years. She recounts that she has noticed a significant change in her energy level for atleast the last 2 years. She states that she has always been a hard worker but
6 months before she had to quit her job as a waitress because of extreme muscle weakness and fatigue. She has also noted increased mood swings, manifested by increased irritability, spontaneous crying episodes, and depression. She reports that her face seems rounder than it was 2 years before. On further questioning, she admits that her menstrual periods have been irregular for the last 2 years. She has also noted that she bruises easily. She denies any other medical problems, and states that she is not taking any medications. She specifically denies any glucocorticoid therapy.
On asking about her family history, you find out that her mother has adult onset DM.
Patient gives a history of alcohol consumption but denies any smoking.

Physical examination reveals an obese white woman who is crying while she sits on the examining table, but otherwise she does not appear to be very ill.
Her weight is 193 lb (87 kg); height, 5 ft 7 in. (167.5 cm);
BP, 165/100 mm Hg; and heart rate, 86 per minute and regular.
Her face is very round and plethoric compared with that in old photographs. Dorsocervical (buffalo hump) and supraclavicular fat pads are noted. She has mild facial hirsutism, some acne is noted over the face and chest, and wide purple striae are present on the lower abdomen. Her extremities are thin and she has proximal muscle weakness.

The following are the laboratory findings:

• fasting blood glucose, 180 mg/dL;
• potassium, 3 mEq/L; HCO3-, 34 mEq/L; 
• liver function tests, all normal; 
• 8 a.m. cortisol, 38 μg/dL, which decreases to 32 μg/dL after the administration of 1 mg of dexamethasone. 
• The 24-hour UFC level is 876 μg.

1. What is the most likely diagnosis in this patient, and why?
2. What studies would you perform to establish the anatomic cause of her hypercortisolism?
3. What is the role of magnetic resonance imaging (MRI) and computed tomographic (CT) scanning of the pituitary and adrenal glands, as well as inferior petrosal sinus sampling, in patients with Cushing's syndrome?
4. What is the optimal therapeutic approach for this patient?
5. Why is there a need for steroid therapy in the postoperative period, and sometimes beyond, in patients with Cushing's disease?

Answers:


1. What is the most likely diagnosis in this patient, and why?
Having excluded exogenous glucocorticoid medications in the history, the differential diagnosis list would include

•  pituitary corticotroph adenoma or hyperplasia (Cushing's disease), 
•  ectopic ACTH or corticotropin-releasing factor (CRF) syndrome, 
•  adrenal adenoma, 
•  adrenal cancer, 
•  obesity, 
•  depression
• Alcoholism

.The most frequently encountered dilemma in the differential diagnosis of Cushing's syndrome is the clinical picture consisting of an obese and a depressed patient These patients can display many of the phenotypic features and laboratory findings consistent with hypercortisolism, and yet not have Cushing's syndrome.

If a patient has a history of alcohol consumption as well then this could also produce alcoholic pseudo-Cushing's syndrome. In this disorder, the effects of chronic alcoholism result in central obesity (ascites), a round plethoric face, easy bruising, and some abnormal results from the screening tests for Cushing's syndrome.

How ever, this patient has no abnormal liver function findings and she has physical findings (a marked change in her facial appearance compared with that in old photographs, hypertension, dorsocervical and supraclavicular fat pads, purple abdominal striae, acne, and hirsutism) and laboratory data (hyperglycemia, hypokalemia, an elevated basal cortisol level that does not suppress in response to the 1-mg DST, and an elevated 24-hour UFC) that are all highly consistent with the clinical suspicion of hypercortisolism.

The lack of virilization and the relatively slow (>2 years) onset of the clinical symptoms argue against adrenal carcinoma. In addition, the lack of a smoking history and any hyperpigmentation, together with the slow onset, suggest that ectopic ACTH arising from small cell lung carcinoma is unlikely to be the cause.

This leaves pituitary adenoma (or hyperplasia), ectopic ACTH or CRF (from a carcinoid, pancreatic islet cell tumor, medullary thyroid carcinoma, or pheochromocytoma), and adrenal adenoma in the differential diagnosis.

Given that pituitary adenomas constitute 68% of all non iatrogenic causes of hypercortisolism, this is the most likely diagnosis. How ever, further workup is required to document the precise source of the elevated cortisol levels in this patient.

2. What studies would you perform to establish the anatomic cause of her hypercortisolism?
Once the diagnosis of hypercortisolism (Cushing's syndrome) has been confirmed by the findings of the clinical evaluation and screening laboratory tests, the combined use of the following diagnostic techniques can establish the diagnosis in almost all instances:

• determination of a basal plasma ACTH level, 
• a high-dose (8 mg) DST, 
• radiographic imaging, and inferior petrosal sampling (with or without CRF stimulation). 

By simultaneously measuring the plasma cortisol and ACTH levels the possibility of an adrenal adenoma can be assessed because the autonomous production of glucocorticoids by the adrenal adenoma suppresses ACTH to levels below 20 pg/mL.

To differentiate between a pituitary adenoma and the ectopic tumor production of ACTH, several tests need to be performed because many of the laboratory and radiographic results can overlap for these two distinct causes of Cushing's syndrome. For example, the ACTH level can range between 40
and 200 pg/mL in the setting of Cushing's disease and between 100 and 10,000 pg/mL in the setting of ectopic ACTH. In the classic 2-day high-dose DST (2 mg of dexamethasone is given every 6 hours for 2 days, and 24-hour UFC samples are collected the day before and on the second day of
dexamethasone administration), patients with pituitary tumors (Cushing's disease) typically exhibit a suppression to less than 50% of baseline values; those with ectopic ACTH or primary adrenal hypercortisolism display little or no reduction. How ever, some carcinoid tumors that produce ACTH ectopically maintain some degree of negative feedback through the influence of exogenous steroids, and the suppression observed may be equivalent to that seen in patients with pituitary tumors.

The abbreviated high-dose DST involves administering 8 mg of dexamethasone at 11 p.m. the night before and measuring the plasma cortisol level the next morning at 8 a.m. In this test, a suppression below 50% of basal plasma cortisol levels is seen in patients with pituitary tumor, but not in those with ectopic ACTH and primary adrenal cortisolism. This version of the high-dose DST is preferred because it appears to be more specific and does not require two 24-hour urine collections. For a more
precise definition of the cause of the disorder, how ever, specific radiographic procedures must be performed.

3. What is the role of MRI and CT scanning of the pituitary and adrenal glands, as well as inferior petrosal sinus sampling, in patients with Cushing's syndrome?
The major problem with the CT and MRI evaluation of the pituitary and adrenal glands is that they can detect asymptomatic lesions in up to 15% and 8%, respectively, of the normal population. Because of this incidence of nonspecific radiographic “lesions”, the clinician must be cautious about
basing the diagnosis of pituitary or adrenal Cushing's syndrome on the results of these imaging studies.
Pituitary adenomas causing Cushing's disease tend to be small (1 to 5 mm; rarely >10 mm), and are therefore detectable by contrast-enhanced CT scanning in as few as 30% to 35% of cases and by gadolinium–DTPA enhanced MRI in 55% of cases. Therefore, because of its better sensitivity, MRI has replaced CT in the assessment of these tumors. Patients whose imaging studies yield negative findings need to undergo inferior petrosal sampling to further document the pituitary anatomic location of the tumor. In addition, as already discussed, even if an abnormality is detected by these
imaging methods, this does not constitute unequivocal evidence that the abnormality is responsible for the syndrome. As the resolution of CT and MRI improves, the ability to detect these “incidental” and clinically silent microadenomas will also increase and further confound the diagnostic  workup. An ectopic CRF syndrome could also result in an enlarged pituitary due to corticotroph hyperplasia, and yet the primary disorder may actually be a carcinoid of the lung.
CT, MRI, ultrasonography, and isotope scanning with iodocholesterol can be used to define the nature of adrenal lesions. These procedures are not necessary in patients with ACTH hypersecretion, how ever. Nevertheless, some physicians use these tests to exclude the presence of a solitary adrenal adenoma or carcinoma, and thereby confirm the presence of bilateral adrenal hyperplasia or nodular adrenal hyperplasia in the setting of pituitary based disease. These procedures are most useful for localizing adrenal tumors because these tumors must usually be larger than 1.5 cm to cause significant cortisol production and result in Cushing's syndrome. How ever, as noted previously, because of the 1% to 8% incidence of silent adrenal nodules biochemical testing must be performed with localization studies to ensure that the lesion identified is biologically significant.

To distinguish between the various causes of Cushing's syndrome when conflicting or overlapping data are obtained, bilateral simultaneous inferior petrosal venous sampling (with or without CRF stimulation) can successfully distinguish Cushing's disease from ectopic ACTH secretion and adrenal disease with greater accuracy than any other test. Because ACTH is rapidly metabolized (half-life, 7 to 12 minutes) and is secreted episodically, advantage can be taken of the concentration gradient between the pituitary venous drainage through the inferior petrosal sinus (central) and the
peripheral venous values of ACTH to further determine whether an ACTH producing corticotroph adenoma is present in the pituitary; the inclusion of CRF stimulation makes the test more sensitive. Bilateral and simultaneous inferior petrosal sinus samples are obtained to circumvent the problem of
isolated secretory bursts or timing issues if catheters have to be repositioned. Therefore, ACTH samples are obtained from the inferior petrosal sinus, from the jugular bulb, and from other sites (e.g., superior or inferior vena cava), and the findings are compared with those from simultaneously obtained peripheral vein samples. In patients w ith Cushing's disease, the inferior petrosal sinus/peripheral (IPS : P) ratio of ACTH exceeds 2. In patients with ectopic ACTH, the ratio is less than 2 and selective venous sampling (e.g., of the pulmonary, pancreatic, or intestinal
beds) may localize the ectopic tumor. The administration of CRF during bilateral inferior petrosal sinus sampling can increase the diagnostic accuracy of the test by eliciting an ACTH response in the few patients w ith pituitary tumors who do not exhibit a diagnostic IPS : P gradient in the basal samples.

Most patients with Cushing's disease have an IPS : P ratio greater than 3 after CRF stimulation, whereas patients with ectopic ACTH or adrenal disease have an IPS : P ratio of ACTH less than 3 after CRF stimulation. Inferior petrosal sinus sampling (with or without CRF stimulation) has not been extensively studied in the context of healthy people, how ever, and therefore the correct interpretation of the results requires that the patient must be hypercortisolemic at the time of the study so that the response of normal corticotrophs to CRF is suppressed.

4. What is the optimal therapeutic approach for this patient, and why?
Once the tumor has been localized to the pituitary, the next goal is to surgically remove the corticotroph adenoma using the technique of selective transsphenoidal surgery. Because the tumors are small, it requires an experienced neurosurgeon to successfully identify and resect the adenoma.
Meticulous exploration of the intrasellar contents is mandatory, and any identified adenoma is selectively removed, leaving the remaining normal pituitary intact. If the tumor cannot be identified, it is necessary to perform larger pituitary resections and, in some cases, a total hypophysectomy may
be necessary.

Transsphenoidal surgery is successful in approximately 85% of patients with microadenomas (tumor <10 mm), and surgical damage to the normal anterior pituitary is rare.

The major side effects of the procedure include transient diabetes insipidus, cerebrospinal fluid leak, sinusitis, and, rarely, postoperative bleeding.

All patients with Cushing's disease who are successfully treated with transsphenoidal surgery become adrenally insufficient for variable periods of time and must receive replacement doses of glucocorticoids (see question 5 which follows).

The success rates for transsphenoidal surgery drop drastically (15% to 25%) in the setting of large (>10 mm) tumors, locally invasive tumors, tumors not identified at surgery, and corticotroph hyperplasia. In these instances, adjunctive radiation therapy is usually administered. How ever, the major problem with radiation therapy is the lag time (6 to 12 months) for it to take effect and the 10% to 20% incidence of hypopituitarism and visual field deficits, even blindness, that may eventuate.

A newer option is the more precise stereotactic radiosurgery using the gamma knife or photon knife.
Risk of visual complications is largely eliminated, and the risk of pituitary deficiency is reduced.

5. Why is there a need for steroid therapy in the postoperative period and beyond, in patients with Cushing's disease?
The successful surgical removal of the ACTH-producing pituitary microadenoma eliminates the drive for adrenal glucocorticoid production and renders the patient dependent on the remaining normal corticotrophs.
How ever, because these cells have been suppressed for years by the excess cortisol they are dormant. Therefore, those patients w ith Cushing's disease who have been successfully treated experience transient (1 to 18 months) adrenocortical insufficiency and require exogenous glucocorticoid support; in those patients not cured by the surgical procedure, the production of excessive amounts of glucocorticoids continues and they do not depend on an exogenous source of steroids.