Review Article: NMJ: Volume 1/ Issue 1/ January-March 2012

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1 Review Article: NMJ: Volume 1/ Issue 1/ January-March 2012 State of the art: Cushing s syndrome Dr Pradeep PV Associate Professor, Dept of Endocrine Surgery, Narayana Medical College, Nellore, AP, India. E mail: pradeepputhenveetil@gmail.com Introduction: The diagnosis, differential diagnosis, and treatment of Cushing s syndrome (hypercortisolism) are challenging problems in endocrine surgery. The Cushing s phenotypes seen in some obese and alcoholics can make the accurate diagnosis difficult. An accurate, but simple screening test is vital if one is to find the relatively unusual patient with true endogenous Cushing s syndrome. Once the diagnosis is made, the accurate differentiation of Cushing s syndrome into its subtypes is essential so that the appropriate treatment option can be selected. Literature review has shown Cushing s syndrome as a diagnostic and treatment dilemma (1-7).The aim of this review is to focus on major issues confronting the endocrinologist and endocrine surgeon while considering the diagnosis, differential diagnosis, and treatment of Cushing s syndrome. In this review a Socratic approach is used in which the questions addressing the most critical clinical problems associated with Cushing s syndrome will be followed by a focused answer to each question. Question 1: Who should be screened? Screening is recommended for a) Weight gain with redistribution of adipose mass centrally (face, neck, trunk and abdomen). The rate at which the weight is gained can vary. Supraclavicular and temporal fossa fullness warrants a screening test for Cushing s syndrome b) Associated clinical features like thinning of the skin with easy bruising, abdominal striae (usually in younger patients), poor wound healing, immune suppression (opportunistic and fungal infections), rib fractures, hirsutism in women, acne, and muscle wasting leading to proximal muscle weakness. Decreased growth velocity in children (8,9). Mood changes including mania, anxiety, and cognitive dysfunction can also be found (10,11). In its extreme, psychosis and suicidal tendencies can occur. Diagnostic testing for spontaneous Cushing s syndrome should also be considered c) In adrenal incidentalomas (> 2 cm) up to 9% of patients have evidence of hypercortisolism. d) Poorly controlled diabetics: 2-5% prevalence of unsuspected Cushing s syndrome is described (12,27) e) 3% of patients with osteoporosis have mild hypercortisolism (13). f) Clinical features of polycystic ovary syndrome (PCOS) may overlap with those of hypercortisolism (14) Question2: What are the usual symptoms and signs of Cushing s syndrome? Cushing s syndrome has a wide range of signs involving all most all systems of the body (15). Fig 1A depicts one such case. A) Physical Signs: Moon Facies, Buffalo hump, Supraclavicular fat pads, Central obesity with increased adipose tissue in peritoneum and mediastinum. (Waist to hip ratio > 1 in men and >0.8 in women). B) Skin changes: Facial plethora, Violaceous striae with a width of more than 1cm, which is thin, non pruritic and distributed over abdomen, upper thigh, lower back, upper arms and breasts, Ecchymosis, purpura, skin atrophy and exposure of subcutaneous vascular

2 markings, Hirsutism, male type balding, increased lanugo facial hair, steroid acne (pustular), Acanthosis nigricans especially over axilla, elbow, neck and breasts. Skin pigmentation is more common in Ectopic ACTH secretion. C) Cardiovascular: Hypertension: Seen in 70-80%. Usually mild to moderate. Cortisol has intrinsic minerallocorticoid activity which leads to hypertension, hypokalemia, fluid and water retention D) Peptic ulceration E) Other Endocrine and Metabolic manifestations: a) Hypothyroidism: Is due to inhibition of TRH and 5 deiodinase which converts T4 to T3.Central hypothyroidism may persist for 3 months after the surgery. b) Galactorrhea c) Polyuria/ nocturia of Diabetes Insipidus d) Menstrual irregularities due to inhibition of pulsatile LH, FSH and LHRH secretion. e) Diabetes Mellitus (DM) due to increased hepatic glycogen and glucose production and decreased peripheral utilization % has DM. f) Increased synthesis of HDL, LDL, and triglycerides g) Hypokalemic metabolic alkalosis in severe cases. F) Skeletal/ Muscular manifestations: Proximal muscle weakness, Osteoporosis, pathological fractures, kyphosis, height loss, avascular necrosis can occur % experience pathological fractures. Steroids have direct effect on osteoblasts, their number and function decrease. It decreases calcium absorption from gut. G) Neuropsychological: Depression, Emotional lability, Visual defects : Bitemporal hemianopia H) Coagulopathy: Cortisol stimulates synthesis of several clotting factors like fibrinogen by liver, vwf, and also synthesis of plasminogen inhibitor. Fig 1: 8 year old child with adrenal Cushing s syndrome before and 6 months after adrenalectomy Question 3: How should patients be screened? Tests chosen have an adequate sensitivity and specificity, ease of use, and reasonable cost. 1) Late-night/midnight serum or salivary cortisol. One of the earliest biochemical abnormalities in Cushing s syndrome of any cause is the failure to fully suppress plasma cortisol at or near its late-night circadian nadir (4). Obtaining a stress-free, sleeping midnight blood sample for serum cortisol sample is not feasible under all but the most controlled clinical environments (16-19). Morning cortisol levels are not elevated in many patients with Cushing s syndrome, whereas late-night cortisol is usually increased (20). Hypertension, advanced age, and psychiatric diagnoses that may lead to falsepositive late-night salivary cortisol results (21). Salivary cortisol has a sensitivity and specificity of >90-95%, is now available at many reference laboratories (22). Salivary cortisol correlates with free serum cortisol. It is stable for 1 week at room temperature. Salivary Cortisol > 4.3nmol/L is diagnostic. In hospitalized sleeping Cushing s patient mid night cortisol value of less than 1.8micogram% has high sensitivity but lacks specificity. Cut off of 7.5 microgram% has 100% specificity. Value of less than 1.8micogram% has high sensitivity but lacks specificity. Cut off of 7.5 microgram% has 100% specificity. 2. Urine free cortisol (UFC) and low-dose dexamethasone suppression testing (LDDST):

3 Although, late-night or midnight assessment of cortisol appears to be the most sensitive and specific screening test, UFC and LDDST are still used for screening endogenous hypercortisolism. UFC measures only free cortisol unlike serum cortisol which measures total cortisol & is influenced by CBG levels. Ideally three 24 hr samples are to be checked. Four fold increases from basal levels are diagnostic. Renal function should be normal for correct interpretation of the test. A GFR of > 30ml/hr is essential. Normal UFC is < 50 micrograms/24 hrs. The sensitivity of UFC for Cushing s syndrome is 45%-71% at 100% specificity (17, 18, 23, 24). Although UFC may be useful to confirm Cushing s syndrome, its sensitivity and specificity are not optimal as an initial screening test (3). LDDST: The cut-off for serum cortisol in the overnight LDDST test should be <1.8 mcg/dl (1). This will improve the sensitivity to > 95%, but will greatly reduce the specificity. Approximately 8% of patients with Cushing s disease can have false negative results (serum cortisol <2.0 mcg/dl). The three commonly performed diagnostic studies for Cushing s syndrome ie late-night salivary cortisol, UFC, and LDDST are complementary to each other. In patients with mild or intermittent hypercortisolism, any of these tests may yield normal results and be misleading. Late-night salivary cortisol appears to be the most useful screening test. UFC and LDDST should be performed to provide further confirmation of the diagnosis. Question 4: Can patient with ACTHindependent (adrenal) Cushing s have ACTH levels in normal reference range? Endogenous ACTH-independent Cushing s syndrome is caused by an increased release of cortisol from the adrenal gland. This is not dependent on stimulation by ACTH. Increase cortisol secretion from the adrenal may be due to two causes. The first is autonomous cortisol production due to an adrenal adenoma or carcinoma. Secondly, ACTH-independent increases in cortisol can by secondary to stimulation of the adrenal gland by secretagogues other than ACTH e.g. GIP, catecholamines (25). Regardless of the etiology, ACTH is usually suppressed due to glucocorticoid negative feedback (4). If morning plasma ACTH is suppressed below the reference range, patients should undergo adrenal imaging by CT or MRI (5, 26). It has been shown that a single plasma ACTH at the lower end of the reference range does not exclude adrenal Cushing s, particularly if there is mild or occult disease (27).Therefore, a peripheral CRH test should be performed in patients with Cushing s syndrome whose plasma ACTH is at the low end of the reference range (28,29). Question 5. What is the indication for IPSS sampling? A woman with mild to moderate hypercortisolism, a normal or slightly elevated plasma ACTH, and normokalemia has at least a 95% likelihood of having Cushing s disease. Pituitary imaging with MRI is the initial study required. Unfortunately, 40-50% of corticotroph micro adenomas causing Cushing s syndrome in adults are not visible with this technique (30). It is also important to realize that there is a 10% rate of pituitary incidentalomas in the normal population (31). Presence of an unequivocal pituitary lesion >6 mm with MRI in the patient without clinical features suggesting an ectopic ACTH secreting tumor (2, 32) is sufficient to proceed with pituitary microsurgery Inferior petrosal sinus ACTH sampling with CRH stimulation is the only study having the potential to yield a diagnostic sensitivity and specificity for Cushing s disease higher than its pre-test probability. In the presence of documented hypercortisolism, the presence of pituitary ACTH gradient (dominant IPS:P- ACTH >2.0 in the basal state and/or >3.0 after CRH) yields a diagnostic sensitivity of nearly 100% (33, 34). However, the absence of a pituitary ACTH gradient may reflect a falsenegative result rather than a true occult ectopic ACTH secreting tumor. False-negative results with IPSS have been attributed to technical problems during catheterization as well as anomalous venous drainage. Any patient without a significant pituitary ACTH gradient during IPSS should have samples retrospectively evaluated for a prolactin gradient to ensure that adequate pituitary venous effluent was obtained.

4 Table 1: Work up and interpretation of a case of suspected Cushing s syndrome Tests Adrenal Cushing s Pituitary Cushing s Ectopic Cushing s 11 PM Salivary cortisol ONDST (1mg Dexa) High High High High High High UFC High High High LDDST Non suppressible Non suppressible Non suppressible Other localizing modalities are: a) Somatostatin receptor scintigraphy (SRS) since they express somatostatin receptors; however, these tumors may be quite small and the resolution of SRS is often not adequate (2, 5). b) Positron emission tomography (PET) with 18- flurodeoxyglucose (36) c) Tumor markers such as plasma calcitonin, gastrin, glucagon, or somatostatin may often be elevated in patients with ectopic ACTH syndrome; they are rarely helpful in identifying the source of the neoplasm (2). S ACTH Low Normal/ High Normal/ Very High HDDST (8mg dexa) No suppression Suppression Rare suppression CT/MRI Adrenal MRI pituitary BIPSS Mass present Normal Not applicable Normal/ hyperplasia Tumor (In 60%) Gradient (Pituitary / Peripheral venous) Normal/ hyperplasia Normal No gradient (Pituitary / Peripheral venous) ONDST: Over night dexamethasonesuppression test; UFC: Urinary free cortisol; LDDST : Low dose dexamethasone suppression test; S ACTH: Serum Adrenocorticotropic hormone HDDST: High dose dexamethasone suppression test, BIPSS: Bilateral inferior petrosal sinus sampling Question 6. What are the best approaches to search for an occult ACTH secreting tumor? Extensive imaging for ectopic ACTH secreting tumors without performing IPSS may result in false positive studies and lead to surgical misaduventures. CECT of the thorax and abdomen with has the highest detection rate for an occult ACTH secreting neoplasm. MRI of the chest is helpful in centrally located bronchial carcinoids (35). Fig 2 depicts and ectopic ACTH secreting thymic carcinoids. Fig2: Ectopic ACTH secreting thymic carcinoids Q 7: What are the approaches to adrenal Cushing s syndrome? In a patient with endogenous hypercortisolism (Raised midnight cortisol/ UFC/ non suppressible LDDST) with suppressed ACTH the investigations are directed to the adrenal gland. CECT of both the adrenal glands preferably 3mm cuts is recommended. If the mass is > 6cm consider malignancy. Lipid rich lesions suggest adenomas. Adenomas are usually < 10 HU and carcinomas are >18 HU. More than 60% of contrast is washed out of adenomas in 15 minutes in benign lesions. Q 8: What are the surgical approaches to adrenal Cushing s syndrome? Adrenal Cushing s syndrome can be treated with laparoscopic or open adrenalectomy depending on the indication, the former being the preferred approach (Fig3). Both these approaches can be transperitoneal/ retroperitoneal.

5 Fig 3 Question 9: What is the approach in patients with failed pituitary surgery? Even under the best circumstances, remission rates following trans- sphenoidal pituitary microsurgery range from 42-86% (37). Decrease in S cortisol below 2-3 mcg/dl within hours after surgery indicates clinical and biochemical remission (37, 38, 39). The absence of secondary adrenal insufficiency 4-6 weeks postoperatively suggests failure of pituitary surgery. Even in patients who have clinical and biochemical remission there is a recurrence rate of 5-25% (37). In cases of failed pituitary surgery, the most important treatment goal must be to control the excessive cortisol secretion. This can be achieved by: a) Repeat Pituitary surgery: With recurrent or persistent Cushing s disease, offering a repeat pituitary operation may be a reasonable approach particularly in those with abnormalities on pituitary MRI. b) Pituitary radiation (conventional or gamma knife) Recommended if surgery fails. Remission rates for radiotherapy is % and 76% in patients utilizing gamma knife radiotherapy. With radiotherapy normalization of cortisol secretion takes 12 to 36 months. Side effects of pituitary radiation (40) described are astrocytoma, temporal lobe necrosis, and temporal lobe epilepsy. c) Pharmacological management of Cushing s disease: Adrenostatic therapies, including ketoconazole, metyrapone, and aminoglutethimide, all competitively inhibit adrenal enzyme activity and decrease cortisol secretion (41). Mitotane, a drug often employed in adrenal carcinoma has adrenolytic activity (41). Mifepristone is the first potent glucocorticoid receptor antagonist. Its long half-life and lack of biochemical markers may be associated with significant adrenal insufficiency (42). d) Bilateral adrenalectomy: It is an attractive choice in patients with Cushing s disease who fail pituitary surgery (43). This procedure is well tolerated with very little morbidity and a nearly 100% cure rate in patients with ACTH-dependent hypercortisolism Conclusions: High index of suspicion and accurate use of diagnostic tests are absolutely necessary for suspecting and diagnosing clinical/ subclinical Cushing s syndrome. Knowledge of the hormonal assay techniques and its interpretation is vital to prevent misdiagnosis to prevent surgical misadventure especially in subclinical Cushing s syndrome. Once endogenous hypercortisolism is proved radiological investigations are used to localize the lesion. Steroid replacement in the post operative period is vital for preventing mortality. Replacement has to be continued till the opposite adrenal has recovered which can be demonstrated by appropriate hormonal tests.

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