Cushing’s syndrome R4 김유진/ Prof. 이상열

Contents Introduction Epidemiology Clinical manifestations Diagnosis Treatment Journal review

Introduction Cushing's syndrome a constellation of clinical features that result from chronic exposure to excess glucocorticoids of any etiology. ACTH-dependent pituitary corticotrope adenoma, ectopic secretion of ACTH by nonpituitary tumor ACTH-independent adrenocortical adenoma, adrenocortical carcinoma, nodular adrenal hyperplasia Iatrogenic administration of exogenous glucocorticoids Cushing's syndrome reflects a constellation of clinical features that result from chronic exposure to excess glucocorticoids of any etiology. The disorder can be ACTH-dependent (e.g., pituitary corticotrope adenoma, ectopic secretion of ACTH by nonpituitary tumor) or ACTH-independent (e.g., adrenocortical adenoma, adrenocortical carcinoma, nodular adrenal hyperplasia), as well as iatrogenic (e.g., administration of exogenous glucocorticoids to treat various inflammatory conditions). The term Cushing's disease refers specifically to Cushing's syndrome caused by a pituitary corticotrope adenoma.

Epidemiology / Causes Cushing's syndrome is generally considered a rare disease. It occurs with an incidence of 1–2 per 100,000 population per year. Cushing's syndrome is generally considered a rare disease. It occurs with an incidence of 1–2 per 100,000 population per year. However, it is debated whether mild cortisol excess may be more prevalent among patients with several features of Cushing's such as centripetal obesity, type 2 diabetes, and osteoporotic vertebral fractures, recognizing that these are relatively nonspecific and common in the population. In the overwhelming majority of patients, Cushing's syndrome is caused by an ACTH-producing corticotrope adenoma of the pituitary (Table 342-1), as initially described by Harvey Cushing in 1912. Cushing's disease more frequently affects women, with the exception of prepubertal cases, where it is more common in boys. By contrast, ectopic ACTH syndrome is more frequently identified in men. Only 10% of patients with Cushing's syndrome have a primary, adrenal cause of their disease (e.g., autonomous cortisol excess independent of ACTH), and most of these patients are women. Overall, the medical use of glucocorticoids for immunosuppression, or for the treatment of inflammatory disorders, is the most common cause of Cushing's syndrome. Williams textbook of endocrinology.—12th ed. P. 504

Clinical manifestations Table 342-2 Signs and Symptoms of Cushing's Syndrome Body Compartment/ System Signs and Symptoms Body fat Weight gain, central obesity, rounded face, fat pad on back of neck ("buffalo hump") Skin Facial plethora, thin and brittle skin, easy bruising, broad and purple stretch marks, acne, hirsutism Bone Osteopenia, osteoporosis (vertebral fractures), decreased linear growth in children Muscle Weakness, proximal myopathy (prominent atrophy of gluteal and upper leg muscles) Cardiovascular system Hypertension, hypokalemia, edema, atherosclerosis Metabolism Glucose intolerance/diabetes, dyslipidemia Reproductive system Decreased libido, in women amenorrhea (due to cortisol-mediated inhibition of gonadotropin release) Central nervous system Irritability, emotional lability, depression, sometimes cognitive defects, in severe cases, paranoid psychosis Blood and immune system Increased susceptibility to infections, increased white blood cell count, eosinopenia, hypercoagulation with increased risk of deep vein thrombosis and pulmonary embolism

Clinical manifestations Figure 15-16 Clinical features of Cushing’s syndrome. A, Centripetal and some generalized obesity and dorsal kyphosis in a 30-year-old woman with Cushing’s disease. B, Same patient as in A, showing moon facies, plethora, hirsutism, and enlarged supraclavicular fat pads. C, Facial rounding, hirsutism, and acne in a 14-year-old girl with Cushing’s disease. D, Central and generalized obesity and moon facies in a 14-year-old boy with Cushing’s disease. E and F, Typical centripetal obesity with livid abdominal striae seen in a 41-year-old woman (E) and a 40-year-old man (F) with Cushing’s syndrome. G, Striae in a 24-year-old patient with congenital adrenal hyperplasia treated with excessive doses of dexamethasone as replacement therapy. H, Typical bruising and thin skin of a patient with Cushing’s syndrome. In this case, the bruising occurred without obvious injury. Williams textbook of endocrinology.—12th ed. P. 501

Clinical manifestations A, Aseptic necrosis of the right humeral head B, Aseptic necrosis of the right femoral head C, Diffuse osteoporosis, vertebral collapse, and subchondral sclerosis D, Rib fracture in a 38-year-old man with Cushing’s disease. Figure 15-17 Bone abnormalities in Cushing’s disease. A, Aseptic necrosis of the right humeral head in a 43-year-old woman with Cushing’s disease of about 8 months’ duration. B, Aseptic necrosis of the right femoral head in a 24-year-old woman with Cushing’s disease of about 41/2 years’ duration. The arrows indicate the crescent subchondral radiolucency, best seen in this lateral view. C, Diffuse osteoporosis, vertebral collapse, and subchondral sclerosis in the same patient as in A D, Rib fracture in a 38-year-old man with Cushing’s disease. (A through C, from Phillips KA, Nance EP Jr, Rodriguez RM, et al. Avascular necrosis of bone: a manifestation of Cushing’s disease. South Med J. 1986;79:825-829.) Bone. In childhood, the most common presentation is with poor linear growth and weight gain149; as discussed earlier, glucocorticoids have profound effects on growth and development.165 Many patients with longstanding Cushing’s syndrome have lost height because of osteoporotic vertebral collapse. This can be assessed by measuring the patient’s sitting height or comparing the height with arm span; in normal subjects, height and arm span should be equal. Pathologic fractures, occurring spontaneously or after minor trauma, are not uncommon. Rib fractures, in contrast to those of the vertebrae, are often painless. The radiographic appearance is typical, with exuberant callus formation at the site of the healing fracture. In addition, osteonecrosis of the femoral and humeral heads is a recognized feature of endogenous Cushing’s syndrome (see Fig. 15-17). Hypercalciuria may lead to renal calculi, but hypercalcemia is not a feature. Williams textbook of endocrinology.—12th ed. P. 501

Diagnosis

Diagnosis – Screening/confirmation 24-h Urine free cortisol excretion increased above normal Overnight dexamethasone suppression test 를 시행하기 어려운 경우 (e.g., in obese or depressed patients) Overnight dexamethasone suppression test (DMST) Plasma cortisol at 8 A.M. >50nmol/L after 1 ㎎ dexamethasone at midnight Low-dose dexamethasone suppression test (DMST) Plasma cortisol >50nmol/L after dexamethasone 0.5㎎ q6h for 48h) → Cushing’s syndrome confirmation urinary free cortisol. Normal values are less than 220 to 330 nmol/24 hours (80 to 120 μg/24 hours), depending on the assay used.

Diagnosis – Differential Dx 1. Plasma ACTH differentiate ACTH-dependent from ACTH-independent causes. Low or undetectable ACTH level [<5 pg/㎖] : adrenal neoplasia High or normal ACTH level [>15pg/㎖] Adrenal hyperplasia secondary to ACTH-prosucing tumor ACTH-secreting pituitary macroadenomas : elevated ACTH ACTH-producing nonendocrine tumors : elevated ACTH (>200pg/㎖ in most patients) Microadenoma or pituitary-hypothalamic dysfunction : ACTH 30-150pg/ ㎖

2. High-dose dexamethsone suppression test (DMST) The response of cortisol output to administration of high-dose dexamethasone (2㎎ every 6h for 2days) Positive : plasma a/o urinary free cortisol is measured at 0 and +48 hours and is greater than 50% suppression of plasma cortisol in comparison to the basal sample (+) : pituitary microadenoma, H-P dysfunction ( - ) : pituitary macroadenoma, ectopic ACTH-producing tumors, adrenal neoplasm, adrenal nodular hyperplasias

3. Metyrapone & CRH infusion test Metyrapone(＋), CRH(＋) : pituitary microadenoma, H-P dysfucntion Metyrapone(±), CRH(＋) : pituitary macroadenoma Metyrapone(－), CRH(－) : adrenal neoplasm, ectopic ACTH- producing tumors 4. Inferior petrosal sinus sampling (IPSS) CRH(100㎍ IV) injection 뒤, baseline, 2, 5, and 10분 후 측정한 ACTH 이용 Petrosal : peripheral ACTH ratio > 2 at baseline Petrosal : peripheral ACTH ratio > 3 at 2-5 min after CRH IV → pituitary ACTH-secreting tumor

Treatment 2. Cushing's disease, 1. ACTH-independent disease, surgical removal of the adrenal tumor 2. Cushing's disease, selective removal of the pituitary corticotrope tumor, usually via a transsphenoidal approach If pituitary disease recurs second surgery, radiotherapy, stereotactic radiosurgery, and bilateral adrenalectomy. Overt Cushing's is associated with a poor prognosis if left untreated. In ACTH-independent disease, treatment consists of surgical removal of the adrenal tumor. For smaller tumors, a minimally invasive approach can be employed, whereas for larger tumors and those suspected of malignancy, an open approach is preferred. In Cushing's disease, the treatment of choice is selective removal of the pituitary corticotrope tumor, usually via a transsphenoidal approach. This results in an initial cure rate of 70–80% when performed by a highly experienced surgeon. However, even after initial remission following surgery, long-term follow-up is important as late relapse occurs in a significant number of patients. If pituitary disease recurs, there are several options, including second surgery, radiotherapy, stereotactic radiosurgery, and bilateral adrenalectomy. These options need to be applied in a highly individualized fashion.

Treatment 4. Metastasized, glucocorticoid-producing carcinomas 3. Very severe, overt Cushing's syndrome medical therapy to rapidly control the cortisol excess during the period leading up to surgery 4. Metastasized, glucocorticoid-producing carcinomas long-term anti glucocorticoid drug treatment. Metyrapone, Ketoconazole, Mitotane 5. Ectopic ACTH syndrome drug treatment or bilateral adrenalectomy In some with very severe, overt Cushing's (e.g., difficult to control hypokalemic hypertension or acute psychosis), it may be necessary to introduce medical therapy to rapidly control the cortisol excess during the period leading up to surgery. Similarly, patients with metastasized, glucocorticoid-producing carcinomas may require long-term anti glucocorticoid drug treatment. In case of ectopic ACTH syndrome, in which the tumor cannot be located, one must carefully weigh whether drug treatment or bilateral adrenalectomy is the most appropriate choice, with the latter facilitating immediate cure but requiring life-long corticosteroid replacement. In this instance, it is paramount to ensure regular imaging follow-up for identification of the ectopic ACTH source.

Treatment - anti glucocorticoid drug Metyrapone inhibits cortisol synthesis at the level of 11-hydroxylase 500 mg/tid for metyrapone (maximum dose, 6 g) Ketoconazole inhibits the early steps of steroidogenesis 200 mg/tid for ketoconazole (maximum dose, 1200 mg) Mitotane a derivative of the insecticide o,p'DDD, an adrenolytic agent adrenocortical carcinoma Oral agents with established efficacy in Cushing's syndrome are metyrapone and ketoconazole. Metyrapone inhibits cortisol synthesis at the level of 11-hydroxylase (Fig. 342-1), whereas the antimycotic drug ketoconazole inhibits the early steps of steroidogenesis. Typical starting doses are 500 mg/tid for metyrapone (maximum dose, 6 g) and 200 mg/tid for ketoconazole (maximum dose, 1200 mg). Mitotane, a derivative of the insecticide o,p'DDD, is an adrenolytic agent that is also effective for reducing cortisol. Because of its side effect profile, it is most commonly used in the context of adrenocortical carcinoma, but low dose treatment (500–1000 mg per day) has also been used in benign Cushing's. In severe cases of cortisol excess, etomidate can be used to lower cortisol. It is administered by continuous IV infusion in low, non anesthetic doses. After the successful removal of an ACTH- or cortisol-producing tumor, the HPA axis will remain suppressed. Thus, hydrocortisone replacement needs to be initiated at the time of surgery and slowly tapered following recovery, to allow physiologic adaptation to normal cortisol levels. Depending on degree and duration of cortisol excess, the HPA axis may require many months or even years to resume normal function.

Journal review We describe a rare case of familial Cushing's disease occurring in a 7-year-old boy, and 19 years of follow up. Our patient first presented soon after his maternal aunt had been treated for Cushing's disease. The clinical presentation was made complicated by the development of an intercurrent eating disorder resembling anorexia nervosa. This resulted in marked weight loss, and even though serum and urinary cortisol levels were elevated, many of the clinical stigmata of Cushing's disease were absent. Eating disorders are relatively uncommon in boys, and in this case there was an organic cause for the abnormal behaviour. This case shows, furthermore, that even the obesity of Cushing's disease can be overcome by the combination of diet and exercise.

The standardized prevalence of obesity was 26. 0%, 29. 2%, and 31 The standardized prevalence of obesity was 26.0%, 29.2%, and 31.3%, in the KNHANES I, II, and III, respectively, and a significant increasing trend was identified (Table 1). However, the prevalence of obesity in the KNHANES IV was 31.1%.

The prevalence of male obesity was 25. 1%, 31. 8%, 34. 7%, and 35 The prevalence of male obesity was 25.1%, 31.8%, 34.7%, and 35.7% in the KNHANES I, II, III, and IV, respectively, and a significant increasing trend was observed (p < 0.001) (Fig. 1A). The prevalence of female obesity was 26.2%, 27.4%, 27.3%, and 25.7% in the KNHANES I, II, III, and IV, respectively, and no significant trend was observed (p = 0.245)

The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder.

The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder.