내분비대사내과 R3 박유민 /Prof 이상열 MGR review

 Cushing's syndrome reflects a constellation of clinical features that result from chronic exposure to excess glucocorticoid of any etiology  Leading to overproduction of cortisol by the adrenal glands and to the signs and symptoms of hypercortisolism

Harrison’s principles of internal medicine 18 th

 The persistence of cortisol hypersecretion despite suppressed plasma corticotropin levels was considered to be the result of an autonomous process  Adrenocortical adenomas and carcinomas – 18 to 20 percent  Primary pigmented nodular adrenocortical disease (PPNAD), also called bilateral adrenal micronodular hyperplasia – less than 1 percent  Bilateral macronodular adrenal hyperplasia (BMAH) – less than 1 percent

 Uncommon cause of Cushing’s syndrome  Characterized by enlarged adrenal glands containing multiple nonpigmented nodules that are greater than 10 mm in diameter  Cushing’s syndrome, but more often in those with subclinical secretion of cortisol  Between the ages of 40 and 60 years  Other nomenclatures  Corticotropin (ACTH)-independent macronodular adrenal hyperplasia (AIMAH)  Massive macronodular adrenocortical disease (MMAD)  Autonomous macronodular adrenal hyperplasia (AMAH)  ACTH-independent massive bilateral adrenal disease (AIMBAD)  "giant" or "huge" macronodular adrenal disease.

 Generally characterized by ectopic expression of receptors not usually found in the adrenal  Luteinizing hormone/hCG  Vasopressin  Serotonin  Interleukin-1  Gastric inhibitory peptide (GIP)  Beta adrenergic  Alpha 2A adrenergic receptor  Activation of these receptors results in upregulation of PKA signaling with a subsequent increase in cortisol production

Harrison’s principles of internal medicine 18 th

 Specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease.  The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed  The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue  Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens N Engl J Med 2013;369:

 Most cases of BMAH were thought to be sporadic however, there are sev eral reports of familial cases of BMAH  Association with MEN1  ARMC5 (armadillo repeat containing 5 gene)  Histone H3 lysine 79 methyltransferase gene (DOTL1)  Histone deacetylase gene (HDAC9)  Prune homolog 2 gene (PRUNE2) Gs alpha-subunit mutations  PRKACA  MC2R gene  APC  Mutations in the fumarate hydratase gene (FH)  Missense germline mutations in phosphodiesterase 11A isoform 4 gene (PDE11A)

Harrison’s principles of internal medicine 18 th

World J Surg (2008) 32:856–862 AV:PV cortisol gradient greater than 6.5 was consistent with a cortisol- secreting adenoma. A cortisol lateralization ratio of 2.3 or greater was consistent with autonomous cortisol secretion from predominantly 1 adrenal gland

Clinically important persistent glucocorticoid autonomy was not present in any of the 8 patients who had either unilateral or subtotal bilateral adrenalectomy

Harrison’s principles of internal medicine 18 th

 Bilateral adrenalectomy  Post-adrenalectomy, these patients are not at risk for Nelson's syndrome  Unilateral adrenalectomy  Patients with moderately increased cortisol production (less than twofold increase in UFC levels) but with clinical evidence of cortisol excess  Consider adrenal vein sampling  Monitoring without surgery  Patients with subclinical cortisol excess  Clinical evaluation and biochemical assessment (1 mg overnight dexamethasone test, UFC, basal ACTH], fasting glucose) every 6 to 12 months and yearly computed tomography (CT) scan

 Adrenal enzyme inhibitors : to control cortisol secretion before surgery  In case of aberrant hormone receptors have been identified  Specific pharmacologic therapies blocking the aberrant receptors have been effective as alternatives to adrenalectomy. Aberrant receptor expressionTreatment option Gastric inhibitory polypeptide (GIP) Octreotide, pasireotide Beneficial effect did not persist in the long-term Catecholamine Beta-adrenergic receptor antagonists (propranolol) Efficient in the long-term control of hypercortisolism luteinizing hormone (LH)/human chorionic gonadotropin (hCG) Leuprolide acetate ACTH, vasopressin, serotonin, or other aberrant receptors Broader range of pharmacologic therapies could become useful

* : blood sampling to measure ACTH, cortisol, other hormones

Lt. adrenalectomy Hypercortisolism 에 의한 증상 호전, urinary free cortisol 정상화 Post Op. mixed meal test, AVP 근주 검사, 기립 검사에서 이상 소견 없었음

Bilateral adrenalectomy

Adrenal vein sampling If there is a dominant side! Consider unilateral adrenalectomy Bilateral adrenalectomy and life long steroid replacement Aberrant receptor screening If there is a culprit! Consider using medication to block culprit receptor To rule out adrenal carcinoma adrenal androgens (dehydroepiandrosterone-sulfate [DHEA-S], androstenedione, testosterone, 17-OH progesterone)