Cushing's syndrome differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Overview

Cushing's syndrome must be differentiated from other diseases that cause hypertension, obesity, and hyperandrogenism, such as Metabolic syndrome X and pseudo-Cushing's syndrome.

Differentiating Cushing's syndrome from Other Diseases

The table below summarizes the findings that differentiate Cushing's disease from other conditions that may cause hypertension, hyperandrogenism, and obesity. Facial plethora, skin changes, osteoporosis, nephrolithiasis and neuropsychiatric conditions should raise the concern for Cushing's syndrome.

Conditions Causes Associated features Diagnostic approach Cushing's syndrome Iatrogenic Pituitary adenoma Adrenal tumor Adrenal hyperplasia Ectopic ACTH secretion Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Osteoporosis Myopathy/cutaneous wasting Neuropsychiatric problems Kidney stones 24-hour urine cortisol Midnight salivary cortisol Low dose dexamethasone challenge test CRH stimulation High dose dexamethasone test MRI brain CT/MRI adrenals Pseudo-Cushing's syndrome Obesity Alcoholism Depression HIV Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Urinary free cortisol Midnight salivary cortisol Low dose dexamethasone challenge test Glucose tolerance test Loperamide test Metabolic syndrome X Familial/genetic Obesity Insulin resistance Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Dyslipidemia Diabetes/Glucose intolerance Waist circumference Low-density lipoproteins High-density lipoproteins Glucose tolerance test Fasting blood sugar HbA1c Other differentials Cushing's syndrome must be differentiated from diseases that cause virilization and hirsutism in female: Disease name Steroid status Other laboratory Important clinical findings Cushing's syndrome Increase cortisol & metabolites Variable other steroids Variable mineralocorticoid excess Cushingoid appearance Non-classic type of 21-hydroxylase deficiency Increased: 17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone in response to ACTH Low testosterone levels No symptoms in infancy and male Virilization in females 11-β hydroxylase deficiency Increased: DOC 11-Deoxy-Cortisol Decreased: Cortisol Corticosterone Aldosterone Low testosterone levels Hypertension and hypokalemia Virilization 3 beta-hydroxysteroid dehydrogenase deficiency Increased: DHEA 17-hydroxypregnenolone Pregnenolone Decreased: Cortisol Aldosterone Low testosterone levels Salt-wasting adrenal crisis in infancy Mild virilization of genetically female infants Undervirilization of genetically male infants, making it the only form of CAH which can cause ambiguous genitalia in both genetic sexes. Polycystic ovary syndrome High DHEAS and androstenedione levels Low testosterone levels Polycystic ovaries in sonography Obesity PCOS is the most common cause of hirsutism in women No evidence another diagnosis Adrenal tumors Variable levels depends on tumor type Low testosterone level Older age Rapidly progressive symptoms Ovarian virilizing tumor Variable levels depends on tumor type Testosterone is high Older age Rapidly progressive symptoms Hyperprolactinemia Normal levels of most of steroids Increased prolactin Infertility, galactorrhea Less common differentials Cushing's syndrome should also be differentiated from other causes of hyperprolactinemia that may present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females) including: Physiological: Normal pregnancy Pathological: Pituitary tumors (other than prolactinoma): Somatotroph adenoma: Acromegaly Corticotroph adenoma: Cushing's syndrome Suprasellar tumors (tumors present in the region of the pituitary stalk) Hypothyroidism Chronic renal failure Liver disease Cirrhosis (with or without encephalopathy) Viral hepatitis (with encephalopathy) Seizure disorder Medication-induced: Antipsychotic medications: Haloperidol Risperidone Antiemetic medications: Metoclopramide Domperidone Antihypertensive medications: Methyldopa Verapamil Disease Clinical Findings Laboratory findings Management Somatotroph adenoma: Acromegaly Clinical features of acromegaly are due to high level of human growth hormone (hGH): Soft tissue swelling of the hands and feet Brow and lower jaw protrusion Enlarged hands Enlarged feet Arthritis and carpal tunnel syndrome Increase in teeth spacing Macroglossia (enlarged tongue) Heart failure Kidney failure Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia) Headache Diabetes mellitus Hypertension Cardiomegaly Elevated insulin-like growth factor-1 (IGF-1) levels Elevated growth hormone levels Medical management: Octreotide Bromocriptine Surgical management: Endonasal transsphenoidal surgery Radiation therapy Corticotroph adenoma: Cushing's syndrome Clinical features of Cushing's syndrome are due to increased levels of cortisol: Rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache The excess cortisol may also affect other endocrine systems and cause, for example: Insomnia Reduced libido Impotence Amenorrhea Infertility Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common. Dexamethasone suppression test 24 hour urinary measurement of cortisol Medical management: Pasireotide Cabergoline Ketoconazole Metyrapone Mitotane Mifepristone Surgical management: Transsphenoidal pituitary resection Hypothyroidism Clinical features of hypothyroidism are due to deficiency of thyroxine: Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain Hoarseness Goiter Fullness in the throat and neck Depression Emotional lability Attention deficit Elevated TSH Low T4 Low T3 Elevated anti-thyroid antibodies(anti-TPO) Levothyroxine Chronic renal failure There are no pathognomonic symptoms associated with chronic renal failure. Common non-specific symptoms of chronic renal failure include: Malaise Nausea Unintentional weight loss Pruritus Lower extremity edema Sleep disorders Urinalysis: Albuminuria Hematuria Pyuria Red cell or white cell casts and crystals Fluid and electrolyte disturbances: Hyponatremia Hyperkalemia Hyperphosphatemia Hyperchloremia Metabolic acidosis Hypocalcemia Endocrine and metabolic disturbances: Hyperuricemia Hypertriglyceridemia Decreased HDL levels Vitamin D deficiency Increased Parathyroid hormone levels Hematologic abnormalities: Normocytic normochromic anemia Lymphocytopenia Leukopenia Thrombocytopenia Medical management: Blood pressure management Control of blood glucose Protein restriction Management of anemia Management of electrolyte disturbance Dialysis Surgical management Kidney transplant Liver disease: Cirrhosis The clinical features of liver cirrhosis are very nonspecific. These include: Right upper quadrant abdominal pain Fever Fatigue and weakness Loss of appetite Diarrhea Nausea and vomiting Weight loss Abdominal pain and bloating when fluid accumulates in the abdomen Itching Menstrual irregularities Elevated aminotransferases (AST & ALT) Elevated alkaline phosphatase (ALP) Elevated gamma-glutamyl transpeptidase Elevated bilirubin Low albumin Elevated prothrombin time Elevated globulin Hyponatremia Anemia Leukopenia and neutropenia Thrombocytopenia Medical management: Treatment is usually directed towards the treatment of complications like ascites, esophageal varices, hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis. Some chronic constitutional symptoms that should be treated include: Pruritis: Cholestyramine is the drug of choice Hypogonadism: Topical testosterone preparations Osteoporosis: Calcium and vitamin D Pain management: NSAIDS, celecoxib, opioids Nutrition: Adequate caloric and protein intake, and multivitamin supplementation Surgical management: Liver transplantation Seizure disorder The clinical features of seizure disorder may include: Change in alertness, orientation and time perception Mood changes, such as unexplainable fear, panic, joy, or laughter Changes in sensation of the skin, usually spreading over the arm, leg, or trunk Vision changes, including seeing flashing lights Rarely, hallucinations (seeing things that aren't there) Falling, loss of muscle control, occurs very suddenly Muscle twitching that may spread up or down an arm or leg Muscle tension or tightening that causes twisting of the body, head, arms, or legs Shaking of the entire body Tasting a bitter or metallic flavor Electroencephalogram Medical management: Antiepileptic medications Medication-induced Clinical features of hyperprolactinemia after a specific period of regular medication ingestion Discontinuation of the medication for 3 days and remeasurement of prolactin levels Change to alternate medication References Template:WH Template:WS