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 Cushing's syndrome must be differentiated from other causes of irregular menses and hirsutism. Disease Differentiating Features Pregnancy Pregnancy always should be excluded in a patient with a history of amenorrhea Features include amenorrhea or oligomenorrhea, abnormal uterine bleeding, nausea/vomiting, cravings, weight gain (although not in the early stages and not if vomiting), polyuria, abdominal cramps and constipation, fatigue, dizziness/lightheadedness, and increased pigmentation (moles, nipples) Uterine enlargement is detectable on abdominal examination at approximately 14 weeks of gestation Ectopic pregnancy may cause oligomenorrhea, amenorrhea, or abnormal uterine bleeding with abdominal pain and sometimes subtle or absent physical symptoms and signs of pregnancy Hypothalamic amenorrhea Diagnosis of exclusion Seen in athletes, people on crash diets, patients with significant systemic illness, and those experiencing undue stress or anxiety Predisposing features are as follows weight loss, particularly if features of anorexia nervosa are present or the BMI is <19 kg/m2 Recent administration of depot medroxyprogesterone, which may suppress ovarian activity for 6 months to a year Use of dopamine agonists (eg, antidepressants) and major tranquilizers Hyperthyroidism In patients with weight loss related to anorexia nervosa, fine hair growth (lanugo) may occur all over the body, but it differs from hirsutism in its fineness and wide distribution Primary amenorrhea Causes include reproductive system abnormalities, chromosomal abnormalities, or delayed puberty If secondary sexual characteristics are present, an anatomic abnormality (eg, imperforate hymen, which is rare) should be considered If secondary sexual characteristics are absent, a chromosomal abnormality (eg, Turner syndrome ) or delayed puberty should be considered Cushing syndrome Cushing syndrome is due to excessive glucocorticoid secretion from the adrenal glands, either primarily or secondary to stimulation from pituitary or ectopic hormones; can also be caused by exogenous steroid use Features include hypertension, weight gain (central distribution), acne, and abdominal striae Patients have low plasma sodium levels and elevated plasma cortisol levels on dexamethasone suppression testing Hyperprolactinemia Mild hyperprolactinemia may occur as part of PCOS-related hormonal dysfunction Other causes include stress, lactation, and use of dopamine antagonists A prolactinoma of the pituitary gland is an uncommon cause and should be suspected if prolactin levels are very high (>200 ng/mL) Physical examination findings are usually normal As in patients with PCOS, hyperprolactinemia may be associated with mild galactorrhea and oligomenorrhea or amenorrhea; however, galactorrhea also can occur with nipple stimulation and/or stress when prolactin levels are within normal ranges A large prolactinoma may cause headaches and visual field disturbance due to pressure on the optic chiasm, classically a gradually increasing bi-temporal hemianopsia Ovarian or adrenal tumor Benign ovarian tumors and ovarian cancer are rare causes of excessive androgen secretion; adrenocortical tumors also can increase the production of sex hormones Abdominal swelling or mass, abdominal pain due to fluid leakage or torsion, dyspareunia, abdominal ascites, and features of metastatic disease may be present Features of androgenization include hirsutism, weight gain, oligomenorrhea or amenorrhea, acne, clitoral hypertrophy, deepening of the voice, and high serum androgen (eg, testosterone, other androgens) levels In patients with an androgen-secreting tumor, serum testosterone is not suppressed by dexamethasone Congenital adrenal hyperplasia Congenital adrenal hyperplasia is a rare genetic condition resulting from 21-hydroxylase deficiency The late-onset form presents at or around menarche Patients have features of androgenization and subfertility Affects approximately 1% of hirsute patients More common in Ashkenazi Jews (19%), inhabitants of the former Yugoslavia (12%), and Italians (6%) Associated with high levels of 17-hydroxyprogesterone A short adrenocorticotropic hormone stimulation test with measurement of serum17-hydroxyprogesterone confirms the diagnosis Assays of a variety of androgenic hormones help define other rare adrenal enzyme deficiencies, which present similarly to 21-hydroxylase deficiency Anabolic steroid abuse Anabolic steroids are synthetic hormones that imitate the actions of testosterone by increasing muscle bulk and strength Should be considered if the patient is a serious sportswoman or bodybuilder Features include virilization (including acne and hirsutism), often increased muscle bulk in male pattern, oligomenorrhea or amenorrhea, clitoromegaly, gastritis, hepatic enlargement, alopecia, and aggression Altered liver function test results are seen Hirsutism Hirsutism is excessive facial and body hair, usually coarse and in a male pattern of distribution Approximately 10% of women report unwanted facial hair There is often a family history and typically some Mediterranean or Middle Eastern ancestry May also result from use of certain medications, both androgens, and others including danazol, glucocorticoids, cyclosporine, and phenytoin Menstrual history is normal When the cause is genetic, the excessive hair, especially on the face (upper lip), is present throughout adulthood, and there is no virilization When secondary to medications, the excessive hair is of new onset, and other features of virilization, such as acne and deepened voice, may be present Cushing's syndrome must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, and adrenal medullary tumors. Differential Diagnosis Clinical picture Imagings Laboratory tests Adrenocortical carcinoma Mass effect symptoms Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid Symptoms related to excess androgen or estrogen secretion Irregular shape Non-homogeneous density because of central areas of low attenuation due to tumor necrosis Tumor calcification Diameter usually >4 cm Unilateral location High unenhanced CT attenuation values (>20 HU) Non-homogeneous enhancement on CT with intravenous contrast Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Hypointensity compared with liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI High standardized uptake value (SUV) on FDG-PET-CT study Evidence of local invasion or metastases Adrenal androgens (DHEAS) Androstenedione Bioavailable testosterone should be measured in every patient. 17-hydroxyprogesterone Serum estradiol in men and postmenopausal women Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime Adrenal adenoma Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid Round, homogeneous with sharp margination Unilateral with diameter less than 4 cm Low unenhanced CT attenuation values (<10 HU) Rapid contrast medium washout after administration of contrast An absolute contrast medium washout of more than 50 percent Chemical shift: evidence of lipid on MRI Isointensity with liver on both T1 and T2 weighted MRI sequences Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime Renin (PRA) or plasma renin concentration (PRC): very low in patients with primary aldosteronism, usually less than 1 ng/mL per hour for PRA and usually undetectable for PRC Cushing's syndrome Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache Imaging may show mass if presents 24-hour urine cortisol Midnight salivary cortisol Low-dose dexamethasone suppression test; high cortisol level after the dexamethasone test is suggestive of hypercortisolism. Pheochromocytoma Palpitations especially in epinephrine-producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered incidentally after screening for MEN patients. Increased attenuation on non-enhanced CT (>20 HU) Increased mass vascularity Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) High signal intensity on T2 weighted MRI Cystic and hemorrhagic changes Variable size and may be bilateral Plasma fractionated metanephrines  24-hour urinary fractionated metanephrines Adrenal metastasis Symptoms and signs of primary malignancy especially lung cancer General constitutional symptoms: Fever Fatigue Weight loss Irregular shape and non-homogeneous nature Tendency to be bilateral High un-enhanced CT attenuation values (>20 HU) and enhancement with intravenous contrast on CT Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Isointensity or slightly less intense than the liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI (representing an increased water content) Elevated standardized uptake value on FDG-PET scan References Template:WH Template:WS