Cushing’s Syndrome

History Taking

Chief Complaint:

• Weight gain, especially central obesity

• Facial fullness or rounding ("moon face")

• Decreased energy or fatigue

History of Presenting Complaint:

• Unexpected and rapid weight gain, particularly in the face, abdomen and chest, despite no significant changes in diet or exercise

• Increased thirst and urination

• Noticeable increase in stretch marks that are purple in color

• Facial changes like a round face (moon face), or fat deposits on the back of the neck and shoulders (buffalo hump)

• Changes in menstruation for women (e.g. irregular periods or amenorrhea)

• Erectile dysfunction or decreased libido in men

• Easy bruising and poor wound healing

• Recent onset of hypertension or glucose intolerance/diabetes

• If the patient has been having symptoms of other illnesses, such as lung disease (which might suggest Ectopic ACTH Syndrome) or headaches and visual changes (which might suggest Cushing's Disease due to a pituitary adenoma)

System Review:

• Muscular: Weakness, muscle wasting, especially proximal muscles (difficulty rising from a sitting position, climbing stairs)

• Skin: Thinning, dryness, acne

• Mental health: Mood swings, depression, irritability, cognitive difficulties

• Sleep: Insomnia, daytime fatigue

• Bone: History of multiple fractures, osteopenia/osteoporosis on previous investigations

• Gastrointestinal: Increased appetite

Past Medical History:

• Recurrent kidney stones (due to associated hypercalciuria)

• Diagnosis of hypertension, diabetes, or osteoporosis at a young age

• Past diagnosis of polycystic ovary syndrome (PCOS) or issues related to hormonal imbalance

Drug History:

• Long term use of glucocorticoid medications for conditions such as asthma, arthritis, or autoimmune conditions

• Use of contraceptive pills (may cause mild symptoms similar to Cushing's syndrome)

Family History:

• Any relatives with similar symptoms

• Family history of endocrine tumors, if present, might suggest a more rare form of Cushing's (e.g., Multiple Endocrine Neoplasia Type 1)

Personal and Social History:

• Occupation and exposure to stress: Cushing's syndrome can sometimes be caused by high levels of stress

• Lifestyle: Sedentary or active, diet habits, sleep patterns

• Smoking, alcohol, and drug use: These factors can impact overall health and contribute to symptoms such as weight gain and mood changes. Smoking history is particularly important for Ectopic ACTH Syndrome, as lung cancer can be a cause

Obstetrics and Gynecological History:

• Changes in menstrual cycle: More frequent, less frequent, or stopped altogether

• Fertility problems or unexpected infertility

Physical Examination

General Examination:

• Central obesity with relatively thin arms and legs

• Plethoric, round ("moon") face

• Supraclavicular and dorsocervical fat pads ("buffalo hump")

• Thin skin, easy bruising, wide purple striae (>1 cm) especially on the abdomen

• Proximal muscle weakness: difficulty getting up from a seated position or difficulty with overhead activities

• Hirsutism or acne in women

• Evidence of excessive sweating

Hands and Arms:

• Thinning of the skin on the dorsum of the hands with visible blood vessels

• Muscle wasting, particularly proximal muscles (shoulder and hip girdle)

• Purple striae on the upper arms

• Evidence of easy bruising

Mouth:

• Hyperpigmentation of the gums or palate might be present if ACTH levels are elevated

Neck:

• Buffalo hump (a hump behind the shoulders)

Cardiovascular Examination:

• Hypertension

• Possible signs of heart failure in long-standing disease (pedal edema, elevated JVP)

Respiratory Examination:

• Generally normal unless complicated by infection due to immunosuppression

Abdominal Examination:

• Central obesity

• Purple striae on the skin

• Possibly hepatomegaly if NAFLD has developed due to metabolic complications

Neurological Examination:

• Proximal myopathy (manifesting as difficulty rising from a squatting position)

• Psychological or cognitive changes including mood swings, depression, irritability, or psychosis

Additional Examination:

• Evidence of osteoporosis on bone examination such as kyphosis or height loss (long-standing disease)

• Posterior subcapsular cataracts during fundoscopy exam (long-term corticosteroid use)

• If a pituitary tumor is suspected, visual field testing for bitemporal hemianopia

Investigations

Laboratory Investigations:

• 24-hour urinary free cortisol: to assess the total cortisol excretion

• Late-night salivary cortisol: to measure cortisol level when it should normally be low

• Serum cortisol and ACTH levels: to assess ACTH-dependent vs ACTH-independent Cushing's syndrome

• Low-dose dexamethasone suppression test: to assess suppression of cortisol, indicating the presence of a normal feedback loop

• High-dose dexamethasone suppression test: to differentiate between pituitary and ectopic sources of ACTH

• Serum glucose, electrolytes, lipid profile: for evidence of diabetes, hypokalemia, or dyslipidemia which can occur with Cushing's

• Complete blood count: for evidence of neutrophilia, lymphopenia which can occur in Cushing's syndrome

Imaging Investigations:

• Pituitary MRI: to identify pituitary adenomas in Cushing's disease

• Adrenal CT scan or MRI: to identify adrenal adenomas or carcinomas

• Thoracoabdominal CT scan or Octreotide Scan: if ectopic ACTH secretion is suspected, to identify the source of ACTH

Invasive Tests:

• Inferior petrosal sinus sampling (IPSS): if pituitary Cushing's disease is suspected but the MRI is negative or equivocal, measures ACTH levels to confirm pituitary source

• Adrenal vein sampling: if adrenal Cushing's syndrome is suspected, measures cortisol and aldosterone levels to confirm adrenal source

Other Tests:

• Bone mineral density scan (DEXA scan): to assess for osteoporosis, a common complication of Cushing's syndrome

• Psychological evaluation: for symptoms of depression, anxiety, or cognitive impairment, which can be associated with hypercortisolism

• Ophthalmological evaluation: in case of pituitary adenoma with symptoms/signs of mass effect

• Electrocardiogram and echocardiogram: to assess for cardiovascular complications, like left ventricular hypertrophy or heart failure

Management

General Management:

• Lifestyle advice: balanced diet, regular exercise

• Psychological support: counselling or psychiatric therapy for depression, anxiety

• Bone health: calcium and vitamin D supplementation, weight-bearing exercise

• Cardiovascular risk management: control of hypertension, diabetes, and dyslipidemia

Medical Management:

• Cortisol-lowering drugs: Ketoconazole, Metyrapone, Etomidate (used in severe cases when immediate control of hypercortisolism is required or before surgery)

• Pituitary-directed drugs: Pasireotide, Cabergoline (used in Cushing's disease)

• Adrenostatic/Adrenolytic agents: Mitotane (used in adrenal carcinoma)

• Mifepristone: Glucocorticoid receptor antagonist (used in patients with glucose intolerance or diabetes)

Surgical Management:

• Transsphenoidal surgery: first-line treatment for Cushing's disease due to pituitary adenoma

• Adrenalectomy: for adrenal adenomas or carcinomas causing Cushing's syndrome

• Ectopic source removal: surgical removal of tumors causing ectopic ACTH production

Other:

• Radiotherapy: for pituitary adenomas not completely removed by surgery or not suitable for surgery

• Bilateral adrenalectomy: last resort if other treatments fail in ACTH-dependent Cushing's syndrome, requires life-long glucocorticoid and mineralocorticoid replacement

• Stereotactic radiosurgery: an alternative to conventional radiotherapy with fewer side effects, used in pituitary adenomas