Cushing’s disease is a ACTH dependent syndrome characterised by excess corticosteroid production from the adrenal glands. It is ACTH dependent because it is triggered by an ACTH-secreting pituitary tumour. Cushing’s syndrome is an over arching term to describe hypercortisolaemia dependent of independent of ACTH. Adrenal Cushing’s syndrome is different because it is hypercortisolaemia independent of ACTH.
Definition
Cushing’s syndrome (CS): is a disease complex that results from chronic hypercortisolemia of any cause. The causes may be classified as ACTH dependent and ACTH independent. Cushing’s disease (CD): is hypercortisolemia from an ACTH-secreting pituitary tumor (ACTH Dependent) ACTH-independent Cushing’s syndrome is due to adrenal tumors (benign and malignant) and is responsible for 10–20% cases of Cushing’s syndrome.
Adrenal Glands Anatomy and Physiology
Regulation of adrenal hormones
Anatomy
The normal adrenal glands weigh 4–5 g.
The cortex represents 90% of the normal gland and surrounds the medulla.
The arterial blood supply arises from the renal arteries, aorta, and inferior phrenic artery.
Venous drainage occurs via the central vein into the inferior vena cava on the right, and into the left renal vein on the left.
Three layers of the adrenal glands
Zona fasiculata
Zona glomerulosa
Zona Reticularis
Physiology
Glucocorticoids (zona fasciculata)
Mineralcorticoids (zona glomerulosa)
Androgens (zona reticularis and zona fasciculata)
Aetiology
The majority of endogenous Cushing’s syndrome is due to ACTH-secreting pituitary adenomas (Cushing’s disease).
Clinical Manifestation
Clinical feautresthat best distinguish Cushing’s syndrome: Facial appearance: moon facie and plethoric complexion, ecchymoses, Violaceous striae on abdomen, thighs and axillae, Proximal muscle weakness. In children, weight gain with decreased growth velocity. Early bone fractures, especially atraumatic rib or vertebral fractures
Diagnosis
Differential Diagnosis and causes of Cushing’s syndrome
ACTH-dependent
Pituitary adenoma (Cushing’s disease): 70–80%
Ectopic ACTH syndrome: 10%
Ectopic CRH secretion: <1%
ACTH-independent
Adrenal adenoma: 10–20%
Adrenal carcinoma: <5%
Nodular (macro or micro) hyperplasia: 1%
Carney’s complex
McCune–Albright syndrome
Exogenous Causes
Iatrogenic etiologies (e.g., oral, inhaled or topical steroids) are the most common cause of CS
Pseudo-Cushing’s disease
Glucocorticoid resistance syndrome
Investigations
Screening tests
24 hour urinary free cortisol (at least 2 measurements) – Gold Standard
Overnight Dexamethasone Suppression test – Can be used initially to rule out Cushing’s syndrome and also to assess function of ACTH
Serum ACTH Levels – differentiate between ACTH dependent and independent
Pituitary imaging
MRI – detects 50% of tumours in Cushing’s disease
CT – hypercortisolaemia from a adrenal source
Overnight dexamethasone suppression testDexamethasone (glucocorticoid) is administered before bed and cortisol levels are measured the following morning. Normally Dexamethasone will send a negative feedback to decrease cortisol production. Elevated cortisol the following morning indicates abnormal secretion of cortisol (Cushing’s syndrome)Cortisol salivary testLate night cortisol should be low because plasma cortisol levels increase during the day and lower at night. Elevated cortisol at night indicates abnormal cortisol secretion due to Cushing’s syndrome.
Remember
Cushing’s Disease is ACTH dependent hypercortisolaemia. Most common cause is pituitary adenoma.
Treatment
Transsphenoidal surgery (TSS) – First-line therapy in most Cushing’s disease cases.
Medical treatment
Metyrapone
Ketoconazole
Mitotane
Pituitary radiotherapy
Adrenalectomy In ACTH-dependent Cushing’s, bilateral adrenalectomy is the treatment of last resort
Summary of the Management of Cushing’s Syndrome based on Aetiology
Pharmacology
Metyrapone reduces cortisol production by inhibiting the 11-ß-hydroxylation reaction in the adrenal cortex. Side effects: arrhythmias, hypotension, dehydration, anxiety, confusion, weakness, impairment of consciousness, nausea, vomiting, epigastric pain, and diarrhea.
Complication and Prognosis
Complications
Adrenal insufficiency
Cardiovascular disease
Hypertension
Diabetes mellitus
Osteoporosis
Nephrolithiasis
Treatment-related
Central hypothyroidism
Growth hormone deficiency
Adrenal insufficiency
Hypogonadism
Diabetes insipidus
Nelson’s Syndrome
Nelson Syndrome is a spectrum of symptoms and signs arising from an adrenocorticotropin (ACTH)–secreting pituitary macroadenoma after a therapeutic bilateral adrenalectomy.
Prognosis
Without treatment, hypercortisolism persists and in many patients worsens. Untreated -survival rate of 50% at 5 years
ACTH dependant Cushing’s Syndrome (Cushing’s Disease) – Microadenomas (size <1 cm) have superior outcomes with remission in 65% to 90% of patients. Of these individuals, 5% to 26% have recurrence at 5 years and >10% to 20% have recurrences by 10 years.
Adrenal Insufficiency
Medical Emergency
Adrenal insufficiency results from inadequate adrenocortical function and may be due to destruction of the adrenal cortex (Addison’s disease) or to disordered pituitary and hypothalamic function (secondary causes). In term’s of Cushing’s Disease, adrenal insufficiency can occur after surgery to remove the pituitary tumour. Loss of pituitary ACTH secretion means low adrenal hormones produced resulting in adrenal insufficiency.
Features of secondary adrenal insufficiency include:
Anorexia and weight loss (>90%)
Tiredness
Weakness—generalized, no particular muscle groups
Pigmentation—generalised —skin is pale
Dizziness and postural hypotensionAbsence of mineralocorticoid deficiency
GI symptoms—nausea and vomiting, abdominal pain, diarrhea
Arthralgia and myalgia
Symptomatic hypoglycemia—rare in adults
Axillary and pubic hair and reduced libido in women
Associated features of underlying cause, e.g., visual field defects if there is a pituitary tumor
Other endocrine deficiencies may manifest due to pituitary failure
Discussion