Cushing's Disease

Endocrinology

Overview

Overview 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)

Signs and Symptoms

Clinical feautres that 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

Differential 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

Cushings Graph

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 test Dexamethasone (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 test Late 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.

Aetiology

The majority of endogenous Cushing’s syndrome is due to ACTH-secreting pituitary adenomas (Cushing’s disease).

Remember Cushing's Disease is ACTH dependent hypercortisolaemia. Most common cause is pituitary adenoma

Pathophysiology

Not up yet sorry guys

Management

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 hypotension~~ Absence 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
Acute onset may occur due to pituitary apoplexy.