6.4 Adrenal & Pituitary Disorders: Addisonian Crisis & Pituitary Disease

Adrenal & Pituitary Disorders: Addisonian Crisis & Pituitary Disease

Adrenal and pituitary diseases encompass complex endocrinopathies requiring precise diagnostic pathways and emergency awareness. The adrenal cortex produces cortisol (zona fasciculata), aldosterone (zona glomerulosa), and adrenal androgens (zona reticularis) under the control of adrenocorticotropic hormone (ACTH) and the renin-angiotensin-aldosterone system (RAAS).

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Primary Adrenal Insufficiency (Addison's Disease)

Addison's disease is caused by progressive bilateral destruction of all three zones of the adrenal cortex. In the UK and developed nations, >80% of cases are autoimmune (autoimmune adrenalitis), with circulating anti-21-hydroxylase antibodies. Worldwide, tuberculosis remains the primary infectious cause. Other etiologies include bilateral adrenal haemorrhage (Waterhouse-Friderichsen syndrome in meningococcal sepsis; antiphospholipid syndrome), fungal infections (histoplasmosis), metastatic malignancy, and drugs (etomidate, ketoconazole).

Clinical Presentation & Biochemical Hallmarks

• Glucocorticoid deficiency: Severe chronic fatigue, generalised muscle weakness, anorexia, unintentional weight loss, nausea, vomiting, diarrhoea, abdominal pain, and hypoglycaemia (loss of cortisol counter-regulatory gluconeogenesis).
• Mineralocorticoid deficiency: Renal sodium wasting and potassium retention leading to hypovolaemia, postural hypotension, dizziness, and intense salt craving.
• Cutaneous hyperpigmentation: The clinical hallmark of primary adrenal disease. Hypocortisolaemia stimulates pituitary pro-opiomelanocortin (POMC) transcription via loss of negative feedback. POMC is cleaved into high levels of ACTH and melanocyte-stimulating hormone (MSH), which bind to melanocortin-1 receptors on dermal melanocytes. Hyperpigmentation is most pronounced in sun-exposed areas, pressure points (elbows, knees, knuckles), palmar creases, recent surgical scars, and the buccal mucosa.
• Biochemical profile: Hyponatraemia (due to aldosterone deficiency and unsuppressed ADH secretion), hyperkalaemia (loss of aldosterone-mediated renal potassium excretion), mild non-anion gap metabolic acidosis, and elevated serum urea (prerenal uraemia).

Primary vs Secondary Adrenal Insufficiency Comparison

Per NICE Clinical Knowledge Summaries (CKS) and Society for Endocrinology UK guidelines, differentiating primary from secondary adrenocortical failure is essential for appropriate mineralocorticoid replacement and investigation:

Diagnostic Confirmation: The Short Synacthen Test

Random serum cortisol measurements are unreliable due to diurnal circadian variation and pulsatile release. Diagnostic confirmation mandates a Short Synacthen (Corticotropin) Test:

1. Measure baseline serum cortisol at 09:00.
2. Administer tetracosactide 250 mcg (synthetic ACTH) intramuscularly or intravenously.
3. Measure serum cortisol at 30 minutes post-injection.

• Normal physiological response: Stimulated peak serum cortisol rises to > 420–450 nmol/L.
• Adrenal insufficiency: Failure to reach a stimulated peak cortisol > 420 nmol/L confirms adrenocortical failure. In primary Addison's disease, baseline plasma ACTH is markedly elevated (> 100 ng/L), whereas in secondary adrenal disease, baseline plasma ACTH is low or inappropriately normal.

Maintenance Hormone Replacement

Patients with Addison's disease require lifelong dual hormone replacement:

1. Glucocorticoid Replacement: Oral hydrocortisone in 2–3 divided doses daily to replicate the physiological circadian rhythm (e.g., 10 mg on waking, 5 mg at midday, and 2.5 mg in the late afternoon). The final dose must not be taken late in the evening to prevent insomnia.
2. Mineralocorticoid Replacement: Oral fludrocortisone (50 – 200 mcg once daily in the morning). Dose titration is guided by clinical blood pressure (absence of postural drop), normalisation of serum electrolytes, and plasma renin activity.

Patient Education & Sick-Day Rules

• Sick-Day Rule 1 (Moderate illness / Fever): Double the daily oral hydrocortisone dose during an illness with fever, an illness needing bed rest, or an infection needing antibiotics (Society for Endocrinology sick-day rules), and for minor procedures as advised, until recovery. Fludrocortisone dose remains unchanged.
• Sick-Day Rule 2 (Severe illness / Vomiting / Diarrhoea): If unable to retain oral tablets due to persistent vomiting or gastroenteritis, immediately administer intramuscular hydrocortisone 100 mg from an emergency home kit and seek urgent hospital admission.
• Safety Equipment: Patients must wear a medical alert identification bracelet and carry an NHS Steroid Emergency Card at all times.

Acute Addisonian Crisis (Adrenal Crisis)

An Addisonian crisis is an acute life-threatening medical emergency caused by absolute physiological cortisol deficiency. It is typically precipitated by acute infection (e.g., gastroenteritis, pneumonia), trauma, surgery, or myocardial infarction in a patient with diagnosed Addison's disease, or by abrupt cessation of long-term therapeutic glucocorticoids.

Clinical Presentation

• Circulatory collapse: Severe refractory hypotension, tachycardia, and shock that fails to respond to standard intravenous fluids and vasopressors (due to loss of cortisol's permissive effect on vascular alpha-1 adrenergic receptors).
• Gastrointestinal symptoms: Intractable vomiting, severe diarrhoea, and acute severe abdominal pain that closely mimics an acute surgical abdomen (peritonism).
• Metabolic collapse: Severe symptomatic hypoglycaemia (sweating, altered consciousness, seizures), marked hyponatraemia, and life-threatening hyperkalaemia with risk of cardiac asystole.

Immediate Emergency Resuscitation Protocol

1. Immediate High-Dose Intravenous Hydrocortisone: Administer IV hydrocortisone 100 mg stat bolus immediately (IV or IM). Continue with 200 mg per 24 hours as a continuous intravenous infusion, or 50 mg IV/IM every 6 hours (Society for Endocrinology adrenal crisis guidance).
2. Vigorous Fluid Resuscitation: Infuse 0.9% sodium chloride rapidly (1000 mL over the first 30–60 minutes, followed by 3–4 litres over the first 24 hours) to restore circulating intravascular volume and correct hyponatraemia.
3. Correct Hypoglycaemia: If blood glucose is < 4.0 mmol/L, administer 10% intravenous dextrose alongside 0.9% normal saline.
4. Cardiac Monitoring: Place the patient on continuous telemetry and record a 12-lead ECG to evaluate for hyperkalaemic changes (tall peaked T waves, flattened P waves, PR prolongation, widened QRS).
5. Identify & Treat Precipitant: Take blood and urine cultures, initiate empirical broad-spectrum intravenous antibiotics if infection is suspected.
6. Note on Fludrocortisone: Fludrocortisone is not required in acute crisis. High-dose hydrocortisone (≥ 100 mg daily) possesses potent intrinsic mineralocorticoid activity that fully saturates renal mineralocorticoid receptors. Fludrocortisone is recommenced only when hydrocortisone is weaned to maintenance levels (< 50 mg/day).

Cushing's Syndrome (Hypercortisolism)

Cushing's syndrome describes the physical and metabolic manifestations of chronic glucocorticoid excess. The most common cause overall is exogenous (iatrogenic) corticosteroid administration. Endogenous causes divide into ACTH-dependent and ACTH-independent forms.

Clinical Features

Central truncal obesity, rounded plethoric "moon face", dorsocervical fat pad ("buffalo hump"), supraclavicular fat pads, thin fragile skin with easy bruising, wide (> 1 cm) violaceous abdominal striae, proximal muscle myopathy (inability to stand from a chair without using arms), osteoporosis, secondary hypertension, glucose intolerance or type 2 diabetes, oligomenorrhoea, hirsutism, and neuropsychiatric disturbances (depression, emotional lability, psychosis).

Diagnostic & Localisation Algorithm

The flowchart at the end of this section summarises the sequence:

1. Exclude exogenous steroids (oral, inhaled, topical, injected), the commonest cause.
2. Confirm hypercortisolism with at least two first-line tests: overnight 1 mg dexamethasone suppression test (09:00 cortisol fails to suppress below 50 nmol/L), 24-hour urinary free cortisol, or late-night salivary cortisol (loss of the midnight nadir).
3. Measure plasma ACTH: suppressed ACTH means an ACTH-independent adrenal cause (adenoma, carcinoma, bilateral hyperplasia) and leads to adrenal CT or MRI; normal or raised ACTH means ACTH-dependent disease.
4. Localise ACTH-dependent disease: pituitary MRI, high-dose dexamethasone and CRH tests, and inferior petrosal sinus sampling distinguish Cushing's disease (pituitary adenoma, about 80% of ACTH-dependent cases) from ectopic ACTH (small cell lung cancer, bronchial carcinoid), which needs CT of the chest, abdomen and pelvis.

Phaeochromocytoma

A phaeochromocytoma is a rare catecholamine-producing neuroendocrine tumour originating from chromaffin cells of the adrenal medulla (90%) or extra-adrenal sympathetic paraganglia (10%, termed paragangliomas). Approximately 10% are bilateral, 10% are malignant, and 25–30% are associated with familial syndromes (MEN 2A/2B, Von Hippel-Lindau disease, Neurofibromatosis type 1).

Clinical Presentation & Diagnostics

• Classic Triad: Paroxysmal headache, profuse sweating (diaphoresis), and tachycardia/palpitations, associated with labile severe hypertension, pallor, anxiety, and postural hypotension.
• Biochemical Confirmation: 24-hour urinary fractionated metanephrines or plasma free metanephrines (high diagnostic sensitivity due to continuous catecholamine O-methylation by tumour cells).
• Imaging: Contrast-enhanced CT or MRI of the adrenals; functional imaging using 123-I-metaiodobenzylguanidine (MIBG) scintigraphy.

Mandatory Pre-Operative Pharmacological Blockade

Definitive treatment is laparoscopic adrenalectomy. Surgical manipulation causes massive catecholamine release, which can trigger lethal hypertensive crisis, myocardial infarction, or cerebral haemorrhage unless complete pharmacological blockade is established:

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Pituitary Apoplexy

Pituitary apoplexy is an acute clinical syndrome caused by sudden infarction, ischaemia, or haemorrhage within a pituitary tumour (typically a non-functioning macroadenoma).

Clinical Presentation

• Acute headache: Sudden-onset, severe "thunderclap" retro-orbital or bifrontal headache.
• Visual failure: Acute visual field defect—characteristically bitemporal hemianopia or superior quadrantanopia caused by acute upward compression of the optic chiasm. Rapid expansion into the cavernous sinuses causes cranial nerve palsies (CN III, IV, and VI) presenting with diplopia, ptosis, and ophthalmoplegia.
• Acute endocrine collapse: Acute secondary hypopituitarism, predominantly life-threatening acute ACTH and cortisol deficiency causing severe hypotension, hypoglycaemia, hyponatraemia, hypothermia, and coma.

Emergency Management

1. Immediate High-Dose Corticosteroids: Administer intravenous hydrocortisone 100–200 mg stat immediately, followed by 50–100 mg 6-hourly or a continuous infusion (UK pituitary apoplexy guidance). Glucocorticoid replacement is life-saving and treats acute secondary adrenocortical collapse.
2. Emergency Imaging: Urgent contrast-enhanced MRI of the pituitary (or urgent CT head if MRI is unavailable) to confirm pituitary haemorrhage and chiasmal displacement.
3. Neurosurgical Decompression: Urgent endocrine and neurosurgical referral for transsphenoidal surgical decompression, indicated urgently if there is progressive deterioration of visual acuity, severe visual field defects, or declining consciousness.

Other Pituitary Disorders

Acromegaly (Growth Hormone Excess)

Acromegaly is almost always caused by a growth hormone (GH)-secreting pituitary adenoma, usually a macroadenoma. GH stimulates hepatic insulin-like growth factor 1 (IGF-1), which drives the clinical features. Before epiphyseal closure the same excess causes gigantism.

• Features: coarse facial features, frontal bossing, prognathism with widened tooth spacing, enlarged hands and feet (rings and shoes no longer fit), macroglossia, deep voice, excessive sweating, skin tags, carpal tunnel syndrome, arthropathy and headache. A macroadenoma may compress the optic chiasm (bitemporal hemianopia) and cause hypopituitarism.
• Complications: hypertension, cardiomyopathy and heart failure, type 2 diabetes or impaired glucose tolerance, obstructive sleep apnoea, and colorectal polyps and cancer (colonoscopy surveillance is advised).
• Investigations: serum IGF-1 is the screening test. Confirm with an oral glucose tolerance test (OGTT): in health 75 g of glucose suppresses GH, while in acromegaly GH fails to suppress (nadir above about 1 microgram/L). Then pituitary MRI, formal visual fields and assessment of other pituitary hormones.
• Treatment: trans-sphenoidal surgery is first-line. Medical options are somatostatin analogues (octreotide, lanreotide; side effects include gallstones), the GH receptor antagonist pegvisomant, and dopamine agonists (cabergoline) in mild cases; radiotherapy is used for residual disease.

Hyperprolactinaemia & Prolactinoma

Prolactin is under tonic inhibition by hypothalamic dopamine, so anything that blocks dopamine or interrupts the pituitary stalk raises prolactin.

• Causes: pregnancy and breastfeeding (always exclude first), drugs that block dopamine (antipsychotics such as risperidone and haloperidol, metoclopramide, domperidone), primary hypothyroidism (TRH stimulates prolactin), stalk compression by a non-functioning macroadenoma ("stalk effect", usually modest elevation), chronic kidney disease, and prolactinoma, the most common functioning pituitary adenoma.
• Features: women present early with galactorrhoea, oligomenorrhoea or amenorrhoea and infertility; men present later with reduced libido, erectile dysfunction and, with macroadenomas, headache and visual field loss. Long-standing hypogonadism reduces bone density.
• Investigations: repeat prolactin (stress raises it), pregnancy test, TFTs, renal function, a drug history and screening for macroprolactin (a biologically inactive complex that causes falsely high results), then pituitary MRI.
• Treatment: dopamine agonists (cabergoline first-line, or bromocriptine) normalise prolactin and shrink most prolactinomas, even large ones with visual compromise; surgery is reserved for intolerance or resistance. High-dose cabergoline needs echocardiographic monitoring for valvular fibrosis, and dopamine agonists can provoke impulse-control disorders. For antipsychotic-induced hyperprolactinaemia, discuss switching to a prolactin-sparing drug (such as aripiprazole) with the psychiatry team rather than adding a dopamine agonist.

Diabetes Insipidus (Arginine Vasopressin Deficiency and Resistance)

In 2022 international endocrine societies renamed cranial diabetes insipidus as arginine vasopressin deficiency (AVP-D) and nephrogenic diabetes insipidus as arginine vasopressin resistance (AVP-R), to avoid confusion with diabetes mellitus.

• Features: polyuria (more than about 3 litres a day in adults) of dilute urine (osmolality usually below 300 mOsm/kg), nocturia and thirst. Serum sodium is high-normal or raised; hypernatraemia develops quickly if access to water is lost (for example after surgery or with reduced consciousness).
• Causes of AVP-D: pituitary or hypothalamic surgery, head injury, craniopharyngioma or metastases, infiltrative disease (sarcoidosis, Langerhans cell histiocytosis) and idiopathic or autoimmune forms.
• Causes of AVP-R: lithium (the commonest acquired cause), hypercalcaemia, hypokalaemia, chronic kidney disease, and inherited AVP receptor or aquaporin-2 mutations.
• Differential: primary polydipsia (excess drinking lowers serum sodium towards the low-normal range) and osmotic diuresis from hyperglycaemia; check glucose, calcium and potassium first.
• Investigations: the water deprivation test: urine fails to concentrate during deprivation; after desmopressin, urine osmolality rises substantially in AVP-D but not in AVP-R. A hypertonic saline-stimulated copeptin test is increasingly used in specialist centres.
• Treatment: AVP-D is treated with desmopressin (oral, sublingual or intranasal), with sodium monitoring because over-treatment causes hyponatraemia; doses must not be omitted in hospital. AVP-R is managed by treating the cause (stop lithium if possible, correct calcium or potassium) and with thiazide diuretics and a low-solute diet.