After reading this note you will be able to describe the clinical approach to adrenal insufficiency and Cushing syndrome, list local aetiologies, interpret key investigations and outline immediate and definitive management – remembering to verify drug choices and dosing against the Kenya MoH guideline and your hospital formulary.
Definition
- Adrenal insufficiency (AI): Inadequate production of glucocorticoids (and often mineralocorticoids) by the adrenal cortex, leading to failure of the hypothalamic‑pituitary‑adrenal (HPA) axis.
- Cushing syndrome (CS): Chronic exposure to excess glucocorticoids from any source (endogenous or exogenous) producing the classic “cushingoid” phenotype.
Anatomy and physiology you need
| Structure | Hormone(s) produced | Main actions |
|---|---|---|
| Zona glomerulosa | Aldosterone | Sodium retention, potassium excretion, water balance |
| Zona fasciculata | Cortisol | Glucose metabolism, anti‑inflammatory, stress response |
| Zona reticularis | Androgens (DHEA, androstenedione) | Peripheral conversion to testosterone/estrogen |
| Adrenal medulla | Catecholamines | Acute stress response (not central to AI/CS) |
| Pituitary ACTH | – | Stimulates cortisol (and, at high levels, aldosterone) |
| Hypothalamic CRH | – | Drives ACTH release |
Key feedback loops: cortisol → negative feedback on CRH & ACTH; renin‑angiotensin → aldosterone regulation.
Causes and risk factors
| Category | AI (primary) | AI (secondary) | CS (endogenous) |
|---|---|---|---|
| Infectious | TB adrenalitis, disseminated fungal (histoplasmosis, cryptococcus) | HIV‑related pituitary disease, TB meningitis | HIV‑associated adrenal hyperplasia (rare) |
| Autoimmune | Autoimmune adrenalitis (Addison’s disease) | Autoimmune hypophysitis | ACTH‑secreting pituitary adenoma |
| Hemorrhagic / Infarct | Waterhouse‑Friderichsen syndrome ( meningococcemia) | Pituitary apoplexy, postpartum pituitary necrosis | – |
| Metabolic / Infiltrative | Amyloidosis, sarcoidosis, hemochromatosis | – | – |
| Iatrogenic | – | Chronic glucocorticoid therapy → suppression | Long‑term oral or inhaled steroids, topical high‑potency steroids |
| Genetic | Congenital adrenal hyperplasia (21‑hydroxylase deficiency) | – | Carney complex, McCune‑Albright syndrome |
| Miscellaneous tropical | Severe malaria with adrenal hemorrhage, sickle‑cell vaso‑occlusion of adrenal vessels | – | – |
| Neoplastic | Metastatic adrenal disease | Pituitary macroadenoma, ectopic ACTH tumour (small‑cell lung, bronchial carcinoid) | Ectopic ACTH secretion, adrenal adenoma/carcinoma |
Risk factors specific to Kenya: high TB prevalence, HIV burden, malaria endemicity, sickle‑cell disease clusters, limited access to early imaging, and widespread use of over‑the‑counter steroids.
Pathophysiology
Adrenal insufficiency
- Destruction or dysfunction of adrenal cortex → ↓ cortisol (and ↓ aldosterone in primary)
- ↓ cortisol → loss of stress‑mediated glucose mobilisation, anti‑inflammatory tone → hypotension, fatigue, hypoglycaemia
- Primary ↓ aldosterone → Na⁺ loss, K⁺ retention, volume depletion → orthostatic hypotension, hyperkalaemia
- Loss of negative feedback → ↑ ACTH (primary) → hyperpigmentation (melanocyte stimulation)
Cushing syndrome
- Excess glucocorticoid source (ACTH‑dependent or independent) → ↑ cortisol
- ↑ cortisol → ↑ gluconeogenesis, insulin resistance → hyperglycaemia, central obesity
- ↑ cortisol → protein catabolism → muscle wasting, skin thinning, easy bruising
- ↑ cortisol → mineralocorticoid activity → hypertension, hypokalaemia
- Suppressed CRH/ACTH (if cortisol is exogenous) → adrenal atrophy (risk of adrenal crisis on withdrawal)
These concise arrows guide the clinical picture and laboratory expectations.
Clinical features
| Domain | Key questions / findings | Why it occurs |
|---|---|---|
| General | • Onset and duration of symptoms (acute vs insidious) <br>• Weight loss or gain, change in appetite <br>• Fatigue, weakness, dizziness on standing <br>• Fever, night sweats, recent infections | Weight loss & anorexia reflect glucocorticoid deficiency (AI) or catabolism in Cushing. Orthostatic dizziness signals mineralocorticoid loss (primary AI). Fever/night sweats may hint at TB or HIV‑related adrenalitis. |
| Skin & integument | • Hyperpigmentation of buccal mucosa, palmar creases, scars (AI) <br>• Easy bruising, thin skin, purple striae, facial rounding, dorsocervical “buffalo hump” (Cushing) | ACTH excess stimulates melanocytes → hyperpigmentation. Excess cortisol impairs collagen → thin skin, bruising, striae. |
| Cardiovascular | • Syncope or presyncope, palpitations <br>• Hypertension (especially in Cushing) <br>• History of electrolyte disturbances (salt craving, polyuria) | Mineralocorticoid deficiency → Na⁺ loss, volume depletion → syncope. Cortisol excess potentiates vasoconstriction → hypertension. |
| Gastro‑intestinal | • Nausea, vomiting, abdominal pain <br>• Diarrhoea or constipation <br>• Change in bowel habits after steroids (Cushing) | Glucocorticoid deficiency reduces gastric mucosal protection; excess cortisol slows gut motility. |
| Genitourinary | • Polyuria, polydipsia (AI) <br>• Decreased libido, menstrual irregularities, hirsutism, acne (Cushing) | Lack of aldosterone → renal water loss. Cortisol excess cross‑reacts with androgen receptors → virilisation. |
| Musculoskeletal | • Proximal muscle weakness, myalgia <br>• Bone pain, fractures (Cushing) | Catabolic effect of cortisol on protein; inhibition of osteoblasts → osteoporosis. |
| Neuro‑psychiatric | • Mood swings, irritability, depression, anxiety <br>• Cognitive slowing, insomnia <br>• Psychosis (severe Cushing) | Cortisol influences neurotransmitter balance; deficiency causes lethargy, excess causes agitation. |
| History of exposures | • Prior TB, HIV status, chronic malaria, rheumatic disease, sickle cell crises, long‑term antifungal or antiretroviral therapy <br>• Use of exogenous steroids (oral, inhaled, topical) <br>• Recent surgery, trauma, or severe illness | TB, HIV, disseminated fungal infection and infiltrative diseases can destroy adrenal cortex. Exogenous steroids suppress HPA axis → secondary AI after abrupt withdrawal. |
Differential diagnosis
| Condition | Points toward it | How to separate from adrenal insufficiency / Cushing |
|---|---|---|
| Primary adrenal TB | History of TB, weight loss, hyperpigmentation, low Na⁺, high K⁺ | Confirm with adrenal imaging (calcifications) and positive TB PCR; cortisol low with high ACTH |
| HIV‑related adrenalitis | Low CD4, opportunistic infections, adrenal enlargement on CT | Same labs as primary AI; viral load and opportunistic screen help |
| Chronic malaria (severe) | Recent malaria episodes, anaemia, splenomegaly | Malaria smear positive; cortisol may be low transiently but recovers |
| Autoimmune adrenalitis (Addison’s disease) | Other autoimmune diseases, family history, hyperpigmentation | Positive 21‑hydroxylase antibodies; adrenal atrophy on imaging |
| Exogenous steroid withdrawal | Recent taper or abrupt stop of steroids, no hyperpigmentation | Low ACTH, normal aldosterone; history of steroid use |
| Ectopic ACTH syndrome | Rapid onset Cushing features, severe hypokalaemia, lung mass | Very high ACTH, lack of diurnal variation, imaging of chest/abdomen |
| Pituitary ACTH adenoma (Cushing disease) | Gradual Cushing signs, menstrual changes, no severe hypokalaemia | Moderate ACTH, pituitary MRI lesion |
| Pheochromocytoma (mimics hypertension) | Paroxysmal headache, sweating, palpitations | Elevated catecholamines, not cortisol related |
| Severe depression / psychosis | Mood symptoms without physical signs | Normal endocrine labs, psychiatric assessment |
| Renal failure (causing electrolyte imbalance) | Edema, reduced urine output, high creatinine | Abnormal renal function tests, not primary adrenal hormone deficiency |
Investigations
| Test | What it answers | Interpretation |
|---|---|---|
| 8 am serum cortisol | Basal adrenal output | < 3 µg/dL → strong AI; > 18 µg/dL → AI unlikely |
| Plasma ACTH | Distinguish primary vs secondary AI | High ACTH → primary; low/normal → secondary |
| Cosyntropin (synthetic ACTH) stimulation | Adrenal reserve | ↑ cortisol ≥ 60 % of baseline at 30‑60 min → adequate; blunted rise → AI |
| Serum electrolytes (Na⁺, K⁺) | Mineralocorticoid effect | Hyponatraemia & hyperkalaemia → primary AI |
| Renin‑angiotensin‑aldosterone panel | Aldosterone deficiency | High renin with low aldosterone → primary AI |
| 24‑h urinary free cortisol | Total cortisol production (Cushing) | > 2‑3× upper limit → Cushing |
| Late‑night salivary cortisol | Loss of diurnal rhythm (Cushing) | Elevated > normal midnight level → Cushing |
| Low‑dose dexamethasone suppression test | Cortisol autonomy (Cushing) | Failure to suppress (< 1.8 µg/dL) → Cushing |
| High‑dose dexamethasone test | Source of ACTH (Cushing) | Suppression → pituitary; no suppression → ectopic |
| Pituitary MRI | ACTH‑producing adenoma | Microadenoma > 6 mm supports Cushing disease |
| Adrenal CT/MRI | Structural lesions (TB, hemorrhage, carcinoma) | Enlargement, calcifications, mass effect |
| 21‑hydroxylase antibodies | Autoimmune adrenalitis | Positive → autoimmune AI |
| TB PCR / GeneXpert on adrenal tissue or sputum | Infectious adrenalitis | Positive → TB adrenal involvement |
| HIV ELISA / viral load | HIV‑related adrenal disease | Positive HIV → consider opportunistic adrenal infection |
| Full blood count, ESR/CRP | Inflammatory/infective state | Elevated ESR/CRP supports TB or fungal infection |
Diagnosis and severity
- Confirm adrenal insufficiency
If 8 am cortisol is low and ACTH is high → primary AI; if ACTH low/normal → secondary.
Cosyntropin test confirming inadequate rise solidifies the diagnosis.
- Classify Cushing syndrome
Elevated 24‑h urinary cortisol or late‑night salivary cortisol confirms hypercortisolism.
Dexamethasone suppression pattern and ACTH level differentiate ACTH‑dependent (pituitary vs ectopic) from ACTH‑independent (adrenal adenoma/carcinoma).
- Assess severity
- Acute adrenal crisis: severe hypotension, hypoglycaemia, hyponatraemia, hyperkalaemia, altered mental status → emergency.
- Chronic AI: stable vitals, mild electrolyte abnormalities, weight loss, hyperpigmentation.
- Mild‑moderate Cushing: BMI ↑, hypertension, glucose intolerance, but no life‑threatening complications.
- Severe Cushing: marked hypertension, severe hypokalaemia, proximal myopathy, osteoporotic fractures, psychiatric disturbance.
- Stage according to clinical burden
For AI, use “crisis”, “moderate” (symptomatic but haemodynamically stable), “mild” (asymptomatic, only biochemical).
For Cushing, use “mild” (only metabolic changes), “moderate” (hypertension, diabetes, skin changes), “severe” (cardiovascular disease, fractures, neuro‑psychiatric crisis).
- Document aetiology – TB, HIV, autoimmune, exogenous, ectopic ACTH, adrenal tumour – as this directs definitive therapy.
Prepared for Year‑4 MBChB clinical rotations (Kenya). No drug dosages are provided; drug classes mentioned in management sections elsewhere.
Management
| Phase | Key actions | Rationale / safety notes |
|---|---|---|
| Immediate stabilisation | • Secure airway, breathing, circulation; give IV isotonic saline bolus (20 mL/kg) <br>• Administer stress‑dose glucocorticoid (hydrocortisone‑type) intravenously <br>• If adrenal crisis suspected, give dextrose‑containing fluid when hypoglycaemia present | Rapid volume expansion restores perfusion; glucocorticoid replaces cortisol that is absent and also provides mineralocorticoid activity. Avoid delay for labs. |
| Definitive treatment – Primary adrenal insufficiency | • Switch to oral glucocorticoid (hydrocortisone‑type) in divided doses mimicking circadian rhythm <br>• Add mineralocorticoid (fludrocortisone‑type) if renin is elevated or symptomatic hypotension persists <br>• Educate on sick‑day rules (double‑dose glucocorticoid during fever, surgery, trauma) | Oral regimen maintains basal cortisol; mineralocorticoid corrects Na⁺ loss and K⁺ retention. |
| Definitive treatment – Secondary/tertiary insufficiency | • Only glucocorticoid replacement (no mineralocorticoid) <br>• Taper slowly if cause is reversible (e.g., after pituitary surgery) | ACTH deficiency does not affect aldosterone. |
| Definitive treatment – Cushing syndrome | Pituitary (ACTH‑dependent): trans‑sphenoidal surgery first line; consider medical adrenal blockade (ketoconazole‑type, metyrapone‑type, osilodrostat‑type) if surgery unavailable or as bridge. <br>Ectopic ACTH: locate tumour (CT/MRI, functional imaging) → surgical resection; medical blockade if not resectable. <br>Adrenal (ACTH‑independent): unilateral adrenalectomy for adenoma; bilateral adrenalectomy only for bilateral hyperplasia or carcinoma. | Surgery offers cure; medical agents control cortisol while awaiting definitive surgery or when surgery contraindicated. |
| Monitoring | • Vital signs, fluid balance, electrolytes (Na⁺, K⁺) daily in acute phase <br>• Serum cortisol and ACTH after 24 h of therapy to confirm adequacy (avoid over‑replacement) <br>• For Cushing: urinary free cortisol, late‑night salivary cortisol, and blood pressure/ glucose trends after treatment | Prevent hypokalaemia, hypertension, hyperglycaemia and ensure adequate replacement. |
| Follow‑up | • Outpatient review 1–2 weeks after discharge, then 3‑monthly for the first year <br>• Long‑term: bone density, cardiovascular risk, infection prophylaxis, psychosocial support | Chronic glucocorticoid excess or deficiency have delayed sequelae. |
| Contra‑indications / safety | • Do not give mineralocorticoid in secondary insufficiency <br>• Avoid abrupt cessation of glucocorticoid – taper to prevent adrenal crisis <br>• In Cushing, avoid drugs that inhibit CYP450 if patient is on ketoconazole‑type therapy (e.g., certain antiretrovirals) | Tailor therapy to underlying axis and drug interactions common in Kenya (e.g., ART, anti‑TB). |
Complications and prognosis
| Condition | Acute complications | Chronic complications | Expected prognosis (with treatment) |
|---|---|---|---|
| Primary adrenal insufficiency | adrenal crisis (shock, arrhythmia, death) | chronic fatigue, salt craving, hyperpigmentation, osteoporosis, increased infection risk | Excellent if lifelong replacement is adhered to; mortality rises markedly with missed crises |
| Secondary/tertiary insufficiency | adrenal crisis (less common, mineralocorticoid spared) | similar to primary but less electrolyte disturbance; possible pituitary hormone deficits | Good with hormone replacement; prognosis depends on underlying pituitary disease |
| Cushing syndrome (any aetiology) | severe hypertension, hyperglycaemia, infection, thrombo‑embolism | osteoporotic fractures, muscle wasting, skin thinning, psychiatric illness, increased cardiovascular mortality | Curative surgery → normal life expectancy; persistent hypercortisolism → markedly reduced survival |
High‑yield exam points
- Look‑alike conditions:
- Addisonian crisis vs. septic shock – both have hypotension, but Addisonian crisis shows hyperkalaemia, hyponatraemia, and low cortisol.
- Cushing disease vs. exogenous steroid excess – ACTH is suppressed in exogenous use, elevated in pituitary disease.
- Commonest wrong first step:
- Giving only oral glucocorticoid in a patient with suspected adrenal crisis before IV fluids and IV steroid.
- Typical bedside examiner questions:
- “What would you give immediately and why?”
- “How would you adjust the glucocorticoid dose for a febrile illness?”
- “Explain the rationale for adding fludrocortisone in primary adrenal insufficiency.”
- “What test distinguishes ACTH‑dependent from ACTH‑independent Cushing?”
- Key mnemonic: “PAUSE” for adrenal crisis – Pressure low, Altered mental status, Urine output ↓, Sodium ↓, Electrolytes (K⁺ ↑).
Clinical case
Case: A 34‑year‑old woman with known HIV on ART presents with 2 weeks of profound fatigue, nausea, and darkening of the oral mucosa. BP 88/56 mmHg, pulse 112 bpm, skin hyperpigmentation of palmar creases, mild hyponatraemia and hyperkalaemia on labs. Random cortisol is low; ACTH is markedly elevated.
Questions
- What is the immediate management?
Answer: Give IV isotonic saline bolus and start IV hydrocortisone‑type replacement; draw blood for cortisol/ACTH before the first dose if possible.
- Which long‑term therapy is required?
Answer: Oral hydrocortisone‑type in divided doses plus fludrocortisone‑type mineralocorticoid; educate on sick‑day rules.
- Why is this presentation more common in HIV patients in Kenya?
Answer: Opportunistic infections (TB, CMV) and adrenal infiltration by Mycobacterium tuberculosis are prevalent, leading to primary adrenal destruction.
Practice questions
Question 1
A 45‑year‑old man with newly diagnosed hypertension and central obesity is found to have a midnight salivary cortisol of 30 nmol/L (normal < 5). What is the next best step?
A. Start antihypertensive therapy only
B. Perform a low‑dose dexamethasone suppression test
C. Order a pituitary MRI immediately
D. Begin empirical ketoconazole‑type therapy
Answer: B. Perform a low‑dose dexamethasone suppression test
Explanation: Confirmation of autonomous cortisol secretion is required before imaging or treatment.
Question 2
A child with sickle cell disease presents with vomiting, hypotension, and a serum potassium of 5.8 mmol/L. Which intervention should be avoided?
A. IV isotonic saline
B. IV hydrocortisone‑type
C. Immediate adrenal imaging
D. High‑dose fludrocortisone‑type
Answer: D. High‑dose fludrocortisone‑type
Explanation: Mineralocorticoid excess worsens hyperkalaemia; acute crisis needs glucocorticoid and volume replacement only.
Question 3
A patient on long‑term inhaled steroids for severe asthma develops facial rounding, striae, and glucose intolerance. Which statement is true?
A. This is primary Cushing disease
B. Serum ACTH will be suppressed
C. Bilateral adrenalectomy is first‑line
D. Ketoconazole‑type agents are contraindicated
Answer: B. Serum ACTH will be suppressed
Explanation: Exogenous glucocorticoid excess suppresses pituitary ACTH.
Question 4
A 60‑year‑old woman with a 2‑cm adrenal incidentaloma has normal blood pressure, normal potassium, and a midnight urinary free cortisol within reference range. What is the appropriate management?
A. Immediate adrenalectomy
B. Start fludrocortisone‑type therapy
C. Observe with repeat imaging in 12 months
D. Begin low‑dose glucocorticoid replacement
Answer: C. Observe with repeat imaging in 12 months
Explanation: Non‑functioning incidentaloma <4 cm without hormonal excess is managed conservatively.
Question 5
A patient with confirmed ectopic ACTH production from a small‑cell lung carcinoma is deteriorating despite ketoconazole‑type therapy. Which drug class is the next logical addition?
A. Mineralocorticoid receptor antagonist
B. Glucocorticoid receptor antagonist
C. Metyrapone‑type steroidogenesis inhibitor
D. Beta‑blocker
Answer: C. Metyrapone‑type steroidogenesis inhibitor
Explanation: Combining two steroidogenesis inhibitors can achieve better cortisol control when one agent is insufficient.
Drafted with AI assistance from standard references and reviewed for structure. Check details against your lecture notes and the Kenya MoH guideline.