• Paired retroperitoneal endocrine organs located at the superior pole of each kidney
• Right adrenal: pyramidal, sits behind IVC; left adrenal: crescentic, medial to upper pole of left kidney
• Each weighs ~4–6 g
• Arterial supply: superior (from inferior phrenic), middle (from aorta), inferior (from renal artery) — rich blood supply from three separate arteries
• Venous drainage: right adrenal vein → IVC directly (short!); left adrenal vein → left renal vein
• This venous anatomy matters for adrenal vein sampling (AVS) in Conn's syndrome

The adrenal gland has two functionally distinct regions:

Adrenal Cortex (mesoderm-derived, ~90% of gland mass):

Mnemonic for zones and hormones: "GFR" — Glomerulosa, Fasciculata, Reticularis → "Salt, Sugar, Sex" (the deeper you go, the sweeter it gets)

Adrenal Medulla (neural crest-derived):

• Chromaffin cells → catecholamines (adrenaline, noradrenaline)
• Functionally part of the sympathetic nervous system
• Not affected in adrenal insufficiency (cortical disease)

• CRH (corticotropin-releasing hormone) from the paraventricular nucleus of the hypothalamus stimulates ACTH (adrenocorticotropic hormone / corticotropin) release from anterior pituitary corticotrophs
• ACTH stimulates cortisol (and to some extent adrenal androgens) from the adrenal cortex
• Cortisol exerts negative feedback on both the hypothalamus (↓CRH) and anterior pituitary (↓ACTH)
• Cortisol has a circadian rhythm — peaks in the early morning (~06:00–08:00, "dawn cortisol") and nadirs around midnight. This is why 9 am cortisol is the standard screening test ^[1][3][5]

• Aldosterone secretion is primarily regulated by the RAAS and serum potassium, not ACTH
• ACTH has a minor permissive role but is not the primary regulator
• This is why secondary/tertiary AI (ACTH deficiency) does NOT cause significant mineralocorticoid deficiency — the zona glomerulosa continues to function under RAAS control
• In primary AI, the adrenal cortex itself is destroyed → both cortisol AND aldosterone are lost → full clinical picture with hyperkalaemia, salt wasting, and volume depletion ^[2]

Based on the location of the pathology, adrenal insufficiency is classified along the HPA axis into primary, secondary, and tertiary ^[1]:

"Primary adrenal insufficiency — disease intrinsic to the adrenal cortex" "Secondary adrenal insufficiency — ACTH insufficiency; pituitary disease that hampers the release of corticotropin (ACTH); lack of responsiveness of adrenal glands to ACTH" "Tertiary adrenal insufficiency — impaired synthesis or action of corticotropin-releasing hormone (CRF)" ^[1]

Cortisol is a stress hormone with diverse metabolic, immunological, and haemodynamic effects:

• Acts on the principal cells of the distal convoluted tubule and collecting duct
• Stimulates ENaC (epithelial sodium channel) → Na⁺ reabsorption → water follows → blood volume ↑
• Stimulates K⁺ secretion (via ROMK channels) and H⁺ secretion
• Net effect: ↑ Na⁺, ↑ H₂O, ↓ K⁺, ↓ H⁺

When ~90% of the adrenal cortex is destroyed:

1. ↓ Cortisol → loss of all cortisol-dependent functions:

   • Fasting hypoglycaemia — loss of gluconeogenic drive
   • Weight loss, anorexia, weakness — catabolic failure, loss of appetite-stimulating effect
   • Nausea, vomiting, abdominal pain — loss of GI support, autonomic instability
   • Hypotension — loss of permissive effect on catecholamines → vasodilation, ↓ vascular tone
   • Dilutional hyponatraemia — cortisol normally inhibits ADH; without cortisol, ADH is uninhibited → inappropriate water retention (SIADH-like mechanism)
   • Fatigue, depression, confusion — CNS effects

2. ↓ Aldosterone → loss of mineralocorticoid function:

   • Depletional hyponatraemia — Na⁺ wasting in urine
   • Hyperkalaemia — K⁺ retention
   • Metabolic acidosis — H⁺ retention (type 4 RTA-like picture)
   • Volume depletion → postural hypotension, salt craving
   • Combined with cortisol deficiency, the hyponatraemia is both depletional (from ↓ aldosterone) and dilutional (from ↓ cortisol/↑ ADH) ^[2]

3. ↑ ACTH → loss of negative feedback from cortisol:

   • ACTH is cleaved from pro-opiomelanocortin (POMC), which also gives rise to α-MSH (melanocyte-stimulating hormone)
   • ↑ ACTH (∼MSH) → hyperpigmentation — especially in sun-exposed areas, palmar creases, buccal mucosa, pressure points, scars, nipples ^[2]

4. ↓ Adrenal androgens (DHEA, DHEA-S):

   • In females: ↓ body hair (axillary and pubic) and ↓ libido (adrenal androgens are the primary source of androgens in women)
   • In males: less noticeable since testes provide the majority of androgens ^[2]

• ↓ ACTH → ↓ cortisol but aldosterone is preserved (RAAS-regulated)
• Therefore:
  • No hyperpigmentation (ACTH is low, not high)
  • No salt craving, normal K⁺, less postural hypotension (aldosterone intact)
  • HypoNa⁺ only dilutional (from SIADH-like mechanism of cortisol deficiency, NOT depletional) ^[2]
  • Hypoglycaemia, weight loss, fatigue, weakness still occur (cortisol-dependent)
  • May have features of other pituitary hormone deficiencies (GH, TSH, LH/FSH, prolactin)

"Similar for many endocrine conditions → along the HPA axis, primary, secondary, tertiary" ^[1]:

• Autoimmune
• Infectious
• Neoplastic
• Genetic/congenital
• Iatrogenic (drugs, surgery, radiation)
• Vascular (haemorrhage, infarction)
• Infiltrative

The symptoms of AI are often non-specific and insidious, which is why it is frequently diagnosed late. Understanding the pathophysiological basis of each symptom makes them easier to remember.

This is a medical emergency — often the first presentation of previously undiagnosed AI, or precipitated by physiological stress in a patient with known AI.

Precipitants:

• Intercurrent illness (infection, trauma, surgery) in a patient on maintenance steroids who fails to increase the dose ("stress dose")
• Abrupt withdrawal of chronic exogenous glucocorticoids
• Bilateral adrenal haemorrhage (Waterhouse-Friderichsen in meningococcaemia; anticoagulant therapy)
• First presentation of AI under acute stress

Clinical Features of Addisonian Crisis:

These are often the first hints picked up on routine bloods:

Key point: "And rule out hypothyroidism and adrenal insufficiency → TSH and morning cortisol before diagnosing SIADH" ^[7] — hyponatraemia with apparently elevated ADH effect should prompt exclusion of AI (and hypothyroidism) before labelling as SIADH. This is a critical exam point.

"When classifying the causes, the first question you would ask — is it ACTH dependent or independent? Think one step back the axis, see if it is appropriately low or inappropriately high" ^[8]. This principle, taught in the context of Cushing's, applies equally in reverse for AI. The key discriminator is the ACTH level relative to the cortisol level.

Primary AI — Differential causes:

Workup for cause of primary adrenal insufficiency: (1) 17-OH-progesterone → (+) classic CAH; (2) 21-hydroxylase Ab → (+) autoimmune destruction; (3) Very long chain FA (VLCFA) in males → (+) adrenoleukodystrophy; (4) CT adrenals → (+) other adrenal pathologies ^[9][10]

Secondary AI — Differential causes:

Tertiary AI — Differential causes:

This is the most common chronic presentation of AI — and has the broadest differential.

Key exam pitfall: Depression is the most common misdiagnosis for chronic AI ^[9][10]. Always check a 9am cortisol in any patient with unexplained chronic fatigue, weight loss, and low mood — especially if there are electrolyte abnormalities.

AI must be excluded in the workup of any hyponatraemia, particularly before diagnosing SIADH.

"Rule out hypothyroidism and adrenal insufficiency → TSH and morning cortisol before diagnosing SIADH" ^[7]

Hyperkalaemia is a feature specifically of primary AI (due to aldosterone deficiency). When you encounter hyperkalaemia, AI is one of many differentials.

When AI presents acutely as shock (Addisonian crisis), the differential includes other causes of undifferentiated shock.

Hyperpigmentation is the most specific clinical clue to primary AI, but other conditions can cause generalised or regional hyperpigmentation.

Fasting hypoglycaemia is particularly prominent in secondary/tertiary AI ("Hypoglycaemia more common in secondary or tertiary adrenal insufficiency — concomitant loss of GH secretion — absence of hypotension and dehydration allows patient to tolerate illness longer and present with symptoms of chronic glucocorticoid deficiency" ^[10]).

Addisonian crisis can present with severe abdominal pain mimicking a surgical abdomen. "Addison's" is listed as a metabolic differential for epigastric/abdominal pain ^[16].

This is the first-line test. The rationale is simple: cortisol is at its physiological peak in the early morning, so a low value at this time is highly significant.

The SST (also called the ACTH stimulation test, or cosyntropin test) is the primary dynamic test used to confirm adrenal insufficiency.

"Synacthen (tetracosactrin): synthetic form of ACTH. Ability of adrenal cortex to respond to synacthen stimulation is measured" ^[3].

Principle from first principles:

• You inject a synthetic ACTH analogue (synacthen/tetracosactrin)
• If the adrenal cortex is healthy, it should respond by producing cortisol → cortisol rises
• If the adrenal cortex is damaged (primary AI) or has atrophied due to chronic ACTH deprivation (secondary/tertiary AI), it cannot respond adequately → cortisol fails to rise

Standard-dose (250 μg) SST Protocol:

Interpretation:

Note on cut-off variation: The lecture notes and Ryan Ho Chemical Path use a cut-off of < 500 nmol/L at 30 or 60 min as diagnostic of AI ^[3], while other sources use 550 nmol/L. The Maksim notes state "cortisol ↑ < 200 nmol/L from baseline and peak ≤ 550 nmol/L" as abnormal ^[2]. In practice, the exact threshold varies slightly by assay — know the principle and the approximate range (500–550) rather than memorising one exact number.

Low-dose (1 μg) SST:

Once AI is confirmed, the basal plasma ACTH level distinguishes the level of pathology:

"Basal plasma ACTH + cortisol: often takes weeks to return" ^[9][10] — in clinical practice, results may be delayed, so clinical decision-making often proceeds in parallel.

"Ix if inconclusive: Insulin tolerance test (rare), glucagon stimulation test, CRH stimulation test" ^[2]

These are the routine investigations that raise suspicion before specific endocrine testing is ordered.

High Yield: "Rule out hypothyroidism and adrenal insufficiency → TSH and morning cortisol before diagnosing SIADH" ^[7]. If a patient presents with hyponatraemia, always check TSH and morning cortisol as part of the workup.

• Draw random cortisol + ACTH BEFORE giving hydrocortisone if time allows (takes seconds)
• But NEVER delay treatment — give IV hydrocortisone 100 mg stat immediately
• A random cortisol < 275 nmol/L during acute illness strongly supports AI (normally cortisol should be markedly elevated during physiological stress)
• Formal dynamic testing (SST) can be done after stabilisation

• In critically ill patients (e.g. septic shock), the HPA axis may be relatively insufficient
• A random cortisol < 275 nmol/L or a delta cortisol (rise after 250 μg synacthen) < 250 nmol/L supports CIRCI
• This is a functional diagnosis — treat empirically with stress-dose hydrocortisone (50 mg IV Q6H) if clinically appropriate

• SST is not reliable ≤ 2 weeks post-pituitary surgery ^[3] — adrenals haven't atrophied yet
• Use ITT or close clinical monitoring with empirical hydrocortisone cover
• Re-test HPA axis at 6–8 weeks post-surgery

• After prolonged steroid use, the HPA axis may take weeks to months to recover
• Serial morning cortisol levels or SST can monitor recovery
• Do not stop steroids abruptly — taper gradually

Once the patient is haemodynamically stable, eating and drinking, and electrolytes are normalising:

1. Reduce IV hydrocortisone gradually — e.g. 50 mg Q6H → 25 mg Q6H over 1–2 days → transition to oral
2. Start oral hydrocortisone at maintenance doses (see below)
3. Introduce fludrocortisone if primary AI and hydrocortisone dose drops below 50 mg/day
4. Complete aetiological workup (SST, ACTH, CT adrenals / MRI pituitary as appropriate)

"Management: glucocorticoid always + mineralocorticoid if needed" ^[17][23]

Drug of choice: Oral Hydrocortisone

Alternative Glucocorticoids:

Hydrocortisone is preferred over prednisolone or dexamethasone for chronic replacement because its short half-life allows a more physiological cortisol profile. Longer-acting glucocorticoids tend to over-replace in the evening and overnight, suppressing the normal early-morning cortisol rise and increasing the risk of metabolic complications.

Only required in PRIMARY adrenal insufficiency — because in secondary/tertiary AI, aldosterone production is preserved (RAAS-regulated, independent of ACTH) ^[2][10][22].

Drug of choice: Fludrocortisone (9α-fludrocortisone)

"Fludro-" from fluorine substitution at the 9α position of cortisol, which massively enhances mineralocorticoid potency.

The healthy adrenal gland increases cortisol output 2–10-fold during physiological stress (illness, surgery, trauma). A patient with AI on fixed replacement doses cannot mount this stress response — so the exogenous dose must be increased manually.

"Stress dose (double dose) in stress, e.g. infection, trauma" ^[2]

"Higher dose if DDI (e.g. anti-TB drugs)" ^[2] — Certain drugs increase the hepatic metabolism of cortisol via CYP3A4 induction, requiring higher replacement doses:

Conversely, drugs that inhibit CYP3A4 (e.g. ketoconazole, ritonavir) may increase cortisol levels — but this is rarely clinically relevant in the context of replacement.

"Steroid coverage may be required for surgery or trauma in patients with suppressed HPA axis" ^[17][22]:

• Currently on steroids regardless of dose ^[10][17][22]
• Patient given supraphysiological dose of glucocorticoid (prednisolone > 7.5 mg daily or hydrocortisone equivalent > 5 mg/m²/day) for > 2 weeks in the past year ^[9][17][22]
• Suspected adrenal or pituitary insufficiency ^[10][17][22]

Note: "If the current dose is larger than stress dose, there is no need for steroid coverage. This is commonly seen in patients in active phase SLE or nephrotic syndrome" ^[9] — if a patient is already on high-dose prednisolone (e.g. 60 mg/day for nephritis), their current dose already exceeds the physiological stress response and no additional cover is needed.

"Adrenal insufficiency (Conn's, Cushing's): IV hydrocortisone upon removal of adrenal gland" ^[21]:

• After unilateral adrenalectomy for Cushing's syndrome or functional adenoma: the contralateral adrenal is suppressed (from chronic cortisol excess) → needs post-operative glucocorticoid (± mineralocorticoid) cover until the remaining adrenal recovers — "Post-op glucocorticoid ± mineralocorticoid supplement until HPA axis recovers ~1 year later → Synacthen test before stopping supplements" ^[21][24]
• After bilateral adrenalectomy: lifelong glucocorticoid + mineralocorticoid replacement (the patient is functionally Addisonian)
• Risk of Nelson's syndrome if bilateral adrenalectomy — loss of cortisol feedback → unrestrained ACTH secretion → corticotroph adenoma growth → hyperpigmentation + mass effect. Prevented by prophylactic pituitary radiotherapy ^[21][24]

This is not just a "severe form" of chronic AI — it is a life-threatening emergency that constitutes the single most important complication of adrenal insufficiency. It is the leading cause of preventable death in patients with AI.

Precipitants of crisis (i.e. the "triggers" to watch for in known AI patients):

• Intercurrent infection (the most common precipitant)
• Surgery or trauma without adequate stress dosing
• Abrupt withdrawal of chronic exogenous steroids
• Non-compliance with replacement therapy
• Severe dehydration (vomiting, diarrhoea — "Admission if severe vomiting or diarrhoea (↓ oral absorption of hydrocortisone)" ^[2])
• Bilateral adrenal haemorrhage (Waterhouse-Friderichsen syndrome in meningococcaemia)

The key preventive strategy: patient education on sick-day rules, stress dosing, steroid card, MedicAlert bracelet, and emergency IM hydrocortisone kit ^[2]. Every crisis is a failure of prevention.

• Recurrent fasting hypoglycaemia impairs cognitive function, increases fall risk (especially elderly), and can cause seizures
• In children, chronic hypoglycaemia from undiagnosed AI can cause neurodevelopmental delay
• In patients with coexisting Type 1 DM (autoimmune polyglandular syndrome type 2), the development of AI causes recurrent unexplained hypoglycaemia because cortisol normally counter-regulates insulin. This is a classic exam scenario: T1DM patient whose insulin requirements suddenly decrease and who has recurrent hypos → consider concurrent AI ^[2]

Patients with AI have a 2–3-fold increased cardiovascular mortality even on replacement therapy:

Even with "adequate" replacement therapy, many AI patients report:

• Persistent fatigue and reduced exercise capacity
• Impaired cognition and concentration
• Depression and anxiety — "Chronic adrenal insufficiency: non-specific, often mis-diagnosed as depression" ^[9][10][17]; conversely, under-treated AI genuinely causes mood disturbance via cortisol deficiency effects on the CNS
• Reduced libido (especially women — ↓ adrenal androgens)
• Social isolation and impaired work productivity

• Cortisol has complex immunomodulatory effects — while excess cortisol is immunosuppressive, adequate cortisol is needed for a balanced inflammatory response
• In AI, the inability to mount an appropriate cortisol stress response during infection leads to an uncontrolled inflammatory cascade → can progress to sepsis → precipitates Addisonian crisis
• This creates a vicious cycle: infection precipitates crisis, and crisis impairs the ability to fight infection

This is an extremely common and under-recognised problem. Because "no Ix available" to precisely titrate hydrocortisone dose ^[2], many patients end up chronically over-replaced.

Monitor with plasma renin activity (target: upper-normal range), serum K⁺, and blood pressure ^[2].

Autoimmune Addison's rarely occurs in isolation. The associated autoimmune conditions are themselves sources of complications:

High Yield: Regular screening for associated autoimmune conditions (TFT, B12, HbA1c, coeliac antibodies) is essential in autoimmune Addison's ^[2].

• Active TB at other sites (pulmonary, meningeal, skeletal) — ongoing infection requires full anti-TB therapy
• Rifampicin-hydrocortisone interaction: rifampicin is a potent CYP3A4 inducer → accelerates cortisol metabolism → may precipitate crisis if hydrocortisone dose is not increased ^[2]. Conversely, when anti-TB therapy is completed and rifampicin stopped, hydrocortisone dose must be reduced or the patient risks over-replacement
• Adrenal calcification — a late sequela of granulomatous destruction; the adrenal function is unlikely to recover

When AI results from surgical removal of adrenal tissue (bilateral adrenalectomy, or post-unilateral adrenalectomy for Cushing's/Conn's):

• Cortisol requirements increase during pregnancy (especially third trimester) due to ↑ cortisol-binding globulin and ↑ metabolic demand
• Inadequate replacement → risk of Addisonian crisis during labour and delivery
• Fludrocortisone may need dose reduction due to the mineralocorticoid effect of progesterone
• Stress-dose hydrocortisone required during labour (treated as major surgery)

• Growth failure from both under-replacement (chronic illness) and over-replacement (glucocorticoid growth suppression)
• Recurrent hypoglycaemia — more dangerous in children (less glycogen reserve, immature counter-regulatory responses)
• Neurodevelopmental delay from chronic hypoglycaemia and electrolyte disturbance
• CAH-specific complications: virilisation, precocious puberty (if under-treated), adrenal rest tumours in testes

• Higher risk of Addisonian crisis (less physiological reserve, concurrent medications, comorbidities)
• Higher risk of falls from postural hypotension and hyponatraemia
• Osteoporosis risk compounded by glucocorticoid replacement on already age-related bone loss
• Drug interactions more likely (polypharmacy)