👋 Returning to practice — adrenal incidentaloma
Two questions. Every time. Is it functioning? Is it malignant?
Adrenal incidentalomas are increasingly common as cross-sectional imaging is used more widely. Up to 5% of all abdominal CT scans reveal an adrenal mass. The vast majority are non-functioning benign adenomas — but you must systematically exclude autonomous cortisol secretion, phaeochromocytoma, primary aldosteronism, and malignancy in every case. ESE/ENSAT 2023 guidelines are the current European standard (updated from 2016 — key changes below). These align closely with UK practice.
Two questions: functioning? malignant?
HU ≤10 + homogeneous = benign at ANY size — no further imaging needed (2023 update: size cut-off removed)
Metanephrines required only if HU >10 or indeterminate features (2023 update: not needed for clearly benign HU ≤10 adenomas)
MACS = any post-DST cortisol >50 nmol/L without overt Cushing's (2023 update: 50–138 / >138 stratification abolished)
ALWAYS exclude phaeochromocytoma BEFORE biopsy or surgery
≥4cm + heterogeneous or HU >20 = MDT discussion, likely surgery
Initial Approach — Two Questions SCE
ESE/ENSAT 2023 · Dr Deyab adrenal clinic framework
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DefinitionAdrenal mass ≥1cm discovered incidentally during imaging performed for another reason. Prevalence on CT: ~4–5% of all abdominal scans. Most are benign non-functioning adenomas.
Question 1 — Is it functioning?Screen ALL incidentalomas ≥1cm for: (1) Autonomous cortisol secretion — 1mg overnight DST. (2) Phaeochromocytoma — plasma or urinary metanephrines (required if HU >10 or indeterminate features; NOT required for clearly benign HU ≤10 homogeneous adenomas — ESE/ENSAT 2023 R.3.9). (3) Primary aldosteronism — ARR (only if hypertensive and/or hypokalaemic). (4) Sex steroid excess (DHEA-S, testosterone, oestradiol) — especially if rapid virilisation, large lesion, or ACC suspected (ideally multi-steroid profiling by LC-MS/MS). Source: ESE/ENSAT 2023.
Question 2 — Is it malignant?Assess: unenhanced CT HU (≤10 + homogeneous = benign at ANY size — no further imaging. 2023 update: 4cm size cut-off removed for clearly benign lesions). HU 11–20 + homogeneous + <4cm = additional imaging or interval CT at 12 months. ≥4cm + heterogeneous or HU >20 = high malignancy risk, MDT discussion, usually surgery. Growth >20% in max diameter + ≥5mm absolute increase = suspicious (RECIST 1.1 adapted). Source: ESE/ENSAT 2023.
🚨 NEVER biopsy before excluding phaeochromocytoma. Biopsy of an unrecognised phaeochromocytoma can precipitate a fatal hypertensive crisis. This rule is absolute. Source: ESE/ENSAT 2023.
CT Imaging — HU Thresholds & Washout SCE
Dr Deyab adrenal washout reference · ACR algorithm (US) · ESE/ENSAT 2023
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Unenhanced CT — first decision point
≤10 HU — lipid-rich adenoma (ANY size)Diagnostic of benign adenoma regardless of size. No washout study needed. No further imaging required. ~70% of adenomas are lipid-rich and caught at this step. 2023 update: the previous 4cm size restriction for this rule has been removed — a homogeneous mass ≤10 HU is benign even if >4cm. Source: ESE/ENSAT 2023 R.2.3.
HU 11–20 + homogeneous + <4cm — low risk indeterminateMost are still benign (~90%). Options: (a) immediate additional imaging (FDG-PET/CT, MRI chemical shift, or washout CT) to resolve, or (b) interval imaging at 12 months by non-contrast CT/MRI. If additional imaging confirms benign: no further imaging needed. Source: ESE/ENSAT 2023 R.2.4.
≥4cm + heterogeneous or HU >20 — high malignancy riskDiscuss in MDT. In most cases, immediate surgery is the management of choice. Stage patient fully before surgery (thoracic CT and/or FDG-PET/CT). If surgery not performed: interval imaging in 6–12 months. Source: ESE/ENSAT 2023 R.2.5.
Other combinations — individualised MDT approachIncludes: ≥4cm + HU 11–20 · <4cm + HU >20 · <4cm + heterogeneous. Risk of malignancy is low but not negligible. Additional imaging (FDG-PET/CT preferred) is usually the first step. If still indeterminate: interval imaging at 6–12 months. Growth >20% max diameter + ≥5mm = surgical resection. Source: ESE/ENSAT 2023 R.2.6.
CT Washout Protocol — three phases
Phases required1. Unenhanced (pre-contrast). 2. Enhanced (60–70 seconds post-contrast). 3. Delayed (15 minutes post-contrast).
Absolute Percentage Washout (APW) — all 3 phases
APW = [(Enhanced HU − Delayed HU) / (Enhanced HU − Unenhanced HU)] × 100
APW ≥ 60% = benign adenoma (Sens/Spec ~90–98%)
Relative Percentage Washout (RPW) — no unenhanced phase
RPW = [(Enhanced HU − Delayed HU) / Enhanced HU] × 100
RPW ≥ 40% = benign adenoma
Non-adenomas retain contrast — interpret with cautionMetastases, phaeochromocytomas, and ACCs tend to retain contrast and wash out slowly: APW <60%, RPW <40%. However, the 2023 ESE/ENSAT guideline notes these thresholds have lower diagnostic accuracy than previously assumed — one study showed 22% of malignant tumours were missed using APW 60%. A cutoff of RPW ≥58% was suggested but needs external validation. Evidence rated ⊕○○○ (very low). FDG-PET/CT is now generally preferred as second-line imaging for indeterminate lesions. Source: ESE/ENSAT 2023; Schloetelburg et al 2021.
The decision tree: HU ≤10 → stop, benign. HU >10 → washout study. APW ≥60% or RPW ≥40% → adenoma. APW <60% and RPW <40% → non-adenoma, escalate. If no unenhanced phase available, use RPW only. Source: Dr Deyab adrenal washout reference.
Biochemical Screening — What to Request SCE
ESE/ENSAT 2023 · Dr Deyab incidentaloma clinic template
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1mg overnight DST — ALL incidentalomasCortisol ≤50 nmol/L (≤1.8 μg/dL) = adequate suppression — no autonomous cortisol secretion. No further endocrine follow-up needed. Cortisol >50 nmol/L (>1.8 μg/dL) = MACS (Mild Autonomous Cortisol Secretion). 2023 update: the previous 50–138 / >138 stratification is abolished — all values >50 without overt Cushing's features are classified as MACS. Interpret as a continuous variable, not categorical. Confirm ACTH-independency (suppressed/low-normal morning ACTH). Repeat DST recommended before any surgical decision. Screen for comorbidities potentially attributable to cortisol. Source: ESE/ENSAT 2023 R.3.2–R.3.4.
Plasma metanephrines — if HU >10 or indeterminate featuresRequired for all lesions with features NOT typical for a benign adenoma (HU >10, indeterminate, or heterogeneous). Must be done BEFORE any biopsy or surgery. Plasma free metanephrines (normetanephrine + metanephrine) — most sensitive test for phaeochromocytoma (~96% sensitivity). 24h urine fractionated metanephrines acceptable alternative. 2023 update: NOT required for clearly benign HU ≤10 homogeneous adenomas (probability of phaeochromocytoma essentially zero). If no unenhanced CT performed, measure metanephrines regardless. Source: ESE/ENSAT 2023 R.3.9; Endocrine Society.
ARR — if hypertensive and/or hypokalaemicNot routine for all incidentalomas — only if clinical features of primary aldosteronism present. ARR >100 (pmol/L per mU/L) with aldosterone >400 pmol/L = suggestive of PHA. Review interfering medications first (see ARR medications tab). Source: ESE/ENSAT 2023.
DHEA-S ± testosterone, oestradiol — if virilisation or large massElevated DHEA-S raises suspicion for adrenocortical carcinoma (ACC). Especially if rapid virilisation or lesion >4cm. Feminisation in a man (gynaecomastia, testicular atrophy) can indicate oestrogen-secreting ACC. Source: ESE/ENSAT 2023.
Additional baseline bloodsFBC · U&E (K+) · HbA1c · Fasting glucose · Lipids · LFTs · Calcium · Bone profile. DEXA scan if MACS with comorbidities (screen for vertebral fractures — ESE/ENSAT 2023 R.3.7). Source: ESE/ENSAT 2023.
MACS (Mild Autonomous Cortisol Secretion, formerly "subclinical Cushing's" or "autonomous cortisol secretion") is the most common functional abnormality in adrenal incidentalomas — found in ~20–50% depending on definition used. The 2023 ESE/ENSAT guideline uses a single threshold: any post-DST cortisol >50 nmol/L without overt Cushing's features = MACS. Even mild elevations are associated with increased rates of hypertension, T2DM, dyslipidaemia, vertebral fractures, and mortality (HR 1.54 in patients >50 nmol/L). Treatment decisions depend on comorbidity burden, age, sex, and patient preference — not degree of cortisol non-suppressibility. Low DHEA-S may help identify clinically relevant MACS. Source: ESE/ENSAT 2023; Prete et al 2022; Deutschbein et al 2022.
Red Flags — When to Escalate SCE
ESE/ENSAT 2023 · Dr Deyab incidentaloma clinic template
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Refer to MDT/Surgery — concern for malignancy
Imaging red flagsSize >4cm · Growth >1cm/year (or >20% increase) · Unenhanced HU >20 · Irregular margins or heterogeneous texture · Washout <60% absolute / <40% relative · Calcification / necrosis / haemorrhage · Known extra-adrenal malignancy (consider metastasis).
Biochemical red flags (ACC)Rapid virilisation + elevated DHEA-S · Elevated oestrogen + feminisation in a man. Source: ESE/ENSAT 2023.
Urgent endocrinology — functioning tumour
Confirmed phaeochromocytomaElevated metanephrines. Urgent α-blockade before surgery. Never operate without at least 10–14 days of alpha-blockade. Source: Endocrine Society; SfE.
MACS with relevant comorbiditiesPost-DST cortisol >50 nmol/L + comorbidities potentially attributable to cortisol. Discuss adrenalectomy in MDT if comorbidities are: (1) progressive, (2) difficult to treat, (3) associated with inappropriate end-organ damage for age, (4) unusual for age or discrepant from family history, or (5) multiple. Age, sex, general health, degree/persistence of cortisol non-suppression, and patient preference should be considered. Confirm ACTH-independency and repeat DST before surgery. Mortality from MACS appears mainly increased in patients <65 years, particularly women. Source: ESE/ENSAT 2023 R.3.8; Deutschbein et al 2022.
Confirmed Conn's syndromeElevated ARR + confirmatory test. Adrenal vein sampling before surgery if bilateral disease suspected. Source: ESE/ENSAT 2023.
Hypertensive crisis / catecholamine stormEmergency — IV phentolamine or nitroprusside. Admit to HDU. Source: SfE; BNF.
Follow-up guidance (ESE/ENSAT 2023 — major updates from 2016)
Benign adenoma (≤10 HU, homogeneous, non-functioning — any size)No further imaging required regardless of size (2023 update: 4cm size restriction removed). No repeated hormonal work-up unless new clinical signs of endocrine activity appear or comorbidities worsen (R.5.3 — strength upgraded from 'suggest' to 'recommend'). Discharge from specialist follow-up. Source: ESE/ENSAT 2023 R.5.1, R.5.3.
Indeterminate (HU >10, not operated)One repeat non-contrast CT or MRI at 6–12 months to exclude significant growth. Surgery if growth >20% in maximum diameter AND ≥5mm absolute increase (RECIST 1.1 adapted). If growth below threshold: consider one further imaging at 6–12 months. If no growth: no further imaging needed. Source: ESE/ENSAT 2023 R.5.2.
MACS — not operatedAnnual reassessment of comorbidities potentially attributable to cortisol ONLY: HbA1c, BP (ideally ambulatory), LDL/HDL cholesterol, triglycerides, body weight. Screen for vertebral fractures (R.3.7 — new 2023 recommendation). No routine repeat DST recommended. Discharge from specialist endocrine follow-up can be considered — monitoring by GP if adequate community surveillance available. Re-refer to endocrinology if comorbidities develop or worsen. Source: ESE/ENSAT 2023 R.5.4.
Post-surgical MACS patientsFollow by endocrinologist until HPA axis recovery documented. Perioperative glucocorticoid cover mandatory for all patients with pre-op post-DST cortisol >50 nmol/L. Glucocorticoid withdrawal syndrome can occur — monitor closely. Source: ESE/ENSAT 2023 R.4.7, R.4.8 (new recommendation).
🚨 Adrenal suppression awareness: Patients with MACS (even mild, post-DST cortisol just above 50 nmol/L) may have HPA suppression. Before any surgery or major illness, treat as at-risk for adrenal crisis — give hydrocortisone cover. The 2023 guideline mandates perioperative glucocorticoid stress doses for all patients with pre-op post-DST cortisol >50 nmol/L (R.4.7). This is easily missed in patients who are "not on steroids" but have MACS. Source: ESE/ENSAT 2023 R.4.7; SfE 2022.
🔬 Cushing's syndrome
Diagnosis first, source second — never skip the sequence
Cushing's syndrome is underdiagnosed because its features overlap with common conditions — obesity, T2DM, hypertension, depression, PCOS. The diagnostic sequence is critical: first confirm hypercortisolism, then localise the source. Never proceed to pituitary or adrenal imaging without biochemical confirmation. The most common cause is exogenous glucocorticoids — always check first.
Exogenous steroids — most common cause, exclude first
Cushing's disease (pituitary ACTH) = 60–70% of endogenous cases
Three first-line screening tests — any two abnormal = hypercortisolism confirmed
1mg ODST cut-off: cortisol <50 nmol/L = suppressed (normal)
After confirming hypercortisolism: ACTH to determine ACTH-dependent vs independent
CRH test + BIPSS to distinguish pituitary vs ectopic ACTH source
📋 Guidelines
Clinical Features — When to Suspect Cushing's SCE
Endocrine Society 2015 · Fleseriu et al Lancet Diabetes Endocrinol 2021
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High discriminatory features — should always prompt investigation
Purple/violaceous striae (>1cm wide)Wide purple striae (especially on abdomen, thighs, axillae) are highly specific. White striae = not Cushing's (can be from weight gain alone). Width and colour matter.
Proximal myopathyDifficulty rising from a chair, climbing stairs, lifting arms overhead. Test: ask patient to rise from squat without using arms. Highly specific and often missed.
Spontaneous easy bruisingWithout trauma or anticoagulation. Thin, paper-thin skin with multiple ecchymoses.
Unexplained osteoporosis in younger patientVertebral fractures in a pre-menopausal woman or a man <50 with no other cause.
Less discriminatory but common
Central obesity, buffalo hump, moon face, supraclavicular fat padsCommon but non-specific — also seen in simple obesity. Require confirmation with other features.
New or worsening T2DM, hypertension, dyslipidaemia in clusterMetabolic syndrome features — low discriminatory value alone but important in context.
Neuropsychiatric: depression, insomnia, cognitive impairmentOften present and may be the primary complaint. Can be mistaken for primary psychiatric illness.
Recurrent or opportunistic infectionsCandida, PCP, TB reactivation. Immune suppression from excess cortisol.
First-line investigation in suspected Cushing's
Exclude exogenous glucocorticoids FIRSTAsk about ALL steroid preparations: oral prednisolone, budesonide, inhaled corticosteroids, steroid creams, joint injections, and intranasal sprays — all can cause iatrogenic Cushing's and suppress the HPA axis. This is the most common cause of Cushing's syndrome. Source: Endocrine Society 2015.
The three features with the highest specificity for Cushing's syndrome are: (1) proximal myopathy, (2) wide purple striae, and (3) spontaneous bruising. If all three are present, the pre-test probability is high enough to warrant formal biochemical screening regardless of other features.
Biochemical Diagnosis — Sequence SCE
Endocrine Society 2015 · Dr Deyab ODST reference · Imperial Endo Bible
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Step 1 — Confirm hypercortisolism (any two abnormal = confirmed)
1mg Overnight DST (ODST)Dexamethasone 1mg PO at 23:00. Cortisol measured at 08:00–09:00 next morning. Normal suppression = cortisol ≤50 nmol/L (≤1.8 μg/dL). Cortisol >50 nmol/L = failed suppression — if no overt Cushing's features, classified as MACS. For Cushing's screening: use as one of three first-line tests (two abnormal = hypercortisolism confirmed). Sensitivity ~95%, specificity ~80%. Source: Dr Deyab ODST reference; Endocrine Society 2015. Note: false positives with OCP (stop 6 weeks before), enzyme inducers (rifampicin, phenytoin, carbamazepine), depression, obesity, alcoholism, shift work.
24h Urinary Free Cortisol (UFC)Two measurements required. Measures unbound cortisol over 24h — bypasses CBG effects. Normal <150 nmol/24h (immunoassay; LC-MS/MS gives lower reference ranges). Limitations: requires accurate 24h collection; fluid intake >5L/day falsely elevates; eGFR <30 reduces excretion. Source: Dr Deyab adrenal testing reference.
Late-night salivary cortisolCortisol nadir normally occurs at 23:00–24:00. In Cushing's the nadir is lost. Two measurements. Normal <4–5 nmol/L (lab-dependent). Sensitivity ~93%, specificity ~90–95%. Practical for outpatients. Avoid contamination (brushing teeth, mouthwash). Source: Endocrine Society 2015.
Urine steroid profile — specialist testMeasures full steroid metabolome (GC-MS or LC-MS/MS). Preferred in specialist centres for: distinguishing Cushing's subtypes, diagnosing CAH, characterising adrenal incidentalomas. Largely supersedes UFC when available. Available at Barts, Edinburgh, Birmingham. Source: Dr Deyab adrenal testing reference.
Step 2 — Determine ACTH dependency
ACTH level (09:00)ACTH <1.1 pmol/L (<5 pg/mL) = ACTH-independent → adrenal source (adenoma, ACC, bilateral hyperplasia). ACTH >2.2 pmol/L (>10 pg/mL) = ACTH-dependent → pituitary (Cushing's disease) or ectopic ACTH. Borderline 1.1–2.2: repeat or proceed to CRH test. Source: Endocrine Society 2015.
Step 3 — Localise ACTH source (if ACTH-dependent)
Pituitary MRIFirst-line for Cushing's disease. Microadenoma (<10mm) found in ~50% — many are <6mm and may be invisible on MRI. A normal MRI does NOT exclude Cushing's disease. Source: Endocrine Society 2015.
High-dose DST (HDDST) — 8mg overnightCushing's disease: cortisol suppresses >50% (pituitary retains some feedback sensitivity). Ectopic ACTH: cortisol does NOT suppress (<50% reduction). Sensitivity ~60–80% for distinguishing pituitary vs ectopic. Source: Oxford Handbook of Endocrinology and Diabetes.
CRH stimulation testCushing's disease: ACTH rises ≥35% and cortisol rises ≥20% after CRH. Ectopic ACTH: absent or blunted response. Used with BIPSS for maximum discrimination. Source: Endocrine Society 2015.
BIPSS (Bilateral Inferior Petrosal Sinus Sampling)Gold standard for confirming Cushing's disease vs ectopic ACTH. Measures ACTH in bilateral petrosal sinuses vs peripheral blood simultaneously. Central:peripheral ratio ≥2 (basal) or ≥3 (after CRH) = Cushing's disease. Ratio <2 = ectopic ACTH. Performed in specialist neuroradiology centre. Also lateralises pituitary adenoma. Source: Endocrine Society 2015.
The BIPSS is the most important and most underused test in Cushing's work-up. It is the only test that reliably distinguishes Cushing's disease from ectopic ACTH when pituitary MRI is normal or ambiguous. Every patient with ACTH-dependent Cushing's should have BIPSS before pituitary surgery is planned — operating on the wrong gland is catastrophic.
Cushing's — Treatment Overview SCE
Endocrine Society 2015 · Fleseriu et al Lancet Diabetes Endocrinol 2021
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Cushing's disease — pituitary surgery first-lineTrans-sphenoidal adenomectomy — remission in ~65–90% of microadenomas. Recurrence in ~20% at 10 years. Post-operative remission: cortisol <50 nmol/L in first 24h = good predictor. Post-op adrenal insufficiency expected — hydrocortisone cover required until HPA axis recovers (can take 6–24 months).
If surgery fails or recurs — second-line optionsRepeat pituitary surgery · Pituitary radiotherapy (stereotactic radiosurgery or fractionated) — takes 6 months–5 years for effect · Bilateral adrenalectomy (immediate cure of hypercortisolism but lifelong replacement + risk of Nelson's syndrome).
Nelson's syndromeAfter bilateral adrenalectomy — loss of cortisol negative feedback → unrestrained ACTH secretion → pituitary adenoma expansion. Risk ~15–25%. Presents with hyperpigmentation and expanding pituitary tumour. Lifelong pituitary MRI surveillance required post-adrenalectomy. Source: Fleseriu et al 2021.
Adrenal Cushing's — adrenalectomyLaparoscopic adrenalectomy for adenoma — curative. Bilateral for bilateral hyperplasia (nodular hyperplasia). Ensure peri-operative hydrocortisone cover — contralateral adrenal will be suppressed and requires 6–18 months recovery.
Ectopic ACTH — treat the sourceResect the ectopic source (bronchial carcinoid most common). If source not found or unresectable: bilateral adrenalectomy or medical therapy (ketoconazole, metyrapone, osilodrostat).
Medical therapy — for pre-op control or unresectableMetyrapone (UK first-line) — blocks 11β-hydroxylase. Ketoconazole — multiple enzyme inhibition. Osilodrostat (Isturisa) — potent 11β-hydroxylase inhibitor, licensed for Cushing's disease. Pasireotide — somatostatin analogue, for Cushing's disease (causes hyperglycaemia). Cabergoline — modest effect in some Cushing's disease.
🚨 Post-treatment adrenal insufficiency: After successful Cushing's treatment — whether surgical or medical — patients have suppressed HPA axis and WILL develop adrenal insufficiency. This can last 6–24 months. All patients need: (1) hydrocortisone replacement, (2) sick day rules, (3) steroid alert card, (4) regular testing for HPA axis recovery. Do not discharge without this. Source: Endocrine Society; SfE 2022.
💊 Addison's disease — primary adrenal insufficiency
A rare diagnosis that you must not miss
Addison's disease has a prevalence of approximately 1 in 10,000. It is most commonly autoimmune in the UK. Diagnosis is often delayed because symptoms are non-specific — fatigue, weight loss, nausea, postural hypotension, skin pigmentation. The short Synacthen test is the definitive diagnostic test. Treatment is straightforward but monitoring requires careful attention to replacement adequacy. Adrenal crisis is life-threatening and preventable — sick day rules must be taught to every patient.
Autoimmune = most common cause in UK (~80%)
SST: ACTH stimulation with peak cortisol <450 nmol/L at 30 or 60 min = adrenal insufficiency
21-hydroxylase antibodies confirm autoimmune aetiology
Standard replacement: hydrocortisone 15–25mg/day in 2–3 doses
Fludrocortisone 50–200mcg once daily — titrate to renin, not Na/K
Every patient must have sick day rules, steroid card, and emergency hydrocortisone injection kit
Diagnosis & Causes SCE
SfE 2022 · ESE/ENEA 2019 · Oxford Handbook of Endocrinology and Diabetes
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Clinical features — what to look for
SymptomsFatigue (most common) · Weight loss · Anorexia · Nausea/vomiting · Abdominal pain · Postural dizziness · Salt craving · Depression/anxiety.
SignsHyperpigmentation — buccal mucosa, skin creases, scars, nipples, pressure areas (primary = ACTH/MSH elevated). Postural hypotension. Vitiligo (autoimmune association). Hyperkalaemia, hyponatraemia, hypoglycaemia.
Note on pigmentationPigmentation occurs in PRIMARY adrenal insufficiency only (due to elevated ACTH/MSH). Central (secondary/tertiary) adrenal insufficiency — NO hyperpigmentation. This distinguishes primary from central clinically.
Causes — in UK practice
Autoimmune (~80% UK)Most common in UK. 21-hydroxylase antibodies positive in ~80–90%. Associated with APS Type 2 (thyroid disease + T1DM). Always check for co-existing autoimmune conditions.
TuberculosisSecond most common worldwide. Adrenal calcification on CT. Consider in patients from endemic areas or with TB history. 21-OH Ab negative.
Bilateral adrenal haemorrhageWaterhouse-Friderichsen syndrome (meningococcal septicaemia). Anticoagulation. Trauma. Presents acutely — haemodynamic collapse.
Metastatic diseaseLung, breast, renal cell carcinoma, lymphoma. Bilateral adrenal enlargement on CT. 21-OH Ab negative. In context of known malignancy.
Infiltrative / rareSarcoidosis · Amyloidosis · Haemochromatosis · Fungal infection (histoplasmosis, paracoccidioidomycosis) · Adrenoleukodystrophy (young men — check VLCFA).
Diagnostic testing
Short Synacthen Test (SST) — definitive test250mcg ACTH (tetracosactide) IV or IM. Cortisol at 0, 30, 60 minutes. Peak cortisol <450 nmol/L at 30 or 60 min = adrenal insufficiency. Source: SfE 2022; Imperial Endo Bible. Note: assay-dependent — imperial uses Abbott Alinity, cut-off 450 nmol/L. Other assays may differ.
09:00 basal cortisol — screening<100 nmol/L = adrenal insufficiency very likely. >450 nmol/L = adrenal insufficiency very unlikely. 100–450 nmol/L = SST required. Source: SfE 2022.
Additional testsACTH (elevated in primary — usually >100 ng/L) · 21-OH antibodies (confirm autoimmune aetiology) · Renin (elevated in primary, guides fludrocortisone) · Electrolytes (hyponatraemia, hyperkalaemia) · Fasting glucose (hypoglycaemia) · FBC (eosinophilia, lymphocytosis).
In a sick, haemodynamically unstable patient with suspected adrenal crisis: do NOT wait for SST results. Take blood for cortisol and ACTH, then give hydrocortisone 100mg IV immediately. A random cortisol <450 nmol/L in a stressed patient = adrenal insufficiency until proven otherwise. Source: SfE 2022.
Replacement Therapy — Principles SfE 2022
SfE 2022 · ESE/ENEA 2019 · Imperial Endo Bible 2025
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Glucocorticoid replacement
Hydrocortisone — dose and regimen15–25mg/day in 2–3 divided doses. Typical split: 10mg on waking + 5mg at midday ± 5mg at 15:00–16:00. Avoid late evening — impairs sleep and suppresses next-morning ACTH surge. Source: SfE 2022; Imperial Endo Bible 2025.
Aim to mimic diurnal rhythmLargest dose on waking (mimics early morning surge). Smallest or no dose in evening. Do not just achieve a "normal" cortisol level — the pattern matters.
Over-replacement risksWeight gain · Osteoporosis · Hypertension · Hyperglycaemia · Cushingoid features. Most patients receive higher doses than needed — err towards the lower end of the range. Source: SfE 2022.
Under-replacement risksFatigue · Hypotension · Nausea · Hyponatraemia · Risk of adrenal crisis under stress. The commonest presenting complaint in clinic is ongoing fatigue — do not automatically increase dose without objective assessment (day curve).
Plenadren (modified-release HC)Once-daily, taken fasting 30–60 min before breakfast. Slower rise, lower peak (200–400 nmol/L at ~1h), more sustained. More physiological profile. Consider if patient struggles with multiple daily doses or has quality of life concerns on standard HC. Source: SfE 2022; Imperial Endo Bible.
Mineralocorticoid replacement
Fludrocortisone 50–200mcg once dailyTaken in the morning. Dose titrated to RENIN — not Na/K alone. Target renin: mid-normal to upper reference range. Na/K are insensitive markers. Source: SfE 2022; Imperial Endo Bible.
Signs of under-replacement (fludrocortisone)Postural hypotension · Salt craving · Hyperkalaemia · Elevated renin · Fatigue / dizziness · Excessive thirst.
Signs of over-replacement (fludrocortisone)Hypertension · Hypokalaemia · Oedema · Suppressed renin. Reduce dose if oedema or resistant hypertension.
Important interactions — dose adjustment needed
Enzyme inducers — increase HC doseRifampicin · Phenytoin · Carbamazepine · St John's Wort — increase hepatic metabolism of HC → effective under-replacement. Double the HC dose when starting these drugs. Source: Imperial Endo Bible 2025; BNF.
HRT/oestrogens — may need dose increaseOestrogens increase CBG → more cortisol bound → effective reduction in free cortisol. May need HC dose increase when starting HRT. Source: Imperial Endo Bible 2025.
Titrate fludrocortisone to renin, not to Na/K. Sodium and potassium are insensitive guides — they can remain normal even with significant over- or under-replacement of mineralocorticoid. Renin is the correct biochemical target. If renin is suppressed → too much fludrocortisone. If renin is elevated → too little. Source: SfE 2022; Imperial Endo Bible.
Sick Day Rules & Adrenal Crisis Prevention SfE 2022
SfE 2022 · ESE/ENEA 2019 · Imperial Endo Bible 2025
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Double dose rule — intercurrent illnessAny illness with fever ≥37.5°C or significant physical stress: DOUBLE the hydrocortisone dose. Continue doubled dose until recovered (usually 24–48h after afebrile). Do NOT reduce dose early. Source: SfE 2022.
Triple dose — major surgery, significant traumaMajor surgery: 100–200mg hydrocortisone/24h by continuous IV infusion or IM injections. Reduce back to double dose as patient recovers. Normal dose when eating and clinically well. Source: SfE 2022; Imperial Endo Bible.
When to inject — self-injection protocolCannot take oral medication (vomiting, drowsy). Give IM hydrocortisone 100mg immediately. Attend A&E. Every patient must have an emergency IM hydrocortisone kit at home and know how to use it. Source: SfE 2022.
Every patient must leave clinic with
1. Steroid alert card (NHS blue card)Carry at all times. Shows healthcare professionals the patient is steroid-dependent and what to give in emergency. Available from pharmacy / specialist nurse.
2. Emergency hydrocortisone injection kitHydrocortisone 100mg/1mL IM ampoule + syringe. Patient/carer trained to use. Renewed regularly (check expiry at every clinic). Source: SfE 2022.
3. Medical emergency alert bracelet/necklaceRecommend MedicAlert® or equivalent. States "adrenal insufficiency — requires emergency hydrocortisone."
4. Written sick day rule guideClearly written instructions for: (a) minor illness, (b) major illness/vomiting, (c) surgery. Give to patient AND their GP. Source: SfE 2022.
🚨 Adrenal crisis = medical emergency. Do not delay treatment while waiting for results. If suspected adrenal crisis: give hydrocortisone 100mg IV immediately + 0.9% saline. Mortality from untreated adrenal crisis is preventable — ensure every patient is equipped and educated. Source: SfE 2022.
📊 Hydrocortisone day curve
The best current tool for monitoring HC replacement adequacy
There is no single validated blood test for adequacy of glucocorticoid replacement. The hydrocortisone day curve (HDC) is the best practical tool for guiding dose timing and distribution. The aim is to mimic the normal diurnal cortisol rhythm — not simply to achieve a "normal" level. Over-replacement carries real risks (osteoporosis, diabetes, cardiovascular disease) and is common in clinical practice.
Know exact dose timing before interpreting any curve
Immediate-release vs Plenadren — very different profiles
Peak (60 min post morning dose): target 400–700 nmol/L
Pre-midday trough: target 100–200 nmol/L
High peak >700 = over-replacement → reduce morning dose
Renin = primary guide to fludrocortisone dose, not Na/K
HDC Protocol — Standard Sampling Schedule SfE/Imperial
Imperial Endo Bible 2025 (Meeran) · SfE Clinical Guidance 2022
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Golden rules before the test
Record EXACT timing of every doseThe curve cannot be interpreted without knowing the precise time of each hydrocortisone dose on the test day. Document dose timing alongside each blood sample.
Know the formulationImmediate-release (standard) vs Plenadren/modified-release — the curves look completely different. Confirm formulation at every test. Do not apply immediate-release target ranges to Plenadren results.
Standardise conditionsNo intercurrent illness. No missed doses before test day. Fasting not essential but avoid large meals immediately before sampling. Avoid caffeine before first sample.
Assay caveatSerum cortisol by immunoassay is affected by CBG — high CBG (OCP, pregnancy) falsely elevates; low CBG (liver disease, critical illness) falsely lowers. If immunoassay doesn't correlate with clinical picture: request LC-MS/MS.
Standard sampling protocol (immediate-release HC)
| Timepoint | Timing | Tests |
|---|---|---|
| Pre-dose (T0) | Before first morning dose | Cortisol ± ACTH (optional), U&E, glucose |
| +30 min | 30 mins after 1st dose | Cortisol — rising phase |
| +60 min | 60 mins after 1st dose | Cortisol — PEAK (most important single reading) |
| Pre-midday | Just before midday dose | Cortisol — trough |
| +60 min post-midday | 60 mins after midday dose | Cortisol — 2nd peak |
| Pre-afternoon | If 3rd dose used | Cortisol — second trough |
| +60 min post-afternoon | 60 mins after afternoon dose | Cortisol — afternoon peak |
| Evening (optional) | ~20:00–21:00 | Cortisol — should be <50 nmol/L |
Minimum practical curve if resource-limited: Pre-dose → +60 min post-morning dose → Pre-midday → +60 min post-midday. This 4-point curve gives adequate information about peak, trough, and dose distribution in most cases. Source: Imperial Endo Bible 2025.
HDC Interpretation — Target Ranges & Patterns SfE/Imperial
Imperial Endo Bible 2025 (Meeran) · SfE 2022
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Target cortisol values — immediate-release HC
| Timepoint | Target Range | Action if outside |
|---|---|---|
| Peak (60 min post morning dose) | 400–700 nmol/L | Primary efficacy target — most important reading |
| Pre-midday trough | 100–200 nmol/L | Should not be <50 (under) or >350 (over) |
| Peak post-midday dose | 300–500 nmol/L | Lower than morning peak — expected and normal |
| Afternoon/evening trough | <100 nmol/L | Should be low — high evening = insomnia risk |
| Pre-morning trough | <50 nmol/L typical | >100 = possible over-replacement or late-dose effect |
Pattern recognition
| Pattern | Action |
|---|---|
| HIGH PEAK (>700 nmol/L) | Over-replacement — reduce morning dose by 2.5–5mg. Risk: Cushingoid features, osteoporosis, glucose intolerance. |
| LOW PEAK (<300 nmol/L) | Under-replacement OR poor absorption. Check timing. Ensure taken fasted. Consider malabsorption if persistent. |
| LOW TROUGH (<50 nmol/L pre-midday) | Dose interval too long — add or increase midday dose. Clinically: fatigue, dizziness before midday. |
| HIGH TROUGH (>300 nmol/L pre-midday) | Morning dose too high — reduce. Or doses given too close together. |
| FLAT CURVE | Normal on Plenadren. Abnormal on IR → check formulation. If IR: absorption issue or non-adherence. |
| HIGH EVENING (>100 nmol/L) | Afternoon dose too late or too large. Move final dose earlier (no later than 15:00–16:00). |
The Imperial Endo Bible (Meeran 2025) target for the morning peak is 400–700 nmol/L. Values >700 suggest over-replacement — a common problem. Many patients in UK practice are over-replaced, leading to iatrogenic metabolic and bone complications. If a patient on 20mg/day has a peak of 850, reduce the morning dose, don't wait for complications. Source: Imperial Endo Bible 2025; SfE 2022.
Fludrocortisone & Renin Monitoring SfE 2022
SfE 2022 · ESE/ENEA 2019 · Imperial Endo Bible 2025
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Fludrocortisone dose range50–200mcg once daily in the morning. Taken with or without food. Source: Imperial Endo Bible 2025; SfE 2022.
Titrate to renin — not Na/KPlasma renin (or renin activity) is the primary biochemical guide. Na and K are insensitive — they may remain within normal range even with significant over- or under-replacement. Target renin: mid-to-upper reference range. Source: SfE 2022; Imperial Endo Bible.
Adjust HC and fludrocortisone independentlyThe two replacement hormones serve different functions and must be titrated separately based on their respective markers (day curve for HC, renin for fludrocortisone).
Under vs over-replacement signs
Under-replacement (↑renin)Postural hypotension · Salt craving · Hyperkalaemia · Fatigue/dizziness · Nausea. Increase fludrocortisone dose.
Over-replacement (↓renin, suppressed)Hypertension · Hypokalaemia · Dependent oedema · Headache. Reduce fludrocortisone dose.
When to re-monitor
Timing of repeat monitoringNewly diagnosed: baseline curve 4–6 weeks after initiating replacement. Dose change: repeat curve 4–6 weeks after adjustment. Annual review: symptoms of over/under-replacement. Weight change >5kg: recalculate dose-to-weight ratio. New medications: enzyme inducers/inhibitors. New HRT or hormonal changes. Source: Imperial Endo Bible 2025; SfE 2022.
Coeliac disease impairs hydrocortisone absorption — an underrecognised cause of a suboptimal day curve (low peak despite adequate dose). Always screen for coeliac (TTG IgA) in Addison's patients with persistent low peaks or unexplained under-replacement pattern. This is particularly relevant as coeliac is part of the APS-2 surveillance screen. Source: Dr Deyab APS screen reference.
💧 Primary hyperaldosteronism (Conn's syndrome)
More common than you think — found in 5–10% of hypertensives
Primary hyperaldosteronism (PHA) is the most common cause of secondary hypertension and is underdiagnosed. It is not only a disease of hypokalaemia — approximately 40% of cases are normokalaemic. Targeted screening is recommended in high-risk groups. The aldosterone-renin ratio (ARR) is the first-line test but requires careful attention to interfering medications. Adrenal vein sampling (AVS) is needed to distinguish bilateral from unilateral disease before surgery.
40% of PHA is normokalaemic — do not rely on K+ alone
ARR >100 (pmol/L per mU/L) + aldosterone >400 pmol/L = suggestive
Stop spironolactone/eplerenone 6 weeks before ARR
Beta-blockers raise ARR (false positive) — stop 2 weeks before if safe
Correct hypokalaemia before testing (suppresses aldosterone)
AVS required before adrenalectomy to confirm unilateral disease
📋 Guidelines
Screening & ARR Testing SCE
Endocrine Society 2016 · Dr Deyab medications washout reference
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Who to screen for PHA
Indications for ARR testingResistant hypertension (>3 antihypertensives) · Hypertension + spontaneous or diuretic-induced hypokalaemia · Hypertension + adrenal incidentaloma · Hypertension at a young age (<40) · Family history of PHA or early CVD · Obstructive sleep apnoea + hypertension. Source: Endocrine Society 2016.
ARR testing conditions
Correct hypokalaemia before testingLow K+ suppresses aldosterone → false negative ARR. Correct to >3.5 mmol/L before testing. Source: Dr Deyab medications washout reference.
Adequate sodium intakeLow sodium diet falsely elevates aldosterone. Ensure normal salt intake during testing period. Source: Dr Deyab medications washout reference.
ARR interpretationARR >100 (pmol/L per mU/L) + aldosterone >400 pmol/L = suggestive of PHA. If elevated ARR while on ARB: highly suggestive (ARB should be lowering the ratio, yet it's still raised). Source: Dr Deyab medications washout reference.
Medications affecting ARR — from Dr Deyab washout reference
| Category | Examples | Effect on ARR | Washout |
|---|---|---|---|
| ARBs | Losartan, candesartan | ↑Renin → FALSE NEGATIVE | 4 weeks |
| ACE inhibitors | Ramipril, lisinopril | ↑Renin → FALSE NEGATIVE | 4 weeks |
| Thiazide/loop diuretics | Furosemide, bendroflumethiazide | ↑Renin → FALSE NEGATIVE | 4 weeks |
| DHP CCBs | Amlodipine, nifedipine | ↑Renin → FALSE NEGATIVE | 2 weeks |
| Beta-blockers | Bisoprolol, atenolol | ↓Renin → FALSE POSITIVE | 2 weeks |
| Central alpha-agonists | Clonidine, methyldopa | ↓Renin → FALSE POSITIVE | 2 weeks |
| NSAIDs | Ibuprofen, naproxen | ↓Renin → FALSE POSITIVE | 2 weeks |
| Spironolactone/eplerenone | Aldactone, Inspra | FALSE NEGATIVE | 6 weeks |
| Non-DHP CCBs | Verapamil, diltiazem | Minimal effect — can continue | — |
| Alpha-blockers | Doxazosin, prazosin | Minimal effect — can continue | — |
If it is unsafe to stop antihypertensives during washout period: switch patient to verapamil AND/OR doxazosin during the washout — both have minimal effect on ARR. Source: Dr Deyab medications washout reference.
Confirmatory Tests, AVS & Treatment SCE
Endocrine Society 2016 · Oxford Handbook of Endocrinology and Diabetes
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Confirmatory tests (after positive ARR)
Saline infusion test2L 0.9% saline IV over 4 hours. Measure aldosterone before and after. Post-infusion aldosterone >170 pmol/L = PHA confirmed (aldosterone not suppressed). Most widely used confirmatory test. Source: Endocrine Society 2016.
Fludrocortisone suppression testFludrocortisone 0.1mg QDS for 4 days + sodium loading. Day 4 aldosterone >170 pmol/L = PHA confirmed. Used if saline test inconclusive. Source: Endocrine Society 2016.
Subtype classification — bilateral vs unilateral
CT adrenalsFirst imaging step. Identifies macronodules, adenoma, or bilateral hyperplasia. CT cannot reliably distinguish unilateral from bilateral disease (false negative and false positive rates ~30%). CT alone is not sufficient to decide on surgery. Source: Endocrine Society 2016.
Adrenal vein sampling (AVS) — required before adrenalectomyGold standard for distinguishing unilateral (adenoma) from bilateral (idiopathic hyperplasia) PHA. Simultaneous sampling of aldosterone and cortisol from bilateral adrenal veins. Lateralisation index >4:1 (with ACTH stimulation) = unilateral disease. AVS is the only test that changes the surgical decision. Performed in specialist centres. Source: Endocrine Society 2016.
Treatment
Unilateral adenoma → laparoscopic adrenalectomyCurative in ~50% (hypertension resolves completely). Remaining 50% improve (require fewer antihypertensives). Pre-operative spironolactone for BP control and to allow the suppressed contralateral adrenal to recover.
Bilateral disease → mineralocorticoid receptor antagonist (MRA)Spironolactone (first-line) 25–100mg OD or eplerenone (if anti-androgenic side effects). Target: normalise K+, control BP. Spironolactone side effects: gynaecomastia, erectile dysfunction in men (consider eplerenone if intolerable). Source: Endocrine Society 2016.
CT adrenals is not sufficient to decide whether to operate. Up to 30% of unilateral adenomas are missed on CT, and bilateral hyperplasia can mimic an adenoma. AVS must be performed before adrenalectomy in all patients >40 years (or in those where CT is normal or bilateral). In younger patients (<40) with classical unilateral CT adenoma, some guidelines allow proceeding to surgery without AVS — but this is a specialist decision. Source: Endocrine Society 2016.
⚡ Phaeochromocytoma & paraganglioma
The great mimic — always think of it, always exclude it first
Phaeochromocytoma is rare (~1 in 100,000) but presents in multiple guises and can be fatal if missed. The classic triad (headache, palpitations, sweating) is only present in ~50% of cases. Up to 40% of phaeochromocytomas are associated with a germline mutation. All patients should have genetic testing. The pre-operative management (alpha-blockade) is as important as the surgery itself — operating without alpha-blockade risks fatal hypertensive crisis.
Classic triad present in only ~50% — do not rely on it
Plasma free metanephrines — most sensitive first-line test (~96%)
Up to 40% have germline mutation — genetic testing for ALL patients
Alpha-blockade BEFORE surgery — minimum 10–14 days, typically phenoxybenzamine
Never biopsy before excluding phaeo
10% rule (historical): 10% bilateral, 10% malignant, 10% extra-adrenal
📋 Guidelines
Diagnosis — Clinical & Biochemical SCE
Endocrine Society · ESE/ENSAT · Dr Deyab incidentaloma clinic template
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Clinical features
Classic triad (present in ~50%)Episodic headache · Diaphoresis (sweating) · Palpitations. Paroxysmal hypertension or hypertensive crises — often triggered by exercise, posture change, anaesthesia, abdominal pressure, contrast agents.
Other featuresPallor · Tremor · Anxiety/panic attacks · Flushing · Sustained hypertension (not always episodic) · Hyperglycaemia · Weight loss · Postural hypotension.
Syndromic associations — always ask about family historyMEN2A/2B (RET mutation) · Von Hippel-Lindau (VHL) · Neurofibromatosis type 1 (NF1) · SDH mutations (SDHB, SDHC, SDHD) — particularly SDHB associated with malignant pheochromocytoma. Carney's triad. Paraganglioma syndrome.
Biochemical diagnosis
Plasma free metanephrines (first-line)Most sensitive test (~96%). Measures normetanephrine and metanephrine. Fasting sample, seated after 30 min rest. False positives: sympathomimetic drugs, tricyclics, alpha-methyldopa, labetalol, catecholamine-producing foods (coffee, chocolate). Refer to specialist if borderline results. Source: Endocrine Society.
24h urine metanephrinesAcceptable alternative or when plasma test unavailable. Less sensitive for small or episodic tumours. Collect urine during or shortly after symptoms if episodic.
24h urine catecholaminesLower sensitivity than metanephrines. Use as adjunct if metanephrines borderline. Source: Endocrine Society.
Imaging
CT adrenals — first-line imagingHigh HU (usually >10), heterogeneous, often >3cm, slow washout (APW <60%). CT for anatomical localisation once biochemically confirmed. Source: ESE/ENSAT.
MIBG scan or DOTATATE-PETFor multifocal, extra-adrenal (paraganglioma), or malignant disease. DOTATATE-PET increasingly preferred (higher sensitivity). Source: ESE/ENSAT.
The 10% rule is outdated but useful for remembering the spectrum: ~10% bilateral, ~10% extra-adrenal (paraganglioma), ~10% malignant, ~10% familial (actually now closer to 40% with germline testing). With better genetic testing, the "familial" figure is now much higher. Source: Endocrine Society.
Pre-operative Management & Genetics SCE
Endocrine Society · ESE/ENSAT · SfE
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Pre-operative alpha-blockade — essential
Phenoxybenzamine (non-selective alpha-blocker)Start at least 10–14 days before surgery. Starting dose 10mg BD, titrate up (typical dose 20–30mg BD, sometimes higher). Target: BP <130/80 with postural hypotension (nasal congestion is expected — confirms adequate blockade). Source: Endocrine Society; Imperial Endo Bible.
Volume expansionHigh-salt diet and adequate fluid intake during blockade — expands the contracted intravascular volume. Reduces post-operative hypotension.
Add beta-blockade ONLY after alpha-blockade establishedFor refractory tachycardia after adequate alpha-blockade. NEVER give beta-blocker before alpha-blockade — unopposed alpha stimulation causes severe hypertensive crisis. This is a critical safety point. Source: Endocrine Society; Imperial Endo Bible.
Metyrosine (metirosine)Blocks catecholamine synthesis. Used as adjunct in high-risk or metastatic disease. Not first-line. Source: Endocrine Society.
Genetic testing — all patients
Who to testALL patients with phaeochromocytoma or paraganglioma should be offered germline genetic testing — 40% have an identifiable germline mutation. Source: Endocrine Society; ESE/ENSAT.
Genes to testRET (MEN2) · VHL · NF1 · SDHB / SDHC / SDHD / SDHA / SDHAF2 (paraganglioma syndromes) · MAX · TMEM127. SDHB mutations carry highest malignant risk. Source: Endocrine Society.
Cascade family testingIf germline mutation confirmed → offer testing to all first-degree relatives. Refer to genetics clinic. Lifelong surveillance for mutation carriers. Source: Endocrine Society.
Post-operative follow-up
Biochemical confirmation of curePlasma/urine metanephrines at 6 weeks post-surgery — should be undetectable. If elevated: residual or metastatic disease.
Long-term surveillanceAnnual biochemical testing for life — recurrence can occur years later. More frequent if SDH mutation or metastatic disease. Imaging surveillance based on genetic risk. Source: ESE/ENSAT.
🚨 NEVER give beta-blocker before alpha-blocker. Beta-blockade without alpha-blockade → unopposed alpha-adrenergic stimulation → severe, potentially fatal hypertensive crisis. This is one of the most dangerous clinical errors in phaeochromocytoma management. Alpha first, always. Source: Endocrine Society; Imperial Endo Bible 2025.
🧬 Autoimmune polyendocrine syndromes (APS)
Annual surveillance is the key — not just at diagnosis
Patients with Addison's disease require lifelong surveillance for associated autoimmune conditions. Most adult patients fall into APS Type 2 — this drives the surveillance list. Thyroid disease and T1DM are the two most commonly uncovered on annual review. Coeliac disease is worth annual checking because it also affects hydrocortisone absorption. Do not miss primary ovarian insufficiency in younger women.
APS Type 2 most common in adults: Addison's + thyroid + T1DM
Annual TSH, fasting glucose/HbA1c, TTG IgA, B12/FBC for all
Coeliac impairs HC absorption — suboptimal day curve → check TTG
APS Type 1 (AIRE gene): Addison's + hypoparathyroidism + CMC — rare
Women <45 — FSH/LH/oestradiol if oligomenorrhoea or amenorrhoea
21-OH antibodies confirm autoimmune aetiology — positive ~80–90%
📋 Guidelines
APS Classification & Baseline Screen SCE
Dr Deyab APS screen reference · SfE 2022 · ESE/ENEA 2019
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APS type classification
| Type | Genetics | Key Features |
|---|---|---|
| APS Type 1 | AIRE gene mutation | Addison's + hypoparathyroidism + chronic mucocutaneous candidiasis (CMC). Rare, childhood onset. → AIRE gene testing if suspected. |
| APS Type 2 | HLA-DR3/DR4 | Addison's + autoimmune thyroid disease + T1DM. Most common in adults. ± coeliac, pernicious anaemia, vitiligo. → Drives annual surveillance. |
| APS Type 3 | HLA-DR3 | Thyroid + T1DM/other. No adrenal involvement (but can develop). → Monitor for Addison's development. |
| APS Type 4 | Variable | Addison's + other autoimmune (not thyroid/T1DM). e.g. RA, PBC, alopecia, vitiligo. → Symptom-directed surveillance. |
AT DIAGNOSIS — full baseline autoimmune screen
| Condition | Tests | Notes |
|---|---|---|
| Autoimmune thyroid | TSH, FT4, TPO Ab, TG Ab | Most common APS-2 co-occurrence. TPO Ab positive in ~40% of Addison's even before thyroid dysfunction. |
| Type 1 Diabetes | Fasting glucose, HbA1c, GAD-65 Ab, IA-2 Ab | Screen even if glucose normal — antibodies precede T1DM by years. HC replacement raises glucose — interpret carefully. |
| Coeliac disease | TTG IgA + total IgA | Always check total IgA — IgA deficiency gives false negative TTG. Untreated coeliac impairs HC absorption. |
| Pernicious anaemia | Anti-parietal cell Ab, anti-IF Ab, B12, FBC | Macrocytic anaemia may be subtle — masked if concurrent iron deficiency. Check both B12 and iron together. |
| POI (women <45) | FSH, LH, oestradiol | Screen all women of reproductive age with menstrual irregularity. Anti-ovarian Ab not routinely used. |
| Hypoparathyroidism | Adj calcium, phosphate, PTH | Essential if APS Type 1 suspected — childhood onset, CMC, family history. |
| 21-OH antibodies | 21-OH Ab | Confirms autoimmune aetiology. Positive ~80–90%. If negative: consider TB, metastasis, haemorrhage, infiltrative. |
| Vitiligo / Alopecia | Clinical exam | Cutaneous markers of polyendocrine autoimmunity. New patches = prompt full autoimmune rescreen. |
Annual Surveillance & Symptom-Triggered Screening
Dr Deyab APS screen reference · SfE 2022
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Repeat every year
| Condition | Annual Test | Why Annual |
|---|---|---|
| Autoimmune thyroid | TSH (± FT4 if abnormal) | Most common new diagnosis on annual surveillance. Can develop years after Addison's onset. |
| Type 1 Diabetes | Fasting glucose or HbA1c | Insidious onset. HC replacement also affects glucose — interpret in that context. |
| Coeliac | TTG IgA | Can develop at any time. Also relevant to HC absorption — untreated coeliac = suboptimal day curve. |
| Pernicious anaemia | B12, FBC | Macrocytic anaemia may be masked by iron deficiency — always check B12 and iron together. |
| POI | FSH/LH/oestradiol (if oligomenorrhoea) | Particularly important under age 45. Often missed until established. |
| Vitiligo / Alopecia | Clinical exam | Marker of evolving polyendocrine disease. |
Screen more frequently — symptom-triggered
New hypothyroid symptomsTFTs immediately — do NOT wait for annual check.
Unexplained hypoglycaemiaUrgent glucose, C-peptide, insulin. Consider T1DM developing. Also consider HC over-replacement raising insulin sensitivity.
Oligomenorrhoea / amenorrhoeaFSH, LH, oestradiol, prolactin. POI vs hypothalamic.
GI symptoms (diarrhoea, weight loss)TTG IgA, consider OGD for coeliac. Also check HC absorption (suboptimal day curve may be coeliac).
Fatigue disproportionate to replacementB12, TFTs, HbA1c, FBC — broad screen before increasing HC dose.
New hypercalcaemiaPTH, calcium — hypoparathyroidism (APS-1) or sarcoidosis.
Coeliac disease is worth annual screening not just because it is an APS-2 association but because untreated coeliac impairs hydrocortisone absorption — an underrecognised cause of a suboptimal day curve. Before increasing the HC dose in a patient with a persistently low peak, check TTG IgA. Source: Dr Deyab APS screen reference.
Overnight Dexamethasone Suppression Test (1mg ODST) SCE
Dr Deyab ODST reference · Endocrine Society 2015 · Imperial Endo Bible
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IndicationScreening for autonomous cortisol secretion (ACS) in adrenal incidentaloma. First-line screening for Cushing's syndrome (as part of 2-test approach).
ProtocolDexamethasone 1mg PO at 23:00. Blood cortisol at 08:00–09:00 the following morning. Fasting not required. Source: Dr Deyab ODST reference; Imperial Endo Bible.
Results interpretationCortisol ≤50 nmol/L (≤1.8 μg/dL) = normal suppression — Cushing's/MACS excluded. Cortisol >50 nmol/L (>1.8 μg/dL) = MACS if no overt Cushing's features (2023 update: single threshold, no further substratification). For Cushing's screening: this is one of three first-line tests — two abnormal tests confirm hypercortisolism. Source: ESE/ENSAT 2023 R.3.3–3.4; Dr Deyab ODST reference.
Medications causing false positives (cortisol not suppressed)
| Drug | Mechanism | Action |
|---|---|---|
| OCP / oestrogen HRT | ↑CBG → ↑total cortisol | Stop 6 weeks before test |
| Phenytoin, carbamazepine, phenobarbital, rifampicin | CYP3A4 inducers → ↑dexamethasone clearance | Use alternative test (UFC, late-night salivary) |
| Topiramate, pioglitazone | ↑dexamethasone metabolism | Discuss with endocrinologist |
Medications causing false negatives (cortisol falsely suppressed)
| Drug | Mechanism | Action |
|---|---|---|
| Itraconazole, ritonavir, diltiazem, amiodarone, fluoxetine | CYP3A4 inhibitors → ↓dexamethasone clearance → more dexamethasone effect | May mask true positive — interpret with caution |
| Any exogenous steroid | Suppresses HPA axis / interferes with cortisol assay | Document ALL steroid use (inhalers, creams, injections) |
Conditions causing false positives
Non-Cushing's causes of failed suppressionSevere obesity · Major depression or psychiatric illness · Chronic alcohol excess · Acute physical illness or hospitalisation · Pregnancy · Shift work / sleep deprivation. These are pseudo-Cushing's states — cortisol may not suppress normally but patient does not have pathological Cushing's syndrome. Source: Dr Deyab ODST reference; Endocrine Society 2015.
A failed ODST alone does not diagnose Cushing's syndrome. Two of three first-line tests must be abnormal. A single failed ODST in an obese, depressed, or alcohol-using patient is very likely a pseudo-Cushing's state — do not start an extensive Cushing's work-up without confirming with a second test. Source: Endocrine Society 2015.
Short Synacthen Test (SST) SCE
SfE 2022 · Imperial Endo Bible 2025 (Meeran)
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IndicationAssessment of adrenocortical reserve. Diagnosis of primary or secondary adrenal insufficiency. Cannot distinguish primary from secondary (ACTH level does that).
ProtocolACTH (tetracosactide) 250mcg IV or IM. Cortisol at 0, 30, and 60 minutes. No fasting required. Can be done at any time of day. Source: Imperial Endo Bible 2025; SfE 2022.
InterpretationPeak cortisol ≥450 nmol/L at 30 or 60 min = adequate adrenal reserve (normal). Peak <450 nmol/L = adrenal insufficiency. Source: Imperial Endo Bible (Abbott Alinity assay). Note: assay-dependent — confirm local cut-off. Different assays have different thresholds.
When SST can be falsely normal in secondary adrenal insufficiencyRecent onset secondary adrenal insufficiency (<4–6 weeks) — the adrenal cortex is not yet atrophied and responds to exogenous ACTH. In this scenario: 09:00 basal cortisol or insulin tolerance test may be more reliable. Source: SfE 2022.
Low-dose SST (1mcg)More sensitive for detecting partial adrenal insufficiency. Used in some specialist centres. Less widely available. Source: SfE 2022.
The SST cortisol cut-off is assay-dependent — always check your local laboratory's reference range. The Imperial Endo Bible uses 450 nmol/L (Abbott Alinity assay). Some older guidelines used 550 nmol/L. Using the wrong cut-off for your local assay can lead to over- or under-diagnosis. Source: Imperial Endo Bible 2025 (Meeran).
24h UFC vs Urinary Steroid Profile SCE
Dr Deyab adrenal testing reference · Endocrine Society 2015
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Key distinction — two related but different tests
| Feature | 24h UFC | Urinary Steroid Profile |
|---|---|---|
| What it measures | Free cortisol only | Full steroid metabolome |
| Method | Immunoassay / LC-MS/MS | GC-MS or LC-MS/MS |
| Cushing's screening | Yes | Yes (+ better subtyping) |
| CAH diagnosis | No | Yes |
| Incidentaloma workup | Limited | Preferred in specialist centres |
| NHS availability | Widely available | Specialist labs only (Barts, Edinburgh, Birmingham) |
24h UFC — normal range and limitationsNormal <150 nmol/24h (immunoassay). LC-MS/MS gives lower reference ranges. Limitations: influenced by fluid intake >5L/day (falsely elevates) · Incomplete collection (falsely lowers) · Renal impairment eGFR <30 (reduces excretion). Requires 2 collections for diagnosis. Source: Dr Deyab adrenal testing reference; Endocrine Society 2015.
24h urinary steroid profile — clinical indicationsDifferentiating Cushing's subtypes (adrenal vs pituitary vs ectopic) · CAH (11β-hydroxylase, 21-hydroxylase deficiency) · Adrenal incidentaloma characterisation (malignant vs benign steroidogenic pattern) · Apparent mineralocorticoid excess · Assessing 5α/5β-reductase activity. The profile largely supersedes UFC when available. Source: Dr Deyab adrenal testing reference.
UFC is your screening tool. The urinary steroid profile is your diagnostic and subtyping tool. When the clinical question goes beyond "does this patient have Cushing's?" — when you need to know what type, or when investigating a complex incidentaloma — the steroid profile is superior. It is increasingly available in UK specialist centres. Source: Dr Deyab adrenal testing reference.
🚨 Adrenal crisis — life-threatening, preventable
Treat first. Investigate second. Do not delay.
Adrenal crisis carries a mortality of 6–15% per crisis episode. Most crises are triggered by intercurrent illness (infection most common) and are preventable with patient education and sick day rule compliance. If you suspect adrenal crisis in any patient — do not wait for investigation results. Draw blood for cortisol and ACTH, then give hydrocortisone 100mg IV immediately. Source: SfE 2022.
Draw cortisol/ACTH — then give IV hydrocortisone immediately
Do NOT wait for results before treating
IV saline — correct hypovolaemia, hyponatraemia
Monitor glucose — hypoglycaemia common
Treat the precipitant (infection is most common)
Every survivor needs education review before discharge
📋 Guidelines
Adrenal Crisis — Recognition & Immediate Management Emergency SCE
SfE 2022 · ESE/ENEA 2019 · Oxford Handbook of Clinical Medicine
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Recognition — suspect adrenal crisis in
Classic presentationKnown adrenal insufficiency + any of: profound fatigue/weakness · Hypotension/shock disproportionate to illness · Nausea/vomiting/diarrhoea · Abdominal pain · Altered consciousness · Fever. Precipitated by: infection (most common), surgery, trauma, missed doses, vomiting, pregnancy, physiological stress.
New presentation (unknown AI)Unexplained haemodynamic collapse · Hyponatraemia + hyperkalaemia · Hypoglycaemia · Hyperpigmentation + hypotension. Think adrenal crisis in any patient with unexplained shock who does not respond to fluids.
Immediate management — in order
Step 1 — Draw blood THEN treat (do not delay)Take blood for: serum cortisol · ACTH (EDTA tube, on ice, process immediately) · U&E · Glucose · FBC · Blood cultures if infection suspected. THEN give treatment immediately. Source: SfE 2022.
Step 2 — Hydrocortisone 100mg IV/IM STATDo not delay for results. Then hydrocortisone 200mg/24h by continuous IV infusion (50mg every 6h IV/IM if infusion not possible). Continue until patient is stable and able to take oral medication. Source: SfE 2022; Oxford Handbook of Clinical Medicine.
Step 3 — IV saline resuscitation0.9% NaCl 1L IV over 30–60 minutes. Repeat as needed to correct hypovolaemia. Hyponatraemia will correct with saline + cortisol replacement — do NOT use hypertonic saline or vasopressors before adequate corticosteroid replacement. Source: SfE 2022.
Step 4 — Correct hypoglycaemiaIf blood glucose <3.0 mmol/L: 50mL 20% glucose IV. Monitor glucose closely — hypoglycaemia is common and can be severe. Source: SfE 2022.
Step 5 — Treat the precipitantIdentify and treat the trigger: antibiotics if infection, surgical management if needed. The adrenal crisis will not resolve until the precipitant is treated. Source: SfE 2022.
Step 6 — MonitoringRegular observations: BP, HR, temperature, blood glucose every hour initially. U&E daily. HDU if haemodynamically unstable. Source: SfE 2022.
Stepping down — when patient is recovering
Transition back to oral HCWhen haemodynamically stable + tolerating oral intake: convert IV to oral HC. Double the usual oral dose until fully recovered (usually 24–48h), then return to maintenance. Source: SfE 2022.
FludrocortisoneHigh-dose IV hydrocortisone has sufficient mineralocorticoid activity — fludrocortisone not needed during IV phase. Resume fludrocortisone when switching to oral replacement. Source: SfE 2022.
Before discharge — education review
Every crisis = education opportunityReview: sick day rules · IM hydrocortisone technique · Steroid alert card · Emergency contact numbers · Trigger that caused this crisis and how to prevent recurrence. Source: SfE 2022.
🚨 Adrenal crisis diagnosis: In a sick patient with known adrenal insufficiency, if you are in ANY doubt — give hydrocortisone first. The risk of giving an unnecessary dose of steroids is far less than the risk of delaying treatment for a true crisis. Source: SfE 2022.
Mortality from adrenal crisis is 6–15% per episode — and most crises are preventable. The most important interventions are: (1) patient education at every clinic visit, (2) checking the emergency kit is in date, (3) GP awareness. If a patient has had a crisis, something in their education or access to emergency medication has failed — identify and fix it before discharge.
Adrenal Incidentaloma Clinic Letter Template
Dr Deyab Endo Unlocked standard template
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It was a pleasure seeing this patient in the Endocrinology Clinic today for assessment of an incidentally detected adrenal mass.
Indication for original imaging: ______________________
Lesion details: Side: L / R / Bilateral | Size: ____ cm | Unenhanced HU: ____ | CT washout: APW ____% / RPW ____%
Radiological classification: Adenoma / Indeterminate / Suspicious
Functional Screen:
1mg ODST: Cortisol _____ nmol/L — [ ] Normal (≤50) / [ ] MACS (>50 nmol/L — confirm ACTH-independency, repeat DST if surgery considered)
Plasma metanephrines: Normetanephrine _____ / Metanephrine _____ — [ ] Normal / [ ] Elevated
ARR (if hypertensive): _____ (aldosterone _____ pmol/L / renin _____ mU/L)
DHEA-S: _____ (if indicated)
Assessment: Based on the above investigations, this is a [ ] non-functioning / [ ] possibly functioning / [ ] confirmed functioning adrenal lesion with [ ] benign / [ ] indeterminate / [ ] suspicious imaging features.
Plan:
[ ] No further investigation required — clearly benign non-functioning adenoma (HU ≤10, homogeneous). Discharge from specialist follow-up.
[ ] Repeat non-contrast CT/MRI adrenals in ___ months (indeterminate mass — 6–12 months per ESE/ENSAT 2023)
[ ] Annual comorbidity surveillance for MACS (HbA1c, BP, lipids, weight) — consider discharge to GP with re-referral criteria
[ ] MDT referral for surgical consideration
[ ] Adrenal vein sampling arranged
[ ] Alpha-blockade initiated — surgery planned
[ ] Genetic testing arranged
⚠️ Adrenal suppression note (if MACS): This patient has evidence of mild autonomous cortisol secretion (MACS). They should be considered at risk of adrenal insufficiency during intercurrent illness or surgery. Perioperative glucocorticoid stress doses are recommended (ESE/ENSAT 2023 R.4.7). They have been advised to carry a steroid alert card and have been counselled regarding sick day rules.
The adrenal suppression note is the most commonly omitted element in adrenal incidentaloma letters. Any MACS (post-DST cortisol >50 nmol/L) carries a risk of perioperative adrenal crisis — the 2023 guideline mandates glucocorticoid cover for surgery in all such patients (R.4.7). Document this clearly so that surgical and anaesthetic teams are alerted.
Patient & Clinician Resources
Verified working links · UK focus
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Patient information
Addison's Clinical Advisory Panel (CAP)addisonsdisease.org.uk — patient charity, sick day rules, steroid cards
Pituitary Foundationpituitary.org.uk — Cushing's disease patient resources
Society for Endocrinology — patient resourcesyourhormones.info
Clinician guidelines
SfE — Adrenal Insufficiency guidanceendocrinology.org — adrenal insufficiency
ESE/ENSAT 2023 — Adrenal Incidentaloma guidelineFassnacht et al, EJE 2023 — Open Access
Endocrine Society — Cushing's guidelineendocrine.org — Cushing's syndrome
Imperial Endo Bible 2025imperialendo.co.uk — Meeran et al, practical protocols