GC153 Biochemical Investigation Of Hypertension
Biochemical investigation of hypertension involves measuring serum electrolytes, renin, aldosterone, catecholamines, cortisol, and related metabolites to identify secondary causes such as primary aldosteronism, pheochromocytoma, or Cushing syndrome.
Biochemical Investigation of Hypertension
This lecture (GC 153) is a Chemical Pathology perspective on the laboratory workup of hypertension. It sits at the intersection of endocrinology, nephrology, and cardiology. While most hypertension (~90-95%) is essential/primary, this lecture focuses on the biochemical detective work needed to find the ~5-10% with a secondary cause — and on screening for complications and comorbidities in all hypertensive patients.
The four themes of the lecture:
- Biochemical investigations for hypertension — in general (why we do them, what we're looking for)
- Primary aldosteronism (the most common endocrine cause of secondary hypertension)
- Phaeochromocytoma (rare but deadly if missed)
- Clinical cases illustrating real-world application
How this fits into exams: This is extremely high-yield for SAQs, MCQs, and minicases on secondary hypertension, electrolyte interpretation, and endocrine data interpretation. Past papers repeatedly test ARR interpretation, drug effects on RAAS, phaeochromocytoma investigation, and the approach to the young hypertensive patient.
Theme 1: Biochemical Investigations for Hypertension — In General
The three aims of biochemical investigations in hypertension are: (1) Locate a secondary cause, (2) Prevent and screen for complications, and (3) Detect and treat comorbidities. [1]
High Yield — Three Aims of Investigation
Every hypertensive patient needs baseline bloods not just to "find a cause" but also to assess target organ damage and cardiovascular risk factors. This is a favourite framing in MCQs.
| Complication Domain | What to Check | Why |
|---|---|---|
| Renal | Creatinine, eGFR, urine protein/albumin | Hypertension causes nephrosclerosis; proteinuria indicates glomerular damage |
| Cardiac | ECG (LVH), Echo (LV mass/function) | Pressure overload → LVH → diastolic then systolic dysfunction |
| Cerebrovascular | Clinical assessment (history of TIA/stroke) | Hypertension is the #1 modifiable risk factor for stroke |
| Comorbidity | Investigation | Why |
|---|---|---|
| Diabetes mellitus | Fasting glucose, HbA1c | DM + HTN synergistically ↑ cardiovascular risk |
| Dyslipidaemia | Lipid profile | Combined metabolic risk drives atherosclerosis |
Secondary causes of hypertension include: Mineralocorticoid excess syndromes, Primary aldosteronism, Cushing syndrome, Hyperthyroidism, Phaeochromocytoma, Renal parenchymal diseases, Obstructive sleep apnoea, Coarctation of aorta. [1]
From supporting material, a useful mnemonic-style DDx for secondary hypertension includes [2][3]:
- Renal: CKD, glomerulonephritis, renovascular disease (renal artery stenosis), polycystic kidneys
- Endocrine: Primary aldosteronism (Conn's), Cushing's, phaeochromocytoma, acromegaly, hyper/hypothyroidism
- Respiratory: OSA
- Cardiovascular: Coarctation of aorta
- Drug-induced: steroids, NSAIDs, OCP, sympathomimetics, immunosuppressants, EPO
When to Suspect Secondary Hypertension
Think secondary when: age < 35 or > 55 at onset, severe/resistant HTN, spontaneous or diuretic-induced hypokalaemia, young stroke, adrenal incidentaloma, or symptoms suggestive of endocrine disease (sweating, flushing, weight changes, Cushingoid features).
Theme 2: Primary Aldosteronism
Mineralocorticoid excess results in: Hypokalaemic hypertension, Metabolic alkalosis, Left ventricular hypertrophy. [1]
Why these three?
- Aldosterone acts on the ENaC sodium channel in the distal tubule → Na⁺ retention (causing hypertension and volume expansion) and K⁺ secretion (causing hypokalaemia).
- K⁺ loss leads to H⁺ loss via the K⁺/H⁺ exchanger → metabolic alkalosis.
- Chronic pressure overload + direct aldosterone-mediated myocardial fibrosis → LVH (worse than other forms of hypertension at the same BP level).
Mineralocorticoids = steroids that activate mineralocorticoid receptors. They include Aldosterone, Cortisol, and Deoxycorticosterone. [1]
Why cortisol? This is a classic exam question. Cortisol has intrinsic mineralocorticoid activity and circulates at concentrations ~100-1000× higher than aldosterone. Normally, the enzyme 11β-HSD2 in the kidney converts cortisol → cortisone (which does not activate MR), protecting the MR from cortisol. When 11β-HSD2 is overwhelmed or defective, cortisol acts as a potent mineralocorticoid. This explains:
- Ectopic ACTH syndrome: Massively elevated cortisol overwhelms 11β-HSD2 → hypokalaemic hypertension + metabolic alkalosis (looks like mineralocorticoid excess)
- Apparent mineralocorticoid excess (AME): Genetic defect in 11β-HSD2
- Liquorice ingestion: Glycyrrhizinic acid inhibits 11β-HSD2
The DDx is organized by level of the pathway: [1]
| Level | Condition | Mechanism |
|---|---|---|
| Mineralocorticoid — Aldosterone | Primary aldosteronism: adenoma vs hyperplasia, familial vs sporadic | Autonomous aldosterone production |
| Mineralocorticoid — Cortisol | Ectopic ACTH syndrome, Glucocorticoid resistance | Cortisol overwhelms 11β-HSD2 |
| Mineralocorticoid — DOC | 11-hydroxylase deficiency, 17-hydroxylase deficiency | Accumulated DOC has mineralocorticoid activity |
| MR level | Activating mutation of MR | Constitutively active receptor |
| MR level | AME, Liquorice | 11β-HSD2 deficiency → cortisol activates MR |
| Signalling protein | Gordon syndrome | Hyperkalaemia + hypertension (WNK kinase gain-of-function → ↑NCC activity) |
| Sodium channel | Liddle syndrome | Gain-of-function of ENaC → ↑Na reabsorption |
Gordon Syndrome — The Exception
Gordon syndrome is unique because it causes hyperkalaemia with hypertension (not hypokalaemia). The WNK kinase mutation increases NCC activity → excess Na reabsorption in the DCT, but the downstream ENaC/ROMK is suppressed. Treatment: thiazide diuretics (which block NCC).
Measurement options include: (1) Individual mineralocorticoid levels — aldosterone, urine metabolites (tetrahydroaldosterone), cortisol, cortisone, DOC; (2) Transtubular potassium gradient (TTKG) — normally 4-10, reflects mineralocorticoid activity. [1]
TTKG prerequisites (must be met or TTKG is not interpretable):
- Urine Osm > serum Osm
- Urine Na > 40 mmol/L
- No potassium supplementation
TTKG > 10 in the setting of hypokalaemia suggests renal K wasting driven by mineralocorticoid excess.
High prevalence: about 8-12% in most countries. In Hong Kong, only 0.106% (Sy WM et al, HKMJ 2012) — this likely represents underdiagnosis. [1]
High-risk patient groups for PA: Severe hypertension, Drug-resistant hypertension, Spontaneous or diuretic-related hypokalaemia, Early onset hypertension or CVA at a young age, Relatives of patients with primary aldosteronism. [1]
High Yield — Who to Screen for Primary Aldosteronism
This list is directly exam-testable. If you see a young patient with resistant HTN + spontaneous hypokalaemia, primary aldosteronism should be at the top of your differential.
The Diagnostic Pathway: Screening → Confirmation → Subtyping
Screening: by Aldosterone-Renin Ratio (ARR). Confirmation: by one or more of four confirmatory tests. Confirmation not necessary in patients with classical presentation of hypokalaemia, undetectable renin, and high aldosterone. Subtyping: CT to exclude cancers + adrenal venous sampling. [1]
First principles: In primary aldosteronism, the adrenal gland autonomously produces aldosterone → aldosterone goes UP. The resulting volume expansion and sodium retention suppress renin via negative feedback → renin goes DOWN. Therefore the ARR increases. [1]
Primary aldosteronism = aldosterone production inappropriately high for sodium status, relatively autonomous of major regulators (angiotensin II & plasma potassium), non-suppressible by sodium loading. [1]
Sample conditions for ARR testing: [1]
- Out of bed for ≥ 2 hours
- Seated for 5-15 minutes
- Unrestricted salt intake
- Current practice: do not withhold most drugs but interpret with reference to current drug regimen
- BUT: MR antagonists (spironolactone, eplerenone), diuretics, and liquorice MUST be withdrawn for at least 4 weeks prior to testing
Best antihypertensives to use prior to ARR testing: Verapamil SR, Hydralazine, Alpha-blockers (Prazosin, Doxazosin, Terazosin) — these have minimal effect on the RAAS axis. [1]
Most drugs have more significant effect on renin than aldosterone. Hence the effect on ARR depends mainly on their action on renin level. [1]
| Drug Class | Effect on Renin | Effect on Aldosterone | Net Effect on ARR | Clinical Consequence |
|---|---|---|---|---|
| Beta-blockers | ↓↓ Renin | ↓ Aldosterone | ↑ ARR | False POSITIVE |
| Central agonists (clonidine, methyldopa) | ↓↓ Renin | ↓ Aldosterone | ↑ ARR | False POSITIVE |
| NSAIDs | ↓↓ Renin | ↓ Aldosterone | ↑ ARR | False POSITIVE |
| ACEi / ARB | ↑↑ Renin | ↓ Aldosterone (ACEi/ARB) or ↑ Aldosterone (diuretics) | ↓ ARR | False NEGATIVE |
| All diuretics (K-wasting or K-sparing) | ↑↑ Renin | ↑ Aldosterone | ↓ ARR | False NEGATIVE |
Exam Trap — Drug Effects on ARR
The most commonly tested trap: beta-blockers cause false positive ARR (because they suppress renin more than aldosterone). ACEi/ARB/diuretics cause false negative (because they raise renin). If a patient is on a beta-blocker and has a high ARR, you cannot confidently diagnose primary aldosteronism without repeating after drug washout or switching to a neutral agent.
Note: Renin inhibitors act differently depending on whether mass or activity assay is used. [1]
Potassium:
Plasma K is a significant regulator of aldosterone secretion. Effects generally NOT mediated by renin. Must correct K prior to testing. Hypokalaemia leads to low aldosterone. Hyperkalaemia leads to high aldosterone. [1]
This means: if your patient is hypokalaemic, aldosterone will be suppressed, potentially giving a false negative ARR. Always correct potassium before screening.
Sodium:
Sodium loading inhibits aldosterone secretion through renin. Should have normal salt diet. High salt diet suppresses renin. Low salt diet stimulates renin. [1]
Other factors:
Old age, Pre-menopausal women (higher renin in luteal phase), Pregnancy (very high renin AND very high aldosterone — because oestrogen stimulates hepatic angiotensinogen production → the entire RAAS axis is upregulated), Renal artery stenosis (high renin → secondary hyperaldosteronism, can confuse the picture). [1]
In HK, PRA (plasma renin activity) is used — no centre uses direct renin concentration. All assays used in HK are LC-MS/MS for both renin and aldosterone. [1]
Cut-off differs from centre to centre. Guideline suggestion: ARR > 750 (when renin in ng/mL/hr and aldosterone in pmol/L). Different HK hospitals use anything from 400-1000. No absolute gold standard. [1]
The guideline also suggests that aldosterone should be > 550 pmol/L for the ARR to be considered a positive screen — a high ARR with a low absolute aldosterone may just reflect very low renin rather than true aldosterone excess. [1]
Oral sodium loading test, Saline infusion test, Fludrocortisone suppression test (considered by some as gold standard), Captopril challenge test (considered by some as not-so-good). [1]
The principle behind all four: attempt to suppress aldosterone through volume/sodium expansion or RAAS blockade. If aldosterone remains high despite suppression, it is autonomous = primary aldosteronism.
Saline Infusion Test (used in Case 1): [1]
- Infuse 2L normal saline over 4 hours
- Post-infusion aldosterone < 140 pmol/L → unlikely PA
- Post-infusion aldosterone > 170 pmol/L → confirms PA
- Values between 140-170 are indeterminate
Confirmation not necessary in patients with classical presentation of hypokalaemia, undetectable renin, and high aldosterone. [1]
This distinction matters because:
- Adenoma → potentially curable by surgery (unilateral adrenalectomy)
- Bilateral hyperplasia → medical treatment with MR antagonists (bilateral adrenalectomy → adrenal crisis)
Balance/Postural Study: [1]
- Patient preparation same as ARR. Supine sample at 9 AM, then ambulate for 4 hours, then erect sample.
- Bilateral adrenal hyperplasia: Physiological, exaggerated rise of aldosterone when upright (because hyperplastic glands are angiotensin II-responsive)
- Adenoma: Paradoxical fall of aldosterone (because adenomas are ACTH-dependent, and ACTH has a diurnal fall by afternoon). Accuracy ~85% — some adenomas are still angiotensin II-responsive.
Frusemide Stimulation Test: [1]
- 40-80mg frusemide orally after overnight fast. PRA at 0 and 4 hours.
- No increase in renin: primary aldosteronism, hyporeninemic hypoaldosteronism
- Increased PRA: essential hypertension, phaeochromocytoma, Bartter syndrome, renovascular hypertension
Adrenal Venous Sampling (AVS): [1]
- Gold standard for lateralization
- Cortisol-corrected ratios: Unstimulated > 2:1 = unilateral; Stimulated > 4:1 = unilateral, < 3:1 = bilateral
- Catheter position confirmed by: adrenal vein cortisol ~10× higher than peripheral
- QMH criterion: Cortisol-corrected ratio > 2.5× peripheral on one side, with contralateral ratio no higher than peripheral → lateralization confirmed
High Yield — Subtyping Summary Table
| Feature | Adenoma | Bilateral Hyperplasia |
|---|---|---|
| Laterality | Unilateral | Bilateral |
| Hormone driver | ACTH-dependent | Angiotensin II-dependent |
| Biochemical severity | More severe (very low K, very high Ald) | Less severe |
| Postural test | Paradoxical ↓ Ald | Exaggerated ↑ Ald |
| AVS | Lateralizes to one side | Bilateral elevation |
| CT/MRI | Unilateral tumour | Normal or slightly enlarged |
| Treatment | Unilateral adrenalectomy | MR antagonist (spironolactone/eplerenone) |
Three familial types: [1]
| Type | Gene/Mechanism | Key Features |
|---|---|---|
| FH-I: Glucocorticoid Remediable Aldosteronism (GRA) | Fusion of 5' CYP11B1 promoter + 3' CYP11B2 coding sequence → aldosterone synthesis driven by ACTH instead of Ang II | AD inheritance; biochemically identical to PA; suppressible by dexamethasone; hybrid steroids 18-hydroxycortisol and 18-oxocortisol elevated; long-range PCR for diagnosis; uncommon in HK |
| FH-II | Molecular basis unclear; AD | Not well characterized |
| FH-III | Germline KCNJ5 mutation (Kir3.4 channel) → ↑Na conductance → depolarization → ↑aldosterone | Often severe; bilateral adrenal hyperplasia; may require bilateral adrenalectomy |
Theme 3: Phaeochromocytoma
A type of biogenic amine producing tumour. Neuro-endocrine tumour of adrenal medulla. [1]
Detected by measurement of plasma free metanephrines or urinary fractionated metanephrines. [1]
Why metanephrines and not catecholamines?
Rationale: COMT (catechol-O-methyltransferase) is NOT found in sympathetic nerve endings. It IS found within adrenal chromaffin cells. Therefore, metanephrines (products of COMT on catecholamines) are produced continuously within the tumour itself, regardless of whether the tumour is actively secreting catecholamines. This makes metanephrines more specific for phaeochromocytoma than catecholamines themselves (which can be elevated by stress, exercise, etc.). [1]
Evidence:
Plasma free metanephrines: 9 studies cited in 2014 ES guidelines — AUC 0.965-1.000. Urine fractionated metanephrines: Perry et al — sensitivity 97%, specificity 91%, AUC 0.991. [1]
Both are excellent tests; plasma free metanephrines are generally considered the initial screening test of choice.
CT rather than MRI is recommended for thorax, abdomen, and pelvis (sensitivity 88-100%) due to superior spatial resolution. For skull base lesions, MRI is better (Sn 90-95%). 18F-FDG-PET is preferred over 131I-MIBG SPECT because MIBG-SPECT is unable to detect some SDHx-related tumours. [1]
Well-known inherited syndromes associated with phaeochromocytoma: [1]
| Syndrome | Gene | Key Features |
|---|---|---|
| Von Hippel-Lindau | VHL | Phaeochromocytoma, clear cell renal cell carcinoma, haemangioblastoma |
| MEN2A | RET | Medullary thyroid carcinoma, phaeochromocytoma, primary hyperparathyroidism |
| MEN2B | RET | MTC, phaeochromocytoma, mucosal neuroma, intestinal ganglioneuroma, marfanoid habitus |
| FMTC | RET | Familial medullary thyroid carcinoma alone |
| Neurofibromatosis type 1 | NF1 | Clinical diagnosis (café-au-lait spots, neurofibromas, etc.) |
Less commonly known — SDH subunit mutations: [1]
| Condition | Gene | Features |
|---|---|---|
| PGL1 | SDHD | Phaeo, recurrent sPGL and hnPGL; 5% malignant; associated with GIST |
| PGL2 | SDHAF2 | Recurrent sPGL and hnPGL |
| PGL3 | SDHC | Onset relatively later |
| PGL4 | SDHB | Multiple/recurrent phaeo & PGL; 40% malignant; associated with GIST |
| PGL5 | SDHA | Rare cause of phaeo |
Even newer genes: TMEM127, MAX, HIF2, FH [1]
The 10% rule (from surgical/traditional teaching) [4]:
- 10% familial, 10% bilateral, 10% extra-adrenal, 10% malignant, 10% in children
- However, modern genetics shows up to 30-40% have germline mutations — the "10% rule" is an underestimate for familial cases.
First-line antihypertensive for phaeochromocytoma: Alpha-blocker (e.g., phenoxybenzamine, phentolamine, or prazosin/doxazosin). [5]
Exam Trap — Beta-blockers BEFORE Alpha-blockers in Phaeo
NEVER start a beta-blocker before alpha-blockade in phaeochromocytoma. Blocking beta receptors while alpha receptors are unopposed leads to unopposed alpha stimulation → severe hypertensive crisis. Always alpha-block first (typically phenoxybenzamine started 10-14 days pre-op), then add beta-blocker for tachycardia.
Theme 4: Clinical Cases
Clinical reasoning: Young-ish woman with hypertension and significant spontaneous hypokalaemia → must screen for primary aldosteronism.
Step 1 — ARR Screening: [1]
- Aldosterone = 1290 pmol/L, PRA = 0.57 ng/mL/hr
- ARR = 1290 / 0.57 = 2263 (which is > 750) → Positive screen
- Note: aldosterone > 550 pmol/L → meets absolute aldosterone threshold
Step 2 — Confirmatory Test (Saline Infusion Test): [1]
- Post-infusion aldosterone > 170 pmol/L → confirms primary aldosteronism
- Pre-infusion cortisol > post-infusion cortisol (confirming seated position and diurnal cortisol fall — this is a quality check, not a diagnostic criterion)
Step 3 — Imaging: [1]
- CT: left adrenal adenoma, 0.6 cm
- Discussion with patient on treatment:
- Medical: MR antagonist (spironolactone/eplerenone)
- Surgical: Adrenal venous sampling first to confirm unilateral disease and lateralization → then laparoscopic adrenalectomy
Presentation: Post-suction evacuation → desaturation, SOB, high BP, chills/rigors → CXR: acute pulmonary oedema → ECG: sinus tachycardia → hsTnI massively elevated (61520 → 126749 → 138780 ng/L) → Echo: global hypokinesia → impression: stress cardiomyopathy + septic abortion → ICU for ECMO.
Imaging finding: CT showed bilateral large adrenal masses (R: 5.1×3.9 cm, L: 3.3×2.6 cm) with central necrosis and peripheral avidity (HU > 120) → features suggestive of bilateral phaeochromocytoma.
Biochemistry: Grossly elevated plasma metanephrines → compatible with phaeochromocytoma.
Management: Bilateral adrenalectomy performed (patient will need lifelong steroid and mineralocorticoid replacement).
Genetics: TMEM127: c.314del; p.(Leu105ArgfsTer19) — heterozygous → Autosomal dominant TMEM127-related hereditary PPGL syndrome. Genetic findings assist family screening.
Teaching Point from Case 2
Phaeochromocytoma can present catastrophically — in this case mimicking stress cardiomyopathy with cardiogenic shock. The catecholamine surge caused a "Takotsubo-like" presentation. Always consider phaeo in unexplained haemodynamic instability + adrenal masses. Bilateral disease should prompt genetic testing.
Exam Intelligence
-
"Interpret this ARR" — You'll be given aldosterone and PRA values. Calculate ARR and state if screen is positive (> 750, or whatever cut-off stated). Check if aldosterone > 550 pmol/L.
-
"What drugs interfere with ARR?" — Know the table cold. Beta-blockers = false positive, ACEi/ARB/diuretics = false negative.
-
"What is the best investigation for phaeochromocytoma?" — Plasma free metanephrines (or 24h urine fractionated metanephrines). NOT VMA (outdated), NOT catecholamines (less specific).
-
"Name inherited syndromes associated with phaeochromocytoma" — VHL, MEN2, NF1, SDH mutations, TMEM127.
-
"Young patient with HTN + hypokalaemia — what is the most likely diagnosis?" — Primary aldosteronism (Conn's) until proven otherwise.
-
"Adrenal incidentaloma + HTN + hypokalaemia — workup?" — ARR, 24h urine catecholamines/metanephrines, 1mg overnight dexamethasone suppression test (to exclude subclinical Cushing's).
| Scenario | Primary Aldosteronism | Renal Artery Stenosis | Cushing Syndrome |
|---|---|---|---|
| Renin | LOW | HIGH | Variable |
| Aldosterone | HIGH | HIGH | May be normal (cortisol acting as mineralocorticoid) |
| ARR | HIGH | LOW (renin >> aldosterone) | Normal or mildly elevated |
| K⁺ | Low | Low | Low |
| Cortisol | Normal | Normal | HIGH |
| Additional clue | Resistant HTN | Renal bruit, atherosclerosis | Cushingoid features, proximal myopathy |
Past Paper Questions
"A 45-year-old man presented with severe hypertension and was suspected to have a phaeochromocytoma. Which of the following investigations would be useful in making the diagnosis of phaeochromocytoma?" [6]
- A. Iodocholesterol scan
- B. Meta-iodo-benzyl guanidine scan
- C. Radioiodine scan
- D. Sestamibi scan
Answer: B. MIBG scan. MIBG is taken up by chromaffin tissue and is used for functional imaging of phaeochromocytoma/paraganglioma. However, note the GC 153 lecture states 18F-FDG-PET is now preferred over MIBG-SPECT because MIBG may miss SDHx-related tumours. For MCQ purposes, MIBG is the classically tested answer for "investigation of phaeochromocytoma." Iodocholesterol = adrenal cortical imaging. Sestamibi = parathyroid. Radioiodine = thyroid.
"A 35-year-old man presented with palpitation and severe hypertension. Investigations showed a left phaeochromocytoma. Which of the following antihypertensive agents would you start first?" [7]
- A. Alpha blocker
- B. ACE inhibitor
- C. Beta blocker
- D. Thiazide
Answer: A. Alpha blocker. Always alpha-block first (e.g., phenoxybenzamine or doxazosin) before adding beta-blocker. Starting beta-blocker first → unopposed alpha stimulation → hypertensive crisis.
"A 30-year-old woman presented with hypertension and investigations were performed for underlying secondary causes. Her plasma renin activity was 9.56 ng/ml/hr (reference range: 0.2-2.8 ng/ml/hr) and aldosterone was 645 pmol/L (reference range: 28-444 pmol/L). Which of the following is the MOST LIKELY diagnosis?" [8]
- A. Adrenal adenoma
- B. Adrenal hyperplasia
- C. Cushing syndrome
- D. Renal artery stenosis
Answer: D. Renal artery stenosis. This is a discriminator question. Both renin AND aldosterone are elevated → this is secondary hyperaldosteronism (high renin driving high aldosterone). In primary aldosteronism (adrenal adenoma or hyperplasia), renin would be LOW. Cushing syndrome does not typically cause this pattern. Renal artery stenosis → reduced renal perfusion → ↑renin → ↑angiotensin II → ↑aldosterone.
"A 36-year-old obese man presented with hypertension and investigations were performed for underlying secondary causes. His morning plasma cortisol was 528 nmol/L (reference range 130-600), plasma renin activity was 0.1 ng/ml/hr (reference range 0.2-2.8) and aldosterone was 546 pmol/L (reference range 28-444). Which of the following is the MOST LIKELY diagnosis?" [9]
- A. Conn syndrome
- B. Cushing syndrome
- C. Essential hypertension
- D. Renal artery stenosis
Answer: A. Conn syndrome (Primary aldosteronism). The ARR = 546/0.1 = 5460 (massively elevated). Renin is suppressed (< lower limit of normal), aldosterone is elevated above reference range. Morning cortisol is normal (excludes Cushing). This is the classic primary aldosteronism pattern: ↑aldosterone + ↓renin. Renal artery stenosis would have ↑renin.
56F, incidental 1cm right adrenal lesion on CT + hypertension on amlodipine and hydrochlorothiazide + K 3.3 mmol/L. [10]
- Q1: "What is her active endocrine problem?" → Adrenal incidentaloma requiring biochemical workup (rule out phaeochromocytoma, primary aldosteronism, subclinical Cushing's)
- Q4: "Give possible causes of her hypokalaemia" → Hydrochlorothiazide (diuretic-induced), primary aldosteronism, GI losses, inadequate intake
- Section 3: Hormonal workup was normal including catecholamines, ARR, and ONDST. After stopping HCTZ, K normalized to 3.9. Subsequently found to have primary hyperparathyroidism.
Teaching point: This minicase tests the systematic workup of adrenal incidentaloma + the importance of recognizing drug-induced hypokalaemia (HCTZ) as a confounder before attributing it to primary aldosteronism.
- GC 066 (Fluctuating BP) [11]: Reinforces the principle of stopping diuretics, beta-blockers, and ACEi ≥ 2 weeks before dynamic biochemical tests for Conn's. Also emphasizes excluding other causes of hypokalaemia before investigating PA.
- GC 058 (High Blood Pressure) [12]: Contains the comprehensive table of hypertensive emergencies and their management. For phaeochromocytoma crisis: phentolamine is the first-line agent.
- IntroEndoInvestigations [13]: Screening algorithm overview — ARR for PA, ONDST for Cushing's, 24h urine catecholamines for phaeo, IGF-1 for acromegaly, TFT for thyroid disease.
- Block A – Endocrine Data Interpretation [14]: Clinical approach to secondary hypertension workup including history, physical exam signs (acromegalic/Cushingoid facies, system review), and targeted investigations.
High Yield Summary
1. Three aims of biochemical testing in hypertension: Find secondary causes, screen for complications (renal, cardiac, cerebrovascular), detect comorbidities (DM, dyslipidaemia).
2. Mineralocorticoid excess → Hypokalaemic hypertension + metabolic alkalosis + LVH. DDx organized by: mineralocorticoid type (aldosterone/cortisol/DOC), MR level (AME/liquorice), signalling (Gordon), sodium channel (Liddle).
3. Primary aldosteronism (8-12% prevalence): Screen with ARR (> 750), confirm with saline infusion test (post-infusion Ald > 170 pmol/L), subtype with postural study + CT + AVS. Adenoma → surgery; bilateral hyperplasia → MRA.
4. ARR drug interference: Beta-blockers/clonidine/NSAIDs → false positive. ACEi/ARB/diuretics → false negative. Best neutral drugs: verapamil SR, hydralazine, alpha-blockers. Withdraw MRA/diuretics/liquorice ≥ 4 weeks.
5. Correct K and ensure normal Na intake before ARR testing.
6. Phaeochromocytoma: Diagnose with plasma free metanephrines (or urine fractionated metanephrines) — metanephrines preferred because COMT is within tumour cells, not sympathetic nerves → more specific. Image with CT. Consider genetic testing (VHL, MEN2, NF1, SDH, TMEM127).
7. Always alpha-block before beta-block in phaeochromocytoma.
8. Primary vs Secondary hyperaldosteronism: Primary = ↑Ald + ↓Renin + ↑ARR. Secondary (e.g., renal artery stenosis) = ↑Ald + ↑Renin + low/normal ARR.
Active Recall - Biochemical Investigation of Hypertension
[1] Lecture slides: GC 153. Biochemical Investigation of Hypertension.pdf [2] Senior notes: Block A - High blood pressure_ hypertension.pdf [3] Senior notes: Maksim Medicine Notes.pdf (Endocrinology, p78) [4] Senior notes: Maksim Surgery Notes.pdf (Phaeochromocytoma, p205) [5] Past papers: 2022 Fourth Summative MCQ.pdf (Q32) [6] Past papers: 2021 Fourth Summative Assessment MCQ.pdf (Q36) [7] Past papers: 2022 Fourth Summative MCQ.pdf (Q32) [8] Past papers: 2023 Fourth Summative MCQ.pdf (Q32) [9] Past papers: 2024 Fourth Summative MCQ.pdf (Q30) [10] Past papers: 2021 Fourth Summative Minicase.pdf (Case 1) [11] Lecture slides: GC 066. I have fluctuating BP.pdf [12] Lecture slides: GC 058. High Blood Pressure.pdf [13] Lecture slides: IntroEndoInvestigations For Students (updated 102025).pdf [14] Senior notes: Block A - Endocrine Data Interpretation.pdf
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