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
Guideline-era warning
The lecture's primary-aldosteronism algorithm and numerical thresholds come from the 2016 Endocrine Society guideline, which was retired and replaced in 2025. The newer guideline conditionally suggests screening all people with hypertension when feasible and uses assay-specific probability-based pathways. Preserve the slide numbers for exams, but do not export the Hong Kong/local ARR or suppression-test cut-offs to another laboratory. [15]
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 and preferably a urine albumin:creatinine ratio (ACR) | CKD may be a cause or consequence of hypertension; albuminuria also refines cardiovascular and renal risk |
| Cardiac | ECG routinely; echocardiography when symptoms, examination or ECG make structural assessment useful | Pressure overload may cause LVH and dysfunction; echo is not a mandatory biochemical baseline test for every patient |
| 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 hypertension is young-onset, abrupt or rapidly worsening; severe/resistant; associated with spontaneous or diuretic-induced hypokalaemia, adrenal incidentaloma, young stroke, renal dysfunction/abdominal bruit, OSA features, drug exposure or a suggestive endocrine phenotype. Older age alone is not a general trigger; the pattern and pre-test probability matter.
Theme 2: Primary Aldosteronism
Mineralocorticoid excess results in: Hypokalaemic hypertension, Metabolic alkalosis, Left ventricular hypertrophy. [1]
This is the classic severe phenotype, not a required triad. Many patients with PA are normokalaemic; normal potassium does not exclude it.
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).
- ENaC-mediated sodium uptake makes the tubular lumen relatively negative and aldosterone increases distal H⁺ secretion; volume effects and hypokalaemia further sustain 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]
Reading the formula shown on the slide: TTKG = (urine K × serum osmolality) / (serum K × urine osmolality).
It attempts to estimate the potassium concentration gradient across the cortical collecting duct after adjusting for water reabsorption. A larger value was historically taken to imply stronger distal potassium secretion, but the calculation is meaningful only if its assumptions hold.
TTKG prerequisites (must be met or TTKG is not interpretable):
- Urine Osm > serum Osm
- Urine Na > 40 mmol/L
- No potassium supplementation
TTKG is a historical teaching tool
The TTKG calculation depends on assumptions about distal water handling and collecting-duct equilibration that often fail clinically. It is no longer a preferred stand-alone test of mineralocorticoid activity or renal potassium loss. Use the slide's prerequisites to understand why it can mislead; assess urine potassium excretion, acid–base status, blood pressure, renin/aldosterone and the clinical context instead.
The slide quotes about 8–12% in most countries and a 2012 Hong Kong recorded prevalence of 0.106%, presented as evidence of underdiagnosis. [1]
These figures use different denominators and case-finding intensity, so they are not directly comparable. The 2025 Endocrine Society materials estimate PA in roughly 5–14% of people with hypertension in primary care and up to 30% in referral centres. [15]
The slide's 2016 high-risk groups are: severe/resistant hypertension, spontaneous or diuretic-related hypokalaemia, early-onset hypertension or young stroke, and relatives of patients with PA. [1]
Current update: the 2025 guideline conditionally suggests ARR-based screening in all people with hypertension, depending on resources and feasibility. The slide's high-risk groups remain the highest-priority patients and the ones in whom a negative result deserves repetition if potassium or medication effects could have masked PA. [15]
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
The slide's flowchart is based on the 2016 sequence: ARR → confirmatory suppression test → adrenal CT → AVS if surgery is desired → unilateral adrenalectomy or MRA. It also permits direct CT when hypokalaemia, undetectable renin and aldosterone > 550 pmol/L make PA overt, or direct MRA treatment when the patient cannot/will not proceed. [1]
The 2025 pathway is more explicitly probability- and preference-based:
| Situation after a positive screen | Next step |
|---|---|
| Patient does not want/is not fit for surgery, or lateralizing disease is unlikely | PA-specific medical therapy can begin; suppression testing and AVS may add little |
| Intermediate probability of lateralizing PA and patient wants a surgical option | Consider an aldosterone suppression test |
| Resistant HTN or HTN + hypokalaemia with overt renin-independent aldosterone excess | Suppression testing may be omitted because false negatives can be harmful |
| Patient with PA is pursuing adrenalectomy | Adrenal CT plus usually AVS for lateralization; CT anatomy alone does not prove secretion |
The current guideline gives assay-specific examples rather than one universal cut-off. For overt disease it cites PRA < 0.2 ng/mL/h or DRC < 2 mU/L with aldosterone > 416 pmol/L by LC-MS/MS or > 554 pmol/L by immunoassay. [15]
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]
- Morning sampling with the patient seated; the slide specifies out of bed for ≥2 hours and seated for 5–15 minutes
- Avoid dietary sodium restriction in the preceding days
- Measure potassium alongside and correct hypokalaemia before repeating a negative/low-aldosterone screen
- Record every antihypertensive and decide between no-withdrawal, minimal-withdrawal or full-withdrawal strategies according to safety and local protocol
- If safe/feasible, the 2025 guideline suggests 4 weeks off MRAs, ENaC inhibitors and other diuretics; ACE inhibitors/ARBs generally require 2 weeks when withdrawal is needed. Beta-blockers/central α2-agonists may need a 2-week withdrawal to reassess a possible false-positive result. [15]
The slide's less-interfering substitutes are verapamil SR, hydralazine and α-blockers (prazosin/doxazosin/terazosin). Substitution must be supervised; do not destabilise severe hypertension merely to obtain a “clean” ARR. [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 | ↓ 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 direction is: beta-blockers can cause a false-positive ARR by suppressing renin, while ACEi/ARB/diuretics can mask PA by raising renin. In practice, interpret the absolute renin and aldosterone, pre-test probability and drug exposure together. A strongly elevated aldosterone with suppressed renin may remain convincing despite a beta-blocker; a borderline screen often needs supervised repeat testing. [15]
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 severe hypokalaemia can make aldosterone lower than it otherwise would be and potentially produce a false-negative screen. Correct potassium and repeat when the initial result is negative but suspicion remains. [15]
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:
The slide flags age, menstrual phase, pregnancy and renal artery stenosis as interpretive factors. Pregnancy markedly changes the RAAS; sex hormones can affect renin assay behaviour; CKD may lower renin with nephron loss while renal ischaemia raises it. Use pregnancy-, assay- and laboratory-appropriate interpretation rather than memorising one directional rule. [1][15]
The slide reports that its Hong Kong centres used PRA rather than direct renin concentration and LC-MS/MS-based local methods. This is a local, time-stamped laboratory statement—not a universal fact. PRA quantifies angiotensin-I generation, whereas DRC measures renin concentration; their ARR units and cut-offs are not interchangeable. [1]
The slide's local example is ARR > 750 with aldosterone in pmol/L and PRA in ng/mL/h; it reports Hong Kong cut-offs of 400–1000. [1]
Never report an ARR without its units, assay and component values. The slide's > 550 pmol/L aldosterone threshold belongs to its 2016 “overt PA/no confirmation” branch, not a universal definition of a positive screen. The 2025 guideline provides assay-specific lower screening examples and stresses that no cut-off is perfect. [15]
The 2016 slide lists oral sodium loading, saline infusion, fludrocortisone suppression and captopril challenge. [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.
| Test | Visual/procedural logic shown on the slide | Major limitation/safety point |
|---|---|---|
| Oral sodium loading | High sodium for 3 days, verify 24-hour urine sodium, maintain normal K, then measure 24-hour urinary aldosterone | Avoid in severe uncontrolled HTN, renal insufficiency, arrhythmia or severe hypokalaemia; collection and assay dependent |
| Saline infusion | 2 L 0.9% saline over 4 hours with BP/HR, K, renin, aldosterone and cortisol monitoring; recumbent and seated protocols differ | Same volume-loading contraindications; posture and assay change the cut-off |
| Fludrocortisone suppression | Four-day fludrocortisone + salt loading with intensive potassium, renin, aldosterone and cortisol monitoring | Labour-intensive and potentially hazardous without an experienced protocol; not a casual outpatient “gold standard” |
| Captopril challenge | Captopril should suppress aldosterone in normal RAAS physiology; persistent aldosterone with suppressed renin supports PA | False-negative/equivocal results occur; protocol and interpretation vary |
The 2025 guideline no longer requires suppression testing after every positive ARR. It is mainly useful when probability of lateralizing PA is intermediate and the patient wants to pursue a surgical pathway; a negative test can still miss lateralizing disease. [15]
Seated saline infusion protocol used in Case 1: [1]
- Infuse 2 L 0.9% saline over 4 hours under monitored conditions
- The slide uses post-infusion aldosterone < 140 pmol/L as unlikely and > 170 pmol/L as confirming PA, with the interval treated as indeterminate
- Do not apply those values to a recumbent protocol, a different assay or a patient in whom volume loading is unsafe
The slide's 2016 bypass rule is hypokalaemia + undetectable renin + aldosterone > 550 pmol/L. The 2025 rule is assay-specific and framed as overt renin-independent aldosterone production rather than a single universal threshold. [1][15]
This distinction matters because:
- Lateralizing unilateral secretion → potentially curable/improvable by unilateral adrenalectomy
- Bilateral or non-lateralized secretion → usually medical treatment with an MRA
CT describes anatomy; it cannot establish which gland secretes aldosterone. Small aldosterone-producing lesions can be invisible, while nonfunctioning nodules are common. In surgical candidates, CT and usually AVS are therefore complementary. [15]
Balance/Postural Study (historical/ancillary): [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 (historical renin-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
Do not use these as modern lateralization substitutes
The postural and frusemide tests explain RAAS physiology but are not substitutes for AVS when a patient is considering surgery. The slide itself quotes only about 85% accuracy for the postural pattern, and aldosterone-producing lesions do not divide cleanly into “ACTH-dependent adenoma” versus “angiotensin-II-dependent hyperplasia.”
Adrenal Venous Sampling (AVS): [1]
- Reference procedure for lateralization in most surgical candidates, performed by an experienced interventional radiology/laboratory team
- Aldosterone is corrected for cortisol in each adrenal sample; selectivity and lateralization indices depend on whether cosyntropin is used and on the centre's validated protocol
- The slide quotes unstimulated > 2:1 and stimulated > 4:1 as unilateral, < 3:1 as bilateral, plus a QMH-specific criterion. Memorise them only when that protocol is explicitly stated; they are not portable universal cut-offs
Reading the localisation calculation shown on the slide:
- Selectivity index = adrenal-vein cortisol / peripheral-vein cortisol. This first asks whether the catheter truly sampled an adrenal vein; it does not establish laterality.
- Lateralisation index = (aldosterone/cortisol on the dominant side) / (aldosterone/cortisol on the other side). Cortisol correction compensates for dilution. Only after adequate bilateral selectivity should this ratio be interpreted, using the centre's stimulated or unstimulated protocol.
Thus an incidental CT nodule and a high ARR do not tell the surgeon which adrenal is responsible. In current guidance, a patient pursuing surgery generally needs CT plus AVS; the potential CT-only exception is narrow (for example, age < 35 years, marked hypokalaemic PA and a unilateral adenoma > 1 cm). [15]
High Yield — Subtyping Summary Table
| Feature | Lateralizing/unilateral PA | Bilateral PA |
|---|---|---|
| Laterality | Unilateral | Bilateral |
| Typical severity | May be marked, but severity overlaps | Often milder, but can be marked |
| Postural test (slide-era pattern) | Some lesions show paradoxical ↓ aldosterone | Some bilateral disease shows ↑ aldosterone |
| AVS | Dominant secretion from one side with protocol-appropriate interpretation | No convincing unilateral dominance |
| CT/MRI | May show a unilateral nodule—or be normal/misleading | May be normal, nodular or enlarged |
| Treatment | Unilateral adrenalectomy | MR antagonist (spironolactone/eplerenone) |
The slide teaches three familial types and states that the FH-II gene was unknown. That was accurate for the 2016 guideline era; current genetics recognises four FH types plus PASNA syndrome. [1][16]
What the FH-I gene diagram shows: unequal crossover fuses the ACTH-responsive CYP11B1 promoter to the CYP11B2 aldosterone-synthase coding sequence. Aldosterone synthase is therefore expressed in ACTH-responsive zona fasciculata tissue rather than remaining under its normal renin-angiotensin/potassium control. This explains the autosomal-dominant family pattern, hybrid steroids and glucocorticoid suppressibility; modern confirmation is molecular rather than relying on a dexamethasone-suppression test alone. [16]
| Type | Gene/mechanism | Key features |
|---|---|---|
| FH-I (glucocorticoid-remediable aldosteronism) | Chimeric CYP11B1/CYP11B2 gene places aldosterone synthase activity under ACTH control | AD; elevated hybrid steroids; molecular confirmation; low-dose glucocorticoid-responsive, with careful avoidance of overtreatment |
| FH-II | CLCN2 gain-of-function → chloride efflux, depolarisation and calcium entry | AD; phenotype resembles other PA; usually MRA treatment |
| FH-III | KCNJ5 variants make the potassium channel abnormally sodium-permeable → depolarisation | AD; severity ranges from mild disease to massive bilateral hyperplasia; MRA first, bilateral adrenalectomy only for selected refractory severe disease |
| FH-IV | CACNA1H gain-of-function calcium channel | Variable age/severity; usually MRA treatment |
| PASNA | De novo CACNA1D gain-of-function | PA with variable seizures/neurological abnormalities and sometimes cardiac/metabolic features |
Young-onset PA (< 20 years) or a family with PA/young haemorrhagic stroke should prompt specialist genetic assessment; first-degree relatives of confirmed familial PA need targeted screening. [15][16]
Theme 3: Phaeochromocytoma
A phaeochromocytoma is a catecholamine-producing chromaffin tumour of the adrenal medulla; the related extra-adrenal tumour is a paraganglioma (together, PPGL). [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 accepted first-line tests. Choose plasma free metanephrines (preferably after 30 minutes of supine rest, with supine reference intervals) or a complete 24-hour urinary fractionated metanephrine collection according to pre-test probability, patient factors and laboratory expertise. Fast overnight when plasma 3-methoxytyramine is included. A positive result is not interpreted as binary: magnitude, sampling conditions, stress/illness and medication interference determine whether to repeat, clarify or image. [17][20]
The slide favours CT for thorax/abdomen/pelvis and MRI for skull-base disease, then states that FDG-PET can outperform MIBG in some SDHx-related tumours. [1]
Start anatomical imaging after clear biochemical evidence in the usual pathway. CT is often first; MRI is preferred when radiation should be limited and for selected head/neck, metastatic or contrast-related contexts. Functional imaging is phenotype- and purpose-specific (location, genotype, metastatic disease and radionuclide-therapy planning). Do not generalise the slide into “FDG-PET is always better than MIBG”; diagnostic MIBG uses ¹²³I, while ¹³¹I-MIBG is principally therapeutic. [18]
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 sympathetic/head-and-neck PGL; hereditary surveillance implications; some metastatic risk |
| PGL2 | SDHAF2 | Recurrent sPGL and hnPGL |
| PGL3 | SDHC | Onset relatively later |
| PGL4 | SDHB | Multiple/recurrent PPGL with comparatively high metastatic risk; associated tumour spectrum can include GIST |
| PGL5 | SDHA | Rare cause of phaeo |
Even newer genes: TMEM127, MAX, HIF2, FH [1]
The slide's percentages labelled “malignant” are historical cohort estimates, not diagnostic properties of a gene. Use metastatic PPGL for tumour deposits in sites that do not normally contain chromaffin tissue (for example lymph node, bone, liver or lung); primary-tumour histology alone cannot reliably declare a PPGL benign or malignant. [22]
Current hereditary practice is broader than “test only the young or bilateral case”: refer every person with PPGL for genetic counselling and molecular testing discussion. Early onset, bilateral/multifocal, recurrent, extra-adrenal, metastatic disease or a family history makes a hereditary syndrome especially likely, but a solitary apparently sporadic tumour does not exclude one. A confirmed familial variant enables targeted testing and gene-specific surveillance for relatives. [21]
The historical “10% rule” (from older surgical teaching) [4]:
- 10% familial, 10% bilateral, 10% extra-adrenal, 10% malignant, 10% in children
- Modern genetics shows roughly one-third or more have a pathogenic germline variant in many series, and bilateral/extra-adrenal/metastatic proportions vary by genotype and cohort. Use the rule only to recognise why it is obsolete. [19]
For preoperative preparation of a functional PPGL, establish α-blockade first (commonly phenoxybenzamine or a selective α1-blocker such as doxazosin); phentolamine is a short-acting IV agent for acute crisis rather than routine oral preparation. [5][19]
Exam Trap — Beta-blockers BEFORE Alpha-blockers in Phaeo
Do not start a pure beta-blocker before adequate alpha-blockade in a catecholamine-secreting PPGL: loss of beta-mediated vasodilation with ongoing alpha vasoconstriction can precipitate crisis. Add beta-blockade only when needed for tachyarrhythmia after alpha control and under the specialist perioperative plan; volume/salt repletion and monitoring are also part of preparation.
Theme 4: Clinical Cases
Clinical reasoning: A 59-year-old with hypertension and severe spontaneous hypokalaemia has a high pre-test probability of primary aldosteronism.
Step 1 — ARR Screening: [1]
- Aldosterone = 1290 pmol/L, PRA = 0.57 ng/mL/hr
- ARR = 1290 / 0.57 = 2263, positive by the slide's local > 750 cut-off
- Aldosterone is also clearly elevated; interpret with the assay, potassium, posture and medications rather than ARR alone
Step 2 — Confirmatory Test (Saline Infusion Test): [1]
- The case panel shows aldosterone 599 pmol/L before and 971 pmol/L after saline: it failed to suppress and was far above the slide's seated > 170 pmol/L threshold → confirms primary aldosteronism under that local protocol
- 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
- The 0.6-cm nodule is anatomical evidence only; AVS is needed if she wants surgery because a small incidental nonfunctioning nodule or occult contralateral source is possible
- 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 hypodensity/possible necrosis and avid peripheral enhancement. These features are suspicious but not specific; the grossly elevated metanephrines establish the functional PPGL context.
Biochemistry: the report image shows normetanephrine > 20,660 pmol/L (reference 110–740), metanephrine > 25,520 pmol/L (40–450) and 3-methoxytyramine 5,020 pmol/L (< 110). These are not borderline stress-related elevations: together with the bilateral adrenal masses, they provide overwhelming biochemical evidence of functional bilateral phaeochromocytoma. [1][20]
Management: The lecture reports bilateral adrenalectomy. If both glands are completely removed, the patient needs lifelong glucocorticoid and mineralocorticoid replacement plus adrenal-crisis education. In selected hereditary bilateral/small tumours, an expert multidisciplinary team may consider cortical-sparing surgery to trade a lower risk of permanent adrenal insufficiency against a higher risk of recurrent tumour; the case slide does not say whether this option was suitable. [20]
Genetics: TMEM127: c.314del; p.(Leu105ArgfsTer19) — heterozygous → Autosomal dominant TMEM127-related hereditary PPGL syndrome. Genetic findings assist family screening.
Teaching Point from Case 2
PPGL can present catastrophically with catecholamine cardiomyopathy and shock. In unexplained haemodynamic instability with adrenal masses, integrate imaging with correctly collected metanephrines rather than diagnosing from CT alone. Bilateral disease strongly supports genetic counselling/testing.
Exam Intelligence
-
"Interpret this ARR" — Calculate it with the stated units, then inspect renin and aldosterone separately. Use > 750 and > 550 pmol/L only when the question explicitly invokes the lecture's local/2016 protocol.
-
"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 under interpretable conditions, plasma free or 24-hour urinary fractionated metanephrines when PPGL testing is indicated, and 1-mg overnight dexamethasone suppression for autonomous cortisol secretion; tailor to imaging and current incidentaloma guidance.
| 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 |
- GC 066 (Fluctuating BP) [11]: Reinforces medication interference and exclusion of other causes of hypokalaemia. Use the current supervised withdrawal windows in this note rather than a blanket “stop everything for ≥2 weeks.”
- GC 058 (High Blood Pressure) [12]: Contains the hypertensive-emergency framework. The lecture highlights IV phentolamine for catecholamine crisis; real management requires ICU/endocrine/anaesthetic input and may use titratable IV vasodilators according to the haemodynamic problem and local protocol.
- IntroEndoInvestigations [13]: Screening overview—ARR for PA, ONDST for cortisol autonomy, plasma free or 24-hour urinary fractionated metanephrines for PPGL, IGF-1 for acromegaly and TFT for thyroid disease. Catecholamines/VMA alone are not preferred PPGL screening tests.
- 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
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Three aims of biochemical testing in hypertension
- Find secondary causes, assess complications/target-organ injury, and detect cardiovascular co-morbidities.
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Mineralocorticoid excess → Hypokalaemic hypertension + metabolic alkalosis + LVH.
- Organise the differential by aldosterone/cortisol/DOC, receptor protection (AME/liquorice), signalling (Gordon: hyperkalaemia) and ENaC (Liddle).
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Screen PA with aldosterone + renin + potassium and an assay-specific ARR.
- The slide's > 750 ARR and > 550 pmol/L aldosterone figures are local/2016-era; the 2025 guideline conditionally suggests screening all hypertensive patients when feasible.
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Prepare and interpret, do not read ARR in isolation.
- Correct hypokalaemia, avoid sodium restriction, record posture/assay/drugs. Beta-blockers/central agonists can inflate ARR; ACEi/ARB/diuretics can mask PA. Medication changes must be supervised.
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The PA pathway is probability- and preference-based.
- Suppression testing is selective; surgical candidates generally need CT + AVS. Lateralizing PA → unilateral adrenalectomy if desired; bilateral/non-lateralized PA → MRA.
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PPGL: biochemical evidence before localisation.
- Use plasma free or 24-hour urinary fractionated metanephrines with correct preanalytics, then tailored CT/MRI ± functional imaging. Refer every confirmed PPGL for genetic counselling/testing; young, bilateral, multifocal, extra-adrenal or metastatic disease makes a hereditary cause especially likely.
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Alpha before beta in functional PPGL.
- Establish specialist alpha-blockade/volume preparation before adding beta-blockade for tachyarrhythmia. In acute crisis, use monitored emergency management.
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Primary vs secondary hyperaldosteronism
- Primary: aldosterone inappropriately high with suppressed renin. Secondary (e.g. renal artery stenosis): both renin and aldosterone raised.
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) [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 [15] Adler GK et al. Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline. JCEM 2025. Official guideline [16] Mulatero P et al. Familial hyperaldosteronism: an Endo-ERN clinical practice guideline. EJE 2024. DOI [17] Eisenhofer G, Pamporaki C, Lenders JWM. Biochemical Assessment of Pheochromocytoma and Paraganglioma. Endocrine Reviews 2023. DOI [18] Timmers HJLM et al. Imaging of Pheochromocytomas and Paragangliomas. Endocrine Reviews 2024. DOI [19] Nölting S et al. Management of Pheochromocytoma and Paraganglioma. Endocrine Reviews 2021. DOI [20] Lenders JWM et al. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. JCEM 2014. Official guideline [21] GeneReviews. Hereditary Paraganglioma-Pheochromocytoma Syndromes. Updated 2023. [22] National Cancer Institute. Pheochromocytoma and Paraganglioma Treatment (PDQ): Pathological Classification.
GC151 The Malformed Child Hereditary Syndromes And Anomalies
Hereditary syndromes and anomalies in the malformed child encompass genetically determined patterns of congenital structural defects arising from chromosomal abnormalities, single-gene mutations, or multifactorial inheritance that result in recognizable dysmorphic features and developmental malformations.
GC154 Biochemical Screening For Early Detection Of Diseases
Biochemical screening for early detection of diseases involves the systematic use of laboratory tests—such as blood glucose, lipid profiles, newborn metabolic panels, and tumor markers—to identify presymptomatic or early-stage conditions in apparently healthy individuals, enabling timely intervention and improved outcomes.