Decision support only — confirm genotype, biochemical iron loading and organ stage before treatment. Verify venesection volume, monitoring, referral criteria and genetic-testing consent locally.
1 From abnormal iron studies to a defensible diagnosis
Ferritin is easy to order and easy to over-interpret. The useful signal is persistent transferrin saturation paired with ferritin, then a genotype that fits the phenotype. A ferritin of 600 in someone with MASLD and a normal saturation is a different problem from progressive iron loading in a C282Y homozygote.
How it presents — often quietly
Many patients are asymptomatic, identified through family testing or incidental iron studies. Clues include fatigue; unexplained liver-enzyme elevation or hepatomegaly; MCP2/3 or ankle arthropathy and chondrocalcinosis; diabetes or hypogonadism; skin pigmentation; cardiomyopathy or arrhythmia. “Bronze diabetes” is a late, now-uncommon presentation. Do not wait for it. EASL 2022
Abnormal iron indices, suggestive organ disease or an adult first-degree relativeRaised ferritin/TSAT · unexplained liver disease · MCP2/3 arthropathy · diabetes/hypogonadism/cardiomyopathy · family cascade testing
Morning TSAT + ferritin; add FBC, CRP, LFTs and the clinical context
CONFIRM PERSISTENCE IF BORDERLINE OR DISCORDANT
FASTING IS NOT THE POINTEASL advises a morning sample; fasting does not improve diagnostic utility. TSAT varies. Repeat an unexpected result when well and check whether low transferrin, acute liver injury or advanced cirrhosis is inflating it. EASL 2022
ISOLATED FERRITIN
TSAT not persistently elevated → inflammation/infection, alcohol, MASLD/metabolic syndrome, malignancy, renal disease or cell injury are more likely.
Do not diagnose iron overload or prescribe venesection from ferritin alone. Reassess the cause; use MRI when the burden remains unexplained.
BIOCHEMICAL IRON LOADING
Women: TSAT >45% + ferritin >200 µg/L.
Men/post-menopause: TSAT >50% + ferritin >300 µg/L; or otherwise unexplained persistent TSAT elevation.
Obtain informed consent, then HFE p.C282Y genotyping. Australian MBS item 73317 also covers repeated high ferritin or adult first-degree family risk.
GENOTYPE + PHENOTYPE
C282Y/C282Y + biochemical loading → HFE haemochromatosis; quantify burden, stage fibrosis and assess organs.
Other genotype → do not label from DNA alone. Confirm hepatic iron by MRI (or rarely biopsy), exclude secondary causes and consider specialist/rare-gene assessment.
Fast-track hepatology / iron-disorders assessment
Ferritin >1000 µg/L, elevated transaminases, hepatomegaly, thrombocytopenia/synthetic dysfunction, suspected cirrhosis, severe unexplained loading, young-onset endocrine/cardiac disease, heart failure or arrhythmia. Start cardiac assessment promptly when clinically involved; do not delay iron removal for cardiac MRI.
2 Read the HFE result without creating disease
| Result | What it means | Action | What not to do |
|---|
| C282Y/C282Y | Highest-risk common HFE genotype, but penetrance varies by sex, age and co-factors. Susceptibility is not inevitable organ disease. | Pair with TSAT/ferritin. If biochemical loading is present, diagnose, stage and treat. If indices are normal, monitor every 2–3 years. | Do not promise future disease or venesect a normal ferritin simply because the genotype is present. |
| C282Y/H63D | Compound heterozygosity; severe iron overload is uncommon without alcohol, MASLD, diabetes or another modifier. | Let the phenotype lead. If substantial loading persists, quantify liver iron by MRI and exclude secondary/rare causes. | Do not treat the genotype alone. Phlebotomy is individualised only after iron overload is confirmed. |
| H63D/H63D or single variant | H63D is common and generally not disease-causing; single C282Y carriers usually do not develop progressive loading. | Look for metabolic, alcohol-related, inflammatory, haematological or other genetic explanations when ferritin is high. | Do not let a common variant end the differential. |
| No common HFE explanation | High TSAT with hepatic iron can reflect rare HAMP, HJV, TFR2 or SLC40A1 disease; anaemia/reticulocytosis suggests a different iron-loading mechanism. | MRI distribution, blood film/reticulocytes and specialist phenotyping; targeted panel when early, severe, familial or unexplained. | Do not order broad rare-gene panels before proving the iron phenotype. |
Genetic penetrance is lower than the old teaching implied
In the Australian HealthIron cohort, objectively defined iron-overload disease developed in 28.4% of male and 1.2% of female C282Y homozygotes over roughly 12 years. That still justifies case-finding and follow-up. It does not justify telling every homozygote that cirrhosis is waiting. HealthIron
3 Stage liver burden and look for organ injury
Liver and fibrosis
- CoreALT/AST, ALP/GGT, bilirubin, albumin, INR, FBC/platelets; ultrasound for morphology, spleen and focal lesions.
- MRIQuantify liver iron when genotype is non-diagnostic, loading is unexplained or total burden will change management. Distribution across liver/spleen helps separate mechanisms.
- FibrosisAssess every confirmed case non-invasively. TE <6.4 kPa can rule out advanced fibrosis, but evidence is weak; FIB-4 evidence is limited in haemochromatosis.
- BiopsyRarely needed for iron diagnosis. Consider for unresolved fibrosis when ferritin >1000 µg/L, enzymes are raised or non-invasive tests conflict.
Co-factors change the liver risk
- AlcoholQuantify in g/week. Iron and alcohol amplify fibrosis and cancer risk.
- MetabolicBMI/waist, BP, HbA1c/glucose, lipids; MASLD commonly elevates ferritin and can coexist with true haemochromatosis.
- OtherHBsAg, anti-HCV; medicines/supplements; transfusion history, haemolysis or ineffective erythropoiesis.
- Low riskFerritin <1000 µg/L with normal transaminases and no hepatomegaly has very low advanced-fibrosis risk, provided coexisting liver disease is absent.
Extrahepatic review
- Joint/boneMCP2/3 or ankle arthropathy, chondrocalcinosis; calcium, vitamin D and DXA when osteoporosis/fracture risk is present.
- EndocrineHbA1c/glucose; libido, erectile function, menses/fertility. Morning testosterone/LH/FSH or other tests if symptomatic.
- CardiacECG + echocardiogram for severe overload, arrhythmia, HF symptoms or examination findings; cardiac MRI for suspected myocardial iron.
- Young/severeCardiomyopathy or hypogonadism before the usual age should trigger urgent non-HFE/juvenile haemochromatosis assessment.
4 Therapeutic venesection — prescribe and monitor it properly
| Phase | Typical prescription | Monitoring | Target / adjustment |
|---|
| Induction | 400–500 mL weekly or every 2 weeks, adjusted to body size, comorbidity and tolerance. Hydrate and follow the treating service’s procedural protocol. | Hb before every session. Ferritin monthly or every fourth session; once <200 µg/L, check every 1–2 sessions. | Ferritin 50 µg/L, not lower. If Hb <120 g/L, reduce frequency/volume; if <110 g/L, pause and reassess. |
| Maintenance | Individualise, often every 1–4 months or about 2–6 sessions/year. Requirement varies substantially after depletion. | Hb each session; ferritin about every 6 months and after unexpected changes. Review organ stage, co-factors and tolerance. | Ferritin 50–100 µg/L. Avoid symptomatic iron deficiency; frail older patients may need a specialist-agreed relaxed target. |
| Lifeblood | Refer through the Australian Lifeblood High Ferritin App. The algorithm uses HFE genetics and ferritin, then donor-safety criteria. | The treating clinician remains responsible. Compensated-cirrhosis therapeutic donors require annual review/re-referral; other schedules vary. | Lifeblood eligibility is a service decision, not proof that venesection is or is not medically indicated. Arrange another provider if donor criteria are not met. |
| Alternative | Personalised erythrocytapheresis can reduce procedure number. Chelation is reserved for patients in whom blood removal is unsafe or impossible. | Specialist centre; modality-specific FBC, renal, hepatic and toxicity monitoring. | Same iron-depletion aim. Chelation evidence is limited and risk–benefit must be explicit. |
Ferritin is the treatment gauge; do not chase TSAT into iron deficiency
TSAT may remain high after ferritin reaches target, and evidence-based TSAT treatment targets are lacking. A persistently high saturation should prompt a check for adherence, unexpected biology or another diagnosis, but not automatic extra venesections. EASL 2022
5 Set expectations: what iron depletion does and does not fix
Often improves or prevents
- PreventionTreatment before cirrhosis or diabetes prevents most serious organ injury and restores normal life expectancy.
- LiverTransaminases and early fibrosis may improve; some advanced fibrosis regresses over years.
- SymptomsFatigue and skin pigmentation often improve. Early cardiac dysfunction may respond when iron is removed promptly.
May persist despite perfect ferritin
- JointsArthropathy usually does not respond to venesection and can progress during maintenance. Treat as OA/CPPD with renal/liver-aware analgesia and rheumatology/orthopaedics when needed.
- EndocrineEstablished diabetes and hypogonadism may not reverse; continue standard disease-specific care.
- CancerHCC risk persists after de-ironing when advanced fibrosis or cirrhosis was present. Ferritin control does not cancel surveillance.
6 Family testing, pregnancy and practical prevention
Adult cascade testing
- WhoOffer HFE testing plus iron indices to adult first-degree relatives after informed consent; prioritise siblings.
- RiskFor an affected proband, a sibling’s Mendelian risk of being affected is 25%. Test the other parent/partner where this simplifies offspring assessment.
- AustraliaMBS item 73317 covers elevated TSAT, repeatedly elevated ferritin, or qualifying first-degree family history. Confirm the live item and local pathology process.
- ChildrenRoutine predictive HFE testing is deferred until adulthood because classical HFE disease is adult-onset.
Pregnancy
- BeforeAvoid iron deficiency; review fibrosis and organ disease before conception.
- DuringWith mild–moderate loading and no advanced liver disease, venesection can usually pause; individualise with obstetric medicine/hepatology.
- IronDo not reflexively forbid indicated antenatal iron. Treat documented deficiency with coordinated monitoring.
Food, alcohol and infection
- DietNo punishing low-iron diet is required. Avoid iron-fortified supplements and high-dose vitamin C supplements; limit frequent red-meat intake.
- AlcoholRestrict during induction and with iron/liver injury; abstain in cirrhosis.
- ShellfishDuring iron overload, avoid raw/undercooked shellfish and seawater exposure to open wounds because of severe Vibrio vulnificus infection risk.
- VaccinesHepatitis A/B and routine chronic-liver-disease vaccination according to serology and Australian recommendations.
7 Long-term review by stage
| Group | Follow-up | Liver surveillance | Escalation trigger |
|---|
| At-risk genotype, normal ferritin | Iron studies every 2–3 years; earlier after menopause, substantial alcohol/metabolic change or symptoms. | No HCC surveillance without advanced fibrosis. | Ferritin rises above normal with persistent TSAT elevation or new organ signal. |
| Treated, no advanced fibrosis | Maintenance venesection, ferritin about 6-monthly; annual LFT/metabolic and symptom review. | No routine HCC surveillance after advanced fibrosis has been excluded. | Unexpected ferritin/TSAT swing, intolerance/anaemia, abnormal enzymes or new cardiac/endocrine disease. |
| F3 advanced fibrosis | Hepatology; treat co-drivers and reassess fibrosis after iron depletion. | EASL suggests ultrasound q6 months, individualised by age, sex, diabetes, alcohol and iron burden. | Portal-hypertension signal, lesion, synthetic dysfunction or decompensation. |
| Cirrhosis | Full cirrhosis bundle, including portal hypertension, nutrition/bone, vaccines and transplant suitability. | Ultrasound ± AFP q6 months regardless of iron depletion; use CT/MRI when ultrasound is inadequate. | Ascites, bleeding, jaundice, encephalopathy, focal lesion or declining synthetic function. |