Haemochromatosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Hepcidin normally restrains ferroportin-mediated iron export from enterocytes and macrophages. Common HFE variants can lower effective hepcidin signalling, permitting continued absorption despite adequate stores. Excess iron deposits particularly in liver, pancreas, heart, pituitary, joints and skin, generating oxidative tissue injury over years. Men often express disease earlier because menstrual and pregnancy iron loss delays accumulation in many women, but age, alcohol, metabolic liver disease and other modifiers are more important than simplistic sex assumptions for an individual.

A raised ferritin is common and usually not hereditary haemochromatosis. Inflammation, infection, alcohol-related injury, metabolic dysfunction-associated steatotic liver disease, kidney disease and cancer frequently elevate ferritin without high transferrin saturation. Conversely, transferrin falls in advanced liver disease and can artifactually increase the calculated saturation. The diagnosis therefore combines repeated iron indices, clinical context and genotype, with MRI or biopsy where phenotype and HFE result disagree. C282Y heterozygosity alone rarely explains substantial loading and should not stop the search for another cause.

Removal of iron by phlebotomy is highly effective before irreversible organ damage. A standard donation-sized volume is often used weekly or fortnightly during induction, but smaller volumes or longer intervals suit low body mass, older age or comorbidity. Maintenance frequency is individual and lifelong for many. Ferritin guides depletion; haemoglobin protects against excessive removal. The person still needs treatment of alcohol and metabolic cofactors, fibrosis-based HCC surveillance, diabetes and cardiac review, and genetic counselling that explains recessive inheritance without deterministic language.

Key points

Classic HFE haemochromatosis is an autosomal recessive disorder of inappropriately increased intestinal iron absorption, most strongly associated with C282Y homozygosity.
Penetrance is incomplete: a genotype confers risk, while biochemical and clinical iron overload determine organ threat and treatment need.
Transferrin saturation rises early and is central to recognising iron loading; ferritin estimates stores but also rises with inflammation, alcohol, metabolic liver disease and malignancy.
Repeat iron studies in a clinically stable state and assess CRP, alcohol, metabolic health, blood count and liver tests before ordering or interpreting HFE testing.
HFE genotyping follows current NHS genomic eligibility and should not be used as indiscriminate population screening.
Liver fibrosis, diabetes, hypogonadism, cardiomyopathy, arrhythmia, MCP arthropathy and skin pigmentation represent clinically expressed disease.
MRI can quantify hepatic iron and help separate primary iron loading from reactive ferritin elevation; biopsy is now reserved for unresolved diagnosis or staging.
Therapeutic venesection is first-line for confirmed iron overload, initially frequent and later maintenance-based, with haemoglobin and ferritin safeguards.
Venesection can prevent or improve some hepatic and endocrine complications but established arthropathy and cirrhosis may not reverse.
HCC surveillance continues in people with cirrhosis even after iron depletion, and adult first-degree relatives should receive informed cascade assessment.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

HFE-related inheritance

Autosomal-recessive HFE variants, most strongly C282Y homozygosity, reduce hepcidin signalling and cause inappropriate intestinal iron absorption with incomplete penetrance.

Non-HFE genetic overload

Less common variants affecting hepcidin, transferrin-receptor or ferroportin pathways can cause earlier, atypical or differently distributed iron loading.

Secondary iron accumulation

Repeated transfusion, ineffective erythropoiesis and chronic liver disease can raise body iron or ferritin without classic hereditary haemochromatosis.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Inappropriately low hepcidin effect
Reduced hepcidin restraint leaves ferroportin active, increasing iron transfer from enterocytes and macrophages into plasma despite systemic iron excess.
2
Progressive tissue deposition
Transferrin saturation rises and excess iron accumulates in liver, pancreas, heart, joints and endocrine organs over many years.
3
Oxidative organ injury
Labile iron catalyses reactive oxygen formation, causing cell damage, fibrosis and irreversible organ dysfunction when loading is advanced.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Biochemical iron loading

Repeated high transferrin saturation accompanies a rising ferritin in a clinically stable adult without a convincing inflammatory, transfusional or secondary explanation.

Hepatic expressionRed flag

Hepatomegaly, raised aminotransferases, fibrosis or cirrhosis occurs with an iron-loading phenotype, often amplified by alcohol or metabolic steatosis.

Endocrine expression

New diabetes, reduced libido, erectile dysfunction, amenorrhoea or pituitary failure can reflect pancreatic or gonadal iron injury but remains non-specific.

Cardiac expressionRed flag

Unexplained cardiomyopathy, conduction disease or arrhythmia with substantial iron loading requires prompt cardiology and specialist iron assessment.

Characteristic arthropathy

Chronic pain or bony swelling at second and third metacarpophalangeal joints and chondrocalcinosis may persist despite successful depletion.

Reactive ferritin phenotype

Ferritin rises during infection, systemic inflammation, alcohol excess or metabolic disease while transferrin saturation is normal or fluctuating, favouring a non-genetic explanation.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Fasting or repeat transferrin saturationFirst step
Why
Identify persistent excess circulating iron availability.
Interpretation and limitations
NHS genomic education thresholds are above 45% in women and above 50% in men alongside raised ferritin, after alternative explanations. Repeat a borderline result when clinically well because diurnal and biological variation occur.
02
Serum ferritin with inflammatory markers
Why
Estimate stores and expose reactive elevation.
Interpretation and limitations
Ferritin above 200 micrograms/L in women or 300 in men supports iron overload only with context and saturation. Values above 1,000 or abnormal liver tests increase concern for fibrosis but remain non-specific.
03
HFE genotyping
Why
Confirm common hereditary haemochromatosis in an eligible iron-loading phenotype.
Interpretation and limitations
C282Y homozygosity has the strongest association but incomplete penetrance. Compound heterozygosity usually carries lower risk; one variant is generally carrier status and should not explain major loading automatically.
04
Liver MRI iron quantification and elastography
Why
Measure hepatic iron and estimate fibrosis non-invasively.
Interpretation and limitations
High liver iron supports true loading when ferritin is ambiguous. Stiffness can rise with inflammation; discordant or advanced findings require hepatology interpretation and cirrhosis management.
05
Liver biopsy
Why
Resolve non-HFE loading, mixed disease or uncertain advanced fibrosis when non-invasive tests will not answer management.
Interpretation and limitations
Distribution and concentration of iron help distinguish parenchymal hereditary from reticuloendothelial secondary patterns, while histology shows steatohepatitis or other cofactors. Use the safest route.
06
Organ complication assessment
Why
Find diabetes, endocrine, cardiac, joint and bone injury.
Interpretation and limitations
Use HbA1c or glucose, ECG and echocardiography or cardiac MRI when indicated, sex-hormone assessment, joint evaluation and DEXA according to symptoms and loading severity rather than a blanket test set.
07
Family cascade assessment
Why
Identify adult relatives at risk before tissue damage develops.
Interpretation and limitations
Offer informed genotype and iron studies through current NHS criteria to first-degree adult relatives. Routine childhood testing is usually unnecessary for adult-onset HFE disease unless specialist circumstances differ.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Inflammatory hyperferritinaemia

Raised CRP, infection, malignancy or systemic inflammation elevates ferritin while transferrin saturation is often not persistently increased.

Metabolic or alcohol-related liver disease

Steatosis, alcohol exposure and metabolic dysfunction commonly raise ferritin; genotype, saturation and objective hepatic iron determine whether true overload coexists.

Transfusional iron overload

A history of chronic transfusion or ineffective erythropoiesis with compatible MRI distribution supports secondary rather than HFE-driven loading.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Raised ferritinProve iron overload before genotypingFirst stepFerritin is elevated on routine or symptom-led blood testing.

1Review infection, inflammation, alcohol, metabolic risk, transfusions, supplements, malignancy and kidney or liver disease and obtain CRP, full blood count and liver tests.
2Measure transferrin saturation and repeat indices when clinically stable if results are borderline or discordant.
3Request HFE testing through current genomic criteria when biochemical iron loading remains unexplained, and refer marked loading or abnormal liver tests to hepatology.
4Use MRI iron and fibrosis assessment, reserving broader genetic testing or biopsy for specialist evaluation of non-HFE or mixed phenotypes.

02Iron depletionUse venesection safely and to a defined targetClinically relevant hereditary iron overload is confirmed and phlebotomy is tolerated.

1Record haemoglobin, ferritin, body size, cardiovascular status and venous access and agree the BSH or local target before the first procedure.
2Remove an individualised blood volume, commonly up to about 500 mL, weekly or fortnightly during induction with haemoglobin safety checks.
3Slow, pause or reduce volume for symptomatic anaemia, haemodynamic intolerance or excessive haemoglobin fall and investigate unexpected cytopenia.
4When depleted, move to a personalised maintenance interval guided by ferritin trend and avoid driving the patient into chronic iron-deficient anaemia.

03Organ protectionTreat the phenotype beyond ferritinIron overload is accompanied by hepatic, cardiac, endocrine or skeletal features.

1Stage liver fibrosis and address alcohol and metabolic cofactors, then enrol cirrhosis in portal and six-monthly HCC surveillance.
2Refer cardiomyopathy or arrhythmia urgently for cardiology assessment and coordinate the pace of depletion with haemodynamic tolerance.
3Manage diabetes, hypogonadism, osteoporosis and arthropathy through the relevant specialties, explaining which established injuries may persist.
4Consider specialist chelation only when clinically important loading cannot be treated by venesection, with product-specific renal, hepatic and marrow monitoring.

04Family careOffer proportionate cascade testingHFE haemochromatosis with a clinically important genotype is confirmed.

1Explain autosomal-recessive inheritance, incomplete penetrance and the difference between carrier, genotype, biochemical loading and organ disease.
2Offer adult first-degree relatives informed testing under the NHS genomic pathway and consider partner testing when it clarifies offspring risk.
3For genotype-positive relatives measure ferritin and transferrin saturation at the locally recommended interval rather than starting automatic venesection.
4Protect privacy and reproductive autonomy and avoid testing young children routinely for a condition that generally does not manifest before adulthood.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

First-line removal of excess iron in HFE haemochromatosis, followed by individualised lifelong maintenance for recurrent accumulation.

Therapeutic venesection

A typical induction removes approximately 500 mL of blood weekly or fortnightly, but use a smaller volume or longer interval for low body mass, older age or comorbidity and follow the current BSH and local ferritin and haemoglobin targets.

Check haemoglobin and clinical tolerance before each procedure and avoid venesection during instability or significant anaemia. Replace fluid where needed, investigate unexpected haemoglobin decline and do not use an arbitrary schedule after depletion.

Provides an alternative route of iron removal for patients with unsuitable veins, anaemia or another contraindication to repeated phlebotomy.

Iron chelation

A specialist may select deferasirox, desferrioxamine or another chelator at its current BNF and commissioning regimen only when significant overload cannot be managed by venesection; this is uncommon and may be off-label for HFE disease.

Renal, hepatic, gastrointestinal, auditory, ocular and marrow toxicity vary by agent and require product-specific baseline and serial monitoring. Chelation should not be offered merely for reactive ferritin elevation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cirrhosis and liver cancer

Advanced hepatic iron causes fibrosis, portal hypertension and substantially increased hepatocellular carcinoma risk once cirrhosis is established.

Diabetes and cardiomyopathy

Pancreatic and myocardial deposition can cause diabetes, arrhythmia and restrictive or dilated cardiac dysfunction, sometimes before liver symptoms.

Arthropathy and endocrine dysfunction

Joint damage, hypogonadism and fatigue may persist despite iron removal because established structural injury is not fully reversible.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During induction measure haemoglobin before venesection and ferritin at the protocol interval, documenting symptoms, volume and recovery after each session.
In maintenance track ferritin and full blood count often enough to prevent both recurrent loading and iatrogenic iron deficiency, adjusting frequency rather than volume automatically.
Repeat liver tests and fibrosis assessment according to baseline risk; continue HCC surveillance indefinitely when cirrhosis has been established.
Monitor glucose, cardiac symptoms, rhythm, gonadal function, bone and joints when clinically affected, recognising that ferritin normalisation does not reverse every complication.
Review alcohol, iron or high-dose vitamin C supplements and metabolic risk without prescribing a nutritionally restrictive low-iron diet.
Maintain a documented adult family-testing plan and revisit untested first-degree relatives without coercion or disclosure beyond consent.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Ferritin is an alarm, not a diagnosis

It rises in common inflammatory and metabolic states; persistent transferrin saturation and phenotype determine whether iron is actually loading tissues.

Genotype is not destiny

Many C282Y homozygotes never develop organ damage, so assessment and treatment are based on biochemical expression and risk.

Transferrin can distort saturation

Advanced liver disease lowers transferrin, making the calculated percentage appear high even without classic hereditary overload.

Joints may not improve

Venesection prevents further iron injury but established MCP arthropathy often persists and deserves conventional pain and rheumatology care.

Depletion does not erase cirrhosis

Once advanced fibrosis exists, portal complications and HCC risk require ongoing surveillance despite a normal ferritin.

11Common pitfallsFrequent interpretation and management errors.

01
Ordering HFE genotyping for every raised ferritin without transferrin saturation or assessment of reactive causes.
02
Attributing severe iron loading to simple heterozygous carrier status and missing alcohol, metabolic or rarer genetic disease.
03
Venesection of an acutely unwell or anaemic patient because ferritin remains high during inflammation.
04
Using ferritin alone to schedule maintenance and causing symptomatic iron-deficient anaemia.
05
Stopping liver cancer surveillance after successful depletion in a person with established cirrhosis.
06
Testing young children routinely without considering adult onset, consent and the current genomic eligibility framework.