Haemophagocytic lymphohistiocytosis (HLH) is one of the most rapidly fatal conditions associated with extreme hyperferritinaemia and must be recognised as an emergency — ferritin levels in HLH typically exceed 10,000 µg/L and can reach 100,000+ µg/L. HLH is caused by uncontrolled activation of macrophages and cytotoxic T-cells (a cytokine storm), leading to phagocytosis of blood cells in the bone marrow, spleen, and lymph nodes. Triggers: EBV (most common in adults), other viral infections, haematological malignancies (particularly T-cell lymphomas), autoimmune diseases (SLE, AOSD), and rarely genetic (familial HLH). The HScore identifies probable HLH: key components include temperature >38.5°C, splenomegaly, bicytopenia or pancytopenia, elevated ferritin (>500 µg/L), elevated triglycerides, low fibrinogen, haemophagocytosis on bone marrow, and known immunosuppression. Ferritin is only one component of the HLH-2004 criteria: diagnosis needs a compatible clinical context and multiple criteria, or specialist interpretation with an HScore/HLH pathway, and bone-marrow haemophagocytosis may be absent early (it should not delay specialist treatment). The BSH notes ferritin >10,000 µg/L may occur in HLH and Still disease but also in renal failure, hepatocellular injury, infection and malignancy. Any patient with unexplained fever + cytopenias + extreme hyperferritinaemia needs same-day haematology/acute medical discussion — untreated HLH has a mortality exceeding 90%.

The ferroportin disease and dysmetabolic iron overload syndrome (DIOS) represent two important and frequently misdiagnosed causes of elevated ferritin in clinical practice. Ferroportin disease (haemochromatosis type 4): caused by mutations in the SLC40A1 gene encoding ferroportin (the iron exporter), presents with elevated ferritin but NORMAL or LOW transferrin saturation (distinguishing it from classical HFE haemochromatosis where transferrin saturation is elevated early). Iron deposits predominantly in macrophages (not parenchymal cells), and patients tolerate venesection poorly (develop anaemia quickly). DIOS: associated with metabolic syndrome (insulin resistance, obesity, dyslipidaemia, NAFLD) — elevated ferritin with normal transferrin saturation, mild hepatic iron loading on MRI, not a classical haemochromatosis gene mutation. Management: treat the metabolic syndrome (weight loss, exercise, alcohol cessation) rather than venesection — the BSH notes there is no evidence supporting venesection to reduce ferritin in NAFLD. The key practical lesson: elevated ferritin with elevated transferrin saturation points to primary iron overload (HFE haemochromatosis); elevated ferritin with NORMAL transferrin saturation is more likely inflammation, DIOS, ferroportin disease, or liver disease.

The transferrin saturation is the most important single test for distinguishing primary iron overload (haemochromatosis) from reactive hyperferritinaemia — in hereditary haemochromatosis, the primary pathological mechanism is excessive intestinal iron absorption leading to progressive loading of parenchymal cells. Transferrin (the iron transport protein) becomes progressively saturated as iron overload develops, and transferrin saturation persistently above 50% in men or 40% in women (BSH; a fasting sample is not routinely essential, but repeat borderline results) is the most sensitive early marker of HFE haemochromatosis — it rises before ferritin becomes markedly elevated. The investigation protocol: elevated ferritin → check transferrin saturation simultaneously. If transferrin saturation is elevated AND ferritin elevated: HFE gene testing (C282Y and H63D) or specialist advice is indicated — ancestry informs pre-test probability but is not a reason to withhold testing or referral. If ferritin elevated with NORMAL transferrin saturation: HFE haemochromatosis is less likely — consider inflammatory, metabolic, alcoholic, or ferroportin causes. Do not send HFE gene testing without transferrin saturation — the clinical context is essential.

The 6-monthly HCC (hepatocellular carcinoma) surveillance with AFP and liver ultrasound in haemochromatosis-related cirrhosis is recommended by NICE NG50 (Cirrhosis, 2016: ultrasound with or without AFP every 6 months) and by EASL (international) — HCC risk in haemochromatosis cirrhosis is approximately 200-fold higher than the general population, with a lifetime risk of approximately 10-30% in those with established cirrhosis. Critically, the HCC risk in haemochromatosis is not completely eliminated by venesection (iron removal) once cirrhosis has developed — the cirrhotic liver retains malignant potential even after iron is removed. This is in contrast to earlier haemochromatosis (stages 2-3) where venesection to normal ferritin prevents HCC development. GPs who receive haemochromatosis-cirrhosis patients in shared care must ensure: (1) 6-monthly liver ultrasound (the core test); (2) AFP if used by local hepatology practice; (3) specialist-directed MRI or CT if ultrasound is technically inadequate; (4) documentation of HCC surveillance compliance. Surveillance is not started solely because ferritin is high or because the patient is a C282Y homozygote. Failure to surveil is associated with late-stage HCC diagnosis and poor outcomes.

The decision to test first-degree relatives of a C282Y homozygous haemochromatosis patient is a cost-effective and potentially life-saving GP intervention — adult first-degree relatives should be offered HFE genotyping, ferritin and transferrin saturation, with clinical assessment where indicated (siblings have a 25% chance of being C282Y homozygous). Children of a C282Y homozygote are obligate C282Y carriers; avoid routine testing of minors unless there is a clinical indication or specialist/genetic-counselling advice (BSH supports testing children over the age of consent). The rationale: haemochromatosis is one of the most treatable genetic conditions if identified before organ damage develops. A sibling identified as C282Y homozygous at stage 1-2 (elevated transferrin saturation, mildly elevated ferritin, no organ damage) can have venesection therapy initiated before any organ damage occurs — preventing diabetes, cirrhosis, arthropathy, and hypogonadism entirely. The NHS does not currently offer population screening for HFE mutations, but the EASL (European Association for the Study of the Liver; international) and the BSH haemochromatosis guideline (2018, endorsed by the BSG) recommend cascade genetic testing for all first-degree relatives of confirmed C282Y homozygous probands. GPs can request HFE gene testing directly in the UK via the NHS genetics laboratory.

The venesection schedule for haemochromatosis is practically managed in NHS primary care or hospital phlebotomy departments, and GPs play a key role in monitoring and coordinating this — the monitoring protocol before each venesection session: Hb before every session (adjust or defer if anaemia, frailty, hypotension or significant comorbidity), ferritin approximately monthly during induction, transferrin saturation periodically, and clinical assessment (symptoms, joint swelling). Targets and intervals are set by the specialist service. The documentation and shared care: hepatology initiates and monitors overall progress; GPs often coordinate venesection appointments at local phlebotomy or blood donation units (NHS Blood and Transplant accepts some people with haemochromatosis as blood donors if they meet its donor criteria — the donated blood is used for transfusion). GPs should be aware that Haemochromatosis UK (haemochromatosis.org.uk) provides excellent patient support and information.

The IL-1 inhibitor anakinra for adult-onset Still disease represents one of the most dramatic treatment responses in rheumatology — the extreme hyperferritinaemia of AOSD (reflecting macrophage activation) drops precipitously within days of starting anakinra (recombinant IL-1 receptor antagonist, 100 mg SC daily). AOSD is driven by IL-1β, IL-6, and IL-18 — the IL-1 pathway is the most important driver of the AOSD cytokine storm. Anakinra is specialist-initiated within NICE TA685. Ferritin can be used as a treatment response biomarker — a falling ferritin with clinical improvement supports the diagnosis and treatment efficacy but does not prove it. For AOSD MAS (macrophage activation syndrome — the most life-threatening complication, equivalent to HLH), IV methylprednisolone + ciclosporin + anakinra is used.

The Vibrio vulnificus raw shellfish risk in haemochromatosis is a clinically critical patient safety warning — Vibrio vulnificus is a marine bacterium found in warm coastal waters and concentrated in filter-feeding shellfish, particularly oysters. In healthy individuals, Vibrio vulnificus ingestion causes mild gastroenteritis. In people with chronic liver disease/cirrhosis, iron overload, diabetes or immunocompromise, the bacterium uses excess free iron as a growth substrate, causing rapid septicaemia with mortality exceeding 50% in iron-overloaded patients. The clinical warning must be explicit at diagnosis: 'Avoid raw oysters and other raw shellfish if you have significant iron overload or chronic liver disease — they can cause a life-threatening Vibrio blood infection.' This warning should be provided in writing at diagnosis.

The ferritin recheck after CRP normalisation is the most important practical step in the primary care evaluation of hyperferritinaemia — because ferritin is a reliable marker of iron stores ONLY in the absence of inflammation, any elevated ferritin result with a concurrent elevated CRP cannot be interpreted as reflecting true iron stores. The protocol: treat the underlying inflammatory cause (infection — antibiotics; IBD flare — steroids; RA — DMARD escalation), then recheck ferritin + CRP together 4-6 weeks after clinical recovery. If CRP has normalised and ferritin remains elevated: this now represents true hyperferritinaemia requiring further investigation (transferrin saturation, HFE gene testing, alcohol history, liver USS). GPs who review a ferritin result in isolation — without checking CRP, without knowledge of the inflammatory context — and either falsely reassure (missing haemochromatosis) or falsely alarm (diagnosing iron overload in an inflamed patient) are making a systematic analytical error.