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. Any patient with unexplained fever + cytopenias + extreme hyperferritinaemia must be referred to haematology as an emergency — 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 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 above 45% in men or 40% in women (fasting, morning sample) 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 strongly indicated (C282Y homozygosity in Northern European individuals). 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 a mandatory NICE and EASL quality standard — 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 AFP blood test; (2) 6-monthly liver ultrasound; (3) documentation of HCC surveillance compliance. 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 — genetic testing of siblings (who have a 25% chance of being C282Y homozygous) and children (who are obligate C282Y heterozygotes) should be offered. 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) and 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 (must be ≥110 g/L in men, ≥100 g/L in women to proceed), ferritin (target reduction to 20-50 µg/L during induction), and clinical assessment (symptoms, joint swelling). 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 haemochromatosis patients as blood donors via the Haemochromatosis Society scheme — donated blood used for transfusion, removing the cost burden of therapeutic phlebotomy). GPs should be aware that the Haemochromatosis Society (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. Response rate approximately 80-90%. Ferritin levels can be used as a treatment response biomarker — a falling ferritin with clinical improvement confirms AOSD diagnosis and treatment efficacy. 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 patients with iron overload (haemochromatosis, liver disease, or other conditions with elevated serum iron), 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: 'Do not eat raw or undercooked shellfish, particularly oysters, ever — this can cause a life-threatening blood infection in people with iron overload.' This warning is on the British Society of Gastroenterology haemochromatosis information sheet and 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.