14 November 2023

Updates in Haemochromatosis



This article is mapped to the following JRCPTB learning objectives:

  • To be able to investigate, diagnose, and treat patients and family members with heavy metal-associated liver disease
  • Recognises the importance but also difficulty in diagnosing heavy metal-associated liver disease; has an understanding of the variants
  • Understands the management of these diseases, including both screening and follow-up of siblings; identifies the possible need for genetic counselling.
  • Recognises the potential need to screen relatives and keeps up to date with contemporary developments in screening protocols

Please email comments or suggestions to Dr John Ong [email protected], section editor.

Background: Guidelines on the diagnosis and management of ‘genetic’ / ’hereditary’ haemochromatosis were previously published by the British Society of Haematology (BSH) and endorsed by the BSG. These were last reviewed and updated in 2017.

What’s new?: The European Association for the Study of the Liver (EASL) has published new guidelines based on expert European consensus. In addition, the international BIOIRON Society has recommended a new classification of ‘haemochromatosis’.

Clinical impact: New recommendations which will influence clinical practice in the UK.


UK guidelines on ‘genetic haemochromatosis’ were originally written in 2000 and updated in 2017.1  Internationally, the solitary term ‘haemochromatosis’ is replacing ‘genetic’ / ’hereditary’ haemochromatosis and is defined as ‘a disease of genetic origin characterised by increased transferrin saturation and liver iron overload, in the absence of anaemia and/or reticulocytosis’.2  Five genetically determined sub-types are described (Table 1).

Table 1: Online Mendelian Inheritance in Man (OMIM) classification of haemochromatosis

TypeAssociated gene(s)Mode of inheritance/penetrance
      1HFE – 90% have a mutation at amino acid 282 (C282Y)Autosomal recessive – variable penetrance
      2Type 2A: HJV

Type 2B: HAMP

Autosomal recessive – severe iron overload / juvenile haemochromatosis
      3TFR2Autosomal recessive – intermediate severity / juvenile haemochromatosis
      4SLC40A1 (>39 mutations identified):

Type 4A – ‘loss of function’ mutation (‘classical’)

Type 4B – ‘gain of function’ mutation

Autosomal dominant with variable penetrance (‘classical’ = mild iron overload)


      5FTH1Autosomal dominant, very rare.

These genetic defects lead to impaired hepcidin synthesis or function resulting in increased intestinal absorption of iron and/or increased release from macrophages and enterocytes. As a result, the high iron content in circulation increases transferrin saturation and this eventually causes iron accumulation in the liver and joints, and in the heart, skin and endocrine glands once severe. The BIOIRON Society (International Society for the Study of Iron in Biology and Medicine) has recently suggested a re-classification to address the molecular complexity and clinical aspects of haemochromatosis adopting the following four terms: ‘HFE-related’, ‘non-HFE related’, ‘digenic’ and ‘molecularly undefined’.3

‘HFE-related’ is by far the most common form of haemochromatosis in the UK. C282Y homozygosity confers the highest risk of iron overload. A study of the UK Biobank data showed a C282Y homozygous prevalence of 1/156 and this was associated with substantial morbidity in both men and women.4  The minor HFE variant H63D has been associated with mild iron overload in the compound heterozygous (C282Y/H63D) and, to a lesser extent, in the homozygous form. Importantly, not all individuals with ‘positive’ HFE genotypes will have biochemical or physical manifestations of iron overload as iron accumulates over time and the disease penetrance is variable. However, the majority of males will express the condition in their lifetime and the morbidity and mortality of the disorder is entirely preventable if treated early.

Patients with raised iron indices, clinical suspicion of haemochromatosis (e.g. fatigue, arthralgia, abnormal LFT) or family history in first-degree relatives should be tested for the condition. Basic tests include but are not limited to, serum ferritin, transferrin saturation (Tsat), full blood count, CRP and LFT. Patients who meet the threshold for genetic testing (below) should undergo HFE genotyping; this test should be readily available in primary care.

Patients with persistent ‘isolated’ hyperferritinemia (normal Tsat) should be screened for alternative causes of elevated serum ferritin, importantly alcohol-related liver disease, metabolic syndrome associated steatotic liver disease / diabetes, inflammatory conditions, haematological disorders and malignancy. If no cause is apparent then referral to a specialist should be considered where in-depth genetic analysis may reveal disorders such as ferroportin disease (SLC40A1 mutations), aceruloplasminaemia and hereditary hyperferritinemia with or without cataracts (FTL promoter and exon 1 mutations).

Patients with haemochromatosis and evidence of iron overload should undergo liver fibrosis assessment (below) and be offered iron depletion therapy with intensive phlebotomy as first-line treatment. Surveillance for hepatocellular carcinoma (HCC), management of extrahepatic manifestations and family screening are important additional aspects of management.  The oral iron chelator deferasirox can be considered where phlebotomy is impossible but requires careful monitoring. Dietary modifications and the use of proton pump inhibition are other measures which can control iron absorption. The National Blood Service will accept otherwise eligible patients (aged between 17 and 65 years) with haemochromatosis and serum ferritin <500 μg/L for donation (up to every 6 weeks if required) – this should be seen as the preferred clinical pathway for maintenance therapy.

Key updates in 2022 EASL CPG (vs. 2017 BSH/BSG update)

(1) Transferrin saturation thresholds for genetic screening are slightly different:

Ferritin > 200μg/L + Tsat > 45% (females)Ferritin > 200μg/L + Tsat > 40% (females)
Ferritin > 300μg/L + Tsat > 50% (males)Ferritin > 300μg/L + Tsat > 50% (males)

(2) Young individuals with biochemical evidence and clinical manifestations of haemochromatosis (liver disease, amenorrhea, hypogonadism, cardiomyopathy) should be tested for rare genetic subtypes.

(3) Genetic testing for H63D is not recommended as a routine investigation but may be performed in specific situations e.g. when the C282Y mutation is present. Other environmental and genetic risk factors should be explored in C282Y/H63D-associated iron overload.

(4) Patients with juvenile haemochromatosis (type 2 / non-HFE) should be investigated for cardiac involvement, including myocardial iron quantification by MRI.

(5) Patients with haemochromatosis and severe iron overload should be evaluated for arrhythmias and cardiac dysfunction (electro/echocardiography).

(6) A liver biopsy is not recommended to diagnose hepatic iron overload. In suspected patients with elevated ferritin and Tsat without C282Y homozygosity, where hepatic iron quantification is required to establish the diagnosis, MRI may be used (as per UK guidelines). Referral to centres offering MRI liver with in- and out-of-phase sequence and T2* method can be made if needed when services are not available locally.

(7) Transient elastography is recommended at diagnosis for fibrosis assessment with a stiffness reading of ≤ 6.4kPa reasonably excluding advanced liver fibrosis.

(8) Liver biopsy should be considered in cases where transient elastography provides indeterminate results and there is suspicion of liver cirrhosis. Six monthly surveillance for HCC is recommended in patients with advanced fibrosis on biopsy (METAVIR F3 or Ishak stages 4-5) as well as in cirrhosis.

(9) Venesection targets are significantly different, the UK guideline is stricter and with emphasis on Tsat though with paucity of evidence to support the clinical benefit:

BSH/BSG 2017
InductionFerritin <50μg/LFerritin 20-30μg/L + Tsat<50%
Maintenance Ferritin 50-100μg/LFerritin <50μg/L + Tsat<50%

(10) Phlebotomy should be avoided in female patients who are pregnant as iron depletion will occur naturally.

(11) Erythrocytapheresis can be offered as an alternative in the induction phase because it reduces the number of venesections needed and it is potentially more cost-effective – however, this is not available in the UK.


The 2022 EASL CPG on haemochromatosis offers additional recommendations and differing perspectives compared with the 2017 UK update. In particular, the use of MRI for hepatic iron quantification and transient elastography to exclude advanced fibrosis are encouraged and HCC surveillance is recommended in advanced fibrosis as well as cirrhosis. Venesection targets are quite different and the EASL recommendation is more achievable – this is an area which would benefit from a randomised controlled trial. Of note, the cross-society Haemochromatosis Special Interest Group is spearheading quality improvement, research and management consensus for patients with haemochromatosis in the UK.

Author Biography

Dr Bill Griffiths is a Consultant Hepatologist and Clinical Lead of the Cambridge Liver Unit. He qualified from the University of Cambridge and was later awarded a PhD for his research in iron metabolism. He set up a haemochromatosis clinic in 2000. He has a specific interest in genetic liver disease and has authored numerous publications in this area. Dr Griffiths was the first BASL Rare Disease Special Interest Group lead and remains the national hepatology training lead.


Question 1

Which one of the following statements about HFE-related haemochromatosis is true?

Question 2

33-year-old male referred by GP for mixed-picture hepatitis with normal bilirubin. Newly diagnosed diabetic with alcohol dependency history, chronic pancreatitis,BMI of 33 kg/m2. Currently drinks 36 units of alcohol /week, 20 cigarettes /day. Non-invasive screen revealed serum ferritin1800 μg/l and transferrin 85%. Full blood count revealed macrocytosis with normal reticulocyte. Platelet count 99 x 109/L and INR 1.5. Genetic screening detected C282Y/H63D compound heterozygosity. Ultrasound showed hepatomegaly with marked steatosis. A fibroscan showed stiffness of 11.5kPa. Which of the following is most appropriate?


  • D
  • A


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  1. Fitzsimons EJ, Cullis JO, Thomas DW, Tsochatzis E, Griffiths WJH. Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). Br J Haematol. 2018;181(3):293–303.
  2. EASL Clinical Practice Guidelines on haemochromatosis. European Association for the Study of the Liver. J Hepatol. 2022 Aug;77(2):479–502.
  3. Girelli D, Busti F, Brissot P, Cabantchik I, Muckenthaler M, Porto G. Hemochromatosis classification: update and recommendations by the BIOIRON Society. Blood 2022;139(20):3018-3029.
  4. Pilling LC, Tamosauskaite J, Jones G, et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ 2019;364:k5222.