Genetic haemochromatosis (GH)

Genetic Haemochromatosis (GH) is common across Scotland, with the highest prevalence in the Outer Hebrides. NHS Scotland should respond to the needs of patients with GH by providing equitable, timely and evidence-based care.

GH places a significant economic burden on both the healthcare system and patients. Resources should therefore be focused where they provide greatest benefit, ensuring care is delivered at the lowest appropriate level of complexity.

The multidisciplinary pathway development group, delivered through the National Centre for Sustainable Delivery, has developed the GH pathway for Scotland. The pathway is informed by specialist society guidelines, input from the British Association for the Study of the Liver Haemochromatosis specialist interest group and the Scottish National Blood Transfusion Service (SNBTS), published research evidence, and expert clinical opinion.

The pathway provides a streamlined, integrated approach between primary care, secondary care and SNBTS to deliver an accessible, equitable and quality service across NHS Scotland.

GH is most common in people of Northern European and especially Celtic ancestry. It is an autosomal recessive condition, characterised by increased intestinal absorption of dietary iron from the small intestine. In some patients, excess iron accumulates in the parenchymal cells of organs including the liver, pancreas, heart and anterior pituitary, leading to the impaired function of these organs in a minority of patients inheriting the relevant genes.

Early diagnosis and treatment prevent disease progression and enable normal life expectancy, particularly through prevention of liver cirrhosis and hepatocellular carcinoma.

Homozygosity for p.C282Y missense mutation on the High Fe++ (HFE) gene on chromosome 6p is the predominant genotype in GH, present in up to 80-90% of clinically diagnosed cases. However, the genotype alone is not sufficient for diagnosis because genetic penetrance of the p.C282Y mutation is variable and is generally higher in men and increases with age. Clinical diagnosis therefore requires evidence of both p.C282Y homozygosity and biochemical iron overload.

Scottish genetic laboratories also test for the second most common HFE mutation, p.H63D. Individuals who are homozygous for p.H63D (p.H63D/p.H63D), or who carry a single copy of either p.C282Y or p.H63D, are not at risk of developing clinically significant iron overload and are not included in the definition of GH.

Compound heterozygosity (p.C282Y/p.H63D) is not considered a disease-causing genotype on its own. It is associated with a risk of mild iron overload, often in the presence of additional factors such as metabolic syndrome, excessive alcohol intake, systemic inflammation, malignancy and infection. Recent studies from the UK Biobank cohort indicate that this group does not have increased risk of death or liver complications, including liver disease and liver cancer (6).

Further information on the risk of GH based on HFE genotype can be found at: https://sites.exeter.ac.uk/ironoverload/

Other rare inherited causes of iron overload (including non‑HFE mutations and ferroportin disease) are outside the scope of this pathway, although guidance is provided on when referral to secondary care should be considered.

Finally, serum ferritin is a sensitive but non-specific biomarker of iron overload. Although elevated serum ferritin is frequently encountered in clinical practice, only around 10% of patients with raised serum ferritin have iron overload. Raised serum ferritin often presents a significant diagnostic challenge and guidance on investigating elevated ferritin in primary care is available at: https://www.bmj.com/content/382/bmj-2023-076750.

For the purposes of this pathway, GH refers to iron overload associated with homozygosity for the p.C282Y mutation in the HFE gene.

First presentation and clinical assessment

Population studies indicate that the majority of men and the vast majority of women with GH remain undiagnosed despite the fact that approximately 1% of the Scottish population is estimated to have a genetic predisposition to develop GH. However, only around 30-35% of male versus 5-10% of female p.C282Y homozygotes develop serious iron overload and even less develop significant complications.

For those who do develop iron overload, the symptoms are often insidious, frequently resulting in late diagnosis when organ damage may have already occurred.

Most common symptoms are:

• Chronic unexplained fatigue and weakness
• Early onset arthralgia or atypical arthropathy
• Liver disease of unknown cause, or incidental abnormal liver function tests
  • serum ferritin and transferrin saturations are part of the full non-invasive liver screen and iLFT protocol

Reported in the literature, but uncommon in clinical practice:

• Early onset male impotency, early menopause and loss of libido in women
• Early onset arrhythmia and cardiomyopathy
• Unexplained increasing skin pigmentation or ‘permanent tan

Family screening criteria:

• First degree adult (≥18 years) relatives of p.C282Y homozygous patients. Patients identified through family screening are often asymptomatic.

Initial investigations

1. Assess for biochemical evidence of iron overload

There is no universally agreed reference range for serum ferritin. Please familiarise yourself with your local laboratory reference ranges for males and females.

• Measure serum ferritin when the patient is clinically well and stable
  • Avoid testing during acute illness and for 6 weeks afterwards.
• If serum ferritin is:
  • <200 ng/mL in pre menopausal females,
  • <300 ng/mL in males and post menopausal females, or
  • below the upper reference range (URR) for the local laboratory, no further tests are required.
• Check early morning fasting transferrin saturation (Tsat) when:
  • Serum ferritin is >200ng/mL (pre-menopausal females)
  • Serum ferritin >300ng/mL (males and post-menopausal females)
  • Serum ferritin is above URR for local laboratory values

Serum ferritin and Tsat assays could be performed simultaneously or sequentially.

2. Genetic testing for HFE mutation:

• Request genetic testing for HFE haemochromatosis only when there is evidence of biochemical iron overload, defined as:
  • Tsat >45% and serum ferritin >200ng/mL in pre-menopausal females
  • Tsat >45% and serum ferritin >300ng/mL in males and post-menopausal females
  • Tsat >45% and serum ferritin above URR for local laboratory values

Initial management of raised serum ferritin

• Most patients with a raised serum ferritin do not have GH. They should be assessed and managed in line with current guidance, with referral to the appropriate specialty where indicated: https://www.bmj.com/content/382/bmj-2023-076750
• All patients should receive lifestyle advice, including:
  • alcohol intake
  • maintaining a healthy weight
  • counselling about viral hepatitis and blood borne virus risk
  • offering BBV testing where relevant risk factors are present
• Patients with abnormal liver function tests should undergo a non-invasive liver screen, in line with national guidelines or local protocols.
• Consider referral to secondary care for unexplained biochemical iron overload, particularly if serum ferritin is persistently >1000 ng/mL. Patients with a clear alternative explanation (for example alcohol excess and/or metabolic syndrome) do not require referral.

C282Y homozygote patients (p.C282Y/p.C282Y)

• Refer to secondary care patients who are p.C282Y homozygous (p.C282Y/p.C282Y) and have evidence of biochemical iron overload and are likely to benefit from further investigation and intervention.
• Patients awaiting review can be signposted to the British Liver Trust for information about haemochromatosis: https://liveruk.org/about-liver-disease/conditions/haemochromatosis/ 
• Patients who are p.C282Y homozygous but do not fulfil above criteria for evidence of biochemical iron overload:
• Primary care management:
  • Advice on family screening for GH (first degree relatives ≥18 years of age)
  • Inform about blood donation. Patients who have never been venesected can self-refer to SNBTS
  • Avoid supplementary iron and vitamin C
  • Monitoring, in line with local arrangements:

• We recommend annual serum ferritin and Tsat for patients under 65
• Refer to secondary care if iron overload develops
• Review the need for ongoing monitoring at age 65, based on frailty, co-morbidity and likely benefit of intervention

C282Y/p.H63D compound heterozygote patients

• No biochemical iron overload
• Reassure and discharge from follow‑up
• Provide lifestyle advice for liver health: https://liveruk.org/support-us/campaigns/love-your-liver/ 
• Patients may self‑refer to the SNBTS if they wish to donate blood
• Serum ferritin above URR, but<1000 ng/mL
• No established consensus on standard of care for this group.
• Mild to moderate hyperferritinaemia is usually due to co‑morbid conditions, most commonly:
  • excess alcohol intake
  • metabolic syndrome / MASLD
• The World Health Organisation (WHO) definition of upper limit of normal for serum ferritin in non‑healthy adult populations is 500 ng/mL.
• UK Biobank data show no increased risk of mortality, liver fibrosis, cirrhosis, joint replacement or depression after a mean follow‑up of 13.3 years.
• Recommended approach:

1. 1. Take a detailed alcohol history
   2. Assess for components of metabolic syndrome
   3. Investigate abnormal liver function tests with a full non‑invasive liver screen
   4. Assess liver fibrosis using FIB‑4 in patients with MASLD or ALD risk. Refer if FIB‑4 >1.3 (or >2.0 in patients aged over 65)
   5. Offer lifestyle advice (alcohol reduction, smoking cessation, weight management) and repeat iron studies after 12–18 months
   6. If ferritin improves to ≤500 ng/mL and there is no evidence of advanced fibrosis, discharge from follow‑up

Serum ferritin ≥1000 ng/mL

When serum ferritin remains ≥1000 ng/mL despite effective lifestyle modification:

• Refer to secondary care for further evaluation
• Assessment of liver iron concentration may be required with MRI liver iron quantification (where available) or liver biopsy, if MRI is not available.
• If liver iron concentration is elevated, secondary care will arrange tests for rare HFE variants/non-HFE genetic mutations. Venesection therapy may be offered where appropriate.

Assessment – Genetic haemochromatosis clinic

Concise clinical assessment:

Fibrosis assessment

There remains a lack of validated non-invasive markers for fibrosis assessment in GH. Recommendations below are based on expert consensus.

First line fibrosis assessment with FIB-4 score

In patients with:

• features of metabolic syndrome and/or
• current or previous harmful alcohol use
• perform FIB‑4 to screen for advanced fibrosis or cirrhosis

In all patients with abnormal LFTs:

• perform full non-invasive liver screen (if not already done)
• calculate FIB-4.

If FIB-4 is >1.3 (>2.0 in over 65yo):

• proceed to second line fibrosis assessment, in line with local guidelines.
• Second line fibrosis assessment (Fibroscan™, ELF, 2D Shear Wave Elastography)
• Proceed straight to second line fibrosis assessment with Fibroscan™ or equivalent in patients with serum ferritin ≥1000ng/mL
• Where possible, performing second line fibrosis assessment during maintenance phase of venesection could be preferable, as fibrosis measurements may decrease post depletion of liver iron
• Liver stiffness measurements (FibroScan™): manufacturer recommends selecting the ‘multi-aetiology’ category to quantify fibrosis. According to Baveno VII:

 *cACLD - compensated advanced chronic liver disease

Enhanced Liver Fibrosis (ELF) test

• If using ELF, suggested ELF cut off for cirrhosis is 10.5
• Consider further investigations when ELF>9.8.
• ELF measurement can be repeated in maintenance phase, if elevated

If using 2-Dimensional Shear Wave Elastography, the following Royal College of Radiologists guidance should be followed:

Please note that none of the secondary tests for liver fibrosis have been validated in Haemochromatosis, and should be interpreted in the clinical context.

Blood tests at diagnosis

• Full blood count (FBC)
• Liver function tests (LFTs)
• Serum ferritin
• Tsat
• HbA1c
• Serum B12 and folate
• In patients with abnormal LFTs, complete a full non-invasive liver screen if not done previously
• In patients with cirrhosis, also check an AFP

Assessment for extra-hepatic manifestations

• Fatigue and arthralgia are the most common symptoms in early disease. Symptoms can significantly affect quality of life.

Fatigue

• Fatigue can improve with treatment of GH. If symptoms do not improve, advise Primary Care to investigate for other causes of fatigue.

Joint pain

• Joint disease resembles osteoarthritis but typically presents at a younger age.
• Typically affects the 2nd and 3rd metacarpophalangeal joints and ankles, but may also involve the hips, knees, wrists, shoulders and elbows.
• Established joint disease does not respond to phlebotomy and can develop on maintenance therapy.
• Some patients will report diminished arthralgia after iron removal.
• Treatment is limited to analgesics and non-steroidal anti-inflammatory agents, physiotherapy and, where appropriate, orthopaedic procedures including joint replacement.

Cardiac and endocrine manifestations

• These are rare, but may be apparent in severe GH (serum ferritin >2000ng/mL) and especially in juvenile forms of the condition. Refer to Cardiology and Endocrinology for specialist assessment where indicated.

Lifestyle advice

• All patients should be signposted to lifestyle advice for good liver health: https://liveruk.org/support-us/campaigns/love-your-liver/ 
• Advise smoking cessation
• Avoid iron and Vitamin C supplements
• Patients in the depletion phase should avoid raw/undercooked shellfish due to the risk of Vibrio vulnificus (bacterial food poisoning)

Family screening advice

Screening of parents of p.C282Y homozygotes should be considered on an individual basis following a clinical decision that takes into account age, sex and serum ferritin level.

Contraindications to phlebotomy

Patients should be assessed for permanent and temporary contraindications to phlebotomy before starting treatment and during yearly follow-up.

If there is uncertainty about prognosis or suitability, discuss the case at the GH multidisciplinary team (MDT) meeting, or seek specialist advice.

The list below is not exhaustive.

Permanent contraindications

• Significant illness that would compromise patient safety during phlebotomy (e.g. active cancer or cancer treatment, any terminal illness)
• Severe or uncontrolled cardiac disease, including:
  • severe coronary artery disease
  • uncontrolled heart failure
  • poorly tolerated or uncontrolled cardiac arrhythmias.

Temporary contraindications

• Iron‑deficiency anaemia
• Hypotension (systolic blood pressure <100 mmHg)
• Severe peripheral vascular disease (where intervention is planned)
• Recent stroke (within the last 6 months)
• Pregnancy
• Intercurrent illness associated with a decline in general health
• Poor venous access in the upper limbs.

On completion of the initial assessment at the dedicated GH clinic, we recommend that all patients are discussed at the dedicated GH MDT. This ensures that the principles of Realistic Medicine are applied to the care of this patient group, and to inform shared decision-making discussions around whether venesection is required and likely to be beneficial (see below).

Assessment – GH Multi-Disciplinary Team (MDT)

The GH MDT is a dedicated team of healthcare professionals, led by the Haemochromatosis Clinical Lead. The MDT is responsible for the diagnosis, management and appropriate follow-up of patients with GH.

The GH MDT also supports:

• implementation of national and local pathways and protocols
• provision of clinical advice and governance, including audit of services
• education and liaison with colleagues and patient charities

Roles of GH MDT

At diagnosis

• Discuss all new referrals following assessment in the GH clinic
• Consider the likelihood of end‑organ damage without treatment, taking into account serum ferritin at presentation and patient’s age and sex
• Recognise that frail, elderly or highly co‑morbid patients are unlikely to benefit from venesection and may be harmed by treatment

During treatment

• Discuss problems related to patient engagement with or tolerability of venesection treatment at any point post diagnosis
• If clinically appropriate, discussion of alternatives to venesection (eg., iron chelation)
• Discuss suspension of venesection if temporary contra-indications

Discharge from venesection and follow-up

• Development of permanent contra-indications
• Patient wishes
• Following annual review at age 65, where there is:
  • no evidence of end organ damage
  • frailty or co morbidity suggesting life expectancy less than 10 years
• For patients continuing venesection beyond age 65:
  • review appropriateness every 1–2 years
  • Participation in local and national audits and clinical research projects

Recommended workforce model for implementation of the GH pathway

We recommend a nurse-led, nurse-delivered GH pathway, with clinical oversight provided through a dedicated GH MDT led by the Haemochromatosis Clinical Lead, or a deputising senior clinician.

Recommended staffing bands

• GH clinic, MDT participation, blood test monitoring and referral initiation to SNBTS
  • Band 5 or above Registered Nurse with experience in managing liver disease patients

• FibroScan™ and venesection
  • Band 3* Healthcare Support Worker (HCSW)

• Venesection
  • Band 2* Healthcare Support Worker (HCSW)

* Venesection sessions provided by band 2 and 3 HCSW to be co-located with Band 5 or above registered nurse to ensure patient safety.

Management – Venesection pathway

Patient information about venesection

• Phlebotomy is expected to occur weekly or fortnightly, removing around 500mL of blood each session.
• The goal is to reduce serum ferritin level to a target range of 50–100ng/mL.
• Alongside serum ferritin, haemoglobin levels will be monitored to ensure anaemia does not develop.
• Once the target serum ferritin level is reached, we will reduce the frequency of phlebotomy to 3–4 times a year.
• There is no need to restrict dietary iron while undergoing phlebotomy.
• Phlebotomy reduces the risk of complications related to liver disease, including liver cancer.
• The following complications may improve with phlebotomy:
  • abnormal liver blood tests and liver fibrosis
  • fatigue
  • arthralgia (joint pain)
  • cardiac dysfunction (very rare in haemochromatosis)
• The following complications are unlikely to improve with phlebotomy:
  • diabetes
  • arthropathy (established joint damage)
  • hypogonadism (low sex hormone levels)

Depletion Phase

Aim to offer a personalised venesection plan agreed with the patient

• Consider the need for vitamin B12 and folate replacement if levels low at diagnosis and/or patient’s diet is poor or restricted
• Remove 450-500ml of blood at each session, weekly or fortnightly
• FBC monitored at each phlebotomy:
  • If Hb <120g/L: reduce rate
  • If Hb <110g/L: pause treatment
• Serum ferritin (SF) monitored after 4-6 phlebotomies until SF of 200ng/mL is reached, then check SF every 1-2 treatment sessions
• Venesection target: SF 50-100ng/mL
• At discretion of the patient and clinical team, SF levels within the reference range could be accepted as target during depletion phase and monitored every 3 months initially, then every 6-12 months thereafter (see Maintenance Phase).

Maintenance Phase

Aim to offer each patient an annual review in the nurse‑led GH clinic, with discussion at the GH MDT where required. Reviews may be conducted face‑to‑face, virtually, by telephone, or through patient‑initiated follow‑up, in line with local arrangements.

At annual review:

• Review the clinical need for ongoing follow up and venesection treatment, especially when permanent contraindications develop.
• Review the frequency of venesection over the previous year and agree a venesection plan for the year ahead. This should be based on:
  • serum ferritin (SF) levels
  • clinical status and patient specific factors

• Development of iron deficiency anaemia and/or an unexplained reduction in venesection requirements should prompt consideration of alternative causes of blood loss, investigated in line with current clinical guidance.
• Review and agree target SF level with the patient. Treatment should be tailored to patient preference wherever possible and safe to do so. When agreeing the maintenance target and venesection plan, consider:
  • patient age and co‑morbidity
  • symptoms and overall well‑being during venesection
  • ability to attend appointments (for example due to travel or work commitments)

• In the absence of significant liver fibrosis or cirrhosis, we recommend maintaining SF within the reference range for example:
  • <300 ng/mL in males and post‑menopausal females
  • <200ng/mL in pre-menopausal females

• Patients with liver cirrhosis should remain under secondary care for venesection and hepatocellular carcinoma (HCC) surveillance, where clinically appropriate:
  • 6-monthly abdominal ultrasound
  • alpha fetoprotein (AFP)
  • aim to maintain serum ferritin at 50–100 ng/mL where safe to do so

• We acknowledge that SF of 50-100ng/mL is the recognised international target proposed in the latest international guidelines. However, in the absence of quality clinical evidence, these guidelines have set the SF maintenance targets are largely based on expert opinion.
• Most patients would require between 2-6 venesections per year
• Check FBC at each phlebotomy session
• Monitor SF every 6 months
• Actively consider referral to SNBTS for acceptance to blood donation in suitable patients (see below)

Scottish National Blood Transfusion Service (SNBTS)

Scottish National Blood Transfusion Service (SNBTS) accepts blood donations from people with Genetic Haemochromatosis. Blood donation is always a choice. Patients must not feel under pressure to give blood to get treatment for their condition and should be given information on how to get in touch with secondary care venesection services to arrange maintenance venesection if they are not eligible to, or don’t wish to, donate. Equally, patients may wish to donate blood to offer mutual benefit to themselves and society, appreciating the positive impact of reducing wastage of blood in the climate of blood stock shortages (https://www.scotblood.co.uk/about-blood/current-blood-stock-levels/).

SNBTS has produced a donor information leaflet entitled ‘Haemochromatosis and blood donation’ to help facilitate discussions about referral for blood donations: Scotblood | Giving blood.

All potential donors (including GH donors) must meet the same eligibility criteria before each donation; no exceptions can be made for GH donors other than with age (GH donors above the usual cut off age of 65 can be accepted at the discretion of the donor clinical support team). UK donor selection guidelines can be viewed at https://www.transfusionguidelines.org/dsg/wb/guidelines

Self-referral of patients in primary care

Patients who have a genetic diagnosis of GH (p.C282Y homozygotes) or who are p.C282Y/H63D compound heterozygotes with no evidence of biochemical iron overload and who have never been venesected can donate blood without clinician’s referral. They can self-refer to SNBTS if they wish to become blood donors (Scotblood | Giving blood).

Referral from secondary care

All GH patients for whom maintenance therapeutic venesection is required or planned must be approved by the SNBTS Donor Medical Team to donate blood. If eligible, they will be registered as an approved Genetic Haemochromatosis donor.

To be eligible, GH patients must:

• Have no end organ damage related to their diagnosis of GH
• Have good venous access and no adverse reactions to venesection
• Not require intravenous fluid replacement
• Be at the maintenance phase of treatment
• Remain under the ongoing care of the referring clinical team who will:
  • monitor their iron status and frequency of venesection
  • provide venesection facilities if the donor is unable/does not wish to donate

Donation parameters

• Acceptable haemoglobin ranges:
  • 125–165 g/L for females
  • 135–180 g/L for males
• In Scotland, patients with GH may donate blood every 12 weeks, and not more frequently.

SNBTS has no mechanism to inform the secondary care team about blood donations and it is the responsibility of the GH donor to inform their GH team of the frequency of donation.

All GH patients attending SNBTS will be reviewed annually in the nurse led GH clinic, as detailed in the Maintenance Phase section above.

The Genetic Haemochromatosis Referral Form for routine blood donation and information about making the referral can be found at https://www.nss.nhs.scot/blood-tissues-and-cells/snbts-transfusion-team/genetic-haemochromatosis/

Click on the image below to open the primary care pathway

Click on the image below to open the secondary care summary

Patient resources

• Patient Information Leaflet (provided by local NHS Board)
• Haemochromatosis and blood donation. Donor information leaflet Scotblood | Giving blood

References

1. Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). British Journal of Haematology, 2018, 181, 293–303. https://doi.org/10.1111/bjh.15164
2. EASL Clinical Practice Guidelines on haemochromatosis 2022. Journal of Hepatology 2022 vol. 77, 479-502. https://doi.org/10.1016/j.jhep.2022.03.033
3. ACG Clinical Guideline: Hereditary Hemochromatosis.  The American Journal of Gastroenterology 114(8):p 1202-1218, August 2019. https://doi.org/10.14309/ajg.0000000000000315
4. Model of Care for Hereditary Haemochromatosis. Health Service Executive, Ireland. https://www.scribd.com/document/844103426/model-of-care-for-hereditary-haemochromatosis 
5. Barton JC, Parker CJ. HFE-Related Hemochromatosis. 2000 Apr 3 [Updated 2024 Apr 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1440/
6. HFE genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: a prospective cohort study in the UK Biobank. BMJ Open. 2024 Mar 13;14(3):e081926. https://doi.org/10.1136/bmjopen-2023-081926
7. Venesection treatment in haemochromatosis – current best practice from the BSG/BASL Special Interest Group. Singh P, Mortimore G, Hicks K, et al. Frontline Gastroenterology Epub ahead of print: 20 June 2025 https://doi:10.1136/flgastro-2025-103172