Hereditary Haemochromatosis | Geeky Medics

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Introduction

Hereditary haemochromatosis is a genetic disorder that causes increased absorption of dietary iron, leading to iron overload and organ damage.¹

It is most common among individuals of Northern European ancestry, with an estimated prevalence of 1 in 200-300 in those homozygous for the most common mutation.² Although symptoms typically present in middle age, earlier or later onset is possible. Early recognition allows the prevention of irreversible organ damage.

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Aetiology

The most common form of hereditary haemochromatosis is caused by mutations in the HFE gene on chromosome six. These mutations reduce the production or function of hepcidin, which is a hormone that normally downregulates intestinal iron absorption.³

Most cases involve homozygosity for the C282Y mutation.² The H63D mutation may cause milder disease or contribute to compound heterozygosity.

Less commonly, non-HFE mutations in other genes result in earlier-onset or more severe iron overload.³

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Risk factors

The key risk factor for hereditary haemochromatosis is genetic predisposition.²

Additional genetic and clinical modifiers influence the age of presentation and disease severity rather than disease risk itself, including:

• Male sex: earlier presentation due to the absence of menstrual iron loss
• Family history: reflects shared genetic risk and increases the likelihood of pathogenic HFE variants
• Compound heterozygosity (C282Y/H63D): typically associated with milder or later-onset disease
• Postmenopausal status: increased iron accumulation following cessation of menstrual blood loss
• Alcohol excess and chronic viral hepatitis: accelerate hepatic injury and complications in affected individuals^2-3

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Clinical features

History

Symptoms often develop insidiously.

Typical symptoms of haemochromatosis include:

• Fatigue and generalised weakness
• Joint discomfort: particularly affecting the second and third metacarpophalangeal (MCP) joints
• Skin hyperpigmentation: giving a bronze or greyish hue (bronze diabetes when associated with diabetes mellitus)
• Abdominal pain: due to liver involvement
• Erectile dysfunction or amenorrhoea: due to hypogonadism
• Symptoms of diabetes mellitus (e.g. polydipsia, polyuria)
• Symptoms of heart failure (e.g. dyspnoea, peripheral oedema)

Other important areas to cover in the history include:

• Family history (e.g. genetic predisposition to haemochromatosis)
• Menstrual history (e.g. reduced or absent menstruation decreases physiological iron loss and may indicate hypogonadotropic hypogonadism secondary to iron overload)

Clinical examination

A complete abdominal examination should be performed to identify signs of organ involvement.

Typical clinical findings in haemochromatosis include:

• Skin hyperpigmentation (bronze or slate-grey discolouration)
• Hepatomegaly
• Signs of chronic liver disease or cirrhosis (e.g. spider naevi, palmar erythema, ascites)
• Signs of heart failure (e.g. elevated jugular venous pressure, peripheral oedema)
• Testicular atrophy in men
• Joint tenderness or bony hypertrophy at the MCP joints

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Differential diagnoses

Possible differential diagnoses include:

• Secondary iron overload (e.g. repeated blood transfusions in haemoglobinopathies)
• Chronic liver diseases (e.g. alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD))
• Rheumatological arthropathies mimicking haemochromatosis
• Inherited disorders of iron metabolism (e.g. thalassaemia, aceruloplasminemia)

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Investigations

Bedside investigations

Relevant bedside investigations include:

Laboratory investigations

Relevant laboratory investigations include:

• Iron studies: transferrin saturation is typically >45%
• Serum ferritin: elevated (can be falsely raised in inflammatory conditions, acute hepatitis and some other chronic conditions, including alcohol related liver disease and MASLD)
• Liver function tests: may show hepatocellular injury
• Full blood count: may show mild anaemia
• HFE genetic testing: to confirm common mutations (e.g. C282Y homozygosity)

Imaging

Relevant imaging includes:

• Hepatic/cardiac MRI: to quantify hepatic and cardiac iron deposition
• Liver ultrasound: to assess liver architecture, hepatomegaly, or cirrhosis
• Echocardiogram: to evaluate cardiac function, if symptomatic

Special tests

Additional investigations may include:

• Liver biopsy: most cirrhosis staging is performed using non-invasive methods (e.g. FibroScan), but a biopsy can still be helpful when there is uncertainty regarding disease stage or the extent of iron overload

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Diagnosis

A diagnosis of hereditary haemochromatosis is confirmed when all of the following are present:

• Elevated transferrin saturation (>50% in men and >45% in women)
• Raised serum ferritin 
• HFE genetic testing positive

Liver biopsy or MRI quantification of hepatic iron concentration may be used for staging when diagnostic uncertainty or suspected cirrhosis is present.

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Management

Conservative management

Conservative management of haemochromatosis includes:

• Lifestyle modifications: including vitamin C supplementation and avoiding excess alcohol
• Hepatitis vaccination: for hepatitis A and B, where indicated (e.g. chronic liver disease, cirrhosis, travel to endemic regions, or other risk factors for HAV exposure), to reduce the risk of viral hepatitis and further liver injury
• Monitoring for complications (e.g. diabetes, cardiac disease, hypogonadism)⁴

Medical management

Medical management of haemochromatosis includes:

• Therapeutic phlebotomy: first-line treatment, aiming to reduce iron stores through regular blood removal. Frequency is adjusted based on monitored iron levels.
• Iron chelation therapy (e.g. deferasirox): considered if phlebotomy is contraindicated, such as in patients with severe anaemia, poor venous access, advanced cardiac disease, or intolerance to phlebotomy⁴

Surgical management

Liver transplantation may be required in cases of decompensated cirrhosis or hepatocellular carcinoma.

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Complications

If hereditary haemochromatosis is not diagnosed and treated promptly, complications can include:

• Cirrhosis: resulting from progressive hepatic iron deposition
• Diabetes mellitus: due to iron-related pancreatic damage
• Arthropathy: particularly affecting the small joints of the hands (e.g. metacarpophalangeal joints)
• Cardiomyopathy and arrhythmias: caused by myocardial iron accumulation
• Hypogonadism and infertility: due to iron deposition in the pituitary and gonads
• Hepatocellular carcinoma: developing because of cirrhosis

With early diagnosis and regular treatment, most complications can be prevented, and life expectancy remains normal.⁵

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Reviewer

Professor Catherine Stedman

Consultant Gastroenterologist and Clinical Professor

Department of Medicine, University of Otago, Christchurch

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Editor

Dr Jamie Scriven

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References

1. Pietrangelo A. Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment. Gastroenterology. 2010. Available from: [LINK].
2. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. The New England Journal of Medicine. 2005. Available from: [LINK].
3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis. Journal of Hepatology. 2022. Available from: [LINK].
4. BMJ Best Practice. Haemochromatosis. 2024. Available from: [LINK].
5. Niederau C, Fischer R, Pürschel A, et al. Long‑term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996. Available from: [LINK].

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