22nd July 2023

Hereditary haemochromatosis

Pathophysiology

Haemochromatosis is a genetic condition characterised by dysfunctional iron metabolism. The hereditary form is the most common genetic disease in people of European descent.

It is inherited in an autosomal recessive pattern. The most common causes are C282Y or H63D mutations in the HFE gene on chromosome 6. Clinical penetrance is low, meaning not all those with genetic mutations will develop the disease.

The HFE gene encodes a protein which is involved in the synthesis of hepcidin, the main regulator in iron metabolism. In hereditary haemochromatosis (HH), there is reduced expression of hepcidin, which results in continued absorption of iron despite normal or increased levels of total body iron. In addition, there is excess iron release from macrophages. This leads to excessive iron accumulation in body tissues.

Assessment and diagnosis

The characteristic iron accumulation in body tissues of HH leads to multi-system manifestations, with the liver, heart, brain and pancreas being the organs most affected. Typically, symptoms develop in later life and include fatigue, arthralgia, hyperpigmentation, loss of libido, neurological or psychiatric symptoms, as well as being an important cause of chronic liver disease. Examination findings reveal hepatomegaly, hyperpigmentation which may range from bronzing of the skin to a slate-grey appearance and/or features of porphyria cutanea tarda. The classical triad of bronzed skin, diabetes mellitus and cirrhosis may not be present in all patients, especially in the early stages of the disease.

If HH is suspected, the recommended initial investigations are a full blood count, liver function tests, ferritin and transferrin saturation. A raised ferritin on incidental testing should be interpreted with caution, as ferritin is an acute phase protein, and therefore there are a number of reasons it may be elevated.

If transferrin saturation is raised, HFE genetic testing should be carried out to confirm the diagnosis. Ferritin level guides the severity of iron overload.

Further testing, once the diagnosis is confirmed, should be carried out to assess the effect of iron deposition on tissues, especially the liver. MRI is used to assess the degree of iron content in the liver. Transient elastography is used as a non-invasive method of assessing fibrosis. The gold standard to assess iron deposition is liver biopsy, however, the British Society for Haematology guidelines advise it is no longer required for diagnosis.

Impact on other organs should be assessed with investigations screening for diabetes, cardiomyopathy, conduction abnormalities and hypogonadism.

Screening

First degree family members of those diagnosed with HH should be screened for the disease, with genetic testing in addition to a full blood count, liver function tests, transferrin saturation and ferritin. Unselected population screening is not recommended.

Genetic counselling should be offered to affected families.

Management

Prognosis is variable depending on the degree of organ involvement. Initial measures are lifestyle advice, with patients advised to avoid iron-containing supplements and to avoid excess alcohol intake in order to protect their liver long term.

Further management is guided by the stage of disease, with earlier stages requiring active monitoring only, and later stages being managed with venesection to maintain serum ferritin <50ng/ml. For those in whom venesection is contraindicated (e.g. anaemia, ischaemic heart disease), iron chelation treatment can be used. Deferasirox is an oral iron chelator.

In many cases, treatment can reverse organ dysfunction and improve overall survival. However, arthropathy does not tend to respond to treatment, and hypogonadism is irreversible.

Liver cirrhosis cannot be reversed, and the increased risk of hepatocellular carcinoma (HCC) persists despite treatment. Those with cirrhosis should undergo screening for HCC with AFP and liver ultrasound every 6 months.