Haemochromatosis & rare hepatic Iron-Loading Diseases (HILD)

Description

Hemochromatosis and rare hepatic iron-loading diseases (HILD) comprise a heterogeneous group of inherited disorders in which abnormalities of iron metabolism may lead to excessive iron accumulation, particularly in the liver and, in some conditions, in the heart, endocrine glands and other organs.

Classic HFE hemochromatosis (HC), a relatively common genetic disease in Caucasians  associated with variants in the HFE gene, has a clear clinical and epidemiologic impact in Caucasians. While testing of HFE remains important, as common HFE variants may sometimes be found together with rarer genetic iron disorders, rare HILD  are caused by variants in other genes regulating iron balance in the body, such as hemojuvelin (HJV), hepcidin antimicrobial peptide (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1).

The clinical presentation is highly variable. Some people remain asymptomatic for many years and are identified through abnormal blood tests, while others - particularly patients with juvenile forms - may develop severe iron overload early in life. Manifestations may include

• Fatigue
• Dark skin
• Diabetes
• Hypogonadism and other endocrine abnormalities
• Joint symptoms
• Cardiac disease

Diagnosis

The first step is usually a blood test measuring transferrin saturation and ferritin. High transferrin saturation can be an early sign that too much iron is circulating in the body. Ferritin gives information about iron stores, but it can also be raised for many other reasons, including inflammation, metabolic conditions, alcohol use and other liver diseases. Therefore, a high ferritin level alone does not mean that a person has hemochromatosis.

If iron overload is suspected, MRI can measure the amount of iron in the liver and, when needed, in the heart. It can also help doctors understand where iron is accumulating. Liver biopsy is now needed only in selected cases.

Genetic Testing

Genetic testing can help identify the cause of inherited iron overload. Testing often includes HFE. If this does not explain the iron overload, particularly in a young patient, in severe disease or when several family members are affected, additional genes such as HJV, HAMP, TFR2 and SLC40A1 may be investigated.

Common HFE variants are frequent in European populations and can sometimes coexist with rare genetic iron disorders. Their importance should therefore be assessed together with blood tests, MRI findings and the patient’s clinical picture. When a genetic cause is identified, testing other family members may allow the condition to be detected before organ damage develops.

Treatment

Treatment depends on the underlying disorder and the amount and location of excess iron. For most forms of hemochromatosis, the main treatment is phlebotomy (venesection), in which blood is removed regularly to reduce excess body iron. Some patients cannot safely undergo phlebotomy or have severe iron overload, particularly involving the heart. In these situations, medicines that remove iron (iron chelation) may be needed under specialist supervision. Not all inherited iron-loading diseases are treated in the same way, which is why establishing the correct diagnosis is important.

Monitoring

People with inherited iron overload usually need long-term follow-up. Blood tests such as ferritin, transferrin saturation and haemoglobin are used to monitor treatment. Liver or heart MRI may be repeated when necessary. Doctors may also monitor the liver, heart, blood sugar, hormone function, bones or joints depending on the type and severity of the disease.

When should an expert centre be involved?

Referral to a centre experienced in rare iron disorders is particularly helpful when:

• iron overload develops in a child or young adult;
• iron accumulation is severe or progresses rapidly;
• routine HFE testing does not explain the findings;
• heart or hormonal problems are present;
• MRI shows an unusual pattern of iron accumulation;
• the genetic result is uncertain;
• a rare inherited iron-loading disease is suspected.

Early diagnosis and appropriate treatment can prevent or reduce many of the complications caused by iron overload.