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Haemochromatosis

Essentials

  • In hereditary haemochromatosis, disturbed regulation of iron absorption causes accumulation of iron in the body.
  • Classic haemochromatosis should be suspected particularly in middle-aged men presenting with excessive fatigue, decreased libido, loss of body hair, diabetes, hepatomegaly, joint symptoms, pigmentation of the skin or an unexplained increase of plasma aminotransferase concentrations.
  • Diagnosis is based on determination of iron parameters in serum or plasma and on detection of a gene mutation predisposing to the disease.
  • Liver biopsy is nowadays only rarely needed for confirmation of the diagnosis and for differential diagnostics.
  • Repeated venesections are an effective, cheap and safe form of treatment.
  • By sufficiently early diagnosis and treatment it is possible to prevent the development of late complications of the disease.
  • Secondary haemochromatosis is usually seen in chronic anaemias which are associated with reduced erythropoiesis and the need for repeated red cell transfusions.

Terminology

  • Haemochromatosis denotes an excessive and harmful accumulation of iron in the body.
  • Hereditary haemochromatosis is currently divided into 5 types (table T1).
  • Types 1, 2, 3 and 4B are characterised by excessive iron absorption in relation to the total body iron content. This will lead to large amounts of iron accumulating in tissues causing fibrotic tissue changes predominantly affecting the liver, pancreas and heart.
  • In types 4A and 5 cellular iron release is impaired, leading to increased iron deposits particularly in the macrophages. Both the clinical picture and treatment differ from those of classic haemochromatosis.
  • Secondary haemochromatosis is usually seen in patients with chronic anaemia (e.g. sideroblastic anaemia or thalassaemia) and in patients who have received repeated blood transfusions for reasons other than iron deficiency anaemia.
    • Causes of secondary haemochromatosis
      • Iron accumulation in association with
        • anaemias (e.g. thalassaemia Thalassaemias, sideroblastic anaemia)
        • blood transfusions
        • dietary factors
        • chronic liver diseases (e.g. hepatitis C, alcoholic liver cirrhosis, non-alcoholic steatohepatitis [NASH])
      • Porphyria cutanea tarda (picture 1)

Genetics of haemochromatosis

  • The classification of hereditary haemochromatosis into 5 types is presented in table T1. Haemochromatosis is inherited in an autosomal recessive pattern, except Type 4 (ferroportin disease) which is distinguished by its autosomal dominant inheritance pattern.
  • Most cases of haemochromatosis are due to three genetic mutations (C282Y, H63D and S65C) of the HFE protein.
  • Heterozygotes, i.e. carriers of the genetic defect, are usually healthy.
  • Haemochromatosis types 2-5 appear to be significantly rarer than type 1, but the prevalence of the disease is not yet fully known.

Classification of hereditary haemochromatosis 1

TypeMutated proteinClinical picture
1Classic haemochromatosisHFEClassic
2AJuvenile haemochromatosisHaemojuvelinOnset of symptoms when aged < 30 years
2BJuvenile haemochromatosisHepcidinOnset of symptoms when aged < 30 years
3HaemochromatosisTransferrin receptor 2Classic
4BHaemochromatosisFerroportinClassic
4AHaemochromatosisFerroportinMacrophage iron deposits
5AceruloplasminaemiaCeruloplasminAnaemia, neurological symptoms

Signs and symptoms

  • The symptoms and signs of classic haemochromatosis: see table T2.
  • Hepatomegaly
    • Signs of chronic liver disease such as jaundice, ascites and portal hypertension are less common.
  • Two-thirds of the patients develop diabetes, which may lead to retinopathy, nephropathy or neuropathy.
  • Pigmentation of the skin. Skin may appear metallic grey ("bronze diabetes").
  • Lowered libido, testicular atrophy. In rare cases, insufficiency of the pituitary, thyroid or parathyroid gland may develop. Addison's disease may also rarely occur.
  • Fatigue
  • Cardiac involvement: right heart failure, arrhythmias
  • Arthralgia
    • Pain or inflammation in the index (2nd) and middle (3rd) MCP joints is a typical articular symptom, but virtually any joint may be affected.
  • If the disease has progressed into cirrhosis, there is an increased risk of hepatoma.
  • In juvenile haemochromatosis, the accumulation of iron begins early and progresses rapidly, usually leading to symptom onset before the age of 30. Early symptoms include abdominal pain, diabetes, hypogonadism and cardiac symptoms, whereas signs and symptoms of a liver disease may be less prominent.
  • The clinical picture of type 4B is classic. However, in type 4A iron accumulates in macrophages and the spleen whilst the iron saturation may remain normal, at least at the early stages of the disease, despite increased ferritin values. Mild anaemia has also been described.
  • The clinical picture of type 5 includes anaemia and neurological symptoms in addition to iron accumulation.

Symptoms and signs of classic haemochromatosis

SymptomsClinical findingsLaboratory examinations and findings
Fatigue
Feeling of weakness
Weight loss
Apathy
Joints
  • Pain
Liver
  • Upper abdominal pain
Heart
  • Arrhythmias
  • Symptoms of heart failure
Hormonal
  • Diabetes
  • Loss of libido
  • Impotence
  • Amenorrhoea
  • Gynaecomastia
  • Loss of body hair
Joints
  • Inflammation
  • Swelling
  • Cartilage calcifications
Liver
  • Hepatomegaly
Pancreas
  • Diabetes
  • Exocrine insufficiency
Spleen
  • Splenomegaly
Skin
  • Hyperpigmentation
Hormonal
  • Diabetes
  • Testicular atrophy
  • Hypogonadism
  • Hypothyroidism
Heart
  • Dilated cardiomyopathy
  • Congestive heart failure
Blood
  • Increased iron parameters: fasting plasma iron, fasting plasma transferrin saturation and/or plasma ferritin concentration
  • HbA1C, glucose tolerance test
  • Increased aminotransferase concentrations (plasma ALT and/or AST)
  • Discretionary: faecal elastase concentration, hormone measurements
Liver biopsy
  • Increased amount of iron in a stained sample
  • Increased hepatic iron content (HIC) and/or hepatic iron index (HII)
  • Fibrosis, cirrhosis
  • HCC (hepatocellular carcinoma)
Source: Arkkila P, Åberg F, Arola J, Nieminen U. Hemokromatoosi - yleisin perinnöllinen maksasairauden aiheuttaja [Hemocromatosis - the most common hereditary cause of liver disease]. Finnish Medical Journal Duodecim 2018;134(24):2444-53. http://www.duodecimlehti.fi/duo14678
Diagnosis
  • Diagnosis of hereditary haemochromatosis: see picture 2.

  • Findings in classic haemochromatosis: see table T2.
  • A fasting plasma iron concentration exceeding 27 µmol/l and fasting plasma transferrin iron saturation exceeding 60% in men, and 50% in women, strongly suggest haemochromatosis.
  • Plasma ferritin concentration is also increased (350-500 µg/l) in haemochromatosis. Ferritin is an acute phase protein and therefore its concentration also increases in many other diseases, particularly inflammatory and hepatic diseases.
  • Determining liver enzyme concentrations is of little benefit in diagnosis, unless the disease has progressed to cirrhosis. Serum aminotransferase concentrations usually increase only a little, < 100 U/l (ALT > AST).
  • The diagnosis is at present confirmed by gene testing; the patient is usually tested for HFE gene mutation.
  • If the diagnosis cannot be confirmed with HFE genotyping or if any other cause for excessive iron accumulation cannot be found, a liver biopsy is taken. It may also be necessary for exclusion of other liver diseases (e.g. NASH).
    • In haemochromatosis, liver iron concentration is usually over 150 µmol/g of dry weight (normal reference range 5-40 µmol/g). The iron content of the liver can also be estimated by magnetic resonance imaging.
  • First-degree relatives of patients who are homozygous for C282Y, or combined heterozygotes (C282Y/H63D, C282Y/S65C), should be screened for HFE gene mutations. However, the ethical considerations related to screening should be kept in mind.
    • Screening of the asymptomatic general population for haemochromatosis with DNA testing is not recommended at present.

Treatment

  • Ferritin concentration of over 300 μg/l in men and over 200 μg/l in women is considered as the threshold for initiating treatment in hereditary haemochromatosis.
  • The treatment aims at removing excessive iron from the body. The amount of iron overload varies between 10 and 45 g.
  • In classic haemochromatosis, venesection is the most effective and safest form of treatment. The treatment is started in specialized care, but further treatment can be carried out in primary health care.
  • Induction therapy
    • Venesection is performed once or twice weekly (500 ml of blood at a time) until plasma ferritin concentration is < 50 µg/l.
    • Treatment duration is 2-3 years.
    • Haematocrit level is checked before each venesection. If the level is < 32%, the treatment is postponed, and the frequency is reduced by a week.
    • Plasma ferritin concentration is determined initially at 1-2-month intervals.
    • After venesection, adequate hydration should be ensured and strenuous physical exertion for the next 24 hours avoided.
  • Maintenance therapy
    • Typically, venesection is performed 2-4 times per year.
    • Target ferritin concentration is 50-100 µg/l.
      • A lower ferritin concentration may lead to iron deficiency symptoms, increased iron absorption and increased need for venesections.
  • Severe anaemia, cardiac symptoms or hypoproteinaemia may prevent the performance of venesections. In such a case, parenteral desferrioxamine may be used for chelating iron. It removes about 10-20 mg of iron daily. In addition, oral iron chelators (deferasirox, deferiprone) are available.
  • The use of iron preparations should absolutely be avoided.
  • The use of excessive amounts of vitamin C (increases iron absorption) and alcohol (increases liver toxicity of iron) should be avoided.

Follow-up and prognosis

  • Follow-up of a patient with hereditary haemochromatosis
    • Basic blood count with platelets, plasma ferritin, fasting plasma transferrin saturation
      • Treatment target: serum ferritin concentration 50-100 µg/l, ferritin saturation < 30%
    • Ultrasonography
    • In cirrhosis: serum AFP and ultrasonography every 6-12 months
  • The most severe complications are insulin-dependent diabetes, heart disease, cirrhosis and hepatoma.
  • The prognosis of untreated patients is poor, but improves significantly with treatment. Five-year survival is 70-90%.
  • Removing iron does not reduce the risk of hepatoma in patients with haemochromatosis that has progressed to cirrhosis.

Related Keywords ⬆

ATC Code:

V03AC03

V03AC02

V03AC01

Primary/Secondary Keywords