Haemochromatosis

Published on 05/05/2015 by admin

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Last modified 22/04/2025

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116 Haemochromatosis

Instruction

Examine this patient’s abdomen.

Look at this patient.

Salient features

History

• Family history

• Skin tan

• Shortness of breath (cardiac failure)

• Diabetes (pancreatic involvement)

• Joint pain (present in 50% of cases): pseudogout usually affects the second and third metacarpophalangeal joints. Any of small joints may be involved (Fig. 116.1)

• Melaena, hematemesis (bleeding from varices).

image

Fig. 116.1 Haemochromatosis. Hooklike osteophyte (arrowhead) at the third metacarpal head with cartilage loss at metacarpophalangeal joints (star) and chondrocalcinosis of triangular fibrocartilage (bent arrow).

(With permission from Firestein et al. 2008.)

Examination

• The patient is a pigmented male over 30 years of age

• Palmar erythema, spider naevi

• Jaundice

• Ascites, hepatomegaly (firm, regular)

• Loss of secondary sexual hair.

Proceed as follows:

• Tell the examiner that you would like to investigate as follows:

• Look for testicular atrophy (caused by iron deposition affecting hypothalamopituitary function)
• Examine the heart for dilated cardiomyopathy, cardiac failure
• Check urine for sugar, looking for evidence of diabetes mellitus (present in 80% of cases).

Remember: Patients with haemochromatosis develop cirrhosis and hepatocellular carcinoma.

Diagnosis

This male patient has generalized hyperpigmentation, hepatomegaly and signs of liver cell disease (lesions) caused by haemochromatosis, which may be hereditary (aetiology).

Advanced-level questions

Does this disease run in families?

Yes, and it is an autosomal recessive condition. At least four different genes encoding proteins involved in iron metabolism have been described: HJV, HAMP, TfR2 and HFE. HFE is on chromosome 6. Two mutations (845A (C282Y) and 187C (H63D)) account for 90% of cases in those of European extraction. HFE is closely associated with HLA-A3 and to a lesser extent with HLA-B14. The responsible alleles are on the short arm of chromosome 6 (Nat Genet 1996;13:399–408). Asymptomatic close relatives of patients with hereditary haemochromatosis, in particular siblings, should be advised to undergo screening (measurements of serum ferritin and iron, and saturation of iron-binding capacity). Hereditary haemochromatosis can occur in adults who do not have pathogenic mutations affecting chromosome 6 (N Engl J Med 1999;341: 718–24, 725–32). A substantial number of homozygous relatives of these patients (more commonly men) have disease-related conditions such as cirrhosis, hepatic fibrosis, elevated amiotransferase and haemochromatotic arthropathy that may not have been detected clinically (N Engl J Med 2000;343:1529–35).

However, 10% or more of the patients with clinically severe hereditary haemochromatosis do not have these mutations and this limits the value of diagnostic DNA testing. Ferroportin-associated iron overload, currently classified as hereditary haemochromatosis type 4, was clinically recognized in 1999 and was linked to SLC40A1, which encodes ferroportin, a protein involved in cellular iron export.

What is the mechanism of increased iron uptake?

Iron absorption is mediated by the duodenal metal transporter DMT-1 (also called NRAMP-2). It has been suggested that increased expression of mRNA for NRAMP-2 in the duodenal mucosa of patients with hereditary haemochromatosis may promote duodenal uptake of iron and result in iron overload (Lancet 1999;353:2120–23).

What is the benefit of early identification?

Early venesection has shown benefits, particularly in those who have not developed diabetes mellitus or cirrhosis. Early venesection prevents progression of hepatic disease and may consequently prevent complication of hepatocellular carcinoma.

How would you confirm your diagnosis?

• Transferrin saturation is increased

• Serum ferritin levels are raised

• Liver biopsy to measure iron stores is a definitive test

• MRI is now the modality of choice for non-invasive quantification of iron storage in the liver. It allows repeated measurements and reduces sampling errors (Fig. 116.2).

image

Fig. 116.2 T2-weighted MRI image demonstrating abnormally low liver signal in haemochromatosis.

(With permission from Adam et al. 2008.)

How would you manage such a patient?

• Avoidance of alcohol and Indian balti curries, which are prepared in cast iron cookware (BMJ 1995;310:1368)

• Avoidance of uncooked shellfish and marine fish, since these patients are susceptible to fatal septicaemia from the marine bacterium Vibrio vulnificus

• Phlebotomy: venesection prolongs life and often reverses tissue damage. Initially, weekly venesection (500 ml blood per week) for 2 years (as 50 g iron or more is removed) and then once every 3 months. Iron depletion is confirmed by serum ferritin <50 µg/l and transiferrin saturation <40%. Many manifestations improve (insulin requirements often diminish) except for testicular atrophy and chrondrocalcinosis

• Deferoxamine, an iron chelating agent is used when haemodynamics do no permit venesection

• Screening of family members by measuring fasting transferring saturation and ferritin levels.

What is the commonest cause of death in patients with hereditary haemochromatosis?

The most common cause of death is hepatocellular carcinoma, for which the risk is 200-fold greater than that of the general population. Depletion of iron, and even reversal of cirrhosis, does not totally prevent the occurrence of this fatal neoplasm. Patients diagnosed in the subclinical, precirrhotic stage and treated by regular phlebotomy have a normal life expectancy (N Engl J Med 1985;313:1256–62).

Mention a few causes of generalized pigmentation

Common causes are sun tan and race.

Uncommon causes are:

• liver disease: haemochromatosis in males; primary biliary cirrhosis in females

• Addison’s disease

• uraemia

• chronic debilitating conditions such as malignancy.

The term haemochromatosis was first used by von Recklinghausen (p. 279) in 1889 to describe postmortem findings in men with cirrhosis associated with massive deposition of iron in the hepatocytes (von Recklinghausen FD Ueber Hämochromatose. Tageblatt Versamml Dtsch Naturforsch Artze Heidelberg 1889;62:324–5).

The inherited nature of haemochromatosis was first recognized by Sheldon in 1935.

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