Examine this patient's abdomen. Look at this patient.



· 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 small

joint may be involved.

· Melaena, haematemesis (bleeding from varices).


· 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 (due to iron deposition affecting hypothalamo-pituitary 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. Such patients develop cirrhosis and hepatocellular carcinoma.


This male patient has generalized hyperpigmentation, hepatomegaly and signs of liver cell disease (lesions) due to

haemochromatosis which may be hereditary (aetiology).


Does this disease run in families?

Yes, and it is an autosomal recessive condition. Two mutations of the HFE gene (845A (C282Y) and 187C (H63D)) account for 90%

of the cases of European extraction. It is closely associated with human leukocyte antigen HLA-A3 and to a lesser extent with HLA-B

14 antigen. 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, i.e.

measurements of serum ferritin and iron, and saturation of iron-binding capacity. Recent data have shown that hereditary

haemochromatosis can occur in adults who do not have pathogenic mutations on the gene on chromosome 6 (N Engl J Med 1999;

341: 725-32; N Engl J Med 1999; 341: 718-24). A substantial number of homozygous relatives of these patients (more commonly

men) have disease-related conditions such as cirrhosis, hepatic fibrosis, elevated aminotransferase and haemochromatotic

arthropathy that have yet to be detected clinically (N Engl J Med 2000; 343: 1529-35). Also, 10% or more of the patients with

clinically severe hereditary haemochromatosis do not have either mutation. These facts limit the value of diagnostic DNA testing.


What is the mechanism of increased iron uptake?

Iron absorption is mediated by the duodenal metal transporter, DMT-I (also called NRAMP-2). It has been suggested that increased

NRAMP-2 mRNA expression in the duodenal mucosa of patients with hereditary haemochromatosis may promote duodenal uptake

of iron and result in iron overload (Lancet 1999; 353: 2120-3).

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 the 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.

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 patients are susceptible to fatal septicaemia from the marine bacterium

Vibrio vulnificus.

· Venesection prolongs life and often reverses tissue damage. Initially, weekly venesection for 2 years (as 50 g iron or more is

removed) and then once every 3 months. Many manifestations improve (insulin requirements often diminish except for

testicular atrophy and chrondrocalcinosis.

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 in

the general population. Depletion of iron, and even reversal of cirrhosis, do 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 as follows:

· 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 (see p. 199) in 1889 to describe autopsy findings in men with

cirrhosis associated with massive deposition of iron in the hepatocytes (von Recklinghausen FD 1889 Ueber Hemochromatose.

Tageblatt Versamrnl Dtsch Naturforsch Aertze Heidelberg 62: 324-5).

The inherited nature of haemochromatosis was first recognized by Sheldon in 1935 (Sheldon JH 1935 Haemochromatosis. Oxford

University Press, London).