This condition, also called idiopathic or primary haemochromato sis, is the most common autosomal recessive genetic disorder in people of northern European ancestry, with a prevalence of 4–5 per 1000. The classic triad of diabetes, cirrhosis, and bronzed hyperpigmentation of the skin was first described by Trousseau in 1865 and called ‘haemochromatosis’ by von Recklinghausen in 1889.
Aetiology and pathology
Genetic basis
Most cases of primary haemochromatosis arise from mutations in the haemochromatosis gene (HFE), located on the short arm of chromosome 6, close to the major histocompatibility complex (MHC), which explains the linkage with human leucocyte anti gen (HLA) A3. The HFE protein encoded by this gene is expressed on the cell surface of various tissues, including the enterocytes of the duodenal brush border, where iron is chiefly absorbed. The HFE gene modulates iron absorption by binding to the transferrin receptor. In two- thirds of cases, a C282Y mutation (substitution of cysteine by tyrosine at position 282) in the HFE gene is responsible. Another mutation, H63D, seems to act synergistically with C282Y. These mutations inhibit the binding of HFE to transferrin, leading to an excessive and inappropriate increase in intestinal iron absorption and greatly increased body iron stores. Non- HFE mutations are also rarely found to be responsible in some cases.
Pathophysiology
The primary defect is excessive iron absorption across the mucosa of the proximal small intestine, which continues even in the setting of greatly increased total body iron stores (often 15–20 g; cf. normal adult iron stores of 1–2 g). Excess iron is deposited preferentially in the liver, pancreas (exocrine tissue as well as islets), pituitary, heart, and parathyroids (Figure 1). Tissue injury is postulated to occur as a result of rupture of iron- laden lysosomes, generation of free radicals (by decomposition of hydrogen peroxide catalysed by the ferrous and ferric ions – the Fenton reaction), and the stimulation of collagen synthesis by activated stellate cells.
Fig1. Hereditary haemochromatosis. Perls stain shows heavy iron deposition (blue) in exocrine and islet tissue in the pancreas (arrows). Original magnification ×375. Source: Courtesy of Dr A. Clark, Wirral Hospital, UK.
Clinical features
The classic clinical features are hepatic cirrhosis, diabetes, and skin hyperpigmentation (‘bronzed diabetes’) (Figure2). Hepatic fibrosis and cirrhosis usually only develop in those aged over 40 years, unless other factors such as alcoholism are present. Portal hypertension, hepatic failure, and hepatocellular carcinoma (in 15% of cases) are late sequelae. Bronzing of the skin, which occurs in 70% of cases but may be less evident in darker- skinned races, is caused by both iron deposition in the subcutaneous tissue and increased melanin in the basal dermis. Hypopituitarism, hypogonadism, hypoparathyroidism, and chondrocalcinosis with pseudogout are less common features.
Fig2. Clinical features of hereditary haemochromatosis. The classic triad comprises diabetes, cirrhosis, and hyperpigmentation of the skin (‘bronzed diabetes’).
Presenting symptoms include weakness, weight loss, diabetes symptoms, arthralgia, erectile dysfunction, and skin pigmentation. Signs include hepatosplenomegaly, heart failure, skin pigmentation, testicular atrophy, arthropathy, hypogonadism, and occasion ally hypothyroidism. Many people with haemochromatosis, however, are asymptomatic and may be detected during investigation for unrelated reasons or through genetic screening of family members of those with haemochromatosis.
Diabetes in primary haemochromatosis
The prevalence of diabetes depends on the severity of iron over load and presence of cirrhosis. Up to 50% of these individuals have glucose intolerance and 25% have overt diabetes, although the disease is an extremely rare cause of diabetes in the general population. The prevalence is steadily declining as the diagnosis is being made earlier, before significant pancreatic dam age has occurred. Both insulin resistance and β- cell failure contribute to the development of diabetes, and most individuals eventually require insulin. These individuals are prone to both microvascular and macrovascular complications, the risk of nephropathy being particularly high in those carrying the H63D mutation.
Investigations and diagnosis
The diagnosis should be suspected in any person with diabetes, hepatomegaly or liver disease, skin pigmentation, arthritis, and hypogonadism. A high index of suspicion is required to make an early diagnosis, because significant iron overload can exist with few or none of these clinical manifestations.
The total- body iron stores can be assessed using measurement of serum ferritin and percent saturation of transferrin. Serum ferritin is a useful screening test for relatives of affected individuals, but because ferritin is an acute- phase reactant, the levels of which can be elevated in inflammatory states, abnormally high results should be confirmed by other tests (Table 1). Serum iron and per centage saturation of transferrin are elevated early in the course of the disease, but lack specificity. A combined measurement of the percentage transferrin saturation and serum ferritin levels provides a simple and reliable screening test for hemochromatosis. A positive test mandates genetic testing.
Table1. Diagnostic tests in hereditary haemochromatosis.
The role of liver biopsy in the diagnosis and management of haemochromatosis has significantly diminished following the development of genetic testing for the C282Y mutation. The major role of liver biopsy at the present time is to exclude the presence of cirrhosis, which is a major risk factor in the development of hepatocellular carcinoma. Hepatic iron overload can also be detected using imaging techniques such as CT scanning or MRI.
All first- degree adult relatives of individuals with haemochromatosis should be tested for C282Y and H63D mutations in an attempt to detect disease in the early pre- cirrhotic phase, at which stage treatment can prevent further progression.
Treatment
Treatment of hereditary haemochromatosis is by repeated venesection, which must be started as early as possible. Removal of excess iron by venesection prevents diabetes and cirrhosis and prolongs survival. Chelating agents such as desferrioxamine and deferasirox are more expensive, less safe, and less effective than venesection. Diabetes may be improved by venesection, but usually requires insulin treatment. Management is often complicated by hypoglycaemia caused by concomitant α- cell damage and glucagon deficiency. Hepatic transplantation for hereditary haemochromatosis was previously associated with a poor prognosis, but survival rates have improved of late. Diabetes tends to worsen after transplantation because of the use of immunosuppressant drugs. Hepatocellular carcinoma is a late complication and may be an indication for transplantation if the disease remains localized.
Secondary haemochromatosis
Iron overload can also occur as a consequence of repeated blood transfusion and disorders of erythropoiesis such as thalassemia and sickle cell anaemia, in which case the condition is termed secondary haemochromatosis or hemosiderosis. Pancreatic dam age and diabetes frequently result. The duration of disease and number of transfusions correlate well with the degree of glucose intolerance. Iron overload may induce autoimmune attack against the β cells, thereby contributing to the development of diabetes.
