Hemochromatosis: clinical implications of genetic testing.

Hemochromatosis is one of the most common genetic diseases affecting Canadians of European ancestry. However, too often this disease is diagnosed in people who do not have it and is missed in those who do. By the time a diagnosis is made on the basis of symptoms, irreversible organ damage has often occurred. A missense mutation (the C282Y cysteine-to-tyrosine substitution) on chromosome 6 of the HFE gene (previously known as HLA-H) is present in 95% of Canadian patients with hemochromatosis and can be readily detected by a simple blood test based on a polymerase chain reaction (PCR). Since the description of a candidate gene for hemochromatosis in August 1996 by Mercator Genetics, studies have suggested that the population prevalence of the homozygous C282Y mutation is as high as 1 per 100 in Ireland and 1 per 150 in Australia. The discrepancy between such estimates of genetic prevalence and the clinical impression that hemochromatosis is an uncommon condition has 2 explanations, which are not mutually exclusive. First, the disease goes undetected in some cases because of its nonspecific symptoms, such as arthritis, diabetes, fatigue, impotence and minor liver dysfunction. Second, because of the incomplete penetrance of the hemochromatosis mutation, iron overload does not always develop. Within families affected by hemochromatosis, some individuals have been found with a homozygous C282Y mutation but no demonstrable iron overload; investigations for occult blood loss in such patients have been unrevealing. Canadian population screening studies have also identified asymptomatic young adults who are homozygous for the mutation without iron overload. The value of detecting such cases is controversial. On the one hand, these people may be predisposed to develop iron overload later in life and may therefore benefit from surveillance. Family studies may lead to the discovery of relatives who are homozygous for the mutation and do have iron overload. On the other hand, indiscriminate testing can cause unnecessary anxiety and could lead to discrimination with regard to health or life insurance. Population screening studies using genotyping have suggested that the C282Y mutation is more prevalent than the clinical symptoms associated with iron overload. For example, in the first patient identified in our population screening study as homozygous for the mutation, the disease was not expressed (i.e., serum transferrin saturation and serum ferritin concentration were normal). Her sister had been under investigation for 2 years at another centre for an undiagnosed liver disorder. After the proband notified her sister about her genetic status, the sister underwent liver biopsy; a diagnosis of hemochromatosis with significant iron overload was confirmed. Another common problem is the misdiagnosis of hemochromatosis in some patients with abnormally high serum transferrin saturation or serum ferritin concentration or both. It is now recognized that end-stage liver disease from any cause can result in high serum transferrin saturation or ferritin levels and minor iron overload, and many patients previously classified by liver biopsy as having hemochromatosis have now been shown by genetic testing not to have the C282Y mutation. This is particularly relevant to patients with alcoholic liver disease and chronic viral hepatitis. 15511 July 28/98 CMAJ /Page 156