Triad of pigment cirrhosis of liver, diabetes mellitus and bronze or slate gray pigmentation of the skin
Haemochromatosis - The Genetic Disease of 21st century
Haemochromatosis is a clinically and genetically unique entity first described in the second half of the 19th century.
Since its discovery hemochromatosis has fascinated and challenged doctors around the world.
In the 1970s genetic evidence emerged supporting the apparent inheritable feature of the disease.
In 1996 a new "haemochromatosis gene" called HFE was described which was mutated in about 85% of the patients.
From the year 2000 onward remarkable progress was made in revealing the complex molecular regulation of iron trafficking in the human body and its disturbance in haemochromatosis.
Hemochromatosis is defined as the accumulation of large amounts of iron in parenchymal cells of various organs and tissue.
Primary hemochromatosis (also known as hereditary hemochromatosis or idiopathic hemochromatosis) is a disorder of iron metabolism that appears in middle aged patients.
80% of cases appear after 40 years of age.
It is characterized clinically by the triad of pigment cirrhosis of liver, diabetes mellitus and slate gray to bronze-coloured pigmentation of the skin, which is caused by increased melanin deposition rather than iron.
In some instances heart failure is added to the triad, attributable to presumably to injury of heart muscle cells resulting from intracellular accumulation of iron.
Primary hemochromatosis is more common in men.
Women presumably are protected by their periodic loss of blood by menstruation, and therefore the disease is usually manifest during the postmenopausal years.
The average women may lose between 10 to 35 gm of iron through menstruation, pregnancy, and lactation during her lifetime.
Approximately 50% of women with the disease have a history of scant or absent menstruation.
The protective effect of menstruation on the development of this genetic disease is an excellent example of sex-determined modification of gene expression.
Since normal function of the X chromosome is responsible for normal menstruation, its abnormal function, allows the autosomal dominant gene defect to be expressed.
Liver, pancreas, spleen, heart, and all other tissues contain increased amounts of iron and are brown to chocolate brown in colour.
Affected organs are enlarged and firm.
The liver is cirrhotic with numerous nodules measuring from several millimeters to 1cm in diameter and may contain more than 50gm of iron.
Granular deposits of hemosiderin are present in the cytoplasm of affected cells.
ln the liver, granules are present in both hepatocytes and Kupffer cells.
The basic metabolic defect in this disease is still not clear, however, results of careful clinical studies indicate an increased uptake of iron by the duodenal mucosa and an absence of iron-binding protein gastroferrin, which has been found in gastric juice.
The protein has been implicated in the regulation of iron absorption from the gut.
The latter defect may have a genetic basis and may ultimately fit into the complex pathogenetic mechanism responsible for this disease.
Iron accumulation in tissues is common in chronic alcoholics, but alcohol consumption may occasionally help to unmask a genetic predisposition to primary hemochromatosis.
In general, iron accumulation in alcoholism remains confined to the reticuloendothelial system and hepatic scarring is more prominent than tissue accumulation of iron, where as in primary hemochromatosis the reverse is true.
Hemochromatosis can be diagnosed long before irreversible tissue damage has occured.
Sceening for the disease is carried out by measuring serum iron, total iron binding capacity, ferritin levels.
Liver biopsy should be done if indicated.
Most important for identification of patients with asymptomatic hemochromatosis is genetic testing.
The rare disease hemochromatosis is genetically determined by a locus on chromosome 6 with variable penetrance, the full clinical disorder having an autosomal recessive inheritance.
A linkage to HLA type A3, B7, B14 or Bw35 has been found in relatives.
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