Hemochromatosis, hereditary

Two missense mutations (C282Y and H63D) in the HFE gene have been identified in hereditary hemochromatosis. The substitution of a tyrosyl residue for a cysteinyl residue at position 282 results in the loss of formation of a 

Treatment of hereditary hemochromatosis is therapeutic phlebotomy (discussed earlier). This method is safe, effective, and life saving, and ideally should begin before symptoms develop. Serum ferritin levels are used as a surrogate marker for estimating total-body iron stores. Morphologic studies and quantitative determination of iron in liver tissue obtained by biopsy have been used in the assessment of early hereditary hemochromatosis and the degree of liver injury. 

Finally, hereditary hemochromatosis is a treatable disease. Biochemical screening for the identification of the 

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A scheme of the likely main events in the causation of hereditary hemochromatosis is set forth in Figure 50-5. 

Transferrin binds iron, transporting it to sites where it is required. Ferritin provides an intracellular store of iron. Iron deficiency anemia is a very prevalent disorder. Hereditary hemochromatosis has been shown to be due to mutations in HFE, a gene encoding the protein HFE, which appeats to play an important role in absorption of iron. 

Waheed A et al Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad USA 2002 99 3117. 

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

Iron is an extremely important element present in all living organisms correspondingly, iron metabolism is well studied. Both iron deficiency and iron excess are origins of serious pathologies (iron-deficit anemias, hereditary hemochromatosis, thalassemia, etc.) associated with the overproduction of oxygen radicals. Free radical-mediated processes, characteristic of these pathologies, are considered in Chapter 31 here we will look at some mechanisms of toxic effects of iron. 

The option to remove the toxin from the environment of susceptible persons is taken in hemochromatosis, a common disorder of iron metabolism(101) that affects 1 in 300 persons of northern European descent. Most cases of hereditary hemochromatosis are attributed to a polymorphism of HFE, which results in substitution of tyrosine for cysteine at codon 282. The disease, untreated, causes liver cirrhosis, heart failure, diabetes and arthritis and leads to early death treatment by phlebotomy to remove excess iron allows affected persons to live a normal life span. 

Under normal circumstances, transferrin is one-fourth to one-third saturated with iron. The level of saturation may decrease in systemic infection or cancer and in iron deficiency anemia, the most common nutritional deficiency in the United States. In individuals with iron deficiency anemia, transferrin levels are increased. The level of saturation with iron increases in iron overload syndromes such as hereditary hemochromatosis or as a result of repeated blood transfusions, as is the case in thalassemia patients. Determinations of total plasma iron (TI) and plasma total iron binding capacity (TIBC) are routinely performed in the clinical biochemistry laboratory. The TIBC value reflects transferrin levels in plasma the amount of iron that can be bound by transferrin is equal to TIBC x 0.7. Total plasma iron levels in iron deficiency anemia become abnormal before hemoglobin levels show any change. 

Given the diagnosis of hereditary hemochromatosis (HH), his two siblings were tested for HFE mutations. Both were heterozygous for the C282Y mutation and showed no evidence of iron overload. 

Abnormally high systemic iron levels can lead to cirrhosis of the liver, diabetes mellitus, and heart failure. Although a number of disease processes can lead to iron overload, this chapter focuses on hereditary hemochromatosis, the prototypical disease of iron overload. 

Harrison SA, Bacon BR Hereditary hemochromatosis update for 2003- J Hepatol 38 S14-S23, 2003. 

Zhou XYjTomatsu S, Fleming RE, et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 95 2492-2497,1998. 

Iron is another essential metal that can overload the body as a result of genetic disorders. Hereditary hemochromatosis and sub-Saharan African hemochromatosis are two examples. These two disorders differ in that hereditary hemochromatosis results in excessive iron when iron intake levels are normal, while sub-Saharan African hemochromatosis requires excessive intake of Fe coupled with a genetic predisposition to poorly regulate iron. Generally speaking, toxicity associated with excess essential metals tends to be rare, and it most frequently occurs in people who inappropriately consume dietary supplements. 

Hereditary hemochromatosis is a disorder of iron metabolism in which the uptake of iron from the digestive... 

Once diagnosed hereditary hemochromatosis can be treated by weekly venesection of approximately 0.5 L of blood. The amount of iron removed in this way is usually around 250 mg per 0.5 L of blood. The intensive therapy lasts for 2-3 years depending on the iron present. A recent study reported patient compliance with this form of treatment. Another treatment option is chelation therapy by deferoxamine but this is an expensive treatment and the iron removal is slower its main use is with non-HFE hemochromatosis. 

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