Primary hemochromatosis

Hereditary (primary) hemochromatosis is a very prevalent autosomal recessive disorder in certain parts of the world (eg, Scodand, Ireland, and North America). It is characterized by excessive storage of iron in tissues, leading to tissue damage. Total body iron ranges between 2.5 g and 3.5 g in normal adults in primary hemochromatosis it usually exceeds 15 g. The accumulated iron... 

Figure SOS. Tentative scheme of the main events in causation of primary hemochromatosis (MIM 235200). The two principal mutations are CY282Y and H63D (see text). Mutations in genes other than HFE are also involved in some cases.

Contraindications Severe renal disease, anuria, primary hemochromatosis, hypersensitivity to deferoxamine mesylate or any component of the formulation... 

DFO is generally indicated for treatment of acute iron intoxication and chronic iron overload due to transfusion depended anemias (including thalassemia). DFO is not recommended in primary hemochromatosis (PDR). 

Niederau, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis NEngl J Med 313 1256-1262,1985. 

Multiple liver abscesses due to Yersinia enterocolitica discloses primary hemochromatosis three case reports and review. Clin. Infect. Dis. 1994 18 938-941... 

Hsing, A.W., McLaughlin, J.K., Olsen, J.H., MeUemkjar, L., Wachol-der, Fraumemi, J.F.jr. Cancer risk following primary hemochromatosis a population-based cohort study in Denmark. Int. J. Cancer 1995 60 160-162... 

Iron-overload disease, or hemochromatosis, may occur as a consequence of an, as yet, undefined genetic defect, or as a secondary effect of another medical disorder, such as thalassemia. In the former condition, primary hemochromatosis, iron accumulates in various tissues because of a lack of control of iron absorption from the gut. In the latter, or secondary hemochromatosis, the accumulation of iron results from the breakdown of red blood cells and the consequent need for frequent blood transfusions, which lead to an increase in the levels of tissue iron. In both cases the predominant store for iron is hemosiderin (147). 

Hereditary hemochromatosis is the most common hereditary form of hemochromatosis. It results from hereditary abnormalities of proteins that regulate iron hemosta.sis. In recent years, the genetic lesions responsible for many forms of the disease have been discovered. It is an adult onset disorder, formerly called primary hemochromatosis or idiopathic hemochromatosis, which is linked to the HLA loci on chromosome 6. 

For chronic iron intoxication e.g., thalassemia), an intramuscular dose of 0.5-1.0 g/day is recommended, although continuous subcutaneous administration (1-2 g/day) is almost as effective as intravenous administration. When blood is being transfused to patients with thalassemia, 2 g deferoxamine (per unit of blood) should be given by slow intravenous infusion (rate not to exceed 15 mg/kg/h) during the transfusion but not by the same intravenous fine. Deferoxamine is not recommended in primary hemochromatosis phlebotomy is the treatment of choice. Deferoxamine also has been used for the chelation of aluminum in dialysis patients. Deferoxamine is metabohzed principally by plasma enzymes, but the pathways have not been defined. The drug also is excreted readily in the urine. 

Familial dysbetalipoproteinemia (type III) is characterized by the accumulation of chylomicron and VLDL remnants, which are enriched in cholesterol compared to their precursors. The primary molecular cause of familial dysbetalipoproteinemia (type III) is the homozygous presence of the apolipoprotein E2 (apoE2) isoform, which is associated with recessive inheritance of the disorder [62]. However, only 1 in 50 homozygotes for apoE2 will develop type III hyperlipoproteinemia, which is clinically characterized by palmar and tuberous xanthomas, arcus lipoides, and premature atherosclerosis of coronary, peripheral, and cerebral arteries. Precipitating factors include diabetes mellitus, renal disease, hemochromatosis, but also familial hypercholesterolemia. In addition, some rare mutations in the apoE gene have been found to cause dominant and more penetrant forms of type III hyperlipoproteinemia. 

Metabolic Ih/er disease Hemochromatosis Wilson s disease a titiypsin deficiency Nonalcoholic steatohepatitis (l atty liveO Cholestatic Ih/er diseases Primary biliary cirrhosis... 

Blumberg, R.S., Chopra, S., Ibrahim, R., Crawford, X, Farraye, F.A., Zeldis, XB., Berman, M.D. Primary hepatocellular carcinoma in idiopathic hemochromatosis after reversal of cirrhosis. Gastroenterology 1988 95 1399-1402... 

Morcos, M., Dubois, S., Bralet, M.P., Belghiti, J., Terris, B. Primary liver carcinoma in genetic hemochromatosis reveals a broad histological spectrum. Amer. J. Clin. Path. 2001 116 738-743... 

A 39-year-old army officer had bouts of palpitation and dizziness. There were no risk factors for chronic liver disease apart from a family history of hemochromatosis. His cardiovascular and nervous systems were normal but there was 5 cm hepatomegaly. Percutaneous liver biopsy showed grade 4 siderosis in parenchymal and non-parenchymal liver cells and a mild inflammatory infiltrate with minimal portal fibrosis. He had 45 liters of blood venesected over the next 18 months and a repeat biopsy 3 years later showed a non-cirrhotic liver with no stainable iron. He developed a non-resectable primary hepatocellular clear cell carcinoma 17 years after the initial diagnosis. 

Mclaren CE, Barton JC, Adams PC, Harris EL, Acton RT, Press N, et al. Hemochromatosis and iron overload screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults. 

It appears, however, that hemochromatosis-induced diabetes results in complications that are indistinguishable from diabetes mellitus (Becker and Miller, 1960 Dymock et al., 1972). Indeed several authors have suggested a common denominator that exists in both primary diabetes (e.g., IDDM and NIDDM) and diabetes secondary to pancreatic destruction and hemochromatosis, which eventually leads to the same vascular complications (Sheldon, 1935 Becker and Miller, 1960 Dymock et al., 1972). Conversely, iron mobilization and utilization appear to be delayed in diabetes mellitus. A possible link between iron overload and complications is further suggested by the observation that desferrioxamine treatment decreased hyperglycemia and hyperlipidemia in diabetic patients with high ferritin but without hemochromatosis (Cutler, 1989). 

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