Hemochromatosis - New Treatments, January 15, 2006

Iron overload can be classified according to whether it is due to inherited disorders leading to increased iron absorption, to conditions of increased ineffective erythropoiesis that are associated with increased iron absorption, or to multiple blood transfusions.

A. Geographic distribution, prevalence and genetics of iron overload. As shown in Table 2, a number of inherited forms of iron overload.


Table 1. Inherited forms of iron overload
Condition	Population at risk	Inheritance	Defect	Mechanism of iron loading
Common conditions
HLA-linked hemochromatosis African iron overload	Caucasian African	Autosomal recessive Gene by environment interaction	Mutation in HLA-H gene, chromosome 6p Unknown	Increased absorption Increased absorption and increased dietary iron
Thalassemias (major and intermedia)	Asian, Middle Eastern, Mediterranean	Autosomal recessive	Ineffective erythropoiesis 2^E to decreased ß- or a-globin gene synthesis	Increased absorption and blood transfusions
Uncommon conditions
Congenital atransferrinemia	Sporadic	Autosomal recessive	Absent transferrin	?Increased absorption
Congenital aceruloplasminemia	Japanese	Autosomal recessive	Absent ceruloplasmin	?Increased absorption
Iron overload in Melanesia	Melanesian	?Autosomal dominant	Unknown	?Increased absorption

1. HLA-linked hemochromatosis in populations of European derivation. Recently, the gene for HLA-linked hemochromatosis has been cloned and partially characterized (Feder et al, 2006). The gene is somewhat telomeric to the HLA region on the short arm of chromosome 6. It encodes a major histocompatability Class I-type molecule.

Geographic distribution and prevalence. HLA-linked hemochromatosis is thought to exist only in populations derived from Europe (Whittaker et al, 1989); its incidence in population groups from other parts of the world is not known. The condition appears to be one of the most common genetic abnormalities affecting white populations.

Genetics. The genetic transmission of hemochromatosis in Caucasians was clarified almost two decades ago in France through the work of Marcel Simon and colleagues who demonstrated that the hemochromatosis locus is linked to the I-ILA region on the short arm of chromosome 6, and that the mode of inheritance is autosomal recessive (Simon et al, 1976; 1977).

1. Pattern of iron-loading in the liver. The various types of iron overload lead to fairly characteristic and distinct patterns of iron deposition in the liver.

HLA-linked hemochromatosis. In HLA-linked hemochromatosis, iron is deposited mainly in hepatic parenchymal cells. A pronounced gradient in iron deposition exists, with maximal accumulations in periportal hepatocytes and decreasing quantifies towards the terminal hepatic venule. This periportal accentuation is most obvious early on in the process, but it can usually be discerned even in the presence of severe iron deposition (grade 3 or 4, see below). Iron deposition in biliary epithelium usually is present in advanced disease.

African iron overload. The pattern of iron deposition includes pronounced deposition of iron in Kupffer cells and macrophages as well as extensive accumulations in parenchymal cells. Iron deposition in macrophages is in excess of that typically seen even in advanced I-ILA-linked hemochromatosis (Bothwell et al, 1965). Also, a periportal accentuation of parenchymal cell iron deposition is usually not present.

Ineffective erythropoiesis. Ineffective erythropoiesis leads to increased gastrointestinal iron absorption and would be predicted to show patterns of iron deposition similar to that seen in HLA-linked hemochromatosis. Indeed, in the absence of transfusions, the magnitude and pattern of iron-loading is quite similar to that seen in HLA-linked hemochromatosis. The excess absorbed iron is initially deposited in parenchymal cells of the liver, but other organs such as the heart and pancreas eventually become involved as well. Diseases associated with ineffective erythropoiesis often are treated by transfusions. In the presence of ineffective erythropoiesis and multiple blood transfusions, the pattern of iron-loading.

Transfusional overload. Transfusional overload in individuals without ineffective erythropoiesis typically results in extensive iron deposition in Kupffer cells and macrophages in portal triads, and fibrosis and cirrhosis are uncommon until the transfused iron burden becomes massive.

2. Pattern of iron-loading in other organs. As noted in previous sections, iron-loading in HLA-linked hemochromatosis and in anemias characterized by ineffective erythropoiesis.

4. Clinical consequences of iron overload. The toxicity of iron at the cellular level leads to dysfunction of various organ systems, and these clinical consequences of iron overload are similar, whatever the specific condition that gave rise to the excess build-up. Hepatotoxicity, which progresses from portal fibrosis to cirrhosis, is one of the most consistent fmdings in patients with iron overload. The amount and duration of excess hepatocellular iron are critical determinants of liver injury. The threshold liver iron concentration, above which a substantial risk for fibrosis and cirrhosis exists, is about 360 umol/g dry weight for both HLA-1inked hemochromatosis and African iron overload. The threshold for hepatic injury with transfusional iron overload is an iron concentration of about 720 umol/g dry weight or more, about double the level required for hepatic injury in HLA-linked hemochromatosis.

1. Diagnosis. The importance of determining hepatic iron level. Measurement of hepatic iron is of central importance in confirming the diagnosis and determining the severity of established iron overload, whatever the etiology. Iron stain of histologic section. Tissue sections of liver biopsy specimens are stained with Prussian blue or Perl's stain to determine the cellular.

Non-heme iron concentration. A portion of the hepatic biopsy material should be reserved for chemical quantitation of iron, as this provides a more accurate estimate of liver iron content than semi-quantitative estimates from histological sections. The determination is accomplished by acid digestion of the weighed sample, followed by determination of iron concentration.

Noninvasive tests for hepatic iron overload. Noninvasive tests for hepatic iron overload include magnetic susceptometry, computed tomography, and nuclear magnetic resonance. Of these methods, measurement of magnetic susceptibility offers the greatest accuracy over the widest range of liver iron concentrations, but the necessary instrumentation.

HLA-linked hemochromatosis in Caucasians. The importance of early diagnosis cannot be overemphasized, because it is crucial to begin treatment before complications of iron overload occur.

Transferrin saturation. The most sensitive test currently available for identification of individuals possibly affected with HLA-linked hemochromatosis is determination of the transferrin saturation, which is derived from measurements of the serum or plasma iron concentration and total iron-binding capacity (TIBC). To avoid the confounding effects of random fluctuations, diurnal variation and recent dietary intake, fasting blood samples should be obtained in the morning on at least three occasions.

Serum ferritin. Another useful test in patients suspected of having HLA-linked.

HLA-linked hemochromatosis- phlebotomy therapy. Removal of excess iron by phlebotomy is the most effective treatment for HLA-linked hemochromatosis. The blood removed is quickly replaced by mobilization of iron from tissue stores. The removal of 500 mL of blood from a patient whose hematocrit is 0.45 represents a loss of approximately 225 mg of iron and will result in mobilization of an equivalent amount of iron from storage sites. Phlebotomy therapy, with removal of 450-500 mL at a time.

African iron overload. Phlebotomy to remove excess body iron would be the logical approach to the therapy of African iron overload, and the single report of its use described benefit among the twelve individuals.

Ineffective erythropoiesis. Iron overload in certain subjects with ineffective .erythropoiesis can be managed by the removal of blood. In general, this implies that the patient is not transfusion dependent and that the hematocrit is maintained at the level of at least 8.5-10 mg/dL. A standard program is the removal of 450 mL of blood weekly until the serum ferritin.

Transfusional iron overload- iron chelation therapy. When iron overload occurs in conjunction with severe anemia, phlebotomy therapy is not feasible. Therefore, chelation .therapy to promote iron excretion is necessary. Desferrioxamine B, which leads to excretion of non m the urine and bile, is the only drug approved for chelation therapy of iron overload. This drug is not effective orally and intramuscular injection of deferoxamine B usually does not promote sufficient iron excretion to achieve negative iron balance. Therefore, effective iron removal from the body can be accomplished only through continuous desferrioxamine infusion.