Hemochromatosis refers to a group of disorders in which excessive iron absorption, either alone or in combination with parenteral iron loading, leads to a progressive increase in total body iron stores. Iron is deposited in the parenchymal cells of the liver, heart, pancreas, synovium, and skin, and the pituitary, thyroid, and adrenal glands. Parenchymal deposition of iron results in cellular damage and functional insufficiency of the involved organs.
Classification of hemochromatosis
Primary. Heredity hemochromatosis.
- Refractory anemias (e.g., thalassemia, spherocytosis, sideroblastic anemia).
- Chronic liver injury (e.g., alcoholic cirrhosis, chronic viral hepatitis B and C, post-portacaval shunt).
- Dietary iron overload (e.g., Bantu, medicinal).
- Porphyria cutanea tarda. Thalassemia; sideroblastic, hypoproliferative, anemias with increased bone marrow turnovers; and repeated transfusions combined with increased intestinal iron absorption can lead to iron overload. Each unit of transfused blood contains 200 mg of iron; thus a patient receiving 4 units of blood per month over a period of 2 years will receive about 20 g of iron, an amount that overwhelms the limited capacity of the reticuloendothelial system to excrete the element. The mechanisms responsible for secondary iron overload in patients with porphyria cutanea tarda, post-portacaval shunt, chronic viral hepatitis B and C, and alcoholic liver disease are not understood.
Parenteral iron overload
- Multiple blood transfusions.
- Excessive parenteral iron. Hemodialysis (rare since the introduction of recombinant erythropoietin).
The total body iron in healthy, iron-replete individuals is approximately 4 to 5 g. Hemoglobin iron constitutes about 60%, and myoglobin, cytochromes, catalase, and peroxidase about 10% of the total body iron. Less than 1% is present as circulating iron bound to transferrin. About 35% is in the storage form as ferritin and hemosiderin, located mainly in the macrophages of the liver, spleen, and bone marrow as well as the parenchymal cells of the liver, muscle, and other organs. Approximately one third of the storage iron is found in the liver, primarily as ferritin. This provides an internal reserve that can be mobilized when needed.
A normal adult on the average ingests about 10 to 15 mg of iron per day. Only about 10% of this is absorbed into the circulation through the mucosal cells of the duodenum and proximal jejunum. Heme iron (meats) is absorbed four times more effectively than inorganic iron (vegetables and grains). There is no physiologic mechanism for excretion of iron out of the body in any appreciable quantity. Therefore, the intestinal absorption of iron is finely regulated in the normal individual. This permits the entry of only the amount necessary to replace the iron lost from exfoliated epithelial cells of the gastrointestinal tract and skin, and menstrual blood loss in women, which amounts to 1.0 mg per day in men and 1.5 mg per day in women.
Iron transport and storage proteins
Transferrin is a beta globulin found in the plasma that transports inorganic ferric irons from the gastrointestinal tract to the reticulocyte and tissue stores as well as from the tissue stores to the bone marrow. The rate of synthesis of transferrin by the liver is regulated by the total body iron stores rather than the hemoglobin level. Thus the decreased transferrin levels in hemochromatosis are due to increased total body iron stores. Low transferrin levels are also seen in conditions such as inflammation, ineffective erythropoiesis, and liver diseases. Normally transferrin is about 30% saturated with iron; thus the total iron binding capacity of the serum is about 250 to 400 mg/dL.
Ferritin is an intracellular protein made up of 24 subunits that sequesters inorganic iron within its core. When fully saturated, iron composes 23% of molecule. It is found in the macrophages, reticulocytes, intestinal mucosa, testis, kidney, heart, pancreas, skeletal muscle, and placenta. Serum and tissue ferritin are regulated by total body iron stores, with each 1 mg/mL of ferritin in the serum corresponding to 8 to 10 mg of stored tissue iron. The serum level of ferritin is a good estimation of total body iron stores.
Multiple aggregates of ferritin make up this more stable form of iron storage. Iron stored in ferritin, as well as hemosiderin, can be mobilized by venisection.
Pathogenesis of Heredity hemochromatosis
The primary defect does not reside in the liver. Three defects appear to contribute to the iron overload.
Increased intestinal absorption of iron despite increased total body stores. Absorption of other metals such as manganese, cobalt, and zinc also seems to be enhanced, although to a lesser degree.
Inability of reticuloendothelial cells to retain iron, leading to a shift of iron transport to parenchymal cells of the liver, myocardium, pancreas, and other organs.
Expansion of the pool of non-transferrin-bound iron and its preferential uptake by parenchymal cells as the iron level and transferrin saturation increase in plasma. The result is total body iron overload with predominant deposition in parenchymal liver cells, leading to hepatic fibrosis and cirrhosis. A growing body of experimental evidence suggests that iron induces membrane lipid peroxidation, possibly as a consequence of free radical formation.
This process damages lysosomal, microsomal, and other cellular membranes, resulting in cell death. Because iron is a cofactor for proline and lysine hydroxylase, two critical enzymes involved in the synthesis of collagen, some investigators have postulated that elevated tissue iron levels may promote an increased deposition of collagen and hepatic fibrosis. In addition, iron overload may activate and enhance the expression of some target genes in the liver, such as genes for ferritin and procollagen. Parenchymal cell deposition of iron also occurs in other tissues and may result in cardiac failure, diabetes mellitus, gonadal insufficiency, and arthritis.
It has been estimated that the prevalence of homozygous and heterozygous Heredity hemochromatosis in populations of northern European descent is about one in 200 to 400 and one in eight to ten, respectively. The disease is rarely identified in Africans or Asians. It is more common in men. The male-female ratio is 5 to 10:1. Nearly 70% of the patients have their first symptoms between the ages of 40 and 60 years. It is rarely clinically evident below the age of 20.
Heredity hemochromatosis has an autosomal recessive mode of inheritance. The gene is located in the short arm of chromosome 6 near the HLA-A locus. In 1996, the gene (called HFE) was found to code for a novel major histocompatibility complex (MHC) class 1-like molecule that requires interaction with B2-microglobulin for normal presentation on the cell H63D. Most (approximately 83%) of patients with Heredity hemochromatosis are homozygous for C282Y mutation, an additional 4% are compound heterozygotes (C282Y/H63D). Ten to fifteen percent of patients have a clinical syndrome similar to Heredity hemochromatosis, but do not have C282Y mutation.
Approximately one third of the males and one sixth of the females sharing one haplotype (heterozygotes) exhibit partial biochemical expression. However, these individuals rarely develop clinical manifestations of the disease.
Phenotypic expression of the inherited abnormality is modified by a variety of factors, including dietary iron intake, iron supplementation, chronic hemodialysis, alcohol consumption, menstrual blood loss, multiple pregnancies, and accelerated erythropoiesis.
Pathophysiology of HFE
Since the discovery of HFE as the gene responsible for Heredity hemochromatosis, its role in the dysregulated iron absorption seen in Heredity hemochromatosis has been elucidated. HFE protein is found in the crypt cells of the duodenum, associated with B2-microglobulin and transferrin receptor. It is thought that HFE protein may facilitate transferrin receptor-dependent iron uptake into crypt cells and that mutant HFE protein may lose this ability, leading to a «relative» iron deficiency in the duodenal crypt cells.
In turn, this may result in an increase in the expression of an iron transport protein called divalent metal ion transporter 1(DMI-1) that is responsible for dietary iron absorption in the villous cells of the duodenum. Up-regulation of DMT-1 expression has been confirmed in humans with Heredity hemochromatosis, providing further evidence for this mechanism explaining increased iron absorption in Heredity hemochromatosis.
Early in the course of IHC, patients may signs or symptoms: lethargy, weight loss, change in skin color, congestive heart failure, loss of libido, abdominal pain, joint pain, or symptoms related to diabetes mellitus. Hepatomegaly, skin pigmentation, testicular atrophy, loss of body hair, and arthropathy are the most prominent physical signs.
Patients with hemochromatosis secondary to transfusion therapy for chronic anemia present with clinical symptoms at a young age. The typical patient with thalassemia, having received more than 100 blood transfusions, experiences failure of normal growth and sexual development in adolescence and hepatic fibrosis. Many patients die of cardiac disease by early adulthood.
The liver is the first organ affected in IHC, and hepatomegaly is present in 95% of the symptomatic patients. Hepatomegaly may exist in the absence of symptoms and abnormal liver tests. In fact, serum aminotransferases are frequently normal or only slightly elevated in patients with IHC, even in the presence of cirrhosis. This finding reflects the relative preservation of the hepatocyte integrity, which usually persists throughout the course of the disease.
Palmar erythema, spider angiomata, loss of body hair, and gynecomastia are often seen. Manifestations of portal hypertension may occur but are less common than in alcohol-related cirrhosis. Hepatocellular carcinoma develops in approximately 30% of the patients with cirrhosis. This increased incidence of Hepatocellular carcinoma may be due to chronic iron- overload- induced damage to hepatic deoxyribonucleic acid.
Skin pigmentation, which may be absent early in the course of the disease, is present in a large percentage of symptomatic patients. The dark metallic hue is largely due to melanin deposition in the dermis. There is also some iron deposition in the skin, especially around the sweat glands. Pigmentation is deeper on the face, neck, exterior surfaces of the lower arms, dorsa of hands, lower legs, and genital regions, and in scars. Ten to fifteen percent of the patients have pigmentation of the oral mucosa. Skin is usually atrophic and dry.
Diabetes mellitus develops in 30% to 60% of the patients with advanced disease. The presence of a family history of diabetes mellitus and the presence of liver disease and direct damage to the beta cells of the pancreas by deposition of iron all probably contribute to the development of diabetes mellitus in IHC. Complications of diabetes mellitus such as retinopathy, nephropathy, and neuropathy may occur. IHC spares the exocrine pancreas.
Loss of libido and testicular atrophy
Hypogonadism is common with symptomatic IHC and is most likely due to hypothalamic or pituitary failure with impairment of gonadotropin secretion. Liver damage, alcohol intake, and other factors may contribute to sexual hypofunction.
Other endocrine disorders
Addison’s disease, hypothyroidism, and hypoparathyroidism are less common in IHC.
Arthropathy is present in about one fifth of the patients with IHC. It is more common in patients over 40 years of age and occasionally may be the presenting symptom.
Osteoarthritis involving the metacarpophalangeal and proximal interphalangeal joints of the hands, and later of the knees, hips, wrists, and shoulders, is most commonly seen.
Pseudogout (chondrocalcinosis) occurs in approximately 50% of the patients with arthropathy. Knees are most commonly affected, but wrists and metacarpophalangeal joints are also usually involved.
The pathogenesis of arthritis is not known. However, iron deposition in the synovial cells may predispose to calcium pyrophosphate deposition.
Approximately 15% to 20% of the patients present with cardiac disease, most commonly cardiomyopathy, leading to heart failure. The heart is diffusely enlarged. Because iron is also deposited in the conduction system, a great variety of arrhythmias, such as tachyarrhythmias, conduction blocks, and low-voltage patterns, may also be present.
Patients with hemochromatosis seem to have an increased risk of development of severe bacterial infections, particularly with Yersinia enterocolitica, Yersinia pseudotuberculosis, Vibrio vulnificus, Neisseria species, enteric gram-negative bacteria, Staphylococcus aureus, and Listeria monocytogenes. Sepsis, meningitis, enterocolitis, peritonitis, and intraabdominal abscesses have been reported. The ingestion of raw seafood appears to contribute to the risk of these infections and should be avoided. It is hypothesized that the increased availability of iron heightens susceptibility to infection because most bacteria utilize iron in growth.
Diagnostic criteria are based on demonstration of excessive parenchymal iron stores in the absence of other causes of iron overload such as refractory anemia, thalassemia, and alcoholic cirrhosis.
Serum iron and total iron binding capacity. The normal range for serum iron is 50 to 150 mg/dL. If the level is greater than 180 mg/dL, the patient should be questioned with regard to intake of iron-containing medicines. The serum iron should be rechecked 1 month after these medicines are discontinued. The serum iron and percent saturation of transferrin or total iron binding capacity are elevated (> 45%) early in the course of the disease, but their specificity is reduced by a relatively high frequency of false-positive and false-negative tests in young patients or in patients with other illnesses.
Serum ferritin accurately reflects both hepatic and total body iron stores. The levels are lower in women than in men. It is the most specific screening test for increased iron stores. However, normal levels may be found occasionally in patients with latent or precirrhotic Heredity hemochromatosis. Ascorbic acid deficiency in patients with iron overload results in inappropriately low serum ferritin concentration. Elevated serum ferritin levels in the absence of iron overload may be attributable to infection, acute or chronic liver disease especially when associated with hepatocellular necrosis (e.g., viral, drug-related, or steatohepatitis), lymphoma, lymphocytic leukemia and other malignancies, rheumatoid arthritis, hyperthyroidism, and uremia.
Genetic testing is recommended in patients with an elevated fasting transferrin or ferritin level. If individuals are C282Y-homozygotes or compound heterozygotes (C282Y/H630) younger than 40 years with normal liver enzyme (alanine aminotransferase [alanine aminotransferase] and aspartate aminotransferase [aspartate aminotransferase]) levels, no further workup is necessary. In patients with abnormal liver tests or who are older than 40 years, a liver biopsy is recommended to define the liver disease and extent of fibrosis.
For patients older than 40 years with elevated liver chemistry tests, liver biopsy should be performed. Liver biopsy permits the following:
Estimation of tissue iron by histochemical staining. The amount of stainable parenchymal iron is graded from 0 to 4, but the relation between histochemical grading and hepatic iron concentration is not linear. Grades 1 and 2 (slight-to-moderate siderosis) are quite common in the normal liver. Grade 4 siderosis indicates heavy iron excess. Grade 3 (submaximal siderosis) is difficult to interpret in quantitative terms.
Early in Heredity hemochromatosis, stainable iron is almost exclusively present in the hepatocytes, whereas in early secondary iron overload, the iron is predominantly in the Kupffer’s cells. With progressive iron accumulation, the histologic features and pattern of stainable iron in various etiologic types of iron overload become indistinguishable, and iron is seen throughout the lobule, biliary duct epithelium, Kupffer’s cells, and connective tissue.
Measurement of hepatic iron concentration by dry weight by chemical analysis is the most objective means of assessing total body iron stores. The normal range is 7 to 100 Вµg/100 mg of dry weight of liver tissue. In IHC, values are greater than 1,000 Вµg/100 mg of dry weight.
Patients with alcoholic cirrhosis and increased stainable iron usually have a hepatic iron concentration less than twice normal. There is evidence that alcoholic patients with gross iron overload carry the IHC gene.
The hepatic iron index, which is the hepatic iron concentration in mol/g of dry weight per age, seems to discriminate homozygous from heterozygous Heredity hemochromatosis before the development of frank iron overload in homozygotes.
Histologic assessment of liver damage. In the early stages, the histologic appearance of the liver may be normal despite increased iron in the hepatocytes. Necrosis and inflammation are usually absent. Before cirrhosis is fully established, there is fibrosis radiating from expanded portal tracts. The hepatic iron concentration and the duration of exposure are critical determinants of the extent of liver injury. In the absence of coexistent alcoholic liver disease, fibrosis or cirrhosis usually does not occur in Heredity hemochromatosis until the hepatic iron concentration reaches 4,000 to 5000 Вµm/g liver (wet weight), or 2.2% dry weight.
In patients with thalassemia major, the apparent threshold concentration for the development of hepatic fibrosis is about twice this level. Whether this difference is due to the initial location of iron in the reticuloendothelial cells or a shorter duration of exposure of the hepatocytes to high iron concentration is uncertain. As cirrhosis develops, the histology may resemble cirrhosis from chronic biliary obstruction. Some patients may have histology similar to that of alcoholic cirrhosis.
The treatment of IHC involves the removal of excess iron and therapy of functional insufficiency of the organs involved, such as congestive heart failure, liver failure, and diabetes mellitus.
Iron is best removed from the body by phlebotomy. There are 250 mg of iron in 500 mL of blood. Because the body burden of iron in IHC may be in excess of 20 g, 2 to3 years of weekly phlebotomy of 500 mL of blood may be necessary to achieve a hemoglobin of 11% and serum ferritin level of 10 to 20 Вµg/L. Thereafter, the frequency of phlebotomy may be decreased to one unit of blood every 3 months for the rest of the patient’s life.
Chelating agents such as deferoxamine remove only 10 to 20 mg of iron per day. In patients with anemia, hypoproteinemia, or severe cardiac disease precluding phlebotomy, this technique may be used. However, it is difficult to achieve a negative iron balance by this means. In patients with refractory anemia, if it is initiated early in the course of iron loading, this approach can lower the risk of cardiac disease, promote sexual maturation, and generally improve the prognosis.
Nightly subcutaneous infusion of deferoxamine induces excretion of chelatable iron into urine and, probably via the bile, into stool. The recommended dosage is approximately 40 to 80 mg/kg per day. At daily dosages of more than 50 mg/kg, the potential increases for hypersensitivity and ocular and otologic complications, including night blindness, visual field changes, irreversible retinal pigmentation, optic neuropathy, deafness, and other adverse reactions. In addition, the iron chelator deferoxamine can promote infections, including gram- negative sepsis and abscesses, by functioning as a siderophore, delivering iron to bacteria that use it in growth. Chelating compounds that can be taken orally, most notably including ОІ-hydroxypyridine, are being developed.
Despite the potential of vitamin C deficiency to exacerbate iron overload, vitamin C supplementation is contraindicated in patients with hemochromatosis. Sudden cardiac deaths have occurred in patients receiving chelation therapy and vitamin C supplements. The cause of these events may involve sudden shifts of iron from reticuloendothelial to parenchymal cells of the myocardium or increased cellular injury from increased lipid peroxidation.
In patients treated with phlebotomy, there is a decrease in the size of the liver and spleen, skin pigmentation, cardiac failure, serum aminotransferases, and glucose intolerance. Removal of iron has no effect on hypogonadism, arthropathy, or portal hypertension. Hepatic fibrosis may decrease, but cirrhosis is irreversible. Hepatocellular carcinoma occurs in one- third of the patients with IHC and cirrhosis, despite iron removal. This complication does not seem to develop if the disease is treated in the precirrhotic stage. Hepatomas in IHC are usually multicentric and not amenable to surgical resection. Only 30% to 40% of the patients have elevated serum alpha-fetoprotein levels.
Early diagnosis of IHC in family members. To prevent the development of permanent organ damage, cirrhosis, and hepatocellular carcinoma, it is very important to diagnose and treat the disease in relatives at an early stage. The following are guidelines for screening relatives of patients with Heredity hemochromatosis:
Once a proband with Heredity hemochromatosis is identified, genetic family screening is recommended for all first-degree relatives. In young proband with children, it is useful to perform HFE mutation analysis in the spouse to accurately predict the genotype in the children. If the spouse has either mutation, then the children will also need to undergo HFE mutation analysis. If C282Y homozygosity or compound heterozygosity (C282Y/H63D) is found in adult relatives of the proband, serum iron studies should be obtained. If ferritin or transferrin levels are increased, therapeutic phlebotomy should be considered. If alanine aminotransferase and aspartate aminotransferase levels are normal and ferritin is <1,000 Вµg/L, liver biopsy is probably not necessary.