Hemochromatosis is a common inherited disorder of iron metabolism in which dysregulation of intestinal iron absorption results in deposition of excessive amounts of iron in parenchymal cells with eventual tissue damage and impaired function in a wide range of organs. The iron-storage pigment in tissues is called hemosiderin because it is believed to be derived from the blood. The term hemosiderosis is used to describe the presence of stainable iron in tissues, but tissue iron must be quantified to assess body-iron status accurately (see below and Chap. 103). Hemochromatosis refers to a group of genetic diseases that predispose to iron overload, potentially leading to fibrosis and organ failure. Cirrhosis of the liver, diabetes mellitus, arthritis, cardiomyopathy, and hypogonadotropic hypogonadism are the major clinical manifestations.
Although there is debate about definitions, the following terminology is widely accepted.
Hereditary hemochromatosis is most often caused by a mutant gene, termed HFE, which is tightly linked to the HLA-A locus on chromosome 6p (see “Genetic Basis,” below). Persons who are homozygous for the mutation are at increased risk of iron overload and account for 80 to 90% of clinical hereditary hemochromatosis in persons of northern European descent. In such subjects, the presence of hepatic fibrosis, cirrhosis, arthropathy, or hepatocellular carcinoma constitutes iron overload–related disease. Rarer forms of non-HFE hemochromatosis are caused by mutations in other genes involved in iron metabolism (Table 357-1). The disease can be recognized during its early stages when iron overload and organ damage are minimal. At this stage, the disease is best referred to as early hemochromatosis or precirrhotic hemochromatosis.
Secondary iron overload occurs as a result of an iron-loading anemia, such as thalassemia or sideroblastic anemia, in which erythropoiesis is increased but ineffective. In the acquired iron-loading disorders, massive iron deposits in parenchymal tissues can lead to the same clinical and pathologic features as in hemochromatosis.
Table 357-1 Classification of Iron Overload States |Favorite Table|Download (.pdf)
Table 357-1 Classification of Iron Overload States
Hemochromatosis, HFE-related (type 1)
C282Y/H63D compound heterozygosity
Juvenile hemochromatosis (type 2A) (hemojuvelin mutations)
Juvenile hemochromatosis (type 2B) (hepcidin mutation)
Mutated transferrin receptor 2 TFR2 (type 3)
Mutated ferroportin 1 gene, SLC11A3 (type 4)
|Acquired Iron Overload|
Chronic hemolytic anemias
Transfusional and parenteraliron overload
Dietary iron overload
Chronic liver disease
Alcoholic cirrhosis, especially when advanced
Porphyria cutanea tarda
Dysmetabolic iron overload syndrome
Iron overload in sub-Saharan Africa
HFE-associated hemochromatosis mutations are among the most common inherited disease alleles, although the prevalence varies in different ethnic groups. It is most common in populations of northern European extraction in whom approximately 1 in 10 persons are heterozygous carriers and 0.3–0.5% are homozygotes. However, expression of the disease is variable and modified by several factors, especially alcohol consumption and dietary iron intake, blood loss associated with menstruation and pregnancy, and blood donation. Recent population studies indicate that approximately 30% of homozygous men develop iron overload–related disease and about 6% develop hepatic cirrhosis; for women, the figure is closer to 1%. Nearly 70% of patients develop the first symptoms between ages 40 and 60. The disease is rarely evident before age 20, although with family screening (see “Screening for Hemochromatosis,” below) and periodic health examinations, asymptomatic subjects with iron overload can be identified, including young menstruating women.
In contrast to HFE-associated hemochromatosis, the non-HFE-associated forms of hemochromatosis (Table 357-1) are rare, but they affect all races and young people (juvenile hemochromatosis).
The HFE gene responsible for the most common form of hemochromatosis was identified in 1996. A homozygous G to A mutation resulting in a cysteine to tyrosine substitution at position 282 (C282Y) is the most common mutation. It is identified in 85–90% of patients with hereditary hemochromatosis in populations of northern European descent but is found in only 60% of cases from Mediterranean populations (e.g., southern Italy). A second, relatively common HFE mutation (H63D) results in a substitution of histidine to aspartic acid at codon 63. Homozygosity for H63D is not associated with clinically significant iron overload. Some compound heterozygotes (e.g., one copy each of C282Y and H63D) have mild to moderately increased body-iron stores but develop clinical disease only in association with cofactors such as heavy alcohol intake or hepatic steatosis. Thus, HFE-associated hemochromatosis is inherited as an autosomal recessive trait; heterozygotes have no, or minimal, increase in iron stores. However, this slight increase in hepatic iron can act as a cofactor that may modify the expression of other diseases such as porphyria cutanea tarda (PCT) or nonalcoholic steatohepatitis.
Mutations in other genes involved in iron metabolism are responsible for non-HFE-associated hemochromatosis, including juvenile hemochromatosis, which affects persons in the second and third decades of life (Table 357-1). Mutations in the genes encoding hepcidin, transferrin receptor 2 (TfR2), and hemojuvelin (Fig. 357-1) result in clinicopathologic features that are indistinguishable from HFE-associated hemochromatosis. However, mutations in ferroportin, responsible for the efflux of iron from enterocytes and most other cell types, result in iron loading of reticuloendothelial cells and macrophages as well as parenchymal cells.
Pathways of normal iron homeostasis. Dietary inorganic iron traverses the brush border membrane of duodenal enterocytes via DMT1 after reduction of ferric (Fe3+) iron to the ferrous (Fe2+) state by duodenal cytochrome B (DcytB). Iron then moves from the enterocyte to the circulation via a process requiring the basolateral iron exporter ferroportin (FPN) and the iron oxidase hephaestin (Heph). In the circulation, iron binds to plasma transferrin and is thereby distributed to sites of iron utilization and storage. Much of the diferric transferrin supplies iron to immature erythrocyte cells in the bone marrow for hemoglobin synthesis. At the end of their life, senescent red blood cells (RBC) are phagocytosed by macrophages and iron is returned to the circulation after export through ferroportin. The liver-derived peptide hepcidin represses basolateral iron transport in the gut as well as iron released from macrophages and other cells and serves as a central regulator of body-iron traffic. Hepcidin responds to changes in body-iron requirements by signals mediated by diferric transferrin through two mechanisms. One involves HFE and TfR2, while the other involves hemojuvelin (HJV) and the Bone Morphogenetic Protein (BMP)/SMAD pathway. Heme is metabolized by heme oxygenase within the enterocytes and the released iron then follows the same pathway.
Mutations in the genes encoding HFE, TfR2, hemojuvelin and hepcidin all lead to decreased hepcidin release and increased iron absorption, resulting in hemochromatosis (Table 357-1).
Normally, the body-iron content of 3–4 g is maintained such that intestinal mucosal absorption of iron is equal to iron loss. This amount is approximately 1 mg/d in men and 1.5 mg/d in menstruating women. In hemochromatosis, mucosal absorption is greater than body requirements and amounts to 4 mg/d or more. The progressive accumulation of iron increases plasma iron, saturation of transferrin, and results in a progressive increase of plasma ferritin (Fig. 357-2). A liver-derived peptide, hepcidin, represses basolateral iron transport in the intestine and iron release from macrophages and other cells by binding to ferroportin. Hepcidin, in turn, responds to signals in the liver mediated by HFE, TfR2, and hemojuvelin (Fig. 357-1). Thus, hepcidin is a crucial molecule in iron metabolism, linking body stores with intestinal iron absorption.
Sequence of events in genetic hemochromatosis and their correlation with the serum ferritin concentration. Increased iron absorption is present throughout life. Overt, symptomatic disease usually develops between ages 40 and 60, but latent disease can be detected long before this.
The HFE gene encodes a 343-amino-acid protein that is structurally related to MHC class I proteins. The basic defect in HFE-associated hemochromatosis is a lack of cell surface expression of HFE (due to the C282Y mutation). The normal (wild-type) HFE protein forms a complex with β2-microglobulin and transferrin receptor 1 (TfR1). The C282Y mutation completely abrogates this interaction. As a result, the mutant HFE protein remains trapped intracellularly, reducing TfR1-mediated iron uptake by the intestinal crypt cell. This impaired TfR1-mediated iron uptake leads to upregulation of the divalent metal transporter (DMT1) on the brush border of the villus cells, causing inappropriately increased intestinal iron absorption (Fig. 357-1). In advanced disease, the body may contain 20 g or more of iron that is deposited mainly in parenchymal cells of the liver, pancreas, and heart. Iron may be increased 50- to 100-fold in the liver and pancreas and 5- to 25-fold in the heart. Iron deposition in the pituitary causes hypogonadotropic hypogonadism in both men and women. Tissue injury may result from disruption of iron-laden lysosomes, from lipid peroxidation of subcellular organelles by excess iron, or from stimulation of collagen synthesis by activated stellate cells.
Secondary iron overload with deposition in parenchymal cells occurs in chronic disorders of erythropoiesis, particularly in those due to defects in hemoglobin synthesis or ineffective erythropoiesis such as sideroblastic anemia and thalassemia (Chap. 104). In these disorders, iron absorption is increased. Moreover, these patients require blood transfusions and are frequently treated inappropriately with iron. PCT, a disorder characterized by a defect in porphyrin biosynthesis (Chap. 358), can also be associated with excessive parenchymal iron deposits. The magnitude of the iron load in PCT is usually insufficient to produce tissue damage. However, some patients with PCT also have mutations in the HFE gene, and some have associated hepatitis C virus (HCV) infection. Although the relationship between these disorders remains to be clarified, iron overload accentuates the inherited enzyme deficiency in PCT and should be avoided along with other agents (alcohol, estrogens, haloaromatic compounds) that may exacerbate PCT. Another cause of hepatic parenchymal iron overload is hereditary aceruloplasminemia. In this disorder, impairment of iron mobilization due to deficiency of ceruloplasmin (a ferroxidase) causes iron overload in hepatocytes.
Excessive iron ingestion over many years rarely results in hemochromatosis. An important exception has been reported in South Africa among groups who brew fermented beverages in vessels made of iron. Hemochromatosis has been described in apparently normal persons who have taken medicinal iron over many years, but such individuals probably had genetic disorders.
The common denominator in all patients with hemochromatosis is excessive amounts of iron in parenchymal tissues. Parenteral administration of iron in the form of blood transfusions or iron preparations results predominantly in reticuloendothelial cell iron overload. This appears to lead to less tissue damage than iron loading of parenchymal cells.
In the liver, parenchymal iron is in the form of ferritin and hemosiderin. In the early stages, these deposits are seen in the periportal parenchymal cells, especially within lysosomes in the pericanalicular cytoplasm of the hepatocytes. This stage progresses to perilobular fibrosis and eventually to deposition of iron in bile-duct epithelium, Kupffer cells, and fibrous septa due to activation of stellate cells. In the advanced stage, a macronodular or mixed macro- and micronodular cirrhosis develops. Hepatic fibrosis and cirrhosis correlate significantly with hepatic iron concentration.
At autopsy, the enlarged nodular liver and pancreas are rusty in color. Histologically, iron is increased in many organs, particularly in the liver, heart, and pancreas, and, to a lesser extent, in the endocrine glands. The epidermis of the skin is thin, and melanin is increased in the cells of the basal layer and dermis. Deposits of iron are present around the synovial lining cells of the joints.
C282Y homozygotes can be characterized by the stage of progression as follows: (1) a genetic predisposition without abnormalities; (2) iron overload without symptoms; (3) iron overload with symptoms (e.g., arthritis and fatigue); and (4) iron overload with organ damage—in particular, cirrhosis. Thus, many subjects with significant iron overload are asymptomatic. For example, in a study of 672 asymptomatic C282Y homozygous subjects—identified by either family screening or routine health examinations—there was hepatic iron overload (grades 2–4) in 56% and 34.5% of male and female subjects, respectively; hepatic fibrosis (stages 2–4) in 18.4% and 5.4%, respectively; and cirrhosis in 5.6% and 1.9%, respectively.
Initial symptoms are often nonspecific and include lethargy, arthralgia, change in skin color, loss of libido, and features of diabetes mellitus. Hepatomegaly, increased pigmentation, spider angiomas, splenomegaly, arthropathy, ascites, cardiac arrhythmias, congestive heart failure, loss of body hair, testicular atrophy, and jaundice are prominent in advanced disease.
The liver is usually the first organ to be affected, and hepatomegaly is present in more than 95% of symptomatic patients. Hepatic enlargement may exist in the absence of symptoms or of abnormal liver-function tests. Manifestations of portal hypertension and esophageal varices occur less commonly than in cirrhosis from other causes. Hepatocellular carcinoma develops in about 30% of patients with cirrhosis, and it is the most common cause of death in treated patients—hence the importance of early diagnosis and therapy. The incidence increases with age, it is more common in men, and it occurs almost exclusively in cirrhotic patients.
Excessive skin pigmentation is present in patients with advanced disease. The characteristic metallic or slate-gray hue is sometimes referred to as bronzing and results from increased melanin and iron in the dermis. Pigmentation usually is diffuse and generalized, but it may be more pronounced on the face, neck, extensor aspects of the lower forearms, dorsa of the hands, lower legs, and genital regions, as well as in scars.
Diabetes mellitus occurs in about 65% of patients with advanced disease and is more likely to develop in those with a family history of diabetes, suggesting that direct damage to the pancreatic islets by iron deposition occurs in combination with other risk factors. The management is similar to that of other forms of diabetes, although insulin resistance is more common in association with hemochromatosis. Late complications are the same as seen in other causes of diabetes mellitus.
Arthropathy develops in 25–50% of symptomatic patients. It usually occurs after age 50 but may occur as a first manifestation, or long after therapy. The joints of the hands, especially the second and third metacarpophalangeal joints, are usually the first joints involved, a feature that helps to distinguish the chondrocalcinosis associated with hemochromatosis from the idiopathic form (Chap. 333). A progressive polyarthritis involving wrists, hips, ankles, and knees may also ensue. Acute brief attacks of synovitis may be associated with deposition of calcium pyrophosphate (chondrocalcinosis or pseudogout), mainly in the knees. Radiologic manifestations include cystic changes of the subchondral bones, loss of articular cartilage with narrowing of the joint space, diffuse demineralization, hypertrophic bone proliferation, and calcification of the synovium. The arthropathy tends to progress despite removal of iron by phlebotomy. Although the relation of these abnormalities to iron metabolism is not known, the fact that similar changes occur in other forms of iron overload suggests that iron is directly involved.
Cardiac involvement is the presenting manifestation in about 15% of symptomatic patients. The most common manifestation is congestive heart failure, which occurs in about 10% of young adults with the disease, especially those with juvenile hemochromatosis. Symptoms of congestive heart failure may develop suddenly, with rapid progression to death if untreated. The heart is diffusely enlarged; this may be misdiagnosed as idiopathic cardiomyopathy if other overt manifestations are absent. Cardiac arrhythmias include premature supraventricular beats, paroxysmal tachyarrhythmias, atrial flutter, atrial fibrillation, and varying degrees of atrioventricular block.
Hypogonadism occurs in both sexes and may antedate other clinical features. Manifestations include loss of libido, impotence, amenorrhea, testicular atrophy, gynecomastia, and sparse body hair. These changes are primarily the result of decreased production of gonadotropins due to impairment of hypothalamic-pituitary function by iron deposition. Adrenal insufficiency, hypothyroidism, and hypoparathyroidism are rare manifestations.