Chapter 407: Hemochromatosis

Hemochromatosis results from a relatively common inherited genetic mutation in European populations. Once thought to be a single disease entity it is now known to be an iron-storage disorder with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to an increase in intestinal iron absorption and the deposition of excessive amounts of iron in parenchymal cells with eventual tissue damage and organ failure. Thus, the term hemochromatosis now 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.

The following terminology is widely accepted.

1. Hereditary hemochromatosis is most often caused by a mutant gene, termed HFE, which is tightly linked to the HLA-A locus on chromosome 6p. Persons who are homozygous for the mutation are at increased risk of iron overload and account for 80–90% 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 407-1). 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.

2. 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.

Although HFE-associated hemochromatosis mutations are common, the prevalence varies in different ethnic groups. It is most common in populations of northern European extraction in whom ~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, dietary iron intake, blood loss associated with menstruation and pregnancy, and blood donation. Recent population studies indicate that ~30% of homozygous men develop iron overload–related disease and about 6% develop hepatic cirrhosis; for women, the figure is closer to 1%. Presumably there are as yet unidentified modifying genes responsible for expression. Nearly 70% of untreated 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 407-1) are rare, but they affect all races and young people (juvenile hemochromatosis).

These result from mutations in one or more of the genes for proteins in the hepcidin pathway (Fig. 407-1), i.e., hemojuvelin, transferrin receptor 2 (TfR2), or ferroportin. The resultant clinical disease is very similar to HFE-related disease because they all lead to hepcidin deficiency, which is the final common pathway (Fig. 407-1).

A rare autosomal dominant form of hemochromatosis results from two types of mutations in the gene for the iron transporter ferroportin. Firstly, loss of function mutations decrease the cell surface localization of ferroportin, thereby reducing its ability to export iron (“ferroportin disease”). A second mutation abolishes the hepcidin-induced ferroportin internalization and degradation resulting in a “gain-of-function.” Here the tissue iron distribution is similar to that in HFE-related disease (e.g., in parenchymal cells).

A homozygous G to A mutation in the HFE gene 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. 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 (NASH).

Thus, 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 407-1). Mutations in the genes encoding hepcidin, transferrin receptor 2 (TfR2), and hemojuvelin (Fig. 407-1) 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.

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 ~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. The progressive accumulation of iron increases plasma iron and saturation of transferrin and results in a progressive increase of plasma ferritin (Fig. 407-2). The key regulatory hormone that allows the liver to communicate with the bone marrow was discovered quite serendipitously and has transformed our understanding of the coordination of absorption, mobilization, and storage of iron to meet the requirements of erythropoiesis. It was called hepcidin based upon its anti-bacterial activity (“HEPatic bacterioCIDal proteIN”). This liver-derived peptide 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. 407-1). The development of minihepcidins, i.e., small peptides that mimic the action of hepcidin, is promising for the development of new therapeutic approaches for iron overload disorders caused by low hepcidin levels.

The HFE gene encodes a 343-amino-acid protein that is structurally related to MHC class I proteins (HFE). 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. 407-1). 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 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. 94). 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. 409), 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 (see later). 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 to 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.

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, skin pigmentation, 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 >95% of symptomatic patients.

Manifestations of portal hypertension and esophageal varices occur less commonly than in cirrhosis from other causes. Hepatocellular carcinoma develops in ~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.

Diabetes mellitus occurs in ~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.

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. 365). 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 ~15% of symptomatic patients. The most common manifestation is congestive heart failure, which occurs in ~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.

The association of (1) hepatomegaly, (2) skin pigmentation, (3) diabetes mellitus, (4) heart disease, (5) arthritis, and (6) hypogonadism should suggest the diagnosis. However, as stated above, significant iron overload may exist with none or only some of these manifestations. Therefore, a high index of suspicion is needed to make the diagnosis early. Treatment before permanent organ damage occurs can reverse the iron toxicity and restore life expectancy to normal.

The history should be particularly detailed in regard to disease in other family members; alcohol ingestion; iron intake; and ingestion of large doses of ascorbic acid, which promotes iron absorption (Chap. 326). Appropriate tests should be performed to exclude iron deposition due to hematologic disease. The presence of liver, pancreatic, cardiac, and joint disease should be confirmed by physical examination, radiography, and standard function tests of these organs.

The degree of increase in total body iron stores can be assessed by (1) measurement of serum iron and the percent saturation of transferrin (or the unsaturated iron-binding capacity), (2) measurement of serum ferritin concentration, (3) liver biopsy with measurement of the iron concentration and calculation of the hepatic iron index (Table 407-2), and (4) magnetic resonance imaging (MRI) of the liver. In addition, a retrospective assessment of body-iron storage is also provided by performing weekly phlebotomy and calculating the amount of iron removed before iron stores are exhausted (1 mL blood = ~0.5 mg iron).

Each of these methods for assessing iron stores has advantages and limitations. The serum iron level and percent saturation of transferrin are elevated early in the course, but their specificity is reduced by significant false-positive and false-negative rates. For example, serum iron concentration may be increased in patients with alcoholic liver disease without iron overload; in this situation, however, the hepatic iron index is usually not increased as in hemochromatosis (Table 407-1). In otherwise healthy persons, a fasting serum transferrin saturation >45% is abnormal and suggests homozygosity for hemochromatosis.

The serum ferritin concentration is usually a good index of body-iron stores, whether decreased or increased. In fact, an increase of 1 μg/L in serum ferritin level reflects an increase of ~5 mg in body stores. In most untreated patients with hemochromatosis, the serum ferritin level is significantly increased (Fig. 407-2 and Table 407-1), and a serum ferritin level >1000 μg/L is the strongest predictor of disease expression among individuals homozygous for the C282Y mutation. However, in patients with inflammation and hepatocellular necrosis, serum ferritin levels may be elevated out of proportion to body-iron stores due to increased release from tissues. Therefore, a repeat determination of serum ferritin should be carried out after acute hepatocellular damage has subsided (e.g., in alcoholic liver disease). Ordinarily, the combined measurements of the percent transferrin saturation and serum ferritin level provide a simple and reliable screening test for hemochromatosis, including the precirrhotic phase of the disease. If either of these tests is abnormal, genetic testing for hemochromatosis should be performed (Fig. 407-3).

The role of liver biopsy in the diagnosis and management of hemochromatosis has been reassessed as a result of the widespread availability of genetic testing for the C282Y mutation. The absence of severe fibrosis can be accurately predicted in most patients using clinical and biochemical variables. Thus, there is virtually no risk of severe fibrosis in a C282Y homozygous subject with (1) serum ferritin level <1000 μg/L, (2) normal serum alanine aminotransferase values, (3) no hepatomegaly, and (4) no excess alcohol intake. However, it should be emphasized that liver biopsy is the only reliable method for establishing or excluding the presence of hepatic cirrhosis, which is the critical factor determining prognosis and the risk of developing hepatocellular carcinoma. Biopsy also permits histochemical estimation of tissue iron and measurement of hepatic iron concentration. Increased density of the liver due to iron deposition can be demonstrated by computed tomography (CT) or MRI, and with improved technology, MRI has become more accurate in determining hepatic iron concentration.

When the diagnosis of hemochromatosis is established, it is important to counsel and screen other family members (Chap. 457). Asymptomatic and symptomatic family members with the disease usually have an increased saturation of transferrin and an increased serum ferritin concentration. These changes occur even before the iron stores are greatly increased (Fig. 407-2). All adult first-degree relatives of patients with hemochromatosis should be tested for the C282Y and H63D mutations and counseled appropriately (Fig. 407-3). In affected individuals, it is important to confirm or exclude the presence of cirrhosis and begin therapy as early as possible. For children of an identified proband, testing for HFE of the other parent is helpful because if normal, the child is merely an obligate heterozygote and at no risk. Otherwise, for practical purposes, children need not be checked before they are 18 years old.

The role of population screening for hemochromatosis is controversial. Recent studies indicate that it is highly effective for primary care physicians to screen subjects using transferrin saturation and serum ferritin levels. Such screening also detects iron deficiency. Genetic screening of the normal population is feasible but is probably not cost effective.

The principal causes of death are cardiac failure, hepatocellular failure or portal hypertension and hepatocellular carcinoma.

Life expectancy is improved by removal of the excessive stores of iron and maintenance of these stores at near-normal levels. The 5-year survival rate with therapy increases from 33 to 89%. With repeated phlebotomy, the liver decreases in size, liver function improves, pigmentation of skin decreases, and cardiac failure may be reversed. Diabetes improves in ~40% of patients, but removal of excess iron has little effect on hypogonadism or arthropathy. Hepatic fibrosis may decrease, but established cirrhosis is irreversible. Hepatocellular carcinoma occurs as a late sequela in patients who are cirrhotic at presentation. The apparent increase in its incidence in treated patients is probably related to their increased life span. Hepatocellular carcinoma rarely develops if the disease is treated in the precirrhotic stage. Indeed, the life expectancy of homozygotes treated before the development of cirrhosis is normal.

The importance of family screening and early diagnosis and treatment cannot be overemphasized. Asymptomatic individuals detected by family studies should have phlebotomy therapy if iron stores are moderately to severely increased. Assessment of iron stores at appropriate intervals is also important. With this management approach, most manifestations of the disease can be prevented.

There is considerable interest in the role of HFE mutations and hepatic iron in several other liver diseases. Several studies have shown an increased prevalence of HFE mutations in PCT patients. Iron accentuates the inherited enzyme deficiency in PCT and clinical manifestations of PCT. The situation in NASH is less clear, but some studies have shown an increased prevalence of HFE mutations in NASH patients. The role of phlebotomy therapy, however, is unproven despite an intriguing fall in liver enzyme levels. In chronic HCV infection, HFE mutations are not more common, but some subjects have increased hepatic iron. Before initiating antiviral therapy in these patients, it is reasonable to perform phlebotomy therapy to remove excess iron stores, because this reduces liver enzyme levels.

HFE mutations are not increased in frequency in alcoholic liver disease. Hemochromatosis in a heavy drinker can be distinguished from alcoholic liver disease by the presence of the C282Y mutation.

End-stage liver disease may also be associated with iron overload of the degree seen in hemochromatosis. The mechanism is uncertain, although studies have shown that alcohol suppresses hepatic hepcidin secretion. Hemolysis also plays a role. HFE mutations are uncommon.

Whether subjects homozygous for C282Y are at increased risk of breast and colorectal cancer is controversial.

The HFE mutation is of northern European origin (Celtic or Nordic) with a heterozygous carrier rate of ~1 in 10 (1 in 8 in Ireland). Thus, HFE-associated hemochromatosis is quite rare in non-European populations, e.g., Asia. However, non-HFE-associated hemochromatosis resulting from mutations in other genes involved in iron metabolism (Fig. 407-1) is ubiquitous and should be considered when one encounters iron overload.

African iron overload occurs primarily in sub-Saharan Africa and was previously thought to be due to the consumption of an iron-rich fermented maize beverage. However, recent evidence suggests that it is primarily the result of a non-HFE-related genetic trait that is exacerbated by the dietary iron loading. A similar form of iron-overload has been described in African Americans. Further research is needed to clarify this condition.