Lawrie W. Powell

A population-based study of the clinical expression of the hemochromatosis gene

BACKGROUND AND METHODS Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body. To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia. In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults. We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation. We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher. The subjects were followed for up to four years. RESULTS Sixteen of the subjects (0.5 percent) were homozygous for the C282Y mutation, and 424 (14.1 percent) were heterozygous. The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent. Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not. Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated. The serum ferritin levels in the four other homozygous patients remained in the normal range. Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis. Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis. CONCLUSIONS In a population of white adults of northern European ancestry, 0.5 percent were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.

Iron-overload-related disease in HFE hereditary hemochromatosis.

BACKGROUND Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial. METHODS We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. RESULTS The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1000 mug per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene. CONCLUSIONS In persons who are homozygous for the C282Y mutation, iron-overload-related disease developed in a substantial proportion of men but in a small proportion of women.

Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association.

Molecular medicine and hemochromatosis: At the crossroads

Abstract Summary of a conference sponsored by the Division of Digestive Diseases and Nutrition and the Division of Kidney, Urology and Hematology of the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland GASTROENTEROLOGY 1999;116:193-207

Management of Hemochromatosis

Diagnosis and Initial Evaluation Diagnosis of Hemochromatosis Persons with hemochromatosis have an inherited propensity to absorb excess iron; most persons are of European origin and are homozygotes or compound heterozygotes for a mutant gene or genes on chromosome 6p [1, 2]. Hyperferremia and increased iron saturation of transferrin are essential attributes of hemochromatosis. A transferrin saturation of 60% or more for men and 50% or more for women on at least two occasions in the absence of other known causes of elevated transferrin saturation suggests the diagnosis of hemochromatosis [1, 2] and permits affected persons to be identified before iron overload develops. Normal or subnormal serum transferrin saturation values occur in unusual circumstances [3]. Many persons who have hemochromatosis without iron overload are children, young adults, and premenopausal women. Although iron overload often develops in patients with hemochromatosis, the demonstration of hepatic or systemic iron overload and associated complications is not needed to confirm the diagnosis (Table 1) [1, 2, 4]. Table 1. Evaluation of Patients with Hemochromatosis and Iron Overload Evaluation of Iron Overload Iron overload develops primarily because mechanisms to eliminate excess iron are limited. Many persons, particularly men, eventually develop severe iron overload. Women are at lower risk, partly because of iron losses during menstruation, childbirth, and lactation [1, 2]. The severity of iron overload is most often determined by measuring the serum ferritin level, although inflammation or cancer can elevate this level in the absence of iron overload. Approximately 90% of excess iron is retained in the liver. Therefore, many patients benefit from analysis of liver biopsy specimens to identify liver disease and to determine the presence or absence of cirrhosis, which directly affects prognosis. Biopsy specimens should be evaluated for iron by histochemical methods (Perls staining) and quantitative techniques (atomic absorption spectrometry) [4-7]. The quantity of iron removed by therapeutic phlebotomy is a valuable retrospective indicator of the severity of iron overload [8]. Radiologic imaging techniques are too insensitive for the evaluation of most young, asymptomatic persons with little or no excess hepatic iron [1, 2]. The hepatic iron index is useful in distinguishing persons who are homozygous for hemochromatosis from heterozygotes and persons with other hepatic disorders [5, 9]. Some patients have coincidental conditions that augment iron absorption and thus increase iron overload (for example, excessive dietary iron supplementation, excess ethanol ingestion, porphyria cutanea tarda, or hemolytic anemia) [1, 2, 10, 11]. Because serum iron variables in patients with viral hepatitis can mimic those in patients with hemochromatosis and because some patients have both disorders, persons with hemochromatosis must often be evaluated for hepatitis [12-14]. Medical Evaluation before Treatment From each patient, physicians should collect information that includes a review of current and past symptoms and health problems, especially those related to liver, joint, and heart disease; diabetes mellitus and other endocrinopathic conditions; sexual function; and skin pigmentation [1, 2]. A dietary history should focus on general dietary habits and food choices, use of dietary supplements, and ingestion of ethanol. Any history of blood donation, receipt of blood transfusion, and illness associated with blood loss should be documented. The details of menstruation, childbirth, lactation, menopause, and hysterectomy are important (women taking oral contraceptives may have decreased menstrual blood loss or may absorb less dietary iron). The history should include inquiries about family members, especially first-degree relatives. The physical examination must include assessment of the liver, joints, heart, endocrine status, and skin coloration. Certain sequelae of iron overload may require additional specific evaluations to assess management needs (Table 1). Therapeutic Phlebotomy Described in 1952, therapeutic phlebotomy was the first successful treatment for iron overload due to hemochromatosis [15] and is still the preferred treatment for this condition today [1, 2]. The removal of 1 unit of blood (450 to 500 mL) results in the loss of 200 to 250 mg of iron. Although iron chelation and erythrocytapheresis have also been used [16, 17], therapeutic phlebotomy is safer, more efficient, and more economical [1, 2]. Selection of Patients for Treatment Most persons with hemochromatosis benefit from therapeutic phlebotomy (Table 2). Rarely, children and adolescents have severe iron overload (often associated with cardiac and anterior pituitary failure) and need aggressive therapeutic phlebotomy for removal of 1.5 to 2.0 units weekly, if possible [18-20]. Withholding therapeutic phlebotomy from older patients on the basis of age alone is not justifiable. In asymptomatic persons with iron overload (Table 2), therapy must not be delayed until symptoms develop. However, some patients are not candidates for treatment because they are intolerant toward phlebotomy or have limited life expectancy. Patients with severe, refractory anemia require iron chelation therapy [21]. Table 2. Criteria for initiating Therapeutic Phlebotomy in Homozygotes or Heterozygotes for Hemochromatosis Gene or Genes and Other Persons with a Hemochromatosis Phenotype, Regardless of Genotype* Approximately 8% of white persons of western European descent inherit one detectable hemochromatosis gene and thus are heterozygotes [22]. Of the 1% to 3% of heterozygotes who develop iron overload [23], many have a coincidental disorder that increases iron absorption or alters iron metabolism [1, 2, 14]; others may have an additional hemochromatosis mutation or mutations undetectable by current testing methods [24]. Many persons with porphyria cutanea tarda have skin lesions that are alleviated with therapeutic phlebotomy, and many are heterozygous for HFE mutations [2, 25-27]. No study has shown the benefits of therapeutic phlebotomy in other persons with iron overload who are heterozygotes or compound heterozygotes for the hemochromatosis gene or genes. However, we recommend that all persons with iron overload who have a clinical phenotype consistent with hemochromatosis, regardless of genotype, receive therapeutic phlebotomy and management similar to that recommended for homozygotes for classic hemochromatosis (Table 2). Performance of Therapeutic Phlebotomy Therapeutic phlebotomy should be done by experienced persons and should be supervised by a physician. It is usually performed in a physicians office but can be done in a medical laboratory, a blood bank, or a patients home. However, comprehensive management of hemochromatosis is usually accomplished best in a physicians office. For many patients, compliance with treatment is proportional to the skill of the phlebotomist and the confidence of the patient in the treatment staff and environment. Adequate hydration and avoidance of vigorous physical activity for 24 hours after treatment minimize the effects of hypovolemia caused by therapeutic phlebotomy. Persons with a hemoglobin concentration less than 110 g/L or a hematocrit less than 0.33 before treatment are more likely to have symptoms of hypovolemia and anemia, and phlebotomy is less efficient in removing iron in these patients. However, many patients with chronic hemolytic anemia and iron overload tolerate phlebotomy well. The hemoglobin concentration or hematocrit and volume (or weight) of blood removed with each phlebotomy session should be documented. Frequency and Duration of Therapeutic Phlebotomy Depletion of iron stores typically involves the removal of 1 unit of blood weekly until mild hypoferritinemia occurs [1, 2]. Some men and persons with large body mass can sustain removal of 1.5 to 2.0 units of blood weekly. Some women; persons with small body mass; elderly persons; and patients with anemia, cardiac problems, or pulmonary problems can sustain removal of only 0.5 units of blood weekly. After a few weeks of therapeutic phlebotomy, erythroid hyperplasia permits more blood to be removed more often in many patients. Although recombinant human erythropoietin therapy also enhances erythrocyte production, this therapy should be reserved for patients who also have renal dysfunction or anemia of chronic disease [28]. Life expectancy may be substantially decreased in patients in whom iron depletion by phlebotomy cannot be completed within 1 year [29]. Serum ferritin and hepatic iron levels permit a relative estimation of the amount of therapeutic phlebotomy required for iron depletion [2]. On average, men require twice as many units of therapeutic phlebotomy as women do [24, 30, 31]. Older persons typically have more severe iron overload, as do persons who are homozygous for HFE mutation C282Y [2, 24, 32]. Hormonal factors, diet, abnormalities that alter iron absorption, and blood loss also influence the severity of iron overload [33]. Persons who have been regular blood donors often have less severe iron overload than do nondonors [1, 34]. The serum ferritin level is the most reliable, readily available, and inexpensive way to monitor therapeutic phlebotomy; the serum iron level and the transferrin saturation are less suitable [1, 2]. In general, patients who have higher serum ferritin levels have more severe iron overload and need more phlebotomy. Among patients who have serum ferritin levels greater than 1000 g/L before treatment, it is sufficient to quantify the serum ferritin level every 4 to 8 weeks during the initial months of treatment. The serum ferritin level should be measured more often in patients who have received many phlebotomy treatments and in those who have mild or moderate iron overload at diagnosis. In all patients, serum ferritin levels should be quantified a

A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation

BACKGROUND & AIMS Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y mutation have been well characterized, the effects of the H63D mutation remain unclear. We accessed a well-defined population in Busselton, Australia, and determined the frequency of the H63D mutation and its influence on total body iron stores. METHODS Serum transferrin saturation and ferritin levels were correlated with the H63D mutation in 2531 unrelated white subjects who did not possess the C282Y mutation. RESULTS Sixty-two subjects (2.1%) were homozygous for the H63D mutation, 711 (23.6%) were heterozygous, and 1758 (58.4%) were wild-type for the H63D mutation. Serum transferrin saturation was significantly increased in male and female H63D homozygotes and heterozygotes compared with wild-types. Serum ferritin levels within each gender were not influenced by H63D genotypes. Elevated transferrin saturation > or = 45% was observed in a greater proportion of male H63D carriers than male wild-types. Male H63D homozygotes (9%) and heterozygotes (3%) were more likely to have both elevated transferrin saturation and elevated ferritin > or = 300 ng/mL than male wild-types (0.7%). Homozygosity for H63D was not associated with the development of clinically significant iron overload. CONCLUSIONS Presence of the H63D mutation results in a significant increase in serum transferrin saturation but does not result in significant iron overload. In the absence of the C282Y mutation, the H63D mutation is not clinically significant.

Diagnosis of Hemochromatosis

Iron overload disease occurs in two general forms, primary and secondary (Table 1). Primary iron overload stems from an inherent defect in iron regulation that results in continuous overabsorption of iron from the gastrointestinal tract. The exact biological mechanism for this overabsorption is not understood. In some cases, iron accumulates in the parenchyma of various organs, particularly the liver, pancreas, and heart, eventually causing organ damage and the characteristic signs and symptoms of iron overload [1]. Table 1. Categories of Iron Overload Hemochromatosis is the most common type of primary iron overload disease, but it remains under-diagnosed because of the lack of awareness of it, its long latency period, and its nonspecific symptoms [2, 3]. Recently, increased emphasis has been placed on early detection, shifting the case definition and diagnosis to earlier stages of the disease. This has led to various views on the best diagnostic methods and the essential components of the diagnostic evaluation. In the next few years, these issues should become clearer as we gain insight into the natural history and expression of hemochromatosis. In this article, we update the description of hemochromatosis and the tests used to diagnose it. Background Hemochromatosis was first recognized more than a century ago as a condition with a triad of symptoms-diabetes, skin bronzing, and cirrhosis-associated with hepatic iron overload [1]. The condition was first called hemochromatosis in 1889 [4], and it was first proposed as an inherited disorder in 1935 [5]. Its inheritability remained controversial for four decades [6], until Simon and colleagues [7] demonstrated the close association between HLA-linked hemochromatosis and HLA-A3 and established that the responsible gene was tightly linked to the HLA-A locus on the short arm of chromosome 6. In recent years, a candidate gene for HLA-linked hemochromatosis, HFE, has been cloned, and a single G-to-A mutation resulting in a cysteine-to-tyrosine substitution (C282Y) has been identified in 60% to 100% of study patients with hereditary hemochromatosis [8-11]. A second mutation, H63D, was linked to an additional 1% to 10% of cases in one series [11], but no large population-based studies have been done to definitively establish the prevalence of this mutation in the general population. Cases of and families with hemochromatosis not associated with either the C282Y or the H63D mutation (non-HFE-associated hemochromatosis) have been reported from studies of European populations, and the genetic basis for these cases is being studied [10, 11]. Historically, hemochromatosis was a clinical and pathologic diagnosis. Diagnosis relied on the classic features of cirrhosis: pigmentation, diabetes, and arthralgia. As a result, hemochromatosis was described as rare, with an estimated frequency of 1 case in 20 000 hospital admissions in the United States [12]. However, autopsy studies [13, 14] found a much higher frequency: 1 to 2 cases per 1000 persons. More recently, population-based screening studies in several western countries [15-18] have established the prevalence of hemochromatosis as approximately 1 case per 300 persons. With the advent of genetic testing, earlier diagnosis is possible. In addition, some long-standing cases of hemochromatosis have been reviewed and found to be due to the heterozygous form of the C282Y mutation [11, 19]. To date, it seems that in case series of patients with hemochromatosis, 0.5% to 14% of patients have actually been heterozygous [11]. Expression and Natural History The natural history of hemochromatosis begins with a genetic potential (Table 2). This condition expresses itself as a tendency to overabsorb iron from the gastrointestinal tract. At least 50% of male and 25% of female persons homozygous for hemochromatosis are likely to develop potentially life-threatening complications of the disease [1, 18, 19], especially in countries with high dietary intake of iron [19-24]. Table 2. Progression of Hemochromatosis throughout the Lifespan: Pathogenesis and Diagnosis* The first phenotypic expression of disease is an elevation in serum transferrin saturation, which represents the transport of excess iron from the intestine and occurs before significant iron loading (Table 2). As iron accumulates in tissue, the serum ferritin concentration increases in direct linear relation to total-body iron stores [1, 24]. Patients usually begin to have symptoms between age 30 and 50 years. This natural history varies; symptoms occur much earlier in some patients. Early symptoms and signs of hemochromatosis include severe fatigue, impotence, arthralgia, arthritis, and an elevated concentration of liver enzymes [1]. Later, patients may experience skin bronzing; arthropathy; cardiomyopathy; and endocrine disorders, including diabetes and hypogonadism [1, 21-26]. Once the hepatic iron concentration reaches 400 mol per g dry weight, cirrhosis is common and the risk for hepatocellular carcinoma and death are markedly increased [26]. However, this threshold may be lower if cofactors, such as ethanol intake and chronic hepatitis, are present [1]. Although persons who are heterozygous for hemochromatosis sometimes have phenotypic expression, they do not generally develop overt clinical disease [1]. Of persons detected through family screening who are established as heterozygous for hemochromatosis (for example, by HLA typing), approximately 25% have mild biochemical abnormalities and increased body iron stores (as assessed by liver biopsy or quantitative phlebotomy) but do not develop clinical disease from progressive iron loading or the consequent organ damage [1, 18, 27, 28]. If a patient is heterozygous for the C282Y mutation and has a coexisting condition (such as hepatitis, alcoholism, or porphyria cutanea tarda) that increases hepatic iron stores, however, symptoms of organ damage may appear [19, 25]. Thus, consideration of coexisting conditions is important for heterozygous as well as homozygous patients. The expression of hemochromatosis is affected by environmental factors. The use of supplementary iron and vitamin C (which increases iron absorption) may lead to earlier phenotypic expression. On the other hand, blood donation, physiologic blood loss (through menstruation and pregnancy), and pathologic blood loss (for example, through peptic ulceration or inflammatory bowel disease) may delay phenotypic expression and decrease the amount of iron stored in the liver. The belief that premenopausal women cannot develop symptomatic or even life-threatening hemochromatosis is a misconception [29-31]. Diagnosis The basis for the early diagnosis of hemochromatosis has shifted from clinical symptoms to biochemical tests. This shift has spared patients the sequelae of protracted iron overload and chronic disease, although it has also spawned differences of opinion about the role and necessity of certain diagnostic tests, particularly liver biopsy. As more information about the disease is gathered, the case definition for hemochromatosis is likely to continue to evolve in this rapidly changing field. Clinical Features Hemochromatosis has many clinical presentations, and heightened awareness on the part of the physician is required for early diagnosis [1]. Fatigue and arthralgia are the most common symptoms prompting a visit to a physician. Patients may also present with hepatomegaly, diabetes mellitus, arthritis, heart failure, increased skin pigmentation, or abdominal pain, any of which might lead to referral to a specialist. The prevalence of hemochromatosis in patients attending diabetes and rheumatology clinics is greater than that expected in the general population [25, 32, 33]. Another mode of presentation may be cardiomyopathy, particularly in younger patients [1, 2]. Patients may present with congestive heart failure or arrhythmia. Occasionally, no clinical symptoms are seen even when hemochromatosis is advanced and cirrhosis is present [24]. Biochemical Tests Indicating Phenotypic Expression Biochemical measures of iron status are used to screen for hemochromatosis (Table 2); tests for transferrin saturation (serum iron concentration divided by total iron-binding capacity, multiplied by 100) and serum ferritin level are recommended. A persistently elevated transferrin saturation in the absence of other causes of iron overload strongly suggests hemochromatosis. A fasting transferrin saturation of 45% or more is typically used as the screening threshold because it identifies 98% of affected persons while producing relatively few false-positive results [34]. An alternative screening strategy may use the test for unsaturated iron-binding capacity, which is inexpensive and may be best used in population screening. However, this test has yet to be thoroughly evaluated. The follow-up evaluation also includes physical examination, estimation of the serum ferritin level, complete blood count, and liver function tests. A high transferrin saturation is the earliest phenotypic evidence of hemochromatosis. If a patient has a transferrin saturation of more than 45% but less than 55% on a repeated test and the elevation has no other evident cause, such as inflammatory liver disease, hemochromatosis may be present. If the serum ferritin level is normal, the patient should have repeated tests after 2 years to identify any change. The patient may be either homozygous or heterozygous for hemochromatosis. We do not have enough information to know the usual course of disease detected at this stage. If the transferrin saturation is 55% or more on a repeated test, the first step is to check for the presence of increased body iron stores. Patients who have an elevated transferrin saturation on repeated tests but have a normal serum ferritin level may be classified as having nonexpressed hemochromatosis. These patients warrant annual or biennial assessment to watch for increases in ir

Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation

BACKGROUND & AIMS In the absence of a genetic test, diagnostic criteria for hereditary hemochromatosis have been imprecise. The identification of the HFE gene and the C282Y mutation allow definition of expression of this disease and reassessment of diagnostic criteria. The aim of this study was to analyze the concordance between the genetic diagnosis and the previous clinical diagnosis in families with hemochromatosis. METHODS Three hundred subjects were tested for the C282Y mutation and were grouped as homozygous, heterozygous, or homozygous normal. RESULTS All adults previously diagnosed as homozygous or heterozygous for HLA-linked hereditary hemochromatosis carried at least one C282Y mutation. Two adolescents, previously thought to be homozygous, had no C282Y mutation. Of 127 subjects homozygous for the mutation, 105 met criteria for diagnosis. Iron overload was not expressed in 6.7% of homozygous men and 32.7% of homozygous women. The iron indices in 8 of 171 subjects heterozygous for the C282Y mutation were within the range previously regarded as indicative of homozygosity. Seven of these 8 carried the H63D mutation. CONCLUSIONS In Australia, 17.3% of subjects homozygous for the C282Y mutation do not express iron overload to meet current diagnostic criteria of hemochromatosis. In subjects heterozygous for the mutation, 4.8% have iron overload in the range previously diagnosed as homozygous. Nonexpression is common, particularly in women.

Prevalence of haemochromatosis amongst asymptomatic Australians

We determined the prevalence of iron overload due to homozygous haemochromatosis in an asymptomatic Australian (predominantly Caucasian) population by surveying 1968 employees of two large corporations. Subjects were screened by measurement of transferrin saturation and serum ferritin concentration and, in all subjects with elevation of both indices, percutaneous liver biopsy was performed to establish whether significant iron overload was present. The prevalence of iron overload due to haemochromatosis in this population was 0·36%. The prevalence rate was not significantly different between males and females, suggesting that this autosomal recessive disease is expressed equally in females given an adequate dietary iron supply. The positive predictive value of a transferrin saturation consistently >45% together with an elevated serum ferritin concentration was 64%. It is concluded that the prevalence of significant iron overload due to homozygous haemochromatosis warranting treatment is approximately 1:300 and that transferrin saturation should be included in existing adult health screening programmes.

Primary liver cancer in genetic hemochromatosis: A clinical, pathological, and pathogenetic study of 54 cases

BACKGROUND Although liver cancer arises frequently in the course of genetic hemochromatosis (GH), it has not been previously studied in a large series of patients with well-defined GH. METHODS The bioclinical and pathological data from 1 cholangiocarcinoma and 53 hepatocellular carcinomas (HCCs) complicating GH in 32 untreated and 22 de-ironed patients are reported. RESULTS This study (1) adds three new well-documented cases of HCC in noncirrhotic but only fibrotic hemochromatotic liver, (2) shows the high prevalence (83%) of proliferative and often dysplastic (70%) iron-free foci in the nontumorous liver of untreated patients, and (3) emphasizes the significant increase of cirrhosis (81% vs. 28%) and of associated noniron-related risk factors, mainly chronic alcoholism (48% vs. 25%) and tobacco smoking (50% vs. 18%) in patients with HCC compared with matched hemochromatotic patients without HCC. CONCLUSIONS These data (1) suggest that iron-free foci may be markers of an early stage of HCC in GH and (2) supply the basis for defining a cost-effective policy for the screening of HCC in GH patients.