Sharon M. McDonnell

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

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

A survey of 2,851 patients with hemochromatosis:: Symptoms and response to treatment

PURPOSE Hemochromatosis is a genetic disorder of iron absorption that affects 5 per 1,000 persons and is associated with reduced health and quality of life. We sought to determine the type and frequency of symptoms that patients experienced before the diagnosis and the treatments that they received. METHODS We mailed a questionnaire to 3,562 patients with hemochromatosis who were located using patient advocacy groups, physicians, blood centers, newsletters, and the Internet. RESULTS Of the 2,851 respondents, 99% were white and 62% were men. Circumstances that led to diagnosis of hemochromatosis included symptoms (35%), an abnormal laboratory test (45%), and diagnosis of a family member with hemochromatosis (20%). The mean (+/- SD) age of symptom onset was 41 +/- 14 years. Symptoms had been present for an average of 10 +/- 10 years before the diagnosis was made. Among the 58% of patients with symptoms, 65% had physician-diagnosed arthritis and 52% had liver disease. The most common and troublesome symptoms were extreme fatigue (46%), arthralgia (44%), and loss of libido (26%). Physician instructions to patients included treatment with phlebotomy (90%), testing family members (75%), and avoiding iron supplements (65%). CONCLUSIONS The diagnosis of hemochromatosis in most patients was delayed. Physician education is needed to increase the detection of patients with the disease and to improve its management.

Iron Overload, Public Health, and Genetics: Evaluating the Evidence for Hemochromatosis Screening

As many as 1 million persons in the United States are affected by hemochromatosis, a genetic condition characterized by excess iron absorption and pathologic iron deposition in tissue [1]. If undetected and untreated, hemochromatosis can result in illness (such as cirrhosis, hepatoma, diabetes, cardiomyopathy, arthritis, arthropathy, and hypopituitarism with hypogonadism) and death. The identification and treatment of asymptomatic persons in whom iron measures are elevated but hemochromatosis is not clinically apparent have been recommended as a potentially cost-effective strategy for preventing hemochromatosis-associated illness and death [1-10]. Nonetheless, some experts argue that before universal screening can be recommended, the clinical expression and natural history of hemochromatosis must be clarified and the infrastructure necessary to support a universal screening program (including laboratory standardization and physician education) must be established [11]. The recent discovery of a gene [12, 13] associated with hemochromatosis has made it possible to use DNA testing along with, or instead of, iron measures in screening. Although this discovery has increased interest in hemochromatosis, it has also raised new questions about screening for and diagnosis of the disease. One objective of the meeting on Iron Overload, Public Health, and Genetics, sponsored by the Centers for Disease Control and Prevention and the National Institutes of Health in March 1997 [14], was to review the scientific information available on population screening for hemochromatosis. Our assessment of the evidence and recommendations for action are presented here. Methods for Evaluating the Evidence for Population Screening for Hemochromatosis We used U.S. Preventive Services Task Force criteria [15] to evaluate evidence related to population screening for hemochromatosis that was presented at the meeting on Iron Overload, Public Health and Genetics or was published before August 1997. In this paper, we examine six assumptions that have been used to support the case for population screening for hemochromatosis in the United States. 1. Prevalence: Hemochromatosis is relatively common. 2. Burden of suffering: Hemochromatosis is associated with significant morbidity and mortality. 3. Efficacy of treatment: Phlebotomy can prevent complications by reducing the iron burden in persons with hemochromatosis. 4. Accuracy of screening tests: The available screening tests detect hemochromatosis earlier than no screening and do so with sufficient accuracy. 5. Effectiveness of screening: Screening and early treatment of persons with hemochromatosis improves health compared with treatment of patients after the development of clinical signs and symptoms. 6. Safety and adverse effects: The potential benefits of screening and treatment outweigh the adverse effects. The studies of effectiveness that we reviewed were each assigned one of five grades of evidence on the basis of study design (Table 1). Table 1. U.S. Preventive Services Task Force Criteria for Judging Quality of Evidence* Prevalence Determination of the prevalence of hemochromatosis is complicated by variation in case definitions of the disease and by uncertainty about the progression from genetic susceptibility through iron overload to clinical disease. Case definitions of hemochromatosis may include one or more of the following: genetic mutations, abnormal iron measures, and clinical signs and symptoms [16]. It is difficult to reach agreement on a standard because each case definition has strengths and weaknesses. Clinical case definitions have two chief weaknesses. First, such definitions (for example, bronze diabetes and cirrhosis) often represent the end stages of disease and have limited usefulness for prevention. Second, many clinical signs and symptoms that occur early in the course of hemochromatosis are nonspecific (for example, fatigue, abdominal pain, joint pain, and elevated liver enzyme concentrations) and may be attributed to other causes. Case definitions more specific to hemochromatosis, such as persistently elevated serum transferrin saturation or liver iron deposition without cirrhosis, allow for the detection of hemochromatosis before clinical signs and symptoms occur, but the rate and degree of progression from abnormal iron measures to clinical symptoms are uncertain. Even more uncertainty exists about progression from genetic susceptibility to clinical disease. Although the autosomal recessive nature of hemochromatosis and its link to the HLA region on chromosome 6 have been recognized for 20 years [17], two mutations associated with hemochromatosis-C282Y and H63D-were found only in 1996 [12]. Several investigators have estimated the frequency of the mutations in small groups of persons without clinical evidence of hemochromatosis (45 to 381 persons) [12, 18-24]. In the largest study published to date [25], the prevalence of homozygosity for C282Y was 1 in 1000, the prevalence of heterozygosity for both C282Y and H63D (compound heterozygosity) was 16 in 1000, and the prevalence of homozygosity for H63D was 20 in 1000 among 1450 persons from northern Europe. None of the study participants from other regions (Africa, Asia, and Australia) carried two C282Y mutations. These studies [12, 19-25] were drawn from convenience samples, and none was designed to represent the general population. Therefore, these studies may overestimate or underestimate the prevalence of genetic susceptibility to hemochromatosis. On the basis of case definitions that use elevated iron measures (such as body iron stores) in screening studies, the prevalence of hemochromatosis is 2 to 5 per 1000 persons in white populations [11, 26-30]. The estimated prevalence of hemochromatosis in black populations is lower, less than 1 in 1000 [1, 26, 31, 32]. These estimates are higher than the estimated prevalence of homozygosity for the major mutation, C282Y, but they are lower than the prevalence of compound heterozygosity or homozygosity for H63D. This discrepancy suggests either the presence of as yet undiscovered mutations for hemochromatosis or reduced penetrance of compound heterozygosity and homozygosity for H63D. Burden of Suffering The prevalence of clinical disease due to hemochromatosis is uncertain. Hemochromatosis can lead to cirrhosis and other liver diseases, hepatocellular carcinoma, diabetes, cardiomyopathy, arthritis, hypopituitary hypogonadism, fatigue, joint pain, skin bronzing or graying, abdominal pain, impotence, amenorrhea, and cardiac arrhythmias [1]. The most common early symptom is weakness or fatigue [1]. Although diabetes and heart disease occur more often in cirrhotic patients, they are also seen in patients with hemochromatosis who do not have liver disease [33, 34]. The classic triad of liver disease (cirrhotic or noncirrhotic), diabetes, and skin bronzing occurs in a minority of patients (for example, 17% of patients in one case series [33] and 3% of patients identified through screening studies [11]). Deaths in persons with hemochromatosis are most often associated with liver disease, hepatocellular carcinoma, diabetes, or cardiomyopathy. Morbidity Estimates of morbidity have usually been derived from case series of patients with known hemochromatosis [33-35]. The proportion of patients with hemochromatosis who have associated illness is probably greater in case series than in the general population because a disproportionate number of patients in case series may be detected because of their symptoms (selection bias). A review of family-based screening studies was done to address this limitation [36]. In that review, 52% of 146 family members 15 to 72 years of age in whom hemochromatosis had been diagnosed by HLA haplotyping were asymptomatic. The other 48% had at least one clinical manifestation of disease, such as cirrhosis, other liver disease, diabetes, cardiomyopathy, arthropathy, skin bronzing, fatigue, weight loss, abdominal pain, or impotence. In addition, the risk for symptoms associated with hemochromatosis increased with age-73% of men and 44% of women older than 40 years of age had at least one clinical finding. Siblings and other family members identified through HLA testing may have a different risk for disease expression than do persons with hemochromatosis in the general population. Among persons with hemochromatosis (defined by elevated iron measures [16]) in population screening studies, 45% of men and 43% of women older than 40 years of age had at least one clinical finding [11]. Screening studies have not compared the prevalence of clinical findings in persons with hemochromatosis and persons without hemochromatosis. Many clinical findings associated with hemochromatosis (such as abdominal pain, fatigue, arthritis, and diabetes) are also common in persons without hemochromatosis. Therefore, some of the illness attributed to hemochromatosis may be due to other causes. The studies with the least biased methods to date [37-51] have estimated the proportion of persons with selected clinical conditions who have underlying hemochromatosis (Table 2). The prevalence of hemochromatosis ranges from 11.0% to 15.0% in patients with hepatocellular carcinoma to 0.0% to 1.5% in patients with diabetes. If the population prevalence is assumed to be 0.2% to 0.5% [11, 26, 27], these studies suggest that the risk for hemochromatosis may be elevated in persons with hepatocellular carcinoma, liver disease, hepatitis, cardiac arrhythmias, arthropathy, and diabetes. The risk for hemochromatosis may be further elevated in persons with combinations of these diseases (for example, diabetes and liver disease), as was suggested by an analysis of death certificates [52]. Table 2. Estimated Prevalence of Elevated Iron Status and Iron Overload Due to Hemochromatosis among Patients with Chronic Diseases* In the studies listed in Table 2, with the exception of one recent casecontrol

Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri ☆

BACKGROUND Hemochromatosis reportedly affects 3 to 8 persons per 1,000 and is associated with an elevated risk of morbidity and mortality. We sought to ascertain its prevalence in a community and to assess the association between phenotype and genotype. METHODS All health maintenance organization employees were invited to participate in hemochromatosis screening using a repeated elevation of the transferrin saturation test as the case definition (> or = 50% in women and > or = 60% in men with no other cause). Iron overload from hemochromatosis was defined as serum ferritin concentration > or = 95th percentile and mobilizable iron > or = 99th percentile for age and sex, or hepatic iron index > or = 1.9. The HFE gene was analyzed for mutations. RESULTS Participation among employees was 28% (1,653 of 6,000); 83% were women. The prevalence of hemochromatosis was 8 per 1,000 (13 of 1,653), and the prevalence of iron overload from hemochromatosis was 4 per 1,000 (5 of 1,653). Compared with those who had no HFE mutation, the relative risk (RR) for hemochromatosis was greatest for C282Y homozygotes (RR = 147), compound heterozygotes (RR = 19), and H63D homozygotes (RR = 9). Overall, 38% of participants had at least one HFE mutation. Screening based on an initial elevated transferrin saturation test had the best sensitivity, whereas DNA testing offered the best specificity and predictive value positive for iron overload disease. CONCLUSIONS In this population, we found a greater than expected prevalence of hemochromatosis and demonstrated a clear association with the HFE genotype. Promotion of screening is complicated by controversies in case definition and the large number of persons who will be detected before they have clinically significant iron loading, in whom the risk of clinical disease is unknown. Larger screening studies in more diverse populations are necessary to characterize the burden of disease and to follow those at risk (based on HFE or iron status measures) to establish the natural history of hemochromatosis.

Contribution of different HFE genotypes to iron overload disease: a pooled analysis.

Purpose: To determine the contribution of the C282Y and H63D mutations in the HFE gene to clinical expression of hereditary hemochromatosis.Methods: Pooled analysis of 14 case-control studies reporting HFE genotype data, to evaluate the association of different HFE genotypes with iron overload. In addition, we used data from the pooled analysis and published data to estimate the penetrance of the C282Y/C282Y genotype.Results: Homozygosity for the C282Y mutation carried the largest risk for iron overload (OR = 4383, 95% Cl 1374 to >10,000) and accounted for the majority of hemochromatosis cases (attributable fraction (AF) = 0.73). Risks for other genotypes were much smaller: OR = 32 for genotype C282Y/H63D (95% Cl 18.5 to 55.4, AF = 0.06); OR = 5.7 for H63D/H63D (95% Cl 3.2 to 10.1, AF = 0.01); OR = 4.1 for C282Y heterozygosity (95% Cl 2.9 to 5.8, with heterogeneity in study results, making this association uncertain); and OR = 1.6 for H63D heterozygosity (95% Cl 1 to 2.6, AF = 0.03). Estimates of penetrance for the C282Y/C282Y genotype were highly sensitive to estimates of the prevalence of iron overload disease. At a prevalence of 2.5 per 1000 or less, penetrance of the C282Y/C282Y genotype is unlikely to exceed 50%. Penetrance of other HFE genotypes is much lower.Conclusions: C282Y homozygosity confers the highest risk for iron overload but the H63D mutation is also associated with increased risk. Our data indicate a gradient of risk associated with different HFE genotypes and thus suggest the presence of other modifiers, either genetic or environmental, that contribute to the clinical expression of hemochromatosis.

Screening for Hemochromatosis in Primary Care Settings

Hemochromatosis is an inherited disease, characterized by excessive absorption of dietary iron, that can lead to progressive iron accumulation in tissues and organ damage [1]. It has been proposed as a candidate for routine screening with measurement of transferrin saturation [1-20]. To evaluate screening as a primary care strategy, four programs in the United States integrated iron status screening, with an emphasis on hemochromatosis, into their routine health care services for adults. In March 1997, at a meeting at the Centers for Disease Control and Prevention, the directors of these four programs described the major challenges that they faced and the lessons that they learned in implementing their programs. Seven issues were consistently reported to need resolution in the implementation of hemochromatosis screening: 1) changes in case definitions of hemochromatosis from the classic description, 2) selection of screening threshold values and identification of false-positive cases, 3) variability and lack of standardization of screening test measurements, 4) physician education, 5) informed consent and concerns about medical and genetic discrimination, 6) patient compliance with screening and therapy, and 7) incidental detection of iron deficiency. The four programs described here are in different stages of operation and in different settings (Table 1). They are at Rochester General Hospital at the University of Rochester, Rochester, New York; the Kaiser Permanente Medical Care Program, San Diego, California; the Veterans Affairs Medical Center, Fargo, North Dakota; and St. Johns Health System, Springfield, Missouri. Table 1. Description and Results of Four Screening Programs for Hemochromatosis in the United States in 1997* Changes in Case Definitions of Hemochromatosis The definition of hemochromatosis has traditionally been based on late clinical and pathologic findings of iron overload [1], and the diagnosis has typically been made by excluding other conditions (such as secondary iron overload or primary liver disease) and finding characteristic pathologic evidence on liver biopsy [21]. Recently, as a result of increased emphasis on early diagnosis and population-based screening, it has been proposed that the definition of hemochromatosis be changed [1, 21, 22]. The difficulties raised by exploring new case definitions in the four hemochromatosis screening programs discussed here are threefold. First, comparisons between program findings and previous research must be made by using reported prevalences based on similar criteria (the presence or absence of iron overload and clinical symptoms). Second, the penetrance of hemochromatosis is not 100%; thus, genetic tests and even biochemical criteria for the early diagnosis of hemochromatosis are new and are not yet fully correlated with clinical outcomes [1, 21]. Third, participating physicians may be unfamiliar with these new criteria; moreover, the existing literature may contradict screening protocols and confuse patient care. Selection of Screening Threshold Values and False-Positive Cases When these screening programs were being planned, transferrin saturation threshold values were chosen to establish a screening threshold that would be sensitive enough to identify most cases of hemochromatosis without producing too many false-positive results [18-20]. Recommended threshold values range from 45% to 70% [6-16]. However, the underlying demographic characteristics of the population being screened may influence the transferrin saturation threshold and the prevalence of hemochromatosis [23-26]. For example, a lower cut-point has been suggested for women because it has been shown that at a relatively high transferrin saturation, such as 62% or more, 40% of putative female homozygotes do not screen positive for hemochromatosis even though almost 100% of male homozygotes do [12, 20]. In addition, studies suggest that threshold values should be lower for black persons than for white persons [23, 24]. These lower cut-points have not been directly tested for their association with the newly described genetic HFE mutations or clinical outcomes [27-29]. Because of the low prevalence of hemochromatosis in the population (at most, 8 per 1000 among white persons in the United States), the positive predictive value of the initial random transferrin saturation test for hemochromatosis is also low. In this case, it is only 0.08, with a sensitivity of 0.96 and a specificity of 0.94. In the four screening programs, the transferrin saturation was elevated on initial testing in 2.5% to 5.8% of the several populations screened (Table 2). A repeated test, done while the patient is fasting, with a threshold equal to or higher than that used for the initial test (Table 1) markedly improves the tests positive predictive value [4]. In most patients, hemochromatosis was excluded because the result of the second test was normal. However, 30% of patients who had an elevated transferrin saturation on a repeated test were found to have a primary liver disorder or secondary iron overload. The underlying prevalence of these conditions in a population affects the number of false-positive results for hemochromatosis. In some instances, hemochromatosis coexists and acts synergistically with these other conditions, resulting in a more complicated clinical picture and possibly an altered treatment plan. Table 2. Proportion of Hemochromatosis Screening Test Results That Were Positive in Four Programs in the United States in 1997* Variability and Lack of Standardization of the Transferrin Saturation Screening Test Serum transferrin saturation is considered a sensitive and specific marker for hemochromatosis [5, 16], but biological and analytic variability complicate its use. The variation may be greater than physicians are accustomed to, and the proper interpretation of such high within-subject variation must be explained. For example, the results of initial and repeated transferrin saturation tests may vary by as much as 50% in the same person (that is, the second value may be 50% lower than the first). Biological (individual) variability requires that the second test be done while the patient is fasting, and the patient has to have taken no vitamins or iron supplements for 24 hours. Even with these dietary restrictions, however, transferrin saturation can still vary considerably in the same person. Each program described here used only a single laboratory to perform transferrin saturation testing; thus, variations were not due to interlaboratory differences. The persistent variation that the Kaiser Permanente program experienced despite standardized blood sampling conditions led them to investigate the cause of the variation. By sending split specimens to an outside laboratory and comparing the results with in-house results, they documented that the variation was due to biological and not analytic causes. Lack of laboratory standards and proficiency testing for transferrin saturation testing may also cause variability of test results and may affect the proportion of positive results (Table 2). Laboratory proficiency in testing transferrin saturation and its total iron-binding capacity component are not routinely monitored by any national agency. Many methods and instruments are available for measuring transferrin saturation, but which ones are most reliable or valid is not known [30]. Individual physicians can send serum specimens to laboratories that have been evaluated by the College of American Pathologists or the Centers for Disease Control and Prevention and can encourage participating laboratories to be evaluated by these agencies before initiating iron status screening. Physician Education and Involvement Early diagnosis and management of hemochromatosis are possible only when physicians are knowledgeable about the techniques involved. Many physicians, however, are not well versed in these areas or in basic genetics [31-33]. Little information is available on newer case definitions of hemochromatosis and the management of young or asymptomatic patients. In all of the screening programs discussed here, participating primary care physicians were initially unconvinced that hemochromatosis existed in their patient population. Many physicians were unfamiliar with the transferrin saturation test, and this resulted in the ordering of inappropriate tests instead. Resistance to diagnostic algorithms is common, particularly when they differ from protocols learned during medical training. All of the screening programs reported that a one-time continuing medical education session for participating physicians was inadequate preparation for screening: Physicians require in-depth, ongoing education about hemochromatosis screening and management. To address this need, Kaiser Permanente created videotapes showing clinical manifestations and patient concerns; St. Johns Health System mailed educational packets on diagnosis and management to physicians when a patients initial test result was positive. This mailing was followed by a telephone call or a personal visit from the primary investigator. All programs reported that physician involvement in hemochromatosis screening and in education programs increased as cases were detected. The screening and diagnostic algorithms for hemochromatosis and the record keeping required to track laboratory and therapeutic phlebotomy are complicated, and it is difficult to standardize patient care among primary care physicians and specialists. To address these problems, the Kaiser Permanente program adopted a centralized approach to hemochromatosis screening and management that relied on two primary care physicians and on selected referral physicians who were familiar with the protocols. Most physicians wanted assistance not only with the logistics of screening but also with the process of giving information on screening and disease to their patients. In addition, pa

A survey of phlebotomy among persons with hemochromatosis.

BACKGROUND: One in 10 whites in the United States is a carrier for hemochromatosis and an estimated 1 in 200 is clinically affected. Early treatment with therapeutic phlebotomy to remove excess iron can prevent associated chronic diseases. However, little information is available on the amount of blood withdrawn or the rates of withdrawal from hemochromatosis patients. The patterns of therapeutic phlebotomy and the magnitude of charges in persons with hemochromatosis were surveyed.

Screening for hemochromatosis

CONTEXT The discovery of the HFE gene in 1996 has introduced DNA testing as a possible tool for screening and diagnosis of hemochromatosis and increased interest in the disorder. Population screening using transferrin saturation has been advocated by experts to permit early detection and treatment with phlebotomy before the onset of clinical disease. METHODS Based on a literature review, we consider the relative risks and merits of two screening tests as part of a broader look at the evidence required for the recommendation of universal screening for hemochromatosis. RESULTS Several questions must be answered before universal screening can be recommended. Uncertainties remain about the penetrance and preventable disease burden, laboratory standardization, and optimal strategies to minimize potential risks of screening for hemochromatosis. CONCLUSIONS As a common genetic disorder with simple, effective therapy, hemochromatosis offers a model for other genetically influenced chronic diseases that some day may have interventions to improve prognosis. Resolution of questions related to prevention of chronic diseases from hemochromatosis, therefore, will have broad usefulness in the future.

Hemochromatosis: genetics helps to define a multifactorial disease

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder that can result in iron overload and a wide range of clinical complications, including hepatic cirrhosis, diabetes mellitus, hypopituitarism, hypogonadism, arthritis, and cardiomyopathy. People with HH can be detected at an asymptomatic stage of the disease by abnormalities in serum iron measures. Early detection is desirable, because periodic phlebotomy provides effective treatment for iron overload and may prevent complications of the disorder. The natural history of HH is poorly understood, however, and the proportion of people detected by screening who will develop serious complications of HH is unknown. The genetics of HH may help to resolve these questions. The gene, HFE, and two mutations, C282Y and H63D, have been identified; the C282Y mutation has a higher penetrance than the H63D mutation, and appears to result in a greater loss of HFE protein function. Most people with HH are C282Y homozygotes, a small proportion are compound heterozygotes or H63D homozygotes, and some have no identifiable HFE mutation or are HFE heterozygotes, suggesting that additional mutations associated with HH are yet to be found. Gender and environmental agents, such as alcohol and dietary iron, influence phenotypic expression of HH. The severity of HH is thus determined by an interaction between genotype and modifying factors. HFE mutations also appear to increase the likelihood of iron overload in inherited anemias and to promote the clinical manifestations of porphyria cutanea tarda. HH is an important paradigm for medical genetics because it offers an opportunity to explore the complexity of gene–gene and gene–environment interactions.