RSS Feeds
Iron Overload, Public Health, and Genetics: Evaluating the Evidence for Hemochromatosis Screening
- Mary E. Cogswell, DrPH;
- Sharon M. McDonnell, MD, MPH;
- Muin J. Khoury, MD, PhD;
- Adele L. Franks, MD;
- Wylie Burke, MD, PhD; and
- Gary Brittenham, MD
- From the Centers for Disease Control and Prevention, Atlanta, Georgia; University of Washington, Seattle, Washington; and Case Western Reserve University School of Medicine, Cleveland, Ohio. Acknowledgments: The authors thank Laurence Grummer-Strawn, PhD, for helpful comments on an earlier version of this manuscript. Requests for Reprints: Mary E. Cogswell, DrPH, Centers for Disease Control and Prevention, Mailstop K-25, 4770 Buford Highway, NE, Atlanta, GA 30341; e-mail, mec0{at}cdc.gov. Current Author Addresses: Drs. Cogswell and McDonnell: Centers for Disease Control and Prevention, Mailstop K-25, 4770 Buford Highway, NE, Atlanta, GA 30341. Dr. Khoury: Centers for Disease Control and Prevention, Mailstop K-28, 4770 Buford Highway, NE, Atlanta, GA 30345. Dr. Franks: Centers for Disease Control and Prevention, Mailstop K-24, 4770 Buford Highway, NE, Atlanta, GA 30345. Dr. Burke: Women's Health Care Center, University of Washington, 4245 Roosevelt Way, NE, Seattle, WA 98105. Dr. Brittenham: Department of Pediatrics, Columbia University, Harkness Pavillion HP-550, 180 Fort Washington Avenue, New York, NY 10032. Note: This article is one of a series of articles comprising an Annals of Internal Medicine supplement entitled “Iron Overload, Public Health, and Genetics.” To view a complete list of the articles included in this supplement, please view its Table of Contents.
Abstract
Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease.The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing.
Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes.Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures, a family history of hemochromatosis, or consistent early signs and symptoms of the disease.
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).
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].
In the studies listed in Table 2, with the exception of one recent case–control study [44], lack of appropriate comparison samples (for example, a sample matched for age and sex) hampers estimation of the proportion of clinical disease resulting from hemochromatosis. If we assume that the odds ratio is a close approximation of the risk for diabetes in persons with hemochromatosis compared with persons without hemochromatosis, then persons with hemochromatosis are 7.3 times (95% CI, 1.3 to 41.9 times) more likely than persons without hemochromatosis to develop diabetes. If the prevalence of hemochromatosis in the general population is 0.3%, the estimated proportion of the general population in which type 2 diabetes is due to hemochromatosis is 1.9%. These compelling results deserve further study in other populations. In general, heterogeneity in sample selection, population characteristics (such as age, sex, and ethnicity), and case definitions of hemochromatosis hamper comparison across studies of morbidity (Table 2). Precise estimation of the actual elevation in risk for chronic disease from hemochromatosis will require further study that addresses the limitations described.
Mortality
Compared with the estimated prevalence of hemochromatosis (2 to 5 per 1000) in the United States, the rate of 1.8 deaths from hemochromatosis per 1 million persons in the United States in 1992 [52], obtained from death certificates, suggests that hemochromatosis is underdiagnosed or underreported or that the risk for death from hemochromatosis is low. Until recently, case detection of hemochromatosis relied on a strict clinical case definition [1, 11, 53], possibly biasing mortality estimates [52, 54]. Results of screening studies (Table 2) indicate that hemochromatosis is unlikely to be recognized in patients who have diabetes or liver disease alone; most patients in these studies received new diagnoses of hemochromatosis. Further studies of disease burden should estimate the risk for chronic disabling conditions and death resulting from hemochromatosis.
Efficacy of Treatment
Iron overload is treated by removing excess body iron through therapeutic phlebotomy [55, 56]. The efficacy of therapeutic phlebotomy in reducing clinical disease both before and after the onset of clinical signs and symptoms is of interest. For ethical reasons (removing excess iron is the accepted treatment for hemochromatosis), no randomized, controlled trials comparing therapeutic phlebotomy with no treatment have been done [33, 35]. Until recently, no animal models for hemochromatosis were available, but a new mouse model of hereditary hemochromatosis [57] may provide opportunities to evaluate therapeutic strategies for the prevention or correction of iron overload. In this review, we rely on evidence from human studies only.
Results from one retrospective cohort study and a series of descriptive studies indicate that therapeutic phlebotomy decreases body iron stores and improves survival among patients with hemochromatosis who have clinical disease. In the retrospective cohort study [58], the average survival time was 5.25 years among patients who received phlebotomy and 1.5 years among patients identified during the same time period (1950 to 1974) who received no treatment. Reasons for lack of treatment included refusal of treatment and death before initiation of treatment. The difference in survival between the two groups was adjusted for possible differences in age and clinical presentation [58]. Other studies indicate that the average life expectancy after diagnosis of hemochromatosis increased dramatically, from 1 to 6 years [59] to 11 to 21 years [33-35, 58-63], after therapeutic phlebotomy was adopted as standard practice. Part of this trend may be related to earlier diagnosis of hemochromatosis and to improved treatment of diabetes and liver disease, but the proportion of patients with diabetes or liver disease did not change over the time period studied and all studies were done after the advent of insulin treatment for diabetes. Hence, most of the improvement in life expectancy is probably due to therapeutic phlebotomy.
Evidence from two case series (one with 251 patients and the other with 85) suggests that survival in patients who had hemochromatosis without cirrhosis (many of whom were asymptomatic) and received phlebotomy was similar to that in an age- and sex-matched sample from the general population [33, 35, 60]. For ethical reasons, no data describe the natural history of untreated hemochromatosis in noncirrhotic patients; thus, the effect of treatment on life expectancy cannot be determined. Results from case series also suggest that therapeutic phlebotomy alleviates various clinical manifestations of hemochromatosis that occur in the precirrhotic or asymptomatic stages of the disease [33, 35, 58]. Niederau and colleagues [33], for example, documented an improvement after therapeutic phlebotomy in patients with hemochromatosis, as indicated by improved glucose tolerance (37% of patients), better findings on electrocardiography (34% of patients), improved liver enzyme concentrations (73% of patients), and decreased hepatic fibrosis (23% of patients). Although this study was limited by lack of an adequate comparison group, the magnitude of these improvements indicates that therapeutic phlebotomy can prevent illness in asymptomatic persons with hemochromatosis.
Accuracy of Screening Tests
The most common screening strategy for hemochromatosis starts with a random transferrin saturation test. If the test result is positive (that is, if the serum transferrin saturation is elevated), the test is repeated after the patient has fasted overnight [1, 5-11, 16]. The recommended cut-off value defining an elevated transferrin saturation on initial and repeated screening tests varies from greater than 45% to greater than 62% [1, 5-1116, 26, 27, 29]. It has been recommended that cut-off values be lower for women than for men because the distribution of transferrin saturation is lower in women and because the transferrin saturation test has lower sensitivity in women than in men at the same threshold [64, 65].
Other tests (for example, tests for unbound iron-binding capacity, serum iron concentration, and serum ferritin level) and strategies (such as measuring the serum iron concentration and then performing a transferrin saturation test under fasting conditions) have also been considered for use in screening [2-4]. However, because these alternatives are less sensitive and less specific than or have not been evaluated as extensively as the transferrin saturation test [64, 65], we focus here on the transferrin saturation test.
Evaluation of the sensitivity, specificity, and positive predictive value of screening tests for hemochromatosis is limited by lack of a standard case definition-hence, the absence of an agreed-on gold standard. Until recently, the standard for evaluating the sensitivity and specificity of hemochromatosis screening tests was HLA haplotyping of family members of clinically diagnosed index patients (as a proxy for a more specific genetic test). Regardless of clinical signs and symptoms, any family member with an HLA haplotype identical to that of an identified index case was considered to have hemochromatosis. The index case was usually identified by the clinical criterion of iron overload due to hemochromatosis [16]. This type of case definition presents three difficulties. First, a genetic predisposition does not necessarily express itself in iron overload due to hemochromatosis. Second, HLA typing is unlikely to correlate perfectly with the presence of a gene for hemochromatosis. Finally, this approach to evaluating sensitivity and specificity is not applicable to general population screening.
The sensitivity of the transferrin saturation test is equal to the proportion of persons with hemochromatosis who have a positive test result [65]. The specificity is equal to the proportion of persons without hemochromatosis who have a negative test result [65]. In one review of studies that used HLA haplotyping in family members as the standard [36], the sensitivity of the transferrin saturation test ranged from 94% (cut-off value> 50%) to 86% (cut-off value> 60%) in men and from 82% (cut-off value> 50%) to 67% (cut-off value> 60%) in women. The specificity of the test ranged from 93% (cut-off value> 50%) to 98.5% (cut-off value> 60%) in men and from 95% (cut-off value> 50%) to 99.4% (cut-off value> 60%) in women.
In family members with positive results on HLA haplotyping, a few studies have used clinical indications of iron overload (such as elevated liver iron stores) to further differentiate among cases [64, 66]. One study [66] suggested that the sensitivity of the transferrin saturation test is better in patients with iron overload due to hemochromatosis (n = 162) than in family members at earlier stages of disease (n = 12), but the number of family members included in the study was small [66].
The positive predictive value of the transferrin saturation test is the probability that a patient with a positive test result actually has hemochromatosis [65]. The positive predictive value depends on several factors, including the sensitivity and specificity of the test, the case definition or standard used, and the prevalence of hemochromatosis in the population [65]. The frequency of an elevated transferrin saturation on an initial test is greater than the estimated prevalence of hemochromatosis [63], indicating a high ratio of false-positive to true-positive cases (and, thus, a low positive predictive value). It is customary to improve the predictive value of the transferrin saturation test by repeating it in persons with initial positive results because elevated transferrin saturation can be due to factors other than hemochromatosis, such as diet or the time of day at which serum is collected [67]. In one study of blood donors, for example, the positive predictive value of an initial transferrin saturation test was as low as 3.8% when HLA typing was used as the standard [29]. Repeating the test under fasting conditions or increasing the cut-off value decreased the number of false-positive results obtained (that is, it increased the specificity) and increased the positive predictive value. The positive predictive value of repeated tests (a result>50% under nonfasting conditions followed by a result>62% under fasting conditions) was 68% when HLA typing was used as the standard and 43% when elevated liver iron stores were used as the standard [29].
The positive predictive value of the transferrin saturation test increases with the increasing prevalence of hemochromatosis. In screening studies done in patients with hemochromatosis-associated diseases (such as liver disease), the prevalence of hemochromatosis is probably elevated; thus, the positive predictive value of the transferrin saturation test may be increased. In one study done in patients with liver disease [40], the positive predictive value of a single transferrin saturation test was 41%. In patients with diabetes, the positive predictive value of repeated transferrin saturation tests was 63% to 80% when elevated liver iron stores were used as the standard [44, 45, 50]. Hence, estimates of positive predictive value in high-risk persons (such as persons with an affected family member or patients with hemochromatosis-associated illness) are much greater than estimates in blood donors or in the general population [28, 30].
Finally, the specific laboratory method used can also affect the diagnostic usefulness of the screening test because variability in iron tests causes both false-positive and false-negative results. Methods for transferrin saturation measurement vary widely among laboratories, and within-laboratory variation for total iron-binding capacity (the denominator of transferrin saturation) is substantial. As we have learned from experience with cholesterol screening, laboratory variation, if not addressed, decreases the diagnostic usefulness of a test and can decrease the effectiveness of a screening program [68].
Since the recent discovery of the gene for hemochromatosis, DNA testing has been done on an experimental basis [18, 20, 25]. With respect to accuracy or the association of the test with the clinical expression of hemochromatosis, we know much less about the genetic test than about the transferrin saturation test. In recent clinical series of unrelated white patients with hemochromatosis (these studies included between 65 and 178 patients), 69% to 97% of affected patients carried two mutations (C282Y/C282Y, C282Y/H63D, or H63D/H63D) [12, 18-24]. Therefore, up to 31% of affected patients may carry one mutation or no mutations and would not be identified by the current DNA test. Most clinically affected patients (60% to 92%) were homozygous for C282Y. In control populations, the carrier rate of H63D is higher than the carrier rate of C282Y, suggesting that C282Y has higher penetrance than H63D. Thus, a genetic test that includes H63D might have better sensitivity but poor specificity. Case definitions varied across studies, but most of the studies were done in symptomatic patients who had progressed to iron overload disease, as determined by phlebotomy or liver biopsy [12, 18-24].
In studies in control populations (these studies included between 50 and 381 patients), 0% to 8% of participants carried two mutations (C282Y/C282Y, C282Y/H63D, or H63D/H63D) [12, 18-24]. Population screening studies and, thus, estimates of positive predictive value are unavailable. Most important, the penetrance of these mutations has not been established.
Laboratory variability in DNA testing may also be an issue in determining the accuracy of this testing. The Task Force on Genetic Testing of the National Institutes of Health-U.S. Department of Energy Working Group on Ethical, Legal and Social Implications of Human Genome Research [69] has stated that the technical accuracy of genetic tests is not adequately addressed by current legislation. The Task Force has called for a national accreditation program for genetic testing laboratories similar to the programs now run by the College of American Pathologists or the American College of Medical Genetics.
Effectiveness of Screening
Evidence for the effectiveness of screening in the prevention of chronic disease resulting from hemochromatosis comes mainly from expert opinions, descriptive studies, and a time series analysis (grade III) (Table 1). No controlled trials (grade I or II-1) or observational studies (grade II-2) have compared chronic disease outcomes in populations screened for hemochromatosis using iron or DNA tests with those in unscreened populations. Because of the large number of participants and the follow-up time required, these studies would be logistically difficult and expensive. As noted, case series (grade III) suggest that survival in patients treated early in the continuum of disease expression is significantly better than that in patients with cirrhosis [33, 35, 60, 62]. Niederau and coworkers [33] indicated that the survival of patients with hemochromatosis improved over time (grade II-3), possibly in association with increases in the proportion of patients who received a diagnosis before the onset of symptoms. The proportion of asymptomatic patients with hemochromatosis in that series increased from 4.8% in the period from 1947 to 1969 to 30.1% in the period from 1982 to 1991 [33].
Taken together, these data suggest that the detection and treatment of hemochromatosis in asymptomatic persons increase survival. However, data on survival from the time of diagnosis do not constitute true proof of benefit from screening. Survival analysis has two major limitations in assessing the effectiveness of population screening. First, because asymptomatic persons are likely to be identified earlier in the continuum of expression of hemochromatosis, it is unclear whether the increased length of time between diagnosis and death is the result of earlier diagnosis or of increased survival (lead-time bias) [70]. Second, neither the natural history of hemochromatosis nor the likelihood that disease progresses more rapidly in persons with hemochromatosis who present with cirrhosis or cardiomyopathy than it does in other persons with hemochromatosis is known. Increased severity of disease in persons whose cases are detected in the symptomatic phase could decrease the length of time during which persons with hemochromatosis could be detected by screening (length bias) [70]. Therefore, the proportion of illnesses and deaths averted by early detection in persons with hemochromatosis is unknown.
Safety and Adverse Effects
As with all screening, the benefits of screening for hemochromatosis (early detection and treatment) must be balanced against its adverse effects, which may include complications of diagnostic procedures (such as liver biopsy) and legal, social, and psychological problems (such as discrimination, loss of insurance benefits for a person with a known genetic condition, and increased costs of health care or insurance).
Liver biopsy is often considered the final and definitive diagnostic test for hemochromatosis [16, 71]. Complications of liver biopsy can include pain, hemorrhage, bilious or infectious peritonitis, penetration of abdominal viscera, pneumothorax, and death [72]. Complications are reported in 0.06% to 0.32% of patients, and death occurs in 0.01% to 0.12% [71]. Safer diagnostic options exist, but they do not provide information on some factors (such as the presence of cirrhosis or other liver disease) that affect treatment and prognosis [16].
Individual cases of loss of insurance and employment associated with hemochromatosis have been reported [73] but, on a population level, the scale of concern about these events is unknown and must be weighed against the potential for increases health benefits from treatment. Other possible risks of screening include increased anxiety and a decreased sense of well-being caused by diagnosis and misinformation due to inaccurate results. These risks need to be balanced against the psychological benefits of finding an explanation for symptoms, alleviating symptoms with treatment, and preventing disease progression.
Population screening for hemochromatosis raises concern about diagnosis in the absence of evidence that persons can benefit from testing. Changing the case definition of hemochromatosis from iron overload to the presence of a laboratory abnormality or a mutation increases the uncertainty of eventual clinical expression. The kinds of concerns raised by the early initiation of treatment on the basis of iron status are compounded by the DNA test because we are more uncertain about the clinical expression of disease in asymptomatic persons with positive genetic test results than we are about the clinical expression of disease in asymptomatic persons with abnormal iron status. An asymptomatic person who is homozygous for a genetic abnormality may be exposed to years of unnecessary testing, follow-up, and treatment and to stigmatization and discrimination by employers, insurers, and society at large [72, 74-76] without ever developing hemochromatosis. The DNA test is more likely to offer benefits when it is used for case finding in family members of affected patients.
Economic Costs
The economic costs of population screening have been estimated for both phenotypic [2-68, 10] and genotypic testing [77]. Major determinants of the cost-effectiveness of screening are the prevalence and disease burden of hemochromatosis; the sensitivity and specificity of the screening tests; compliance with screening, diagnosis, and therapy; and the costs of screening, diagnosis, and therapy [2-68, 10, 77]. Cost-effectiveness analyses have traditionally based the probability of developing major clinical manifestations (such as diabetes, cirrhosis, and heart failure) on data from hospital registries of patients affected by hemochromatosis [2-68, 10]; this may overestimate morbidity and mortality [78]. Compliance with screening, diagnosis, and treatment is usually assumed to be greater than 80% but may be substantially lower in practice [27]. Finally, the costs associated with screening and treatment are variable and subject to change. Commercially, the cost of the genetic test (about $150; range, $75 to $250 for two mutations) is greater than that of the transferrin saturation test (about $20; range, $2 to $30). The costs of the genetic test may change as new mutations are discovered, as efficiency in laboratory procedures increases, or as patents are awarded. The costs of the phenotypic test may decrease if the efficiency and diagnostic usefulness of laboratory procedures increases.
The cost of therapeutic phlebotomy, which varies in frequency and duration, contributes substantially to the cost of implementing population screening. The current policy of the U.S. Food and Drug Administration dictates that blood donated by a person with hemochromatosis must be labeled as a product of therapeutic phlebotomy. Most blood banks have policies and practices that recommend against the use of such products, and they discard them [79]. Thus, patients are charged for therapeutic phlebotomy. Changing this policy (for example, allowing use of blood products that have undergone regular safety screening) could reduce the cost of treatment for hemochromatosis and could provide additional benefits to society.
Conclusions
Hemochromatosis represents a new paradigm for genetics and public health. It meets many of the U.S. Preventive Services Task Force criteria for candidacy for population screening. Screening studies have shown that it is common in comparison with many genetic disorders; case series have demonstrated that the disease generally develops in adulthood and that illness can be prevented with treatment. The potential for preventing hemochromatosis-associated illness and death through screening and treatment may be great. Thus, timely resolution of questions about penetrance of clinical disease among persons with hemochromatosis-associated mutations or early biochemical expression of hemochromatosis is needed (Table 3).
Collaboration among primary care providers, scientists, and policymakers is crucial to the gathering of the additional information required to determine the most effective preventive strategy for decreasing morbidity from hemochromatosis. The need for population data to answer questions about penetrance among asymptomatic persons should not impede increased case detection in high-risk groups or efforts to increase laboratory standardization of screening tests. We hope that our paper and others in this issue will increase knowledge and awareness about iron overload due to hemochromatosis and will motivate physicians to examine and establish strategies to prevent the morbidity and mortality associated with this disorder.
- Copyright ©2004 by the American College of Physicians
References
- 1.↵
- 2.↵
- 3.↵
- 4.↵
- 5.↵
- 6.↵
- 7.↵
- 8.↵
- 9.↵
- 10.↵
- 11.↵
- 12.↵
- 13.↵
- 14.↵
- 15.↵
- 16.↵
- 17.↵
- 18.↵
- 19.↵
- 20.↵
- 21.↵
- 22.↵
- 23.↵
- 24.↵
- 25.↵
- 26.↵
- 27.↵
- 28.↵
- 29.↵
- 30.↵
- 31.↵
- 32.↵
- 33.↵
- 34.↵
- 35.↵
- 36.↵
- 37.↵
- 38.↵
- 39.↵
- 40.↵
- 41.↵
- 42.↵
- 43.↵
- 44.↵
- 45.↵
- 46.↵
- 47.↵
- 48.↵
- 49.↵
- 50.↵
- 51.↵
- 52.↵
- 53.↵
- 54.↵
- 55.↵
- 56.↵
- 57.↵
- 58.↵
- 59.↵
- 60.↵
- 61.↵
- 62.↵
- 63.↵
- 64.↵
- 65.↵
- 66.↵
- 67.↵
- 68.↵
- 69.↵
- 70.↵
- 71.↵
- 72.↵
- 73.↵
- 74.↵
- 75.↵
- 76.↵
- 77.↵
- 78.↵
- 79.↵
- 80.
