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Screening for Hereditary Hemochromatosis: A Systematic Review for the U.S. Preventive Services Task Force
E. Whitlock, Betsy A Garlitz, E. Harris, T. Beil, Paula R. Smith
The U.S. Preventive Services Task Force (USPSTF) has not previously considered screening for hereditary hemochromatosis for a recommendation as a clinical preventive service for primary care clinicians. We examined key questions to assess hemochroma…
The U.S. Preventive Services Task Force (USPSTF) has not previously considered screening for hereditary hemochromatosis for a recommendation as a clinical preventive service for primary care clinicians. We examined key questions to assess hemochromatosis penetrance in C282Y homozygotes (key question 1), address health outcomes of therapeutic phlebotomy (key question 2), and examine the possibility of targeted genetic screening (key question 3). Key questions for this focused systematic review were limited to addressing critical evidence gaps in order for the USPSTF to recommend screening (1, 2), and were applied using strict and consistent definitions of disease, which are described in more detail below. Background Condition Definition Hemochromatosis was originally thought to be a rare idiopathic disorder characterized by end-stage disease (cirrhosis, diabetes, and bronzed skin) but is now recognized as having a hereditary component due to an autosomal recessive inherited disorder of iron metabolism (3). In hemochromatosis, body iron accumulates and can lead to iron overload (4). In iron overload, excess iron is deposited in the liver, pancreas, heart, joints, and endocrine glands, resulting in tissue damage that can lead to disease conditions (such as cirrhosis, diabetes, heart failure, arthropathy, and impotence) (46). Iron overload can be primary (as in hereditary hemochromatosis) or secondary (for example, due to anemias with inefficient erythropoiesis or repeated blood transfusions) (7). In 1996, 2 base-pair alterations, termed C282Y and H63D, of the HFE gene on the region of HLA-A on chromosome 6 were identified in hereditary hemochromatosis (8). C282Y homozygosity is now recognized as the most common genotype in hereditary hemochromatosis (9). Estimates are that 82% to 90% of cases of hereditary hemochromatosis among white persons occur in C282Y/C282Y homozygotes (10). The other 10% to 18% of cases appear to be due to environmental factors or other genotypes. While other HFE-related and nonHFE-related genetic mutations are associated with hereditary hemochromatosis in a small number of cases (4), other genotypes do not appear to be as strongly associated with hereditary hemochromatosis (3, 9). HFE mutations are fairly common in the United States, with 1 in 10 white persons heterozygous for the HFE C282Y mutation (carriers) and 4.4 homozygotes per 1000 (4, 6). The frequency of C282Y homozygosity is much lower among Hispanic persons (0.27 in 1000), Asian Americans (<0.001 per 1000), Pacific Islanders (0.12 per 1000), and black persons (0.14 per 1000) (11). The availability of genotyping has permitted identifying persons who have the susceptible genotype but have little or no evidence of disease. Thus, individuals homozygous for the C282Y genotype can be characterized in 1 of 4 general stages: genetic predisposition without any other abnormality; iron overload without symptoms; iron overload with early symptoms; and iron overload with organ damage, especially cirrhosis (4). Clinically recognized hereditary hemochromatosis is twice as common in males and occurs predominantly in white populations (12). While the natural history is not well understood, the condition appears to have a long latent period, with wide individual variation in biochemical expression (13). This is because iron accumulation and disease expression are modified by environmental factors, such as blood loss from menstruation or donation, alcohol intake, diet, and comorbid disease (for example, viral hepatitis) (14, 15). If symptomatic organ involvement develops, it generally occurs in mid-life with nonspecific signs and symptoms (such as unexplained fatigue, joint pain, and abdominal pain) (14). Age of onset is delayed in females (16), perhaps because of blood loss through menstruation (3). The liver is the first target organ thought to be affected by iron accumulation (17) and is central to both diagnosis and prognosis (13). While a clinical diagnosis is based on serum iron studies and clinical evaluation, documented iron overload relies on 1 of 2 methods: quantitative phlebotomy with calculation of the amount of iron removed, or liver biopsy with determination of quantitative hepatic iron (18). Although liver biopsy was once essential to the diagnosis, it is currently used more as a prognostic tool (19). While hepatic iron concentration greater than 283 mol/g (reference range, 0 to 35 mol/g) is associated with cirrhosis in C282Y homozygotes (20), many patients with much higher levels do not have cirrhosis (13). Even in the absence of systemic iron overload, iron accumulates when the liver is inflamed or cirrhosed because of other causes (such as alcoholic steatohepatitis, transfusion and chronic hemolytic disorders, or chronic viral hepatitis) (21). Cirrhosis is a late-stage disease development and has been reported to shorten life expectancy (2225). Cirrhosis is also a risk factor for hepatocellular carcinoma (13) and typically occurs between the ages of 40 and 60 years (6). Cirrhosis prevention would be a major goal of screening and treatment (26). Prevalence and Burden of Disease Estimates of the general population prevalence of hemochromatosis vary because of the long preclinical period and lack of a consistent case definition. The prevalence of cases of hemochromatosis defined biochemically (elevated serum iron indices) will be higher than the prevalence of cases based on documented iron overload, with or without clinical signs and symptoms. The prevalence will be lowest for cases based on diagnosed disease (cirrhosis, diabetes) (27). Experts have recommended defining iron overload as distinct from hemochromatosis (4), and this provides an objective, although not universally accepted, standard for early disease based on documented increases in body iron stores (27). On the basis of clinically diagnosed hemochromatosis or hemochromatosis-compatible disease, 79850 hemochromatosis-associated hospitalizations (2.3 per 100000 residents) were projected in the United States over 18 years (1979 to 1997), although annual rates could not be reliably calculated (28). Of 29 million deaths from 1979 to 1992, 4858 (0.017%) were consistent with hemochromatosis as an underlying cause (12). Age-adjusted mortality rates for hemochromatosis-consistent deaths increased from 1.2 per million in 1979 to 1.8 per million in 1992. These rates were about twice as high in males as in females and in white persons as in nonwhite persons. Both of these estimates of the burden of disease suggest a disease prevalence much lower than the prevalence of associated genetic mutations, which has fueled the debate about disease penetrance. While these statistics are probably underestimates, primarily because of underdiagnosis (29), the extent of this underestimation is not clear. The prevalence of hemochromatosis-attributable morbid conditions (such as cirrhosis, diabetes, arthralgias, and fatigue or other symptoms) has been proposed as an estimate of the burden due to undiagnosed disease, particularly since diagnosis may commonly be delayed as a result of the nonspecific nature of hemochromatosis-related signs and symptoms (30). Since these signs and symptoms are also prevalent and nonspecific, however, relevant evidence must establish their prevalence due to iron overload, or their excess prevalence in association with iron overload compared with controls. In a previous study, 297 middle-aged patients with previously undetected hereditary hemochromatosis (homozygous for C282Y) had a higher prevalence of diagnosed osteoarthritis, knee symptoms, hypothyroidism, and use of antihypertensive or thyroid replacement medications than sex- and age-specific controls (31). However, general health, mental health, and 52 other questionnaire-based and clinical examinationbased measures of cardiovascular, respiratory, and liver diseases were not statistically different between case-patients and controls. In another cross-sectional comparison of 124 C282Y screening-detected adult homozygotes with 22394 wild-type/wild-type genotypic controls, common symptoms (chronic fatigue, joint symptoms, impotence, and limited general health) and signs (diabetes) were no more frequent in C282Y homozygotes than controls (32). While the relative risk for physician-diagnosed liver problems or hepatitis was increased (relative risk, 2.1 [95% CI, 1.1 to 4.0]), the proportion of C282Y homozygotes with liver problems was modest (10%). Similarly, in the Hemochromatosis and Iron Overload Screening (HEIRS) study, C282Y homozygotes had an increased odds of self-reported liver disease (odds ratio, 3.28 [CI, 1.49 to 7.22]) compared with wild-type controls. Almost one fourth, however, were not identified by screening (11). Clearly, the prevalence of hemochromatosis-attributable morbid conditions is not a simple, reliable way to estimate the disease burden associated with hemochromatosis. Rationale for Population Screening Screening for hemochromatosis or iron overload is theoretically attractive and has been widely discussed over the past 10 to 15 years, with renewed interest and a focus on hereditary hemochromatosis since the discovery of the HFE mutations (4, 3336). Although hereditary hemochromatosis appears to be ideal for population screening (7, 16, 3739) and for a new paradigm for genetics and public health (34), inadequacies in the evidence supporting genetic screening for hereditary hemochromatosis have precluded widespread support for population-based screening (4, 9, 34, 40). Aims of Focused Systematic Review This review addresses 2 major uncertainties in the evidence: How much disease is actually caused by HFE mutations? and Does therapeutic phlebotomy treatment, initiated through earlier identification of those with hereditary hemochromatosis, lead to better outcomes? We also considered evidence for high-risk (as opposed to general population) screening. Methods We focused on hereditary HFE-associ
Published in
Annals of Internal Medicine
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25
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7 | 2006 |
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