Evelyn P. Whitlock, MD, MPH; Betsy A. Garlitz, MD; Emily L. Harris, PhD, MPH; Tracy L. Beil, MS; Paula R. Smith, RN, BSN
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S. Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Acknowledgments: The authors thank Kevin Lutz, MFA, and Taryn Cardenas for their help in preparing this manuscript, and Daphne Plaut, MLS, for conducting the literature searches. They also thank the USPSTF, AHRQ staff, and expert reviewers for their contribution to this project.
Grant Support: This study was conducted by the Oregon Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality, Rockville, Maryland (contract 290-02-0024, task order no. 2).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Reprints are available from the Agency for Healthcare Research and Quality Web site (http://www.preventiveservices.ahrq.gov) and through the Agency for Healthcare Research and Quality Publications Clearinghouse (telephone, 800-358-9295).
Current Author Addresses: Drs. Whitlock and Harris, Ms. Beil, and Ms. Smith: Center for Health Research, Kaiser Permanente, 3800 North Interstate Avenue, Portland, OR 97227-1110.
Dr. Garlitz: Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098.
Whitlock E., Garlitz B., Harris E., Beil T., Smith P.; Screening for Hereditary Hemochromatosis: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006;145:209-223. doi: 10.7326/0003-4819-145-3-200608010-00009
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Published: Ann Intern Med. 2006;145(3):209-223.
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.
To conduct a focused systematic review of heredita-ry hemochromatosis screening relating to 2 USPSTF criteria, the burden of suffering and the potential effectiveness of a preven-tive intervention, to determine whether evidence is sufficient for a USPSTF recommendation.
MEDLINE, CINAHL, and Cochrane Library databases from 1966 through February 2005. The authors supplemented literature searches with source materials from experts in the field and the bibliographies of key reviews and included studies.
Studies were retrieved to answer 3 key questions: 1) What is the risk for developing clinical hemochromatosis among those with a homozygous C282Y genotype? 2) Does earlier therapeutic phlebotomy of individuals with primary iron overload due to hereditary hemochromatosis reduce morbidity and mortality compared with treatment after diagnosis in routine clinical care? 3) Are there groups at increased risk for developing hereditary hemochromatosis that can be readily identified before genetic screening? The authors critically appraised studies using quality criteria specific to their design.
The authors abstracted all studies into evidence tables using condition definitions and diagnostic criteria.
Data were insufficient to define a very precise estimate of penetrance. Available data suggest that up to 38% to 50% of C282Y homozygotes may develop iron overload, with up to 10% to 33% eventually developing hemochromatosis-associated morbidity. Prevalence of C282Y homozygosity is higher in family members of probands and other high-risk patient groups defined by signs, symptoms, and phenotypic screening.
This review considered genetic screening for HFE-related hereditary hemochromatosis in C282Y homozygotes only. Available research is limited, is based solely on observational designs, and is plagued by poor or inconsistent reporting.
Research addressing genetic screening for hereditary hemochromatosis remains insufficient to confidently project the impact of, or estimate the benefit from, widespread or high-risk genetic screening for hereditary hemochromatosis.
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.
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) (4-6). 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 non–HFE-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 μmol/g (reference range, 0 to 35 μmol/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 (22-25). 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).
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, 79 850 hemochromatosis-associated hospitalizations (2.3 per 100 000 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 examination–based 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 22 394 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.
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, 33-36). Although hereditary hemochromatosis appears to be ideal for population screening (7, 16, 37-39) 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.
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.
We focused on hereditary HFE-associated hemochromatosis due to C282Y homozygosity in persons of northern European descent, which is the most prevalent form of hereditary hemochromatosis in the United States. Other HFE and non-HFE genetic mutations are much rarer causes of hemochromatosis (41), and data for their disease association are more sparse than those for C282Y homozygosity (9).
We developed 3 explicit questions with supporting definitions (Appendix), in conjunction with USPSTF leads and Agency for Healthcare Research and Quality (AHRQ) staff.
Key question 1: What is the risk for developing clinical hemochromatosis among those with a homozygous C282Y genotype?
Key question 2: Does earlier therapeutic phlebotomy of individuals with primary iron overload due to hereditary hemochromatosis reduce morbidity and mortality compared with treatment after diagnosis in routine clinical care?
Key question 3: Are there groups at increased risk for developing hereditary hemochromatosis that can be readily identified before genetic screening?
We developed literature search strategies and terms for each key question (Appendix Table 1) and conducted 4 separate literature searches (for key questions 1, 2, and 3 and for background) in the MEDLINE, CINAHL, and Cochrane Library databases from 1966 through February 2005. Literature searches were supplemented with source material from experts in the field and by examining the bibliographies of included studies. A single investigator reviewed abstracts, and a second reviewer independently reviewed all excluded abstracts. Interreviewer discrepancies were resolved by consensus.
Using inclusion criteria developed for each key question (described in Appendix Table 2), we reviewed 1886 abstracts for inclusion in all key questions (Figure). Literature searches were focused for each key question but were reviewed with all key questions in mind. We reviewed 134 full-text articles for key question 1, 69 articles for key question 2, and 55 articles for key question 3. Two investigators rated all included articles for quality, as well as those excluded for quality-related reasons, using the USPSTF criteria (Appendix Table 3). Excluded articles are listed in Appendix Tables 4, 5, and 6.
To overcome the inconsistent uses of terminology in the literature, we adopted the set of terms in the Appendix for extracting data from studies into tables in a consistent format. We also established a priori screening and diagnostic criteria for elevated iron measures and iron overload due to hereditary hemochromatosis to guide our review and to establish comparability between studies (Table 1; (42-45)). Data were abstracted into evidence tables by a single reviewer and checked by a second reviewer (Appendix Tables 7, 8, 9, and 10; (25, 32, 46-67)).
We critically appraised studies according to USPSTF methods (67) using quality criteria specific to their design (Appendix Table 3). To augment criteria provided for nonrandomized studies of treatment effectiveness, we added criteria from the Cochrane Non-Randomised Studies Methods Group (68). We eliminated any case series or nonrandomized comparative treatment study that used a nonsystematic method of case accrual. We critically evaluated reported results, including the comparability of constructed comparison groups, concerning whether confounding factors (age, sex, alcohol intake, population prevalence of C282Y homozygosity, and comorbid liver disease) and secular trends in disease diagnosis and medical care were adequately considered. We eliminated studies with possible serious biases.
Studies were extremely heterogeneous and could not be easily synthesized quantitatively. To evaluate whether our review identified adequate data to create one or more outcomes tables for illustrating the expected yield from screening, we used an approach adapted from a previous report (35). We considered whether there were adequate data for genetic screening of 2 different screening populations (general population and family-based). Insufficient data were available to create a reliable outcomes table for either screening approach since very few studies reported results for all required measures (genotype, iron measures, iron overload, and disease) among screening study participants, resulting in extremely small numbers for within-study morbidity estimates. Therefore, we summarized screening data in tables, as described later.
We selected data from studies that met minimum a priori criteria for 3 variables: 1) screening positive for elevated iron measures, 2) documented iron overload, and 3) morbidity due to clinical hemochromatosis. For iron overload and morbidity, we calculated 2 proportions (selected and all). Among patients selected for further evaluation, we reported the proportion of positives among those who were actually tested for iron overload or morbidity (maximum penetrance) and, for all, the proportion who screened positive among all those evaluated at the first screening step (minimum penetrance). We evaluated whether results were similar enough to combine across studies and, when they were, we quantitatively combined study results for each variable to generate a single point estimate for that variable. We reported a range of results for any variable for which individual study results were too different to be meaningfully combined. We did not include individual study results with 10 or fewer patients in the denominator to define a range, but we did include these results if they could be combined with other results in a single variable estimate. Study results were reported as raw numbers for denominators of 10 or fewer.
This research was funded by AHRQ under a contract to support the work of the USPSTF. The USPSTF members participated in the initial design and reviewed interim results and the final evidence review. Although AHRQ had no role in the study design, data collection, or synthesis, AHRQ staff reviewed interim and final evidence reports and distributed the initial evidence report for external content review by 7 outside experts, including representatives of professional societies and federal agencies. The subsequently revised systematic review on which this manuscript is based is Available at http://www.ahrq.gov/clinic/serfiles.htm.
Of 134 full-text studies examined, we excluded 120 studies for reasons specified by our inclusion and exclusion criteria (Appendix Table 4). We eliminated all studies that combined outcome measures for C282Y homozygotes from more than one population source (for example, from family, clinical, or healthy population screening) since disease expression potentially differs among these groups. We eliminated studies that did not report data on morbid conditions associated with clinical hemochromatosis (or at least iron overload) among participants. We had 2 other main categories for study exclusion: 1) studies that involved groups of homozygotes that did not derive from any definable population—particularly one that could be subject to screening; and 2) studies with data reported in ways that did not conform to our hemochromatosis-related definitions. One study was identified, but not yet published, at the time we prepared this manuscript (Appendix Table 11). Two studies supplied data that did not meet requirements for our final data synthesis (69-70); 3 studies on genotyping in blood donors (71-73) were not relevant to this paper but are included in our full evidence report (74).
Table 2 summarizes the findings for this key question. The best evidence is from 2 fair- to good-quality longitudinal studies reporting the risk for developing disease in initially nondiseased C282Y homozygotes (46-47). Although neither was done in an inception cohort, these retrospective cohort studies from Australia (46) and Denmark (47) reported on disease expression (penetrance) of 33 C282Y homozygotes (22 women and 11 men) over 17 to 25 years of follow-up. Participants' average age at the end of observation was 47 to 63 years. Most, but not all, C282Y homozygotes (61% to 75%) developed some elevations in serum iron measures during follow-up. When compared with other age- and sex-matched genotypes, C282Y homozygotes tended to have higher mean transferrin saturation and serum ferritin levels, and average measures generally increased with age among all genotypes (47). However, C282Y homozygotes also showed more individual variation in serum iron measures than other genotypes, and many individuals did not show steady increases in these measures over time (46-47). For example, neither blood loss nor donation explained the substantial decreases in serum ferritin levels over 17 years seen in 2 of 10 C282Y homozygotes (46). The Australian study (46) objectively evaluated iron overload using liver biopsy in the 6 of 10 participants who developed serum ferritin levels greater than 500 µg/L. At least moderate iron overload (see Appendix for definition) was detected in 5 patients who underwent biopsy (representing 5 of 10 total study participants). Two of the patients who underwent biopsy had hepatic fibrosis, while the single patient with cirrhosis reported alcohol intake greater than 6 drinks per day. In contrast, none of the 23 Danish patients had liver disease detectable by clinical examination (47). Thus, when both studies were considered together, liver disease developed in 3 of 33 C282Y homozygotes. Similarly, 2 of 33 C282Y homozygotes developed diabetes and 6 of 33 developed arthralgias. No participant developed cardiomyopathy or hypogonadism.
Table 2. *
These retrospective cohort studies have 2 potential limitations. The first limitation relates to whether these data accurately represent lifelong disease expression in C282Y homozygotes. Despite the long follow-up period of 17 to 25 years, 8 women were 50 years of age or younger at final follow-up. Thus, 8 of 33 (24%) of those studied may not yet have reached the age at which clinical expression would be likely. Second, selective mortality bias resulting from follow-up only for survivors could have influenced these findings to represent the experience of healthier C282Y homozygotes. In the Australian study, however, the prevalence of C282Y homozygotes (5.3 per 1000) was within the population range expected, and complete data were available on 83% of the cohort (46). In the Danish study, selective mortality bias may be more likely since 35% of the original cohort did not have genotyping and 3 of the 23 C282Y homozygotes died before they could be examined (47). We calculated the upper bound for disease penetrance as follows to determine the potential impact of selective mortality bias on this study. If all 3 C282Y homozygotes who died were counted as developing hemochromatosis, the proportion developing clinical disease would still be about one quarter (4 of 23). If the 35% of the cohort lost to follow-up had the usual population prevalence of C282Y homozygosity (5 per 1000), then about 25 C282Y homozygotes would have been lost to follow-up. If all 25 homozygotes developed clinical disease, the estimate for disease penetrance would be 60% (29 of 48) after 25 years of follow-up.
While cross-sectional studies were more plentiful, they provided an estimate of disease expression only at the time of genotype identification. Twelve papers (32, 48-58) report cross-sectional genotypic and selected phenotypic and disease expression results from 9 screening studies (Appendix Table 8). C282Y homozygotes were identified at 2 health clinics (32, 48-51) through mass screening (52), through voter rolls or employment screening (53-56), or through family screening (57-58). We combined health clinics, mass screening, voter rolls, and employment screening results to represent “general population” screening based on the similarity of findings for C282Y prevalence and phenotypic expression between settings. A total of 282 C282Y homozygotes were identified from screening 67 771 patients in these general population settings, and 426 C282Y homozygotes were identified from genotyping in an unspecified number of family members of probands. The prevalence of C282Y homozygosity was 4.2 per 1000 screened in the general population and 161 per 1000 family members screened (based on the single family screening study that reported the number of family members screened) (57). Transferrin saturation levels were elevated in 75% or more of male C282Y homozygotes identified from general population screening, and the majority (58% to 76%) had elevated serum ferritin levels. Elevations of transferrin saturation and serum ferritin levels were more variable or less common among female homozygotes from the general population than among male homozygotes. Transferrin saturation and serum ferritin elevations in family members were very common (88% to 96%).
Among C282Y homozygotes identified from general population genetic screening, 38% of those undergoing further evaluation met criteria for iron overload, 25% had liver fibrosis, and 6% had cirrhosis. Data could not be reported reliably for males and females separately. These iron overload and disease estimates could be too high if the C282Y homozygotes who were not evaluated further are less likely to be penetrant. Assuming that all the untested C282Y homozygotes were unaffected, the prevalence of iron overload, hepatic fibrosis, and cirrhosis among newly screening-identified C282Y homozygotes would be 24%, 6%, and 1.4%, respectively. These estimates, however, should be viewed with caution because they are based on very small numbers. We also cannot be sure of the likelihood of disease penetrance (same, higher, or lower) in the large proportion of untested screening-identified C282Y homozygotes.
Data from genotyping of family members of probands may indicate that a higher proportion of C282Y homozygotes' relatives have evidence of iron overload, but not necessarily of clinical disease, at the time of screening compared with homozygotes identified through population screening. Among male first-degree relatives, 74% of those further evaluated have iron overload, 23% have fibrosis, and 6% have cirrhosis. Among female first-degree relatives, 62% of those further evaluated have iron overload, 4% have fibrosis, and 3% have cirrhosis. If we assume that all those not further tested were unaffected, estimates of the prevalence of iron overload, fibrosis, and cirrhosis in male C282Y homozygotes identified through family screening are 41%, 13%, and 4%. The respective prevalences for females are 23%, 2%, and 1%. Iron overload and disease expression at the time of identification were reported only for the limited number of C282Y homozygotes undergoing further evaluation for clinical reasons. Not all studies reported these measures and, within studies, variably selected participants received disease evaluations because of differences in the participants' clinical presentation, in their willingness to be tested, and in clinical practice norms. Estimates across studies cannot be easily compared because of potential detection bias and likely between-group differences in important factors in penetrance (such as age and sex) between C282Y homozygotes, particularly those identified from general population screening compared with those identified through family screening.
We found no controlled studies of phlebotomy treatment in patients with hemochromatosis due to any cause, nor any studies that allowed a valid comparison of early versus delayed treatment. Four fair-quality case series of patients with hemochromatosis reported objective measures before and after, or simply after, treatment (25, 58-61) in 7 publications (22, 23, 25, 58-60, 75. One retrospective observational survey (76) reported recalls of changes in symptoms after treatment among patients with hemochromatosis identified through multiple outreach mechanisms (Appendix Table 9). We excluded 61 full-text articles, primarily because of study quality, small size (<20 patients), or lack of primary data or relevant outcomes (Appendix Table 5).
Table 3 summarizes the findings for this key question. Altogether, treatment studies of patients from referral centers, who were identified and treated over a 50-year period, report on the survival experience of 447 patients over a mean duration of 8.1 (SD, 6.8) to 14.1 (SD, 6.8) years, and the reduction in morbidity after treatment of 370 patients with hemochromatosis (25, 58-60). Only 105 of these patients had genetically confirmed hereditary hemochromatosis (25, 58, and, of these, source of detection (clinical detection or family screening) was available for 85 patients (56% were probands and 44% were family members) (25). Fewer patients with confirmed hereditary hemochromatosis had cirrhosis at diagnosis (3.4% (58) to 32% (25)), compared with reports from patients whose condition was not genetically confirmed (57% (60) to 79% (59)); these findings are consistent with strong secular trends in disease severity at diagnosis (60). Secular trends in survival were also apparent, since survival improved over 10 years of follow-up in patients in whom hemochromatosis was diagnosed in 1982 to 1991, compared with 2 groups who received the diagnosis earlier (P ≤ 0.05, log-rank test) (60). For patients whose hemochromatosis was diagnosed during this later time (1982 to 1991), cumulative survival was not significantly reduced from rates expected for an age- and sex-matched population (60). Similarly, patients with genetically confirmed hemochromatosis who did not have cirrhosis at diagnosis experienced the same survival as population controls (25).
Table 3. *
Among treated patients with hereditary hemochromatosis, cirrhosis at diagnosis appeared to confer a worse prognosis (adjusted relative risk for death, 5.54 [CI, 1.76 to 17.47]) (25). However, comparisons of survival differences between cirrhotic and noncirrhotic patients, between other patient subgroups (for example, diabetic vs. nondiabetic patients (60) or between all patients and historical controls (59)) are not completely reliable because of potential confounding by uncontrolled and unmeasured factors, such as era of diagnosis, age at diagnosis, sex, excessive alcohol use, concomitant hepatitis, and dietary factors.
In the best available evidence on the effects of phlebotomy treatment, pretreatment and post-treatment liver biopsies in 260 patients who received a diagnosis through routine clinical practice suggest some reversibility of hepatic disease, with 7% to 23% showing improvement and 1% to 3% showing worsening (59-60). Improvement in histologic characteristics was more common (32.6%) in patients with less severe, precirrhotic liver disease than in patients with cirrhosis (14.8% improved) (60). In a highly selected subgroup of family (and health check) screening-detected patients (n = 25) who underwent a second biopsy after treatment for persistently elevated liver enzyme levels or uncertainty about cirrhosis on first biopsy, 19 of 20 showed improvement in hepatic fibrosis scores after treatment; the only case with baseline cirrhosis was unchanged (58). These findings are not clearly generalizable because of the selected nature of the patient group and because biopsy results in 5 cases with high alcohol intake were not reported.
Several studies suggest that some, but not all, other disease process and symptoms will respond to phlebotomy treatment. In 183 primarily male symptomatic patients (57% of whom had cirrhosis) who received a diagnosis before 1991, 41% of those with type 1 diabetes mellitus reduced their daily dosage; 73% with elevated levels of liver enzymes (alanine aminotransferase or aspartate aminotransferase) showed improvement; and symptoms such as weakness, lethargy, or abdominal pain improved in more than half (60). Improvements in arthralgias (30%) and potency (19%) were less prominent. A total of 2851 primarily male patients with hemochromatosis, most of whom received a diagnosis after 1990 through family screening or an abnormal laboratory test finding, were asked to recall their experience before and after treatment. They reported comparable improvements in extreme fatigue (50%), abdominal pain (22%), impotence (13%), and joint pain (9%). Many patients also recalled improvement in depression (41%), but many (33%) also recalled onset of new symptoms after treatment (76). This study is weakened by its reliance on recall and the absence of controls to compare nonspecific symptom prevalence and changes over time.
We examined 55 full-text articles and excluded 47 studies from this question for various reasons (Appendix Table 6), such as not reporting relevant measures or results, addressing the wrong population, not using C282Y genotype to define the family risk group, using an ineligible study design, or having poor quality. One fair- to good-quality cross-sectional study of family members of genotyped probands (57) and 6 fair- to good-quality cross-sectional studies (in 7 publications) (51, 61-66) of patients with signs or symptoms consistent with iron overload or hemochromatosis met our inclusion criteria.
Table 4 summarizes the findings for this key question. Potential high-risk groups were examined for a higher prevalence of C282Y homozygosity, including 150 family members of probands and 42 636 patients with fatigue or increased liver enzyme levels from primary care or hepatology, endocrinology, and rheumatology specialty settings. Family screening identified the highest prevalence of undetected C282Y homozygotes (23% overall), particularly among siblings of probands (33% homozygosity). Among symptomatic patients selected from primary care, rheumatology, endocrinology, or referral medicine clinics, 0% to 5.8% were C282Y homozygotes, compared with 0.2% of a random sample of persons attending a health appraisal clinic (27). Overall, the prevalence of C282Y homozygosity did not differ between patients in the health appraisal clinic and primary care patients with an index sign or symptom. Compared with controls, C282Y homozygosity was significantly more prevalent only in hospitalized diabetic patients from an endocrinology clinic (5.8%) and in patients from a referral medicine clinic with chronic fatigue and arthralgias (5.7%). Three other studies confirm or extend these results. Males, but not females, with chronic fatigue symptoms visiting a health appraisal clinic had a slightly higher (0.85%) prevalence of C282Y homozygosity than patients without symptoms (0.14%) (51). The prevalence of C282Y homozygosity in patients from a rheumatology clinic was similar to that in the general population (65). In patients with a history of coronary heart disease, prevalence of C282Y homozygosity was the same as, or lower than, that of patients without symptoms (0.17% to 0.28%) (62). Findings may not be conclusive in comparisons based on fewer than 300 patients, given the population prevalence of C282Y homozygotes (3 to 5 per 1000 white persons).
Table 4. *
Some studies restricted genotyping to symptomatic patients who also had some laboratory abnormality. The prevalence of C282Y homozygosity was somewhat increased in a range of patients with hemochromatosis-compatible signs and symptoms and elevated iron measures (Table 4). Among 667 patients from a liver clinic who had elevated iron measures, 7.1% were homozygous for C282Y (63). For hospitalized patients with diabetes and patients with chronic fatigue or arthralgias who were referred to specialists, C282Y homozygosity was higher in patients with transferrin saturation greater than 0.40 or serum ferritin level greater than 300 µg/L than in patients with disease but without elevated iron measures (6.6% to 17.3% compared with 5.7% to 5.8%) (61). The sensitivity of transferrin saturation greater than 0.40 for detecting C282Y homozygosity in diabetic patients hospitalized for disease-related complications was 100%, but the specificity was 13%. In diabetic patients, the sensitivity of a serum ferritin level greater than 300 µg/L was 86% and the specificity was 56%. For patients referred for arthralgias and unexplained fatigue, transferrin saturation greater than 0.40 and a serum ferritin level greater than 300 µg/L were about equally sensitive and specific for C282Y homozygosity (100% sensitive and 65% to 67% specific). In patients from a health appraisal clinic who had elevated liver enzyme levels, the prevalence of C282Y homozygosity appeared the same (in women), or slightly higher (0.57% vs. 0.28%, in men), compared with those with normal enzyme levels (51).
We have data on the risk for developing signs or symptoms of iron overload and hemochromatosis in 33 C282Y homozygote adults monitored over 17 to 25 years and on the burden of disease at the time of identification for an additional 228 newly identified C282Y homozygote adults from the general population. Taken together, these data suggest that up to 38% to 50% of C282Y homozygotes develop iron overload according to our criteria and up to 10% to 33% develop definite disease (fibrosis, cirrhosis, or diabetes). Much lower estimates are also compatible with available data. Findings from a large case series on the disease expression of 271 patients with hereditary hemochromatosis identified through genetic testing of those with elevated serum iron levels detected at health appraisal screening complement our review (58). Although these patients' disease expression would represent only C282Y homozygotes already exhibiting iron accumulation by definition, rates of cirrhosis (6.3%), fibrosis (10.7%), diabetes (3.6%), or any combination of these (20.6%) were similar to or marginally higher than limited results from general population screening found in our review. Available data remain too limited to clearly establish estimates of disease penetrance, since so few people have been studied in depth (only 10 C282Y homozygotes were evaluated per our criteria for iron overload or hemochromatosis in longitudinal studies), and in those studied over time, disease could still develop with longer follow-up. Indeed, 8 of 33 of those followed longitudinally were women age 50 years or younger at last follow-up, in whom disease may not have yet developed. Also, while a higher proportion clearly develop iron overload, its clinical significance is less clear than that of clinical hemochromatosis. Finally, data reported here (and elsewhere) clearly articulate that a subgroup of untreated homozygotes—perhaps even 40% (58)—do not exhibit any or progressive iron accumulation over years of follow-up, thus complicating any message that would be given to asymptomatic screening-detected individuals.
Family members of individuals with hereditary hemochromatosis are noted to be at higher risk for being homozygous, and family screening has been established as a standard of care based on HLA-typing studies of family members of probands (77-78). We found 1 U.S. study and 1 Australian study using HFE genotyping to determine risk in probands and family members that support this practice. A high proportion of tested biological relatives (23%) were also C282Y homozygotes. Similarly, compared with the general population, a higher proportion (49% to 86%) of C282Y homozygotes identified from family screening met iron overload criteria, although the proportion with fibrosis and cirrhosis did not clearly differ. Direct comparisons in disease penetrance between these different types of screening-detected C282Y homozygotes have very limited value, however, because these groups may differ with regard to who receives more in-depth clinical work-up (selection bias), as well as other ways important to disease expression. For example, a recently published study reporting on C282Y homozygous persons identified over many years through family screening and through phenotypic followed by genotypic screening found significant differences in baseline characteristics between the 2 groups that could affect disease expression (58). In addition, even if it is considered the standard of care, approaches to family screening also need to consider other associated ethical, legal, social, and psychological issues (78).
Studies examining survival are limited to 4 case series reporting on a total of 447 patients who received a diagnosis between 1937 and 1989. Disease severity at diagnosis and survival showed pronounced secular trends. Patients with a more recent diagnosis are less severely affected, and with treatment they have 10-year survival rates similar to those of age- and sex-matched controls. These trends may be due to earlier diagnosis from increased clinical suspicion or enhanced family screening due to recognition of hemochromatosis as a hereditary disease leading to earlier diagnosis, or to increases in adequate treatment after diagnosis.
Liver biopsies before and after treatment suggest arresting disease progression in most individuals and a possible reduction in the severity of hepatic fibrosis, particularly in less severely affected patients. Available data are consistent with improvements in some, but not all, hemochromatosis-related morbid conditions after treatment. None of these data come from controlled trials, however, and studies do not generally ensure minimally valid measures of treatment response. No studies reported harms, limiting the ability to determine net risks and benefits of treatment. Given these caveats, treatment may result in reduced insulin doses in patients with type 1 diabetes and decreases in elevated liver enzyme levels. Symptoms such as extreme fatigue, abdominal pain, and lethargy improve in most patients, while arthralgia and impotence do not.
Some have suggested a targeted approach to screening by identifying persons with signs or symptoms consistent with undiagnosed, early-stage hemochromatosis. Primary care patients selected for symptoms or signs consistent with hemochromatosis did not have a higher prevalence of C282Y homozygosity than healthy controls, and neither did selected symptomatic or diseased patients from rheumatology or other specialty clinics. A slightly higher proportion of C282Y homozygotes could be identified by conducting genotyping only in patients from a liver clinic prescreened to have transferrin saturation greater than 0.45 (7.7% C282Y/C282Y) or by targeting diabetic patients hospitalized for poor control or complications (5.5%) or patients referred to specialists for chronic fatigue and arthralgias (5.7%). While biochemical screening with transferrin saturation and serum ferritin further enriched this patient pool, calculated specificity remained low (56% to 67%).
The quantity of evidence that met quality and relevance criteria for the focused key questions posed by this review was small, despite a very large published literature (Table 5). A great deal was published before the availability of HFE genotyping for hereditary hemochromatosis. After reviewing 1886 abstracts and 256 full-text articles, we located only 23 fair- to good-quality studies that were relevant to some aspect of our 3 key questions on disease burden, benefits of early treatment, and high-risk groups. Some articles cited to support screening and treatment benefits in this field did not meet minimal quality or diagnostic criteria for our review, as was true of often-cited data within the studies we could include. All the reviewed evidence, including treatment studies, was observational, much of it representing the experience of a small number of relatively selected individuals, and much of it without data to allow comparisons with an unaffected or an untreated population. The published research was often difficult to interpret consistently and accurately given incompleteness and extreme variability in reporting standards. While more recent reports are of higher quality with clearer case definitions, authors still fail to acknowledge the impact that selection bias probably has on their estimates of disease expression in C282Y homozygotes; thus, the applicability of their findings to the evaluation of general population screening is limited (58).
In reviewing this field, others have included a larger range of study designs, such as modeling the expected frequency of genotyping in older populations, autopsy studies, and other circumstantial approaches. Our focused key questions did not allow incorporation of this type of evidence into our review, but it is unlikely that their inclusion would be of great use to the USPSTF given its evidence hierarchy and requirement of at least fair-quality evidence for making its recommendations (67).
The articles we included required substantial interpretation for data abstraction and synthesis. For individual articles, we typically reviewed all tables for possibly relevant data and checked text calculations. We made every effort to report data only on adult populations relevant to screening, which required careful reading and data dissection in studies that combined cases from many sources. We excluded studies with serious discrepancies or those in which outcomes could not be related back to a sample or population source we were addressing. Many articles required further hand calculations to extract data in the most comparable form in order to allow cross-study comparisons, and inconsistencies between tables and text in many articles complicated this process. The number of calculations and interpretation from descriptive data raise a concern about data errors. Overall, the difficulties in understanding and interpreting this literature posed challenges to meeting our usual standards of comprehensiveness and consistency.
We primarily focused on hereditary hemochromatosis as the condition of interest for this screening review and, within that, on the most common associated HFE genotype in the United States (C282Y homozygosity), which accounts for 85% to 90% of cases in white persons. We did not examine other hereditary causes or the impact of HFE heterozygosity that may account for 3% to 5% of patients with hereditary hemochromatosis. While we did not review evidence on phenotypic screening in primary care, others have recently done so (79), and the evidence has been found insufficient for phenotypic screening for hereditary hemochromatosis in the general population (80).
On the basis of this focused evidence review, research regarding screening for hereditary hemochromatosis remains very limited. Despite the availability of new studies in response to calls for improved research (18, 40, 81, not enough is known to allow a confident projection of the benefit from widespread genotypic screening for hereditary hemochromatosis. Data are beginning to be reported for targeted high-risk population screening approaches (for example, high-risk identification followed by phenotypic screening followed by genotypic screening), which may prove to be useful.
Recent studies suggest that disease expression or penetrance is certainly less than 100% in C282Y homozygotes identified through some method of screening. How much less than 100%, and for whom, remains uncertain. In the next year or two, the HEIRS follow-up should provide information on short-term disease expression based on clinical examinations of C282Y homozygotes; those with elevated iron measures at the time of screening, regardless of genotype; and a sample of controls. However, only self-reported disease expression data will be available on all 99 000 (genotyped and phenotyped) primary care patients, and follow-up beyond 1 to 2 years is not planned. If funding is provided, this study could be a rich resource of prospective information on disease development, as well as observational data on treatment response in contemporarily diagnosed patients with clear disease definition. Without other data, such as might come from the HEIRS study, the literature on treatment remains quite small, consisting of dated case series in fewer than 500 patients (few of whom have hereditary hemochromatosis documented by genotype). Controlled treatment trials will probably never be undertaken for ethical reasons, so higher-quality observational treatment data would be very useful.
The literature on genotyping family members of C282Y/C282Y probands is also of limited quantity because of the relatively recent availability of HFE testing (1996), but there is a large body of HLA-based literature on which family screening of probands has been established. Research needs in this area remain high (79).
Asymptomatic: With no or only general and vague symptoms, such as arthralgias, emotional distress, fatigue, abdominal pain, and nonspecific signs, such as elevated liver function test results.
Biochemical screening: Measurement of transferrin saturation or serum ferritin to screen for primary iron overload.
Clinical hemochromatosis: Diagnosed liver disease (fibrosis, cirrhosis, liver failure, hepatocellular carcinoma), cardiomyopathy, diabetes mellitus, or arthropathy in the presence of primary iron overload.
Elevated iron measures: Increased levels of body iron as reflected by elevations in serum transferrin saturation or serum ferritin levels.
Genotypic screening: Detecting persons with, or at risk for developing, iron overload or clinical hemochromatosis through genotyping the HFE gene to detect C282Y homozygosity.
Groups at increased risk for developing clinical hemochromatosis: Includes asymptomatic individuals who can be identified by virtue of an associated factor or sign and who might be the focus of a targeted genetic screening program. Factors or signs could include age, sex, ethnicity, family history of iron overload or clinical hemochromatosis, and increased liver function test results. Does not include those with existing disease (diabetes mellitus, cirrhosis, cardiomyopathy) in whom the effort is to detect hemochromatosis in order to treat the disease, as this is tertiary prevention.
Hemochromatosis: Term used variously in the literature, but here to mean manifest disease determined to be due to excess body iron, but not clearly fitting more precise etiologic definitions.
Hereditary hemochromatosis: Iron overload or clinical hemochromatosis due to C282Y homozygosity.
Iron overload: Excess deposition of iron in liver diagnosed by liver biopsy or increased total body mobilizable iron diagnosed by quantitative phlebotomy. Criterion for diagnosis is liver biopsy specimen with hepatic iron index of 1.9, with or without fibrosis. In quantitative phlebotomy, iron overload represents the removal of more than 4 g of mobilizable iron to reach biochemical indicators of iron depletion. This corresponds to approximately greater than 90 μmol/g of hepatic iron or at least “moderate” iron overload (on scale of normal, mild iron overload, moderate iron overload, substantial iron overload, and severe iron overload). “Iron overload” not meeting this standard may be considered possible or provisional primary iron overload.
Morbidity: Organ damage that results in physical disability over and above that not seen in the absence of iron overload.
Phenotypic screening: Detecting persons with or at risk for developing clinical hemochromatosis through biochemical screening by using serum ferritin or transferrin saturation.
Primary iron overload: Iron overload due to an inherent, inherited defect in iron regulation.
Screening population: Group of populations of individuals who are identified and tested in a manner that is not related to their symptoms—that is, they are not identified through disease signs or symptoms. A screening population can be identified by their relationship to a proband, as long as their symptoms did not bring them to the attention of the researchers.
Targeted screening: Screening those identified as high risk for developing hemochromatosis (as opposed to general population screening).
Therapeutic phlebotomy: The process of repeatedly drawing blood until iron measures are within normal limits. Typical treatment schedule is 1 unit (500 mL) of blood biweekly until serum ferritin level is less than 20 μg/L. Maintenance therapy of 3 to 4 units/y is common.
Unselected hemochromatosis: Primary hemochromatosis not clearly due to C282Y homozygosity but with secondary causes eliminated. A term created to describe a category of patients with genetic disease not clearly due to C282Y.
Wild-type: In HFE genotyping, typically refers to individuals who do not have C282Y and/or H63D alleles, the alleles most commonly tested.
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