J Genet Counsel DOI 10.1007/s10897-013-9681-4
ORIGINAL RESEARCH
Insufficient Referral for Genetic Counseling in the Management of Hereditary Haemochromatosis in Portugal: A Study of Perceptions of Health Professionals Requesting HFE Genotyping Bruna Leandro & Milena Paneque & Jorge Sequeiros & Graça Porto
Received: 15 January 2013 / Accepted: 11 December 2013 # National Society of Genetic Counselors, Inc. 2014
Abstract There is a general consensus that HFE- related Hereditary Haemochromatosis (HFE-HH) should be diagnosed at early stages in pre-symptomatic individuals, in order to prevent the most severe consequences of iron overload. In Portugal, despite an increasing number of requests for genetic diagnosis of this rare disease, there is not a corresponding increase in requests for genetic counselling. The objective of the present study was to evaluate physicians’ main motivations for requesting HFE genotyping or genetic counselling for HFE-HH. We assessed current medical practices regarding family testing and diagnosis and discuss whether these can be improved in order to increase the effectiveness of disease prevention. Our results show there is a general lack of knowledge about the selection of patient cases that should be sent for genetic counseling or for molecular testing of HFE-HH by physicians (especially by general practitioners). The lack of
Electronic supplementary material The online version of this article (doi:10.1007/s10897-013-9681-4) contains supplementary material, which is available to authorized users. B. Leandro : M. Paneque : J. Sequeiros : G. Porto ICBAS, Universidade do Porto, Porto, Portugal B. Leandro : M. Paneque : J. Sequeiros : G. Porto Centre for Predictive and Preventive Genetics (CGPP), IBMC – Institute for Molecular and Cell Biology, Universidade do Porto, Rua do Campo Alegre, nº 823, 4150-180 Porto, Portugal G. Porto Serviço de Hematologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal G. Porto (*) Serviço de Hematologia, Centro Hospitalar do Porto - Hospital Geral de Santo António, Lg. Prof. Abel Salazar, 4099-001 Porto, Portugal e-mail: [email protected]
family-based screening may indirectly compromise the efficiency of disease prevention in terms of early diagnosis and treatment. We concluded it is necessary to circulate more information about Hereditary Haemochromatosis among health professionals in order to improve strategies for its early diagnosis. Keywords Haemochromatosis . HFE genotyping . Genetic counseling . Medical education . General practitioners Iron overload in humans is associated with a variety of acquired and genetic conditions. Among these, HFE-related Hereditary Haemochromatosis (HFE-HH), associated with homozygosity for the p.Cys282Tyr (C282Y) mutation in HFE, is by far the most frequent cause (EASL 2010). It is very common in people of Northern European origin, particularly of Nordic or Celtic ancestry, in which it occurs with a prevalence of approximately 1 in every 200–300 individuals (Adams et al. 2005; Phatak et al. 2008). The disease is transmitted in an autosomal recessive manner but the clinical expression is variable depending on the time, rate and amount of iron accumulation. Most patients with HFE-HH do not present before 40 years of age and females are less affected than males (EASL 2010), possibly due to the effect of regular menstruation. However, a full explanation of the variable clinical penetrance of the disease is still not known (Waalen et al. 2005). The HFE gene encodes a membrane protein that functions as a non-classical MHC-class I molecule that associates with beta 2 microglobulin (β2m) to regulate hepcidin, a key molecule of systemic iron homeostasis control (D’Alessio et al. 2012). The C282Y mutated variant of HFE does not bind to β2m and results in a non-functional misfolded protein which is absent from the cell surface (Waheed et al. 1997). In
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addition to C282Y, other HFE variants, most commonly the p.His63Asp (H63D) polymorphism, have been described in iron overloaded patients, either in homozygosity or, most commonly, in compound heterozygosity with C282Y. Historically, these genotypes had been regarded as HFE-HH associated genotypes (European and UK Haemochromatosis Consortium 2000); however, it is now generally recognized that they represent distinct clinical conditions with less severe iron overload which are mostly associated with other iron loading cofactors such as alcohol abuse or non-alcoholic liver steatosis (Walsh et al. 2006). Current clinical guidelines therefore recommend the term HFE-HH be confined to cases with C 2 8 2 Y h o m o z y g o s i t y, a n d t h e o c c u r r e n c e o f hyperferritinemia associated with other HFE genotypes (including C282Y/H63D compound heterozygosity or homozygosity for H63D) be investigated for other causes of acquired iron overload (EASL 2010).
Clinical Aspects of HFE-HH Despite its genetic homogeneity the clinical phenotype of HFE-HH is quite variable, with a significant proportion of individuals homozygous for the C282Y mutation not developing the disease (reviewed in EASL 2010). Available data suggest that 38 % to 50 % of C282Y homozygotes may develop iron overload, with only 10 % to 33 % eventually developing haemochromatosis-associated morbidity (Whitlock et al. 2006). Due to the low penetrance of the disease, and to avoid confusion in nomenclature, the case definition of HFE-HH implicates not only the occurrence of C282Y homozygosity but also the presence of increased body iron stores, with or without symptoms (EASL 2010). Nevertheless, there is a general consensus that HFE-HH should be diagnosed in early pre-symptomatic stages in order to prevent the possible severe consequences of iron overload such as liver cirrhosis or hepatocarcinoma (EASL 2010). Results from uncontrolled case studies have clearly shown that HFE-HH patients diagnosed at early stages, and who undergo repeated phlebotomies to remove excessive iron, have a normal life expectancy with reduced morbidity and mortality (Aleman et al. 2011; Niederau et al. 1996). Taking these studies into consideration, a randomized controlled trial at this stage would therefore be unethical to conduct.
Strategies for Early Detection and Prevention To enhance the early detection of HFE-HH cases recommended strategies include: first, the biochemical screening of various iron parameters followed by the genetic testing in the case of confirmed elevated transferrin saturation levels; and second, the pre-symptomatic genetic testing of first degree
relatives of confirmed cases (EASL 2010) and family screening. Although enough evidence already exists to support the benefit and cost-effectiveness of genetic family screening, HFE genotyping of the population is not recommended because of the low penetrance of the disease (Grosse et al. 2010). The cost-effectiveness of population screening through the implementation of biochemical tests in routine health checkups has still not been appropriately evaluated. In the case of predictive genetic testing for asymptomatic family cases it is recommended that appropriate genetic counselling also be performed (King and Barton 2006; USPSTF 2006). This may be critical for three main reasons: first, to assure a correct understanding of the genetic information which, if inappropriately interpreted, may lead to confusion, false hopes or unnecessary anxiety; second, counselling is important to offer specific clinical orientations in the situation of case detection. This is particularly important in HFEHH, where apparently healthy subjects have to be motivated for disease prevention; and third, genetic testing without counselling favours ambiguous results and reports, associated with increased physician service use and higher societal costs (Speechley et al. 2012).
Purpose of the Study As in most European populations, a high prevalence of the HFE C282Y mutation is found in Portugal, despite a small number of patients identified. Interestingly, the allele frequency of the mutation varies across geographical regions, with decreasing frequencies from the north to the south of the country, corresponding to expected numbers of homozygous individuals between 3.6/1,000 in the north region and 8.1/ 100,000 in Algarve (Cardoso et al. 2001). The Centre for Predictive and Preventive Genetics (CGPP) in Porto (north Portugal) began performing genetic testing for the diagnosis of HFE-HH in 1997. Genetic counselling began to be offered in 2000. One year later, the number of requests for HFE genotyping almost duplicated, then remained stable thereafter. Progressively, CGPP has become a reference centre which provides genetic counselling for late onset neurological disorders and a specialized consultation in Hereditary Haemochromatosis. In fact, among a total of five Genetic Services Centres working within the national reference network, CGPP is the only centre with a specialized consultation for Hereditary Hemochromatosis. The Public National Health System supports a “take in free” system with respect to family doctor referrals to CGPP. In practice individuals are referred to CGPP for diagnostic, predictive or carrier testing of HFE-HH with or without requesting prior genetic counseling. The criteria used by physicians’ can range from known family history, to nonspecific biochemical alterations or associated clinical conditions. In this context, it is not clear how the
Genetic Counseling in Hemochromatosis
requesting physicians from different specialities attribute the importance and role of genetic counselling in their general work up for the diagnosis or screening of HFE-HH. The present study set out to address these questions. The aims of the study were twofold: (1) to explore physician motivations for requesting HFE-HH molecular testing or genetic counseling, and (2) to consider whether current medical practices of screening and early diagnosis could be improved to increase the quality of intervention.
Methods Participants The target population of this study was the population of physicians who requested HFE genotyping (including C282Y and H63D variants) by our laboratory of CGPP. Between 2000 and 2010, we received requests from 570 physicians from 177 Portuguese health units (hospitals, primary care health units and private clinics). The following information about the requesting physicians was available from the CGPP informatics database, which is stored with the consent of requesting physicians (consent included in the requesting form): name, health unit where they worked when the test was requested, medical speciality, and total number of requests for HFE genotyping during the referral period. A substantial fraction of the requests received at our laboratory comes from a specialised consultation for Hemochromatosis at the Centro Hospitalar do Porto, Hospital Santo António where one dedicated physician requests the genetic tests and is also engaged in a program for HFE-HH genetic counselling at CGPP. Because of the risk of bias, this physician was excluded from analyses, as were 3 other medical geneticists also regularly providing genetic counseling for HFE-HH.
Procedures The questionnaire was sent by regular mail with an information sheet and an informed consent form, summarizing the study goals and assuring the confidentiality of their answers. Two return addressed and stamped envelopes were enclosed with these documents: one to return the questionnaire, and another to return the informed consent, so that anonymity could be guaranteed. No incentives were associated with participation and participants were given 1 month to respond (April, 2011). In a second phase after the deadline, phone calls and emails were sent to the health units in order to confirm the current workplace of non-respondents. Once the address was confirmed, a reminder (by normal mail or email) was sent and the deadline to respond was extended for another 3 months (until July 30, 2011). The study was approved by the Ethics Committee of the University of Porto. Data Analysis Differences between categorical variables were analysed by the chi-square test with the Yates correction for small samples using SPSS (Statistical Package for the Social Sciences, version 17.0). A content analysis was performed for responses to the open questions assessing health professionals’ views about the relevance of implementing a screening program for HFEHH in primary health care units. For the content analysis we used inductive and cross-case comparison to extract key themes from responses (Strauss and Corbin 1998). Authors (BL & MP) coded the questions and summarized the content of each one, and then tried to find recurrent themes or patterns. At each point, the profiles of the physicians’ specialties were compared.
Instrumentation Results A questionnaire (provided as supplementary material) with ten closed questions, three Likert scales and one open question was specifically designed for this study to evaluate the following criteria: (1) main sources of information about haemochromatosis; (2) physicians’ annual requests for HFE genotyping; (3) motivations to order a diagnosis or a presymptomatic predictive test; (4) if the reception of a “positive” report (at least one C282Y mutation) further influenced the requesting practice or motivated actions for family screening; (5) relative importance attributed to genetic counseling for the diagnosis of suspected cases or for family screening; and (6) barriers for requesting genetic counseling and family screening. The questionnaire was pre-screened by five experienced research colleagues to ensure that all questions were understandable and could be answered appropriately.
Sample As illustrated in Table 1, a total of 570 questionnaires were mailed, of which only 47 physician responses were obtained. Contact phone calls were made in all of these cases and only those who were confirmed to have actually received the questionnaire were considered valid cases (n=352). The excluded cases corresponded to physicians who were deceased, retired or on leave (n=30), and cases where no information was available (“no information”) about their current workplace (n=188). From the total valid cases, 47/352 questionnaires were completed and returned (“respondents”) corresponding to a response rate of 13.4 %. The remaining 305 were classified as “non-respondents.” Despite the small
Leandro et al. Table 1 Sample distribution and characterization regarding gender, region and medical specialty
Total Gender
Region
Specialty
Female Male Unknown North Centre Lisbon and Tagus Valley Algarve Madeira Unknown GPs Internists Gastroenterologists Other specialtiesb
Questionnaires sent
Respondents
Non- respondents
Excludeda
n
%
n
%
n
%
n
%
570 320 239 11 434 56 56 14 9 1 162 175 97
56.1 41.9 2.0 76.1 9.8 9.8 2.5 1.6 0.2 28.4 30.7 17.0
47 26 19 2 33 3 8 1 1 1 13 19 10
55.3 40.4 4.3 70.2 6.4 17.0 2.1 2.1 2.1 27.7 40.4 21.3
305 176 124 5 244 27 21 8 5 0 109 95 46
57.7 40.7 1.6 80.0 8.9 6.9 2.6 1.6 0.0 35.7 31.1 15.1
218 118 97 3 157 26 27 5 3 0 40 61 41
54.1 44.5 1.4 72.0 11.9 12.4 2.3 1.4 0.0 18.3 28.0 18.8
136
23.9
5
10.6
55
18.0
76
34.9
Results are indicated in total numbers and percentages a
Reasons for exclusion detailed in M & M
b
Haematologists, dermatologists, neurologists, paediatricians, infecciologists, nephrologists, orthopaedic surgeons, clinical pathologists, pneumologists, rheumatologists, cardiologists and general surgeons
sample size, the group of “respondents” was representative of the whole group of requesting physicians in terms of gender, region and medical speciality (see Table 1). Information Sources About Hereditary Haemochromatosis The main sources of knowledge about hemochromatosis reported by clinicians from the different specialties are illustrated in Fig. 1. In general, 30.9 % of the participants indicated they acquired knowledge about haemochromatosis during their undergraduate medical training, and 26.8 % acquired it in continuing education activities (congresses, scientific meetings or post-graduation courses). Other sources of knowledge, such as continuing internal staff education, and informal Fig. 1 Comparison between general practitioners (n=13) and other specialists (n=29) as to their main sources of knowledge about HH
contact with other physicians, were also reported (21.7 %), as well as reading international literature (20.6 %). Although, in general, there were no significant differences among the various groups of medical specialities regarding sources of knowledge, it is of note that only 13 % of GPs referred to postgraduate continuing education as a major source of knowledge, in contrast to 25 % of the other specialists (mainly internists and gastroenterologists). Requests for HFE Testing Table 2 shows summarized results for the reported numbers of physicians’ annual requests according to their speciality. Some participants (about 45 %) requested HFE genotyping only once
Genetic Counseling in Hemochromatosis Table 2 Reported practices of annual requests for HFE genetic testing by physicians of different specialties
Speciality
Number (%) of HFE requests per year
0–1
2 to 5
Total number (%) of respondents
>6
n
%
n
%
n
%
n
%
General and family medicine Internal medicine Gastroenterology
11 6 2
52.4 28.6 9.5
2 9 3
13.3 60.0 20.0
0 4 5
0.0 36.4 45.5
13 19 10
27.7 40.4 21.3
Others (Haematology and neurology) Total n
2 21
9.5
1 15
6.7
2 11
18.1
5 47
10.6
of hyperferritinemia (particularly among GPs) which is not, per se, a recommended reason for referral (EASLD 2010).
or less per year. Significant differences were found among different specialities regarding their requesting practices [X2(6)=16.22, p=0.013] although the statistical power was lost when the Yates correction for small samples was applied. The option “once or less than once per year” was mainly reported by GPs (52.3 %); “2 to 5 times a year” was mostly reported by internists (60.0 %); and “more than six times a year” was mainly reported by gastroenterologists (45.5 %). Respondents were also asked about their most common or valued reasons for referral. A high transferrin saturation (TfSat) and familial screening for HFE-HH were, in general, the most commonly reported reasons for referral; however, the exclusion of hemochromatosis in other hepatic or hematological diseases with iron overload were also commonly reported. Table 3 shows summarized results of the most common, or valued reasons, as reported by general practitioners (GPs) compared with pooled groups of internists and gastroenterologists. These groups represent the physicians who most commonly request HFE genotyping (as shown previously in Table 2). No significant differences in responses were observed between the two groups. Of special note is the finding of the high value attributed to HFE genotyping for diagnosis
Referral for Genetic Counseling Most of the participating physicians (68.0 %) had never requested genetic counseling for HFE-HH at our genetic centre. The majority of those requesting genetic counseling were GPs (40.0 %) and internists (33.3 %). Most specialists (73.0 %) requested counseling once or less than once a year, while 27.0 % requested counseling 2 to 5 times per year, at the most. The vast majority of both GPs or specialists who reported having requested genetic counseling (77.8 % and 81.5 %, respectively) did so in the context of diagnosis of suspected cases, while only a minority (22.2 % and 18.5 %, respectively) had requested it in the context of family screening. The participants identified a number of barriers for referral to genetic counselling including geographic distance (32.0 %), low motivation of the consultants (32.0 %), costs related to transportation (30.0 %), and costs incurred for the National Health System appointment (11.0 %).
Table 3 Most common and valued reasons for requesting HFE genotyping between the General Practitioners (GPs)(n=11) and physicians from other specialities (n=26) Reasons
Most common reasons GPs
High transferrin saturation Family history Exclusion in other hepatic diseases with iron overload Exclusion in iron loading anemias or porphyria cutanea tarda High serum ferritin Genetic confirmation of a clinical diagnosis a
Most valued reasons
Other specialistsa
GPs
Other specialistsa
n
%
n
%
n
%
n
%
52 35 28 26 24 16
28.7 19.3 15.5 14.4 13.3 8.8
100 88 82 55 84 74
20.7 18.2 17.0 11.4 17.4 15.3
31 38 28 20 34 19
18.2 22.4 16.5 11.8 20.0 11.1
100 90 83 67 73 71
20.7 18.6 17.1 13.8 15.1 14.7
This group includes specialists of Internal Medicine and Gastroenterology, the specialities that most commonly request HFE genotyping. No significant differences were found among groups
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Impact of the Receipt of a Report with a HFE Mutation The majority of respondents (64.0 %) declared having received at least one report where at least one C282Y mutation was detected. Within each speciality group, most GPs (75.0 %) never received a report with C282Y mutations, whereas most of the other specialists (79.0 %) reported having already received a “positive” result. When asked if they changed their referrals after receiving a “positive” test, in general, most doctors responded they did (52.0 %), either referring other family members for genetic testing (56.0 %), or for genetic counseling (41.0 %). Of the three GPs who received a report with C282Y mutations, two reported not to have changed their referral practices, while the third reported to have started referring relatives for genetic counseling; 14 of the 23 physicians who mentioned having altered their mode of referral, started asking for molecular testing for other patients. After confirmation of a pre-symptomatic diagnosis of HFE-HH, 87.0 % of the physicians reported having alerted the patients and their relatives further about the genetic disease and for the need to screen the family. Family doctors reported always having conveyed that information to the families. One of the other specialists declared not to have mentioned the risk to the family.
needed.” Some physicians indicated a population-based screening should be made by GPs in order to find cases with high TfSat, but they also commented, “first it is important to sensitize family doctors”; while others stated this screening would be better done by other specialists (haematologists, hepatologists) and should not be made in local health care units.
Discussion To the best of our knowledge, this is the first study addressing physician perceptions of the importance of genetic counseling in the management of HFE-HH. We explored the main motivations physicians have for requesting molecular testing and/ or genetic counseling via a questionnaire about their sources of information on haemochromatosis and their main reasons for referral. Despite sample limitations, the results obtained allowed us to draw some conclusions regarding current medical practices of screening and early diagnosis and how these practices could be improved in order to increase the quality of intervention.
Sources of Information About Haemochromatosis Screening for Prevention of Haemochromatosis Clinical Consequences? Responses to an open question about the value attributed to screening as a strategy to prevent the HFE-HH clinical consequences, revealed there is a general awareness about the importance of implementing a family-based but not a population-based screening, Responses were varied: Many physicians pointed to the relevance of family-based screening by “referring to genetic centres” in the case where carriers of HFE mutation(s) were identified in a family “given the high prevalence of the HFE mutations in the Portuguese population,” mostly in the north of the country. Others were clearly more concerned about the general practice of population screening by stating, for example, “Screening should only be made after the detection of hepatic alterations and of iron overload and never randomly.” In terms of population-based screening, some physicians considered this strategy to be a good means of early detection, better treatment and prevention of symptoms in HFE-HH, especially those related to hepatic disease. Some respondents pointed to the importance of implementing this screening but commented, “it would be very expensive and there are other common pathologies, with a more severe prognosis, that still do not have a screening program.” Mention was also made about the fact that, “given the low incidence and prevalence of the disease in the population, a universal screening is not
In general, the physicians’ knowledge about haemochromatosis was mainly acquired during their undergraduate medical training and, particularly in the case of GPs, this content was generally not supplemented in further medical continuing education. This is an important point to take into consideration if we consider the fundamental role GPs should have in the correct management of HFE-HH, particularly regarding early diagnosis and advising families about screening. They are indeed the first line in detecting cases within the earliest phases. The results of this study clearly point to the need for more efforts to disseminate of knowledge about HFE-HH, particularly in post-graduate education for general practitioners. Although this study was designed to address the perceptions of physicians regarding the importance of genetic counseling in the specific management of HFE-HH, our conclusions are similar to those described in other studies suggesting that GPs must increase their understanding of genetics in general (Liaw 2010). Undergraduate education, training and support of GPs are now being considered by the National Health and Medical Research Council and Human Genetics Advisory Committee (Human Genetics Advisory Committee Meeting 2010), and it is well accepted that medical genetics in general, and genetic diseases in particular, are still underrepresented in postgraduate training programmes for GPs (Baars et al. 2005a, b; Plass et al. 2002).
Genetic Counseling in Hemochromatosis
Reasons for Referral The present study shows that the main reasons for referral for HFE genotyping and/or for genetic counseling are not different between GPs and other specialists. The main reason to request a diagnostic genetic test was, as expected, the finding of increased transferrin saturation, and the main reason for genetic counseling was the identification of a positive case in the family, criteria that fit with international guidelines (EASL 2010). Nevertheless, it is important to note and explore why there is still a high rate of inappropriate indications and lack of requests for genetic diagnosis and genetic counseling in affected families. In addition to some identified factors such as geographical distance, lack of motivation of the patient or associated costs (mostly for travelling since the service is free through the National Public Health System), our results show that physicians are still confused about the proper indications for diagnostic genetic testing as well as about the mandatory genetic counseling in the case of predictive genetic testing in affected families (Portuguese Law nº 12/2005 of 26 January— Genetic Personal Information and Health Information). Limitations of the Study The major limitation of the present study was the small number of questionnaires returned. The high percentage of “non-respondents” (305 out of 352 valid cases, 86.6 %) could be due to different causes. We considered “non-respondents” physicians whom we certified were still working in the place where questionnaires were sent and who declined to participate. Some of them, later contacted by telephone, admitted they were too busy to answer at the time they received the questionnaire and later misplaced it. Others declared they were absent at that time and never received the questionnaire. Others mentioned they had requested the test only once and therefore assumed their responses would not be relevant. It should be stressed that the questionnaires were first sent during the Easter period (April, 2011) and the deadline for response was at the beginning of the summer holiday season (July, 2011), therefore timing should not be a limiting factor. The highest number of requests was from the north of Portugal, due to the localization of our centre in Porto. The medical specialities more often requesting genetic testing and counseling for hereditary haemochromatosis patients and families were evenly represented in that sample. Practical Implications Although this study was specifically designed for the purpose of the management of HFE-HH, the fact that this is a common genetic disorder with clearly established recommendations for early diagnosis through family screening makes it a good model to test, more generally, the importance given by
physicians to the question of genetic counseling. Burke et al. (2006) have stressed core skills and genetics knowledge to evaluate family history, as well as recognition of clinical findings indicating a genetic risk, should be an important part of education for GPs. Without denying the essential role that specialists trained in genetics continue to provide for genetic diagnosis and counseling in a number of rare inherited conditions, one should also recognize that practitioners in both secondary and primary care also need to be equipped to deal with initial patient inquiries. In addition they also need to have an awareness of the potential implications of family history in order to offer information related to their specific area of practice and to refer individuals or family members appropriately to other health-care providers, including specialist genetic services (Skirton et al. 2010). A partnership among genetic counselors, medical geneticists, and primary care providers is also essential to develop effective policies, educational tools, and practice guidelines, including the appropriate uses of genetic testing (Burke et al. 2006). We believe genetic counsellors may come to play an important role in the future for the dissemination of HFE-HH symptoms, hereditary risk and preventive actions, thus putting into practice the desirable partnership between GPs and other healthcare professionals. Additionally, more research on how affected individuals experience the disease, how they transmit information to their family members, and how they perceive preventive actions, could be the focus of future genetic counseling studies. In this context, one should note the first generation of Portuguese genetic counsellors to receive training at the master level graduated in 2011. Therefore, their contribution to genetic counseling practice (including the well-known advantages of population education) within the Portuguese healthcare system should become apparent in the future. Research Recommendations In order to draw more generalizable and definitive conclusions, this study should be validated with a larger sample (in the north and, particularly, in the other regions) and gather more information regarding generic knowledge about the disease among the various specialties involved, particularly about the available prevention methods, such as secondary prevention (early detection with biochemical and genetic testing before it becomes symptomatic), and tertiary prevention (methods to reduce disability and mortality in patients already affected by disease). Nevertheless, one should note that this was the first national study addressing the issue of healthcare professionals managing Hereditary Hemochromatosis and, despite the limitations, the results suggest a previously unknown reality that demands further actions. Future research that includes alternative qualitative research methods such as focus groups or individual interviews may help to increase knowledge on this topic.
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Conclusions The need and opportunities for genetic testing and counseling for HFE-related haemochromatosis are still not fully appreciated by many physicians in Portugal, although there are important steps in the global strategy for early detection and prevention of complications. The role of GPs is particularly important to improve proper and timely referral for genetic testing and counseling of patients and relatives. Towards this aim, GPs should be the main focus of programs aimed at increasing awareness and providing further education about haemochromatosis. These programs are also important, however, for internists and gastroenterologists. In addition, the future role of genetic counsellors in filling the gap of educational needs among the general population should not be neglected. Acknowledgments We are grateful to all participants for their time and valuable contributions to this study. This work was produced within the framework of a research seminar of the professional master course in genetic counseling of ICBAS, Universidade do Porto, and was funded in part by the Calouste Gulbenkian Foundation, through a fellowship to Bruna Leandro, and by the Portuguese Foundation for Science and Technology (FCT), through a postdoctoral fellowship to Milena Paneque (SFRH/BPD/66484/2009) and through the project PIC/IC/82785/2007. We also thank Carol Ann Harley, at the IBMC, for detailed revision of the manuscript. Disclosure of Interest The authors declare that they do not have any actual or potential conflict of interest. They have full control of all primary data and they agree to allow the journal to review their data if requested.
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allelic frequencies between the North and South of Portugal. European Journal of Human Genetics, 9, 843–848. D’Alessio, F., Hentze, M. W., & Muckenthaler, M. U. (2012). The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. Journal of Hepatology, 57, 1052–1060. EASL. (2010). EASLD clinical practice guidelines for HFE hemochromaosis. Journal of Hepatology, 53, 3–22. European and UK Haemochromatosis Consortium. (2000). Diagnosis and management of haemochromatosis since the discovery of the HFE gene: a European experience. British Journal of Haematology, 108, 31–39. Grosse, S. D., Rogowski, W. H., Ross, L. F., Cornel, M. C., Dondorp, W. J., & Khoury, M. J. (2010). Population screening for genetic disorders in the 21st century: evidence, economics, and ethics. Public Health Genomics, 13, 106–115. Human Genetics Advisory Committee Meeting: communique. Canberra, 18 February 2010. Available at www.nhmrc.gov.au/about/ committees/hgac/meeting_100218.htm [Accessed 19 May 2010]. King, C., & Barton, D. E. (2006). Best practice guidelines for the molecular Genetic diagnosis of type I (HFE-related) hereditary haemochromatosis. BMC Medical Genetics, 7, 81. Liaw, S. T. (2010). Genetics and genomics in general practice. Australian Family Physician, 39(9), 689–691. Niederau, C., Fischer, R., & Purschel, A. (1996). Long-term survival in patients with hereditary hemochromatosis. Gastroenterology, 110, 1107–1119. Phatak, P. D., Bonkovsky, H. L., & Kowdley, K. V. (2008). Hereditary hemochromatosis: time for targeted screening. Annals of Internal Medicine, 149, 270–272. Plass, A. M., Baars, M. J., Beemer, F. A., & Ten Kate, L. P. (2002). Genetics education for non-genetic health care professionals in the Netherlands. Community Genetics, 9(4), 246–250. Skirton, H., Lewis, C., Kent, A., & Coviello, D. (2010). Genetic education and the challenge of genomic medicine: development of core competences to support preparation of health professionals in Europe. European Journal of Human Genetics, 18, 972–977. Speechley, M., Alter, D., Guo, H., Harrison, H., & Adams, P. C. (2012). Effect of ambiguous hemochromatosis gene test results on physician utilization. Medical Care, 50, 394–398. Strauss, A., & Corbin, J. (1998). Basics of qualitative research: Techniques and procedures for developing grounded theory (2nd ed.). Thousand Oaks: Sage. U.S. Preventive Services Task Force. (2006). Screening for hemochromatosis: recommendation statement European. Annals of Internal Medicine, 145(3), 204–208. Waalen, J., Nordestgaard, B. G., & Beutler, E. (2005). The penetrance of hereditary hemochromatosis. Best Practice & Research Clinical Haematology, 18(2), 203–220. Waheed, A., Parkkila, S., Zhou, X. Y., Tomatsu, S., Tsuchihashi, Z., Feder, J. N., et al. (1997). Hereditary hemochromatosis: effects of P.CYS282TYR and H63D mutations on association with beta2microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proceedings of the National Academy of Sciences of the United States of America, 94, 12384– 12389. Walsh, A., Dixon, J. L., Ramm, G. A., Hewett, D. G., Lincoln, D. J., Anderson, G. J., et al. (2006). The clinical relevance of compound heterozygosity for the P.CYS282TYR and H63D substitutions in hemochromatosis. Clinical Gastroenterology and Hepatology, 4, 1403–1410. Whitlock, E. P., Garlitz, B. A., Harris, E. L., Beil, T. L., & Smith, P. R. (2006). Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Annals of Internal Medicine, 145, 209–223.
ORIGINAL RESEARCH
Insufficient Referral for Genetic Counseling in the Management of Hereditary Haemochromatosis in Portugal: A Study of Perceptions of Health Professionals Requesting HFE Genotyping Bruna Leandro & Milena Paneque & Jorge Sequeiros & Graça Porto
Received: 15 January 2013 / Accepted: 11 December 2013 # National Society of Genetic Counselors, Inc. 2014
Abstract There is a general consensus that HFE- related Hereditary Haemochromatosis (HFE-HH) should be diagnosed at early stages in pre-symptomatic individuals, in order to prevent the most severe consequences of iron overload. In Portugal, despite an increasing number of requests for genetic diagnosis of this rare disease, there is not a corresponding increase in requests for genetic counselling. The objective of the present study was to evaluate physicians’ main motivations for requesting HFE genotyping or genetic counselling for HFE-HH. We assessed current medical practices regarding family testing and diagnosis and discuss whether these can be improved in order to increase the effectiveness of disease prevention. Our results show there is a general lack of knowledge about the selection of patient cases that should be sent for genetic counseling or for molecular testing of HFE-HH by physicians (especially by general practitioners). The lack of
Electronic supplementary material The online version of this article (doi:10.1007/s10897-013-9681-4) contains supplementary material, which is available to authorized users. B. Leandro : M. Paneque : J. Sequeiros : G. Porto ICBAS, Universidade do Porto, Porto, Portugal B. Leandro : M. Paneque : J. Sequeiros : G. Porto Centre for Predictive and Preventive Genetics (CGPP), IBMC – Institute for Molecular and Cell Biology, Universidade do Porto, Rua do Campo Alegre, nº 823, 4150-180 Porto, Portugal G. Porto Serviço de Hematologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal G. Porto (*) Serviço de Hematologia, Centro Hospitalar do Porto - Hospital Geral de Santo António, Lg. Prof. Abel Salazar, 4099-001 Porto, Portugal e-mail: [email protected]
family-based screening may indirectly compromise the efficiency of disease prevention in terms of early diagnosis and treatment. We concluded it is necessary to circulate more information about Hereditary Haemochromatosis among health professionals in order to improve strategies for its early diagnosis. Keywords Haemochromatosis . HFE genotyping . Genetic counseling . Medical education . General practitioners Iron overload in humans is associated with a variety of acquired and genetic conditions. Among these, HFE-related Hereditary Haemochromatosis (HFE-HH), associated with homozygosity for the p.Cys282Tyr (C282Y) mutation in HFE, is by far the most frequent cause (EASL 2010). It is very common in people of Northern European origin, particularly of Nordic or Celtic ancestry, in which it occurs with a prevalence of approximately 1 in every 200–300 individuals (Adams et al. 2005; Phatak et al. 2008). The disease is transmitted in an autosomal recessive manner but the clinical expression is variable depending on the time, rate and amount of iron accumulation. Most patients with HFE-HH do not present before 40 years of age and females are less affected than males (EASL 2010), possibly due to the effect of regular menstruation. However, a full explanation of the variable clinical penetrance of the disease is still not known (Waalen et al. 2005). The HFE gene encodes a membrane protein that functions as a non-classical MHC-class I molecule that associates with beta 2 microglobulin (β2m) to regulate hepcidin, a key molecule of systemic iron homeostasis control (D’Alessio et al. 2012). The C282Y mutated variant of HFE does not bind to β2m and results in a non-functional misfolded protein which is absent from the cell surface (Waheed et al. 1997). In
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addition to C282Y, other HFE variants, most commonly the p.His63Asp (H63D) polymorphism, have been described in iron overloaded patients, either in homozygosity or, most commonly, in compound heterozygosity with C282Y. Historically, these genotypes had been regarded as HFE-HH associated genotypes (European and UK Haemochromatosis Consortium 2000); however, it is now generally recognized that they represent distinct clinical conditions with less severe iron overload which are mostly associated with other iron loading cofactors such as alcohol abuse or non-alcoholic liver steatosis (Walsh et al. 2006). Current clinical guidelines therefore recommend the term HFE-HH be confined to cases with C 2 8 2 Y h o m o z y g o s i t y, a n d t h e o c c u r r e n c e o f hyperferritinemia associated with other HFE genotypes (including C282Y/H63D compound heterozygosity or homozygosity for H63D) be investigated for other causes of acquired iron overload (EASL 2010).
Clinical Aspects of HFE-HH Despite its genetic homogeneity the clinical phenotype of HFE-HH is quite variable, with a significant proportion of individuals homozygous for the C282Y mutation not developing the disease (reviewed in EASL 2010). Available data suggest that 38 % to 50 % of C282Y homozygotes may develop iron overload, with only 10 % to 33 % eventually developing haemochromatosis-associated morbidity (Whitlock et al. 2006). Due to the low penetrance of the disease, and to avoid confusion in nomenclature, the case definition of HFE-HH implicates not only the occurrence of C282Y homozygosity but also the presence of increased body iron stores, with or without symptoms (EASL 2010). Nevertheless, there is a general consensus that HFE-HH should be diagnosed in early pre-symptomatic stages in order to prevent the possible severe consequences of iron overload such as liver cirrhosis or hepatocarcinoma (EASL 2010). Results from uncontrolled case studies have clearly shown that HFE-HH patients diagnosed at early stages, and who undergo repeated phlebotomies to remove excessive iron, have a normal life expectancy with reduced morbidity and mortality (Aleman et al. 2011; Niederau et al. 1996). Taking these studies into consideration, a randomized controlled trial at this stage would therefore be unethical to conduct.
Strategies for Early Detection and Prevention To enhance the early detection of HFE-HH cases recommended strategies include: first, the biochemical screening of various iron parameters followed by the genetic testing in the case of confirmed elevated transferrin saturation levels; and second, the pre-symptomatic genetic testing of first degree
relatives of confirmed cases (EASL 2010) and family screening. Although enough evidence already exists to support the benefit and cost-effectiveness of genetic family screening, HFE genotyping of the population is not recommended because of the low penetrance of the disease (Grosse et al. 2010). The cost-effectiveness of population screening through the implementation of biochemical tests in routine health checkups has still not been appropriately evaluated. In the case of predictive genetic testing for asymptomatic family cases it is recommended that appropriate genetic counselling also be performed (King and Barton 2006; USPSTF 2006). This may be critical for three main reasons: first, to assure a correct understanding of the genetic information which, if inappropriately interpreted, may lead to confusion, false hopes or unnecessary anxiety; second, counselling is important to offer specific clinical orientations in the situation of case detection. This is particularly important in HFEHH, where apparently healthy subjects have to be motivated for disease prevention; and third, genetic testing without counselling favours ambiguous results and reports, associated with increased physician service use and higher societal costs (Speechley et al. 2012).
Purpose of the Study As in most European populations, a high prevalence of the HFE C282Y mutation is found in Portugal, despite a small number of patients identified. Interestingly, the allele frequency of the mutation varies across geographical regions, with decreasing frequencies from the north to the south of the country, corresponding to expected numbers of homozygous individuals between 3.6/1,000 in the north region and 8.1/ 100,000 in Algarve (Cardoso et al. 2001). The Centre for Predictive and Preventive Genetics (CGPP) in Porto (north Portugal) began performing genetic testing for the diagnosis of HFE-HH in 1997. Genetic counselling began to be offered in 2000. One year later, the number of requests for HFE genotyping almost duplicated, then remained stable thereafter. Progressively, CGPP has become a reference centre which provides genetic counselling for late onset neurological disorders and a specialized consultation in Hereditary Haemochromatosis. In fact, among a total of five Genetic Services Centres working within the national reference network, CGPP is the only centre with a specialized consultation for Hereditary Hemochromatosis. The Public National Health System supports a “take in free” system with respect to family doctor referrals to CGPP. In practice individuals are referred to CGPP for diagnostic, predictive or carrier testing of HFE-HH with or without requesting prior genetic counseling. The criteria used by physicians’ can range from known family history, to nonspecific biochemical alterations or associated clinical conditions. In this context, it is not clear how the
Genetic Counseling in Hemochromatosis
requesting physicians from different specialities attribute the importance and role of genetic counselling in their general work up for the diagnosis or screening of HFE-HH. The present study set out to address these questions. The aims of the study were twofold: (1) to explore physician motivations for requesting HFE-HH molecular testing or genetic counseling, and (2) to consider whether current medical practices of screening and early diagnosis could be improved to increase the quality of intervention.
Methods Participants The target population of this study was the population of physicians who requested HFE genotyping (including C282Y and H63D variants) by our laboratory of CGPP. Between 2000 and 2010, we received requests from 570 physicians from 177 Portuguese health units (hospitals, primary care health units and private clinics). The following information about the requesting physicians was available from the CGPP informatics database, which is stored with the consent of requesting physicians (consent included in the requesting form): name, health unit where they worked when the test was requested, medical speciality, and total number of requests for HFE genotyping during the referral period. A substantial fraction of the requests received at our laboratory comes from a specialised consultation for Hemochromatosis at the Centro Hospitalar do Porto, Hospital Santo António where one dedicated physician requests the genetic tests and is also engaged in a program for HFE-HH genetic counselling at CGPP. Because of the risk of bias, this physician was excluded from analyses, as were 3 other medical geneticists also regularly providing genetic counseling for HFE-HH.
Procedures The questionnaire was sent by regular mail with an information sheet and an informed consent form, summarizing the study goals and assuring the confidentiality of their answers. Two return addressed and stamped envelopes were enclosed with these documents: one to return the questionnaire, and another to return the informed consent, so that anonymity could be guaranteed. No incentives were associated with participation and participants were given 1 month to respond (April, 2011). In a second phase after the deadline, phone calls and emails were sent to the health units in order to confirm the current workplace of non-respondents. Once the address was confirmed, a reminder (by normal mail or email) was sent and the deadline to respond was extended for another 3 months (until July 30, 2011). The study was approved by the Ethics Committee of the University of Porto. Data Analysis Differences between categorical variables were analysed by the chi-square test with the Yates correction for small samples using SPSS (Statistical Package for the Social Sciences, version 17.0). A content analysis was performed for responses to the open questions assessing health professionals’ views about the relevance of implementing a screening program for HFEHH in primary health care units. For the content analysis we used inductive and cross-case comparison to extract key themes from responses (Strauss and Corbin 1998). Authors (BL & MP) coded the questions and summarized the content of each one, and then tried to find recurrent themes or patterns. At each point, the profiles of the physicians’ specialties were compared.
Instrumentation Results A questionnaire (provided as supplementary material) with ten closed questions, three Likert scales and one open question was specifically designed for this study to evaluate the following criteria: (1) main sources of information about haemochromatosis; (2) physicians’ annual requests for HFE genotyping; (3) motivations to order a diagnosis or a presymptomatic predictive test; (4) if the reception of a “positive” report (at least one C282Y mutation) further influenced the requesting practice or motivated actions for family screening; (5) relative importance attributed to genetic counseling for the diagnosis of suspected cases or for family screening; and (6) barriers for requesting genetic counseling and family screening. The questionnaire was pre-screened by five experienced research colleagues to ensure that all questions were understandable and could be answered appropriately.
Sample As illustrated in Table 1, a total of 570 questionnaires were mailed, of which only 47 physician responses were obtained. Contact phone calls were made in all of these cases and only those who were confirmed to have actually received the questionnaire were considered valid cases (n=352). The excluded cases corresponded to physicians who were deceased, retired or on leave (n=30), and cases where no information was available (“no information”) about their current workplace (n=188). From the total valid cases, 47/352 questionnaires were completed and returned (“respondents”) corresponding to a response rate of 13.4 %. The remaining 305 were classified as “non-respondents.” Despite the small
Leandro et al. Table 1 Sample distribution and characterization regarding gender, region and medical specialty
Total Gender
Region
Specialty
Female Male Unknown North Centre Lisbon and Tagus Valley Algarve Madeira Unknown GPs Internists Gastroenterologists Other specialtiesb
Questionnaires sent
Respondents
Non- respondents
Excludeda
n
%
n
%
n
%
n
%
570 320 239 11 434 56 56 14 9 1 162 175 97
56.1 41.9 2.0 76.1 9.8 9.8 2.5 1.6 0.2 28.4 30.7 17.0
47 26 19 2 33 3 8 1 1 1 13 19 10
55.3 40.4 4.3 70.2 6.4 17.0 2.1 2.1 2.1 27.7 40.4 21.3
305 176 124 5 244 27 21 8 5 0 109 95 46
57.7 40.7 1.6 80.0 8.9 6.9 2.6 1.6 0.0 35.7 31.1 15.1
218 118 97 3 157 26 27 5 3 0 40 61 41
54.1 44.5 1.4 72.0 11.9 12.4 2.3 1.4 0.0 18.3 28.0 18.8
136
23.9
5
10.6
55
18.0
76
34.9
Results are indicated in total numbers and percentages a
Reasons for exclusion detailed in M & M
b
Haematologists, dermatologists, neurologists, paediatricians, infecciologists, nephrologists, orthopaedic surgeons, clinical pathologists, pneumologists, rheumatologists, cardiologists and general surgeons
sample size, the group of “respondents” was representative of the whole group of requesting physicians in terms of gender, region and medical speciality (see Table 1). Information Sources About Hereditary Haemochromatosis The main sources of knowledge about hemochromatosis reported by clinicians from the different specialties are illustrated in Fig. 1. In general, 30.9 % of the participants indicated they acquired knowledge about haemochromatosis during their undergraduate medical training, and 26.8 % acquired it in continuing education activities (congresses, scientific meetings or post-graduation courses). Other sources of knowledge, such as continuing internal staff education, and informal Fig. 1 Comparison between general practitioners (n=13) and other specialists (n=29) as to their main sources of knowledge about HH
contact with other physicians, were also reported (21.7 %), as well as reading international literature (20.6 %). Although, in general, there were no significant differences among the various groups of medical specialities regarding sources of knowledge, it is of note that only 13 % of GPs referred to postgraduate continuing education as a major source of knowledge, in contrast to 25 % of the other specialists (mainly internists and gastroenterologists). Requests for HFE Testing Table 2 shows summarized results for the reported numbers of physicians’ annual requests according to their speciality. Some participants (about 45 %) requested HFE genotyping only once
Genetic Counseling in Hemochromatosis Table 2 Reported practices of annual requests for HFE genetic testing by physicians of different specialties
Speciality
Number (%) of HFE requests per year
0–1
2 to 5
Total number (%) of respondents
>6
n
%
n
%
n
%
n
%
General and family medicine Internal medicine Gastroenterology
11 6 2
52.4 28.6 9.5
2 9 3
13.3 60.0 20.0
0 4 5
0.0 36.4 45.5
13 19 10
27.7 40.4 21.3
Others (Haematology and neurology) Total n
2 21
9.5
1 15
6.7
2 11
18.1
5 47
10.6
of hyperferritinemia (particularly among GPs) which is not, per se, a recommended reason for referral (EASLD 2010).
or less per year. Significant differences were found among different specialities regarding their requesting practices [X2(6)=16.22, p=0.013] although the statistical power was lost when the Yates correction for small samples was applied. The option “once or less than once per year” was mainly reported by GPs (52.3 %); “2 to 5 times a year” was mostly reported by internists (60.0 %); and “more than six times a year” was mainly reported by gastroenterologists (45.5 %). Respondents were also asked about their most common or valued reasons for referral. A high transferrin saturation (TfSat) and familial screening for HFE-HH were, in general, the most commonly reported reasons for referral; however, the exclusion of hemochromatosis in other hepatic or hematological diseases with iron overload were also commonly reported. Table 3 shows summarized results of the most common, or valued reasons, as reported by general practitioners (GPs) compared with pooled groups of internists and gastroenterologists. These groups represent the physicians who most commonly request HFE genotyping (as shown previously in Table 2). No significant differences in responses were observed between the two groups. Of special note is the finding of the high value attributed to HFE genotyping for diagnosis
Referral for Genetic Counseling Most of the participating physicians (68.0 %) had never requested genetic counseling for HFE-HH at our genetic centre. The majority of those requesting genetic counseling were GPs (40.0 %) and internists (33.3 %). Most specialists (73.0 %) requested counseling once or less than once a year, while 27.0 % requested counseling 2 to 5 times per year, at the most. The vast majority of both GPs or specialists who reported having requested genetic counseling (77.8 % and 81.5 %, respectively) did so in the context of diagnosis of suspected cases, while only a minority (22.2 % and 18.5 %, respectively) had requested it in the context of family screening. The participants identified a number of barriers for referral to genetic counselling including geographic distance (32.0 %), low motivation of the consultants (32.0 %), costs related to transportation (30.0 %), and costs incurred for the National Health System appointment (11.0 %).
Table 3 Most common and valued reasons for requesting HFE genotyping between the General Practitioners (GPs)(n=11) and physicians from other specialities (n=26) Reasons
Most common reasons GPs
High transferrin saturation Family history Exclusion in other hepatic diseases with iron overload Exclusion in iron loading anemias or porphyria cutanea tarda High serum ferritin Genetic confirmation of a clinical diagnosis a
Most valued reasons
Other specialistsa
GPs
Other specialistsa
n
%
n
%
n
%
n
%
52 35 28 26 24 16
28.7 19.3 15.5 14.4 13.3 8.8
100 88 82 55 84 74
20.7 18.2 17.0 11.4 17.4 15.3
31 38 28 20 34 19
18.2 22.4 16.5 11.8 20.0 11.1
100 90 83 67 73 71
20.7 18.6 17.1 13.8 15.1 14.7
This group includes specialists of Internal Medicine and Gastroenterology, the specialities that most commonly request HFE genotyping. No significant differences were found among groups
Leandro et al.
Impact of the Receipt of a Report with a HFE Mutation The majority of respondents (64.0 %) declared having received at least one report where at least one C282Y mutation was detected. Within each speciality group, most GPs (75.0 %) never received a report with C282Y mutations, whereas most of the other specialists (79.0 %) reported having already received a “positive” result. When asked if they changed their referrals after receiving a “positive” test, in general, most doctors responded they did (52.0 %), either referring other family members for genetic testing (56.0 %), or for genetic counseling (41.0 %). Of the three GPs who received a report with C282Y mutations, two reported not to have changed their referral practices, while the third reported to have started referring relatives for genetic counseling; 14 of the 23 physicians who mentioned having altered their mode of referral, started asking for molecular testing for other patients. After confirmation of a pre-symptomatic diagnosis of HFE-HH, 87.0 % of the physicians reported having alerted the patients and their relatives further about the genetic disease and for the need to screen the family. Family doctors reported always having conveyed that information to the families. One of the other specialists declared not to have mentioned the risk to the family.
needed.” Some physicians indicated a population-based screening should be made by GPs in order to find cases with high TfSat, but they also commented, “first it is important to sensitize family doctors”; while others stated this screening would be better done by other specialists (haematologists, hepatologists) and should not be made in local health care units.
Discussion To the best of our knowledge, this is the first study addressing physician perceptions of the importance of genetic counseling in the management of HFE-HH. We explored the main motivations physicians have for requesting molecular testing and/ or genetic counseling via a questionnaire about their sources of information on haemochromatosis and their main reasons for referral. Despite sample limitations, the results obtained allowed us to draw some conclusions regarding current medical practices of screening and early diagnosis and how these practices could be improved in order to increase the quality of intervention.
Sources of Information About Haemochromatosis Screening for Prevention of Haemochromatosis Clinical Consequences? Responses to an open question about the value attributed to screening as a strategy to prevent the HFE-HH clinical consequences, revealed there is a general awareness about the importance of implementing a family-based but not a population-based screening, Responses were varied: Many physicians pointed to the relevance of family-based screening by “referring to genetic centres” in the case where carriers of HFE mutation(s) were identified in a family “given the high prevalence of the HFE mutations in the Portuguese population,” mostly in the north of the country. Others were clearly more concerned about the general practice of population screening by stating, for example, “Screening should only be made after the detection of hepatic alterations and of iron overload and never randomly.” In terms of population-based screening, some physicians considered this strategy to be a good means of early detection, better treatment and prevention of symptoms in HFE-HH, especially those related to hepatic disease. Some respondents pointed to the importance of implementing this screening but commented, “it would be very expensive and there are other common pathologies, with a more severe prognosis, that still do not have a screening program.” Mention was also made about the fact that, “given the low incidence and prevalence of the disease in the population, a universal screening is not
In general, the physicians’ knowledge about haemochromatosis was mainly acquired during their undergraduate medical training and, particularly in the case of GPs, this content was generally not supplemented in further medical continuing education. This is an important point to take into consideration if we consider the fundamental role GPs should have in the correct management of HFE-HH, particularly regarding early diagnosis and advising families about screening. They are indeed the first line in detecting cases within the earliest phases. The results of this study clearly point to the need for more efforts to disseminate of knowledge about HFE-HH, particularly in post-graduate education for general practitioners. Although this study was designed to address the perceptions of physicians regarding the importance of genetic counseling in the specific management of HFE-HH, our conclusions are similar to those described in other studies suggesting that GPs must increase their understanding of genetics in general (Liaw 2010). Undergraduate education, training and support of GPs are now being considered by the National Health and Medical Research Council and Human Genetics Advisory Committee (Human Genetics Advisory Committee Meeting 2010), and it is well accepted that medical genetics in general, and genetic diseases in particular, are still underrepresented in postgraduate training programmes for GPs (Baars et al. 2005a, b; Plass et al. 2002).
Genetic Counseling in Hemochromatosis
Reasons for Referral The present study shows that the main reasons for referral for HFE genotyping and/or for genetic counseling are not different between GPs and other specialists. The main reason to request a diagnostic genetic test was, as expected, the finding of increased transferrin saturation, and the main reason for genetic counseling was the identification of a positive case in the family, criteria that fit with international guidelines (EASL 2010). Nevertheless, it is important to note and explore why there is still a high rate of inappropriate indications and lack of requests for genetic diagnosis and genetic counseling in affected families. In addition to some identified factors such as geographical distance, lack of motivation of the patient or associated costs (mostly for travelling since the service is free through the National Public Health System), our results show that physicians are still confused about the proper indications for diagnostic genetic testing as well as about the mandatory genetic counseling in the case of predictive genetic testing in affected families (Portuguese Law nº 12/2005 of 26 January— Genetic Personal Information and Health Information). Limitations of the Study The major limitation of the present study was the small number of questionnaires returned. The high percentage of “non-respondents” (305 out of 352 valid cases, 86.6 %) could be due to different causes. We considered “non-respondents” physicians whom we certified were still working in the place where questionnaires were sent and who declined to participate. Some of them, later contacted by telephone, admitted they were too busy to answer at the time they received the questionnaire and later misplaced it. Others declared they were absent at that time and never received the questionnaire. Others mentioned they had requested the test only once and therefore assumed their responses would not be relevant. It should be stressed that the questionnaires were first sent during the Easter period (April, 2011) and the deadline for response was at the beginning of the summer holiday season (July, 2011), therefore timing should not be a limiting factor. The highest number of requests was from the north of Portugal, due to the localization of our centre in Porto. The medical specialities more often requesting genetic testing and counseling for hereditary haemochromatosis patients and families were evenly represented in that sample. Practical Implications Although this study was specifically designed for the purpose of the management of HFE-HH, the fact that this is a common genetic disorder with clearly established recommendations for early diagnosis through family screening makes it a good model to test, more generally, the importance given by
physicians to the question of genetic counseling. Burke et al. (2006) have stressed core skills and genetics knowledge to evaluate family history, as well as recognition of clinical findings indicating a genetic risk, should be an important part of education for GPs. Without denying the essential role that specialists trained in genetics continue to provide for genetic diagnosis and counseling in a number of rare inherited conditions, one should also recognize that practitioners in both secondary and primary care also need to be equipped to deal with initial patient inquiries. In addition they also need to have an awareness of the potential implications of family history in order to offer information related to their specific area of practice and to refer individuals or family members appropriately to other health-care providers, including specialist genetic services (Skirton et al. 2010). A partnership among genetic counselors, medical geneticists, and primary care providers is also essential to develop effective policies, educational tools, and practice guidelines, including the appropriate uses of genetic testing (Burke et al. 2006). We believe genetic counsellors may come to play an important role in the future for the dissemination of HFE-HH symptoms, hereditary risk and preventive actions, thus putting into practice the desirable partnership between GPs and other healthcare professionals. Additionally, more research on how affected individuals experience the disease, how they transmit information to their family members, and how they perceive preventive actions, could be the focus of future genetic counseling studies. In this context, one should note the first generation of Portuguese genetic counsellors to receive training at the master level graduated in 2011. Therefore, their contribution to genetic counseling practice (including the well-known advantages of population education) within the Portuguese healthcare system should become apparent in the future. Research Recommendations In order to draw more generalizable and definitive conclusions, this study should be validated with a larger sample (in the north and, particularly, in the other regions) and gather more information regarding generic knowledge about the disease among the various specialties involved, particularly about the available prevention methods, such as secondary prevention (early detection with biochemical and genetic testing before it becomes symptomatic), and tertiary prevention (methods to reduce disability and mortality in patients already affected by disease). Nevertheless, one should note that this was the first national study addressing the issue of healthcare professionals managing Hereditary Hemochromatosis and, despite the limitations, the results suggest a previously unknown reality that demands further actions. Future research that includes alternative qualitative research methods such as focus groups or individual interviews may help to increase knowledge on this topic.
Leandro et al.
Conclusions The need and opportunities for genetic testing and counseling for HFE-related haemochromatosis are still not fully appreciated by many physicians in Portugal, although there are important steps in the global strategy for early detection and prevention of complications. The role of GPs is particularly important to improve proper and timely referral for genetic testing and counseling of patients and relatives. Towards this aim, GPs should be the main focus of programs aimed at increasing awareness and providing further education about haemochromatosis. These programs are also important, however, for internists and gastroenterologists. In addition, the future role of genetic counsellors in filling the gap of educational needs among the general population should not be neglected. Acknowledgments We are grateful to all participants for their time and valuable contributions to this study. This work was produced within the framework of a research seminar of the professional master course in genetic counseling of ICBAS, Universidade do Porto, and was funded in part by the Calouste Gulbenkian Foundation, through a fellowship to Bruna Leandro, and by the Portuguese Foundation for Science and Technology (FCT), through a postdoctoral fellowship to Milena Paneque (SFRH/BPD/66484/2009) and through the project PIC/IC/82785/2007. We also thank Carol Ann Harley, at the IBMC, for detailed revision of the manuscript. Disclosure of Interest The authors declare that they do not have any actual or potential conflict of interest. They have full control of all primary data and they agree to allow the journal to review their data if requested.
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