Presented in part by b D.J. van Leeuwen at the AASLD Clinical Research Workshop “Investigating the Genetics of Liver Disease” directed by Drs. Edward L. Krawitt and Christopher P. Day during the meeting of the American Association for the Study of Liver Diseases (Digestive Disease Week 2005), Chicago, IL, May 14, 2005.
Potential conflict of interest: Nothing to report.
Advances in molecular genetics challenge the hepatology community to understand and implement genetic knowledge. Despite excitement about the potential benefits of new genetic information, concerns have been raised about the inappropriate use of genetic testing, clinicians' incorrect ordering and misinterpretation of test results, and discrimination in employment and insurability based on tests results. Among the public there is fear and mistrust, in part based on horrifying historical events that were gross violations of medical ethical standards. Clinicians, scientists, patient advocacy groups, and government agencies worldwide are debating the optimal legal protections to prevent abuse. In addition, these groups are developing clinical guidelines for optimal use. Traditional ethical and legal standards of confidentiality between physicians and their patients are under scrutiny. A new principle, “the duty to warn,” is emerging that has applications specific to genetic testing and may conflict with the duty to maintain patient confidentiality. Emerging ethical, legal, and social issues involve the appropriate use and protection of confidential data in tissue and serum banks. Education of the profession and the public at many levels will increase the likelihood that the unraveling of the human genome will maximally benefit society. If fear of genetic testing can be alleviated, selection bias in research could be reduced. Professional and lay organizations concerned with liver disease should consider a more active role in the public and professional debate, and foster education at all levels. (HEPATOLOGY 2006;43: 1195–1201.)
“The problem lies not in our genes, but in the interpretation at a social level. One way we can resist the genetic determinism that constitutes part of the threat of greater discrimination is to demonstrate that we can, as a society, accommodate genetic advances while integrating rather than marginalizing, people with disabilities” Buchanan et al., 20001
Genetic testing is widely available in the developed world. In the United States in January 2005, 587 laboratories offered genetic tests for 1,092 diseases of which 762 were for clinical use and 325 for research use. Eleven tests kits had been approved or cleared by the FDA. However, most tests were “home-brew” tests from laboratories approved by Clinical Laboratory Improvement Amendments (CLIA).2 Genetic tests now are being ordered more frequently for the diagnosis of liver disease by both practicing clinical hepatologists and researchers.
This contribution from a practicing hepatologist/investigator and a neurologist/clinical ethicist considers some of the most pressing ethical, social and legal questions that surround genetic testing for liver disease. We explain the basis of societal fear, and the importance of including the public in study design to minimize fears and enhance the likelihood of obtaining valid genetic information. We review changing ethical, social and legal standards around the “duty to warn.” We examine the exclusiveness of genetic information. We discuss confidentiality and ownership of human material as it pertains to blood and specimen repositories. Finally, we suggest potential roles for the AASLD, the American Liver Foundation, and related societies to address these issues for hepatologists.
Societal Fears About Genetic Testing
The prevailing societal fears of misuse of genetic information were summarized in a letter from the Chair of the Secretary's Advisory Committee on Genetics, Health and Society (SACGHS) to then DHSS Secretary Thompson3 in 2003, the year that the human genome was described in its entirety:
“… it is clear, that genetic information can be used in unfair, unjust and harmful ways and that the people are very fearful of such misuse. These fears are discouraging people from participating in genetic research and from undergoing genetic testing beneficial to their healthcare. They are causing people to pay out-of-pocket for genetic tests to prevent their tests results from entering their medical records. Quite simply, these widely held fears are preventing people from taking advantage of the benefits that genetic technology offers and hindering further advances in genetic research and test development…”
This letter was written in support of the United States Senate Bill 1053 (Genetic Information Nondiscrimination Act of 2003), approved in October 2004. In the U.S. House of Representatives, a bill was introduced (House Resolution 1910), the Genetic Nondiscrimination in Health Insurance and Employment Act encompassing a much broader number of regulations and protections, which therefore was more controversial. In February 2005, the new Senate (109th Congress) again approved the Bill (now Senate Bill 306) unanimously, but the House has yet to act and therefore no bills have been signed into law as of March 2006.2
In addition to regulatory and legislative activities, professional societies are drafting or have drafted guidelines for physicians and other parties.4, 5 Investigators at the Centers for Disease Control and Prevention, recognizing the importance of broad population-based studies to assess the impact of genomic testing, found that 21% of the population was unwilling under any circumstances to allow donation or storage of blood or tissue samples for current or future research.6 This finding emphasizes the importance of guidelines that are developed and understood by the society.
Background of Ethical and Social Fears and Mistrust
Historical events concerning specific genetic and general ethical issues contribute to societal fear and mistrust. The public is only too familiar with the infamous eugenics policies of the Third Reich. They are less aware that in the 19th century, eugenicists with varied political backgrounds and motives worked in the United States, Europe, and elsewhere.7 These eugenicists advocated a role for governments to foster breeding for those with what were then considered socially desirable traits, and sterilization for those who were considered to have socially undesirable traits, including criminals and the poor. Accepted eugenic concepts led to laws allowing coercive sterilization in Scandinavia and many American states by the mid-1930s. In 1927, the U.S. Supreme Court ruled: “The principle that sustains compulsory vaccination is broad enough to cover Fallopian tubes…..”8 As a result of these laws, tens of thousands of women and men were involuntarily sterilized because of the assumption that their offspring would be an “undesirable product.” A recent professional statement was adopted that clearly repudiates forced sterilization programs and asserts that they “never should happen again.”4
A recent example of the misuse of specific genetic testing data is the Burlington Northern Santa Fe Railroad (BNSF) case, discussed in a review of the implications of genomic medicine.9 The BNSF, at the suggestion of their medical advisor and without informed consent, collected blood samples of their employees to test them for a rare mutation causing hereditary neuropathy with liability to pressure palsies, a condition with a prevalence of 3-10/100,000 that is associated with carpal tunnel syndrome, a common cause of worker disability.10 Their intent was to minimize or deny workman's compensation from employees seeking disability from carpal tunnel syndrome. This case exemplifies how misuse of knowledge and bad judgment can enhance societal fears of the abuses of genetic testing. The U.S. Equal Employment Opportunity Committee (EEOC) promptly stopped the testing and settled the claims.
Medical research scandals resulting from violations of ethical principles and undisclosed conflicts of interest in general have further diminished the public's trust. The nature and extent of this mistrust varies among racial and ethnic groups. While it is true that past research scandals victimizing certain racial and ethnic groups, such as the U.S. Public Health Service Tuskegee study, contribute to distrust, other cultural issues and misperceptions play a role.11 In the Tuskegee Syphilis Study, poor black men were enrolled in a study of the natural history of syphilis and were not only purposely left untreated by the researchers even after highly effective therapy with penicillin had become available, they were prevented from accessing available therapies. Disturbingly, the study continued until 1972 when a USPHS investigator reported it to journalists, and the ensuing publicity promptly terminated the study.
Fears also arose from the Human Genome Diversity Project. Despite its laudable goal to better understand biological diversity, it backfired over public concern about stigmatizing groups based on ethnic, racial, or genetic factors.12 The profession and the public may misperceive the scope of testing of patients, especially those investigating genetic predisposition and environmental variables (Fig. 1). Public concern over conflicts of interest between investigators and pharmaceutical companies and data on the frequency of data withholding or misreporting among scientists have further diminished the trust in medical and scientific integrity.13–15
Despite the public's perceived fear of the abuse of their genetic information, only a few cases of such abuse have been referred to courts, which usually have upheld the rights of the individual. A few cases involving liver disease were mentioned in congressional hearings. The health insurer Humana refused insurance coverage to the two children of Heidi Williams because they were known carriers of alpha-1-antitrypsin deficiency. Terri Seargent was fired by her employer when diagnosed with mild alpha-1-antitrypsin deficiency because she required expensive medication. The EEOC (U.S. Equal Employment Opportunity Commission) made a finding of discrimination under the Americans with Disabilities Act (ADA) and the case was settled.16 At a public meeting of SACGHS, Phaedra Malatek testified how her family had refused hemochromatosis testing in spite of a strong family history because of discrimination fears related to health insurance and future employment of her children. A recent study suggests that such fears are not unfounded.17
The few reported cases of discrimination by health insurers and employers have raised important questions. How widespread is the practice? Are affected people aware of discrimination? Are there disincentives for scientists to publish results? Are cases settled out of court?14 Several reports quantify the public perception of fear.2 One study claimed that as many as 22% of respondents or their family members believed they were denied health insurance because of a genetic condition.18 Of 91 participants in a study on hereditary pancreatitis, 22% feared medical insurance discrimination. There is evidence that numerous institutions and businesses continue to discriminate, including life insurance companies, adoption agencies, and the military.19
Regulatory and Legislative Responses
Public fears and publicized cases of genetic testing abuses have led to national and international legislative activities and the drafting of guidelines adopted by professional societies such as the American Society of Human Genetics. A fixed percentage of funding for the Human Genome Project was allocated to promoting studies in ethical, legal and social issues (ELSI). A number of websites are available for further guidance (see Web Resources). A considerable effort has been made to create a transparent and protected environment for the use of human products for future research (blood and tissue banks), as will be discussed below.
Legislative activities have been centered around the issues of (1) denial of health insurance and higher premiums based on individual/familial information; (2) bans on disclosure of information for underwriting purposes; and (3) prohibition of using genetic information for employment decisions. From legal and societal perspectives, different theories govern rules of health insurance (“all are entitled”) and disability/pension agreements (“voluntary choice elements”).
Changing Perspectives on Ethical and Social Standards
In a recent review, Knoppers and Chadwick20 drew attention to “emerging trends in ethics” of human genetic research. They noted a striking evolution of ethical and legal themes in only one decade. At the start of the Human Genome Diversity Project in the early 1990s, ethical concerns targeted genetic counseling, testing and screening, genetic discrimination, stigmatization of certain groups, and prospects for gene therapy. While these issues remain valid, guidelines have helped resolve them. More recent ethical themes include genetic enhancement, genetic essentialism, and reproductive cloning (e.g., Dolly, the cloned sheep), pre-implantation genetic diagnosis, commercialization, patenting, DNA banking, and pharmacogenetics. One of the most challenging emerging ethical issues is establishing an optimal balance between respecting individual rights/personal autonomy and the benefits of genetic knowledge to a society at large when effective prevention and targeted interventions are available.
Debates within international bodies, such as the World Health Organization, reflect the complexity of developing international standards and consensus in societies that differ deeply in cultural values.16, 21 The question has been raised of the obligation for reciprocity in genetic testing: may individuals require selectively potentially beneficial testing (should society provide this?), but have no obligations to offer their blood, tissue and related information to enhance further understanding through research?22
Is Genetic Testing Exclusive Knowledge?
One unresolved question is whether genetic testing is exclusive and therefore requires a greater protection of privacy and confidentiality than other medical information.23 What genetic information may harm patients more than other medical information such as family history or social history (e.g., drug or alcohol abuse, violent behavior), and can this harm be mitigated or prevented? Some have argued that genetic information is more alike, than different from other health information.24 For example, the stigma of a sexually transmitted disease may be more significant than the potential for a genetic disease. The more exclusively the information is treated, the more fears and misapprehensions may become an obstacle for progress.24
In our medical center, medical records are digitized with protective measures taken to prevent inappropriate access. Interestingly, clinical laboratory values of albumin, prothrombin time, blood glucose level, creatinine, and alpha-fetoprotein do not have specific added protection. However, access to the hemochromatosis genetic tests and the alpha-1-anti-trypsin level are restricted identically to HIV serology test results, requiring a double sign-on procedure that monitors users. From a hepatologist's perspective, it is ironic that the most relevant prognostic information is derived from the less-protected than the more-protected information. The novel feature of genetic information is the increased potential that the person carrying a specific gene (mutation) may develop a health problem that can be identified prior to any other test abnormality or clinical symptom. It has become increasingly clear, that the disease manifestation (phenotypic expression, penetrance) is much less predictable than generally assumed.
Recent information about the prevalence verus penetrance of hereditary hemochromatosis (HH) illustrates this point. A decade ago HFE genes were discovered and found to be commonly present in Caucasians (1/200-400). The initial studies were largely performed in patients with clinically apparent hemochromatosis and suggested a major penetrance of the gene, because the majority of patients were homozygous for the most important (C282Y) HFE gene mutation. However, subsequent cross-sectional cohort population studies from Europe, United Kingdom, and North America have shown that biochemical penetrance occurs in up to 75% of subjects, but that the clinical penetrance (symptomatic disease) is much lower, namely 2% to 4%.25, 26 The current information on the prevalence of mutations in both family members after identification of the proband, and the results of population based studies with significant disease as much affecting patients identified by population screening as those in “hemochromatosis families” are furthering the debate as to whether population screening should be recommended.27, 28
Even with the ability to detect a gene that predicts a 100% fatal outcome, such as the gene for Huntington's disease, the natural course and the time of onset can vary tremendously causing a variety of complex social and ethical issues.29
Unexpectedly other issues may arise from genetic knowledge, such as paternity disclosure. To what extent can and should we prospectively explore with and seek consent from families about how much genetic information they want to know — an important aspect of counseling? Who in the family should be involved in the decision-making? What if family members disagree? Although genetic testing can be ordered easily, explaining the results of those tests can be difficult, particularly when unforeseen or unexpected results are found.
Finally, the exclusivity of genetic information recently has been questioned from a novel legal perspective, namely physicians' “duty to warn” a patient's family members about their hereditary or infectious disease risks.30 Until recently, the confidentiality requirement of the patient–physician relationship dictated that no information could be disclosed to another party unless required to do so by law, or unless the patient had a legally reportable disease. In recent legal cases, however, judges questioned these traditional ethical obligations and identified certain circumstances that mandated unconsented notification of others known to be at risk.31
The Superior Court of New Jersey, Appellate Division recognized “a physician's duty to warn those known to be at risk of avoidable harm from a genetically transmissible condition” (Safer v. Estate of Pack).32 In the 1950s, Donna Shafer's father was treated by Dr. George Pack for colon cancer that had developed in the setting of familial polyposis. The court ruled that the physician who knew she was at risk for colon cancer should have warned her so she could seek appropriate surveillance and treatment.
A few similar rulings have spurred debates, for example, over the obligation to report the presence of a breast cancer gene to relatives. Ideally, the patient should take the lead role to inform her relatives, but what if the patient refuses? This new “duty to warn” conflicts with traditional confidentiality rights and HIPAA regulations. How the conflicts will be resolved in unclear.30 Similar issues have emerged around unconsented warning for risk of communicable diseases. For example, should hepatitis B infectivity be communicated to others if the patient refuses?31
In a detailed review,33 Keeling states that genetic harm should be approached using the commonly accepted principles of negligence. Negligence for genetic harm occurs when it “(a) is foreseeable; (b) has the salient features of vulnerability, the health professional's knowledge of the risk of the genetic relative and the determination of the affected class and individual result in a duty of care being owed to the genetic relative; (c) is part of the standard of care required to fulfill the duty to warn should be the expectations of a reasonable person in the position of the relative; and (d) causation is satisfied as the harm is caused by the failure of the intervention of the health professional”. Legislation in Australia is under consideration based on such principles (Report of the Commonwealth of Australia, Review of Law Negligence report 2002). Many jurisdictions favor limited disclosure regulations based on similar principles (World Medical Association, World Health Organization, Council of Europe, Nuffield Council on Bioethics, Privacy Commissioner of Australia). The harm for at-risk individual should be grave and imminent and an effective intervention should be possible.5 However, geneticists have reached no consensus about what “serious harm” means, and many believe that it requires further definition.34
Is There Adequate Understanding of Medical and Genetic Testing?
A recent report by the American Management Association (AMA) provides data on the use of medical and genetic testing by employers.35 Sixty-eight percent of major US firms require medical exams for new hires to assess “fitness for duty.” 1.3% of employers required testing for sickle cell disease and 0.4% of employers required testing for Huntington's disease. A family history was required by 21% of employers. The report commented on the very limited understanding of employers about what they were actually testing and what genetic testing comprised.
In the Netherlands, the homeland of the first author, concerns about genetic testing have led to a covenant that was signed by all insurance companies targeted to prevent the discrimination of asymptomatic individuals using genetic test results. It also formulated rules limiting an obligation to report known positive tests in asymptomatic individuals who requested insurance. At the same time, pathologists incorporated new guidelines to protect sensitive information (after a major scandal concerning the sale of fetuses for research purposes), and they suggested guidelines for the scientific community for use of stored tissue. In other countries and in international organizations such as the World Health Organization, debates and regulations or laws have been proposed or enacted.
Blood and Specimen Repositories
Blood and specimens stored in repositories are vital for future research and funding of many investigators.36 Strict regulations could limit the scope of the investigations, and therefore also limit the access for funding of certain types of research. There is little debate over human material that was to facilitate the diagnosis in a specific patient. But to what extent does one (or a legal representative) maintain “ownership” of the material?22 And to what extent does the investigator need specific and repeated consent in case of future testing? Assuming that blood and tissue samples are completely anonymous, should “society” become their owner or custodian based on the assumption that all should contribute to the common good of advancing science? Is true anonymity feasible? Is anonymity desirable or will it hinder progress when new information becomes available? Is the hepatology community ready to accept full responsibility and liability to implement comprehensive informed consent? We suggest that oversight of some type should be conducted, and the society at large should be represented in major decisions. Several guidelines have been implemented or are under current debate.37 An unresolved and challenging question centers on property rights as they pertain to human tissue specimens.22 The advantage of expanding the size and scope of biobanks can be considerable, but they may also create new challenges from ethical and legal perspectives.38
Potential AASLD Agenda
The AASLD and its members should actively participate in the societal debate, particularly on issues specific to hepatologists. We specifically offer the following suggestions:
1Develop general practice guidelines for the use of genetic testing in clinical and research settings, and add disease-specific recommendations as attachments.
2Develop these guidelines in association with and incorporating input from interested professional and lay organizations.
3Encourage the expansion of knowledge in this field jointly with genetic counselors.
4Encourage appropriate professional education in the proper use of genetic testing. Include issues such as:
How and who will provide pre- and post-test counseling?
What is the predictive value of information? Is the condition treatable?
What information will be disclosed? A specific test only? Will paternity surprises be disclosed?
The potential for harms due to providing information (psychological sequelae for individual and family, stigmatization, discrimination)
The need for consent if samples are obtained for future use (identifiable vs. anonymous use)
The desirability of easy referral and access to information of patients interested in hereditary components of their disease and its implications using or expanding available genetic counseling services.
The establishment of review boards with input from the profession and lay groups to identify potential cultural sensitivities impacting the responsible use of testing in communities and limiting validation of research questions
Educational efforts that focus on the pros of the application of genetics in individuals and society
Undergraduate and graduate education in any of the biomedical sciences
5Enhance community outreach activities that increase knowledge about the applications of genetics in medicine and specifically liver disease. These can be illustrated by positive examples including the rapid advancing field of pharmacogenomics and prevention of drug toxicity and should help to alleviate societal fears. Target groups should include public forums such as high school education/biology classes and lifelong learning programs for retirees and others.
6Educate policy makers, the legal profession, and insurance carriers about the risks and benefits of genetic testing. Make concerted efforts to implement population screening recommendations.
7Textbook and journal editors should emphasize the implications and limitations of recommended or proposed genetic tests.
8Standardize and align policies with the worldwide scientific community for storage and use of stored blood and tissue specimens.
The impact of such an agenda could be considerable. There should also be alignment with national and international professional societies (EASL, APASL, IASL) with a specific responsibility to bring in relevant aspects of liver disease. There is no need to reinvent the wheel, and cooperation with other organizations needs to be sought to take optimal advantage of their expertise. Patient advocacy groups such as the American Liver Foundation and other specific disease oriented groups should be included in the implementation of this agenda. Education on the applications of genetic information should start with a focus on current and future generations of scientists and clinicians.
The Practicing Hepatologist
Finally, we offer a few suggestions for managing and assisting patients who face decisions about genetic testing to optimize their medical care
1Document conversations with patients, relatives and referring physicians. Documentation can offer sentences such as “I discussed…..”, “gave handout and referred to specific website, or to genetic counselor”, but also events that testify to feedback such as “brought the iron studies of his brother and sister.”
2Provide clear recommendations, and in case of uncertainty appropriate referral to a genetic counselor.
3Consider to what extent a protocol/institutional approach to certain diseases would enhance quality of care.
4Follow legal standards such as “What could a physician reasonably be expected to do taking into account specific aspects of the individual case and established standards and guidelines……”
We are most appreciative for the guidance and help from many professionals at Dartmouth-Hitchcock Medical Center and elsewhere. We gratefully acknowledge the help derived through web resources.