GI Ethical Issues

From Gastroenterology Update, sponsored by Cleveland Clinic, Digestive Disease Institute

Educational Objectives

The goal of this program is to help resolve ethical dilemmas in genetic testing in inflammatory bowel disease (IBD) and colorectal cancer. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss some of the ethical dilemmas associated with genetic testing for IBD.

2.   Describe the influence of environmental factors on IBD.

3.   List the genes involved in IBD.

4.   Recognize the genetic features of familial adenomatous polyposis and Lynch syndrome.

5.   Explain the importance of informed consent for genetic testing in IBD and colorectal cancer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Rubin receives grant support from Procter & Gamble Pharmaceuticals, Salix Pharmaceuticals, and Pro­metheus Laboratories, is a consultant for Procter & Gamble Pharmaceuticals, Prometheus Laboratories, Abbott Im­munology, UCB Pharmaceuticals, Given Imaging, Shire US, and Millenium Pharmaceuticals, and is on the Speakers’ Bureaus of Abbott Immunology and UCB Pharmaceuticals. Dr. Burke and the planning committee reported nothing to disclose.

Acknowledgements

Drs. Rubin and Burke were recorded at Gastroenterology Update, held September 11-12, 2008, in Cleveland, OH, and sponsored by the Cleveland Clinic, Digestive Disease Institute. The Audio-Digest Foundation thanks the speakers and the Cleveland Clinic, Digestive Disease Institute for their cooperation in the production of this program.

Ethical Dilemmas with Genetic Testing in IBD

David T. Rubin, MD, Associate Professor of Medicine, University of Chicago Medical Center, Chicago, IL

Genetic testing in inflammatory bowel disease (IBD): one side states genetic testing should be treated like any other diagnostic or prognostic test; other side states genetic testing special, since genetics unchangeable, predictive of future, implies inheritable risks, and IBD affects relationships and person’s identity; dilemmas  —  inadequate in­formation about genes and markers; interpretation, ie, not knowing what to do about information; perception of genes and genetic information; confidentiality issue; testing minors; issue of needing to know vs wanting to know; some issues legislated against (eg, insurance discrimination)

Understanding genetics in IBD: basic and fundamental approach starts with premise that classification system in IBD outdated; patients classified broadly into Crohn’s disease (CD), ulcerative colitis (UC), and 10% to 15% inde­terminate colitis (IC); different types and phenotypes of disease expression, with variable responses to therapy; in families in which >1 member has IBD, discordance of disease type often seen, with changing phenotype over time (biggest influence surgery, especially colectomy with ileal pouch anal anastomosis [IPAA]); current theory about IBD  —  genetically susceptible individual exposed to environmental trigger that leads to dysregulated immune ab­normality, causing dysregulated immune system; may have genetic variants in any of different components of IBD

Goals of IBD management: confirmation of diagnosis; induction and maintenance of remission; avoiding complica­tions of disease and therapy; surgery, when necessary, and avoidance, when possible; possible actions  —  markers to clarify diagnosis and how disease will behave over time; prevention in susceptible individuals and understanding who is most susceptible; genetic marker(s) that predict(s) response to therapy; recognizing who is at greatest risk for side effects; risk for colon cancer (individuals with genetic risks and predisposition to colon cancer have in­creased risk for cancer with IBD); surgery outcomes; cancer risk model  —  does not fit most IBD patients; way to study genetics of IBD; 4% to 8% risk that child of single parent with IBD will develop disease

Family aggregation: well described in IBD; positive family history in 5% to 20% of patients; having sibling with CD or UC single greatest risk for IBD; having both parents with IBD increases child’s risk to »30% by 28 yr of age; with IBD in family, 75% of time, type of disease, location, and extraintestinal manifestations concordant among those individuals

Predictors of discordance: environmental influence;  other possible causes include living in industrialized world, where things “too clean” (hygiene hypothesis); latitude (colder climates have higher incidence of IBD); spread of gene from “founder effect” (relatively rare disease amplified when group of people intermarry); likely many types of IBD; genetic discoveries do not explain “Jewish factor” of IBD; monozygotic twins have »40% likeli­hood of both having CD and 10% likelihood of both having UC, confirming that CD “more genetic” and that something else triggers disease; in dizygotic twins, likelihood similar to that of regular siblings

Environmental factors: smoking  —  potent factor that influences disease; in siblings with IBD, sibling who smokes develops CD and nonsmoking sibling develops UC; onset of IBD after infection acquired during travel; concept of microbiome, ie, interaction of commensal flora with mucosa of gut ; increasing incidence of IBD in India, China, and Japan not explained clearly by genetic shift in population, but may be due to environmental factor; typical fea­tures of complex genetic disorder  —  multiple genes explain disease; having same genotype does not necessarily equate with disease; environmental factors that turn disease on or off

When to consider genetic testing: genetic test factors  —information that must be determined or known about ge­netic test before its use in clinical practice; include predictive value, implications of result, availability and afford­ability, acceptance by population, and whether action can be taken on information

Genes in IBD: associations described in 2 major ways; earlier, linkage studies used; currently, genome-wide associa­tions used; 40 CD genes now confirmed and one UC gene described; NOD2/CARD15  —  on chromosome 16; 3 variants account for most, but not all, of observed mutations; individuals who have variant most often have ileal CD, younger age at onset, and fibrostenotic behavior type; also have 20- to 40-fold increased relative risk of hav­ing CD, compared to non-CD white controls, especially if homozygous (same variant on both chromosomes) and penetrance quite low; having NOD2 variant does not mean individual will have CD, but that individual suscepti­ble (although susceptibility so low, difficult to use information in practice); gene codes for the way that body re­sponds to environment (related to transmembrane exposure and response to bacteria)

Clinical implications: earlier time to surgery, and to reoperation shown in children and adults; individual more likely to get chronic pouchitis (more of CD genotype); pleiotropy means single gene may have multiple func­tions; NOD2 increases likelihood of graft vs host disease in allogeneic stem cell transplant patients and early-on­set breast cancer; issue of whether patient should know about other implications of positive marker; if all identified markers tested, the more markers positive, greater likelihood of developing complicated CD; question of whether patient should be treated more aggressively and how to interpret information; concluded that genotyp­ing may help determine risk profile to identify patients for early effective therapy; pharmacogenomics— thiopurine methyltransferase (TPMT) genotype or phenotype used when starting azathioprine or 6-mercaptopu­rine (6-MP); genetic marker may have other implications for patients; genotype related to sulfasalazine toxicity and corticosteroids, with issue of cost becoming concern

Patient factors: if looking for specific marker, helpful to start with affected individual; individual must have desire for testing; does not require formal informed consent process, but better education; genetic exceptionalism  —  results have special meaning or implications and possibly predictive for other family members and of future events and outcomes; vulnerable child syndrome  — parents suspect or know that children at risk for disease; what predicts patient’s interpretation of information  —  degree of heritability of disease; number of family members affected; se­verity of illness; implications of result; speaker’s survey  — designed to determine   patients’ interest in genetic test­ing for IBD; similar study in Canada; in both surveys, number one patient concern ability to obtain life insurance if known to have marker, even if already had disease; when asked about degree of certainty preferred to allow testing, using standard reference-gamble paradigm, patients willing to accept 40% certainty; focus groups raised issues of employment and insurance discrimination and whether testing helped with treatment; unknown, as yet, what mark­ers mean and how they work together or separately; need to understand who to test, how to test, and when to use test

Challenges of genetic testing: clinical validation; whether it will affect treatment decisions; whether some actions for prevention can be taken; development of protocols for testing; ensuring that tests clinically available, with infor­mation for appropriate interpretation; robust education program; at present, insufficient diagnostic and prognostic information to support use in practice

Ethical Dilemmas in Genetic Testing for Colorectal Cancer

Carol Burke, MD, Director, Center for Colon Polyp and Cancer Prevention, Department of Gastroenterology and Hepatol­ogy, Cleveland Clinic, Cleveland, OH

Inherited colorectal cancer (CRC) syndromes: autosomal dominant and highly penetrant; early onset of colon can­cer and metachronous cancer (risk-reduction surgery offered); extracolonic benign and malignant tumors

Genetic testing: available for Lynch syndrome, familial adenomatous polyposis, MYH-associated polyposis (MAP), and more rare polyposes (eg, Peutz-Jeghers syndrome, juvenile polyposis, PTEN hamartoma tumor syndromes); types  —  diagnostic (for individuals with known disease) and predictive (for at-risk or unaffected members of fam­ily); why testing important  —  genetic conditions often have implications for organs outside of colon; other family members possibly at risk; accuracy of risk assessment and medical management recommendations

Familial adenomatous polyposis (FAP): caused by mutation in adenomatous polyposis coli (APC) gene; phenotype easily recognizable, with hundreds to thousands of colonic adenomas; 100% risk for CRC, if untreated (risk <100% in attenuated or MAP); extracolonic features  —  fundic gland polyposis in £88% of individuals, with low-grade dysplasia in £41% and high-grade dysplasia in 3%; duodenal adenomas seen in all, with overall risk for periampul­lary CA of 4% (£36% in individuals with stage 4 duodenal polyposis); desmoid tumors and thyroid carcinoma in 15%; variety of other  conditions, eg, osteomas, fibromas, lipomas; supernumerary teeth can alert parents to pres­ence of APC gene in child

Lynch syndrome: due to DNA mismatch repair gene mutations (MLH1, MSH2, MSH6, or PMS2); leads to defective DNA mismatch repair (microsatellite instability [MSI]); phenotype right-sided colon cancer with unusual pathol­ogy by 45 yr of age, (ie, mucinous or signet cell tumor pathology, tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction, and absence of “dirty” necrosis); extracolonic tumors mostly endometrial cancer in £60% of women in these kindreds; also see gastric, transitional cell of urinary tract, small bowel, ovary, pancreas, and biliary tract cancers (10%-20%); MSI testing or immunohistochemistry of CRC recommended in individuals who meet re­vised Bethesda criteria; in Lynch syndrome and FAP, genetic testing required to perform early and aggressive sur­veillance for colon and extracolonic organs at risk; first step genetic counseling and testing; colonoscopy started at 21 yr of age or 10 yr before earliest cancer in relative; gynecologic screening between 25 and 35 yr of age; risk-re­duction surgery of female pelvic organs shown to reduce risk of developing peritoneal, ovarian, and endometrial cancers

Genetic testing: performed if 1) individual has personal or family history suggestive of inherited cancer susceptibil­ity, 2) test can be adequately interpreted, and 3) result aids in diagnosis or influences care of individual or at-risk family members; performed in setting of pre- and posttest counseling in individual with disease; if testing per­formed in children and no mutation found, unsure whether unable to find mutation causing disease or absence of disease, so important to test affected individual; if test negative — patient does not have mutation;  interpreted only in context of known family mutation, or current technology unable to detect mutation, or variant of uncertain sig­nificance obtained; requires testing of other family members (with and without disease), and interpretation based on these results

Informed consent:  talk to patient about — specific test and implications of positive or negative result; possibility that test will not be informative; options for risk estimation without genetic testing; risk of passing on disease to children and its implications (be prepared to offer support if psychologic distress seen); risk for employer and in­surance discrimination; confidentiality issues; limitations of surveillance and strategies for prevention; sharing ge­netic test results with at-risk relatives

Case: woman has mother who died from endometrial cancer (had MSH2 mutation or Lynch syndrome); 3 siblings; woman and 2 siblings present for genetic counseling; younger sister unaware of being adopted; patient decides to be tested for MSH2 mutation and tests positive; patient advised that at-risk relatives have 50% chance of having gene; adopted sister decides not to undergo genetic testing but wants to be screened for Lynch syndrome (annual colonoscopy) and is considering prophylactic hysterectomy; should physician tell adopted sister that she is not at risk? nondisclosure  —  60% of geneticists have experienced situations in which patients did not want to disclose re­sults to family members; reasons include fear of estrangement, employment or insurance discrimination, or change in family dynamics; some considered disclosing without obtaining consent but did not, due to fear of disrupting physician-patient relationship, belief that resolution could be obtained by other means, and concern about legal lia­bility; presumed reasons for nondisclosure of genetic information — desire not to cause worry or anxiety; assump­tion that information irrelevant; belief that family unable to cope with news; absence of contact with relatives; reluctance to take on responsibility; in small survey of hereditary nonpolyposis colon cancer (HNPCC), most pa­tients surveyed thought it their duty to warn at-risk relatives and would advise family if they had disease; 73% would give consent for counselor or physician to warn at-risk relatives; >50% wanted disclosure by health care pro­vider, even without their permission

Confidentiality and duty to warn: genetic test results confidential ethically and legally; individual autonomy to dis­close results; obligations to at-risk relatives best fulfilled by communication of familial risk to person undergoing testing; duty to warn acceptable when authorized by patient, in judicial proceedings, in cases of transmissible dis­eases, child abuse, domestic violence, or conditions that constitute danger to public safety; according to American Society of Human Genetics, physician should consider breaching confidentiality when attempts to encourage pa­tient to disclose fail, probability present that relative is affected (eg, Lynch syndrome, FAP), when harm serious and foreseeable, strong evidence present to support benefits of prevention, and harm of nondisclosure outweighs disclo­sure; legal precedents claims of negligence for failure to warn; Safer vs Estate of Pack  —  in 1950s, patient’s father treated for colon cancer with FAP; in 1990s, patient diagnosed with colon cancer and claimed that father’s physi­cian knew of hereditary nature of disease and negligent in failing to warn her of risk; trial court decided that physi­cian had no duty to warn; New Jersey Supreme Court decided physician had duty to warn patient’s family members known to be at risk for avoidable harm from genetic disease; physician found liable; Pate vs Threlkel  —plaintiff di­agnosed with medullary thyroid cancer; claimed that physician had obligation to warn at-risk children; ruling that reasonably prudent health care provider has duty to warn family members at risk for genetically transmissible dis­ease, but because of confidentiality concerns and practicality, Supreme Court of Florida stated that in any circum­stance in which physician has duty to warn of hereditary genetic disease, duty satisfied by warning patient of familial nature of disease

Ethics of decision-making: make best decision in particular circumstance; decision must be balanced; genetic test­ing and counseling should be part of informed consent process; individual must be supported to contact at-risk rel­atives; designate >1 family member to receive test results

Suggested Reading

Al-Sukhni W et al: Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome. Surg Clin North Am 88:819, 2008; Bronner MP et al: Genomic biomarkers to improve ulcerative colitis neoplasia surveillance. Am J Pathol 173:1853, 2008; Clarke AJ et al: Challenges in the genetic testing of children for familial cancers. Arch Dis Child 93:911, 2008; Cummings SA et al: The complexity and challenges of genetic counseling and testing for inflamma­tory bowel disease. J Genet Couns 15:465, 2006; Ensenauer RE et al: Genetic testing: practical, ethical, and counseling considerations. Mayo Clin Proc 80:63, 2005; Gollust SE et al: Community involvement in developing policies for genetic testing: assessing the interests and experiences of individuals affected by genetic conditions. Am J Public Health 95:35, 2005; Koessler T et al: Common variants in mismatch repair genes and risk of colorectal cancer. Gut 57:1097, 2008; Ku­gathasan S et al: Inflammatory bowel disease--environmental modification and genetic determinants. Pediatr Clin North Am 53:727, 2006; Lal S et al: Attitudes toward genetic testing in patients with inflammatory bowel disease. Eur J Gastro­enterol Hepatol 19:321, 2007; Massey D et al: Common pathways in Crohn's disease and other inflammatory diseases re­vealed by genomics. Gut 56:1489, 2007; McGovern D et al: New IBD genes? Gut 54:1060, 2005; Minkoff H et al: Genetic testing and breach of patient confidentiality: law, ethics, and pragmatics. Am J Obstet Gynecol 198:498, 2008; Offit K et al: The "duty to warn" a patient's family members about hereditary disease risks. JAMA 292:1469, 2004; Pasche B: Familial colorectal cancer: a genetics treasure trove for medical discovery. JAMA 299:2564, 2008; Schulmann K et al: Small bowel cancer risk in Lynch syndrome. Gut 57:1629, 2008; von Stein P et al: Multigene analysis can discriminate be­tween ulcerative colitis, Crohn's disease, and irritable bowel syndrome. Gastroenterology 134:1869, 2008.