I. SUMMARY OF THE PROBLEM No area of science has advanced our understanding of human disorders in such a short time as the field of molecular genetics. This research has led to a better understanding of the pathogenesis of many disorders of the gastrointestinal (1) and hepatobiliary system (2). In children, inherited disorders are some of the most common causes of chronic medical problems requiring hospitalization. Genetic testing will also expedite the clinical evaluation of patients, and help to clarify the uncertainty of many clinical diagnoses. It is also the long-term expectation that such gene discoveries will provide us with better insight into pathophysiology of these disorders, and therefore provide prospects for novel therapies. Some of the recent research advancements in the biology of gastrointestinal disorders include those for Hirsch-sprung disease, hereditary pancreatitis, and various forms of polyposis syndromes and congenital diarrheas (Table 1). The recent molecular characterization of disorders of the hepatobilary system includes those for various forms of glycogen storage disease, Alagille syndrome, various types of recurrent familial intrahepatic cholestasis, and Wilson disease. Ongoing research has exposed us to the true complexity of many disorders and has verified that some conditions that were once believed to be single diseases are in fact multiple disorders with similar clinical manifestations. In many instances, each disorder has a specific therapeutic intervention. Therefore, careful classification that may be provided best by genetic testing is imperative.TABLE 1: Biology of gastrointestinal disordersTABLE 1: Continued). Biology of gastrointestinal disordersTABLE 1: Continued). Biology of gastrointestinal disordersTABLE 1: Continued). Biology of gastrointestinal disordersTABLE 1: Continued). Biology of gastrointestinal disordersAlthough the defective genes responsible for many of these disorders have been identified in recent years, the molecular basis of several relatively common disorders have not yet been elucidated. Ongoing research of these disorders will assist in elucidating the underlying cause within the next several years. Current estimates suggest that the human genome project should yield nearly 140,000 genes. Certainly, through the research efforts of many international research groups that are funded by both public and private agencies, the structure of the majority of the human genome should be solved within the next year. The anticipated completion of the human genome project will mark the beginning of a new era in which the research focus will change from gene identification to defining the actual function of the proteins encoded by these various genes, and applying this vast amount of information to more effectively diagnosis and manage patients with both inherited and noninherited disorders. Despite these advancements, the actual integration of genetic technology into the clinical practice of pediatric gastroenterology has not come to fruition. To begin harnessing the tremendous data that will ultimately be provided by the human genome project, the World Congress of Pediatric Gastroenterology must consider ways of improving the interface between molecular research and the clinicians who care for patients with such disorders. The overall task for the working group on genetics was to identify areas of emphasis in which new approaches are required to facilitate the integration of genetic technology into the clinical practice of pediatric gastroenterology, hepatology, and nutrition. The group has identified several solutions designed to promote: 1) studying the molecular basis of all inherited disorders that would eventually lead to effective therapies; 2) educating physicians and other allied health care workers about the field of genetic disorders; and finally, 3) developing of screening criteria, diagnostic, and management guidelines for these inherited disorders. Along with several other specific suggestions, the working group strongly supports the development of an Internet website that would serve as the “centerpiece” for enhancing communication between scientists, physicians, and patients. This site would provide a “live” format to develop and execute ongoing basic and clinical science research projects. The second general recommendation is the development of international basic/clinical focus groups that will work toward developing research protocols, develop patient registries and DNA repositories for these various inherited disorders, and provide up-to-date information useful to the clinical management of patients. Translating the advancements provided by the human genome project into the practice of clinical medicine will be a pressing challenge for our subspecialty in the coming years. II. MAJOR ISSUES IN NEED OF INVESTIGATION OR IMPLEMENTATION The Continued Discovery of Inherited Disorders and Their Specific Treatments Despite the tremendous breakthroughs made in recent years in the area of inherited diseases, the underlying cause of a large number of disorders have not been determined. The working group fully supports and encourages further studies to define the pathogenesis of these remaining disorders. Because of the lifelong nature of many inherited disorders, the committee also encourages setting research priorities for disorders that present during childhood. Although some of these disorders are relatively uncommon, understanding the pathogenesis of even a rare inherited disorder will certainly have important implications that reach beyond the scope of the particular disease and provide us with a better framework to understand other more common noninherited disorders. For instance, the identification of the gene responsible for hereditary pancreatitis has given us better insight into the pathogenesis of other forms of pancreatitis, including alcohol-and trauma-induced forms of pancreatitis. Through the use of techniques such as targeted gene disruption, realistic animal model systems that mimic many human conditions have been developed for the first time and will provide real opportunities to elucidate many inherited and noninherited disorders. One of the significant obstacles to genetic mapping of monogenic disorders is the limited access that genetic researchers have to well-defined kindreds with particular disorders. This is particularly true for some of the relatively rare disorders. Investigators interested in mapping the gene responsible for a specific disorder generally rely on kindreds that have been previously published in the literature. It has become more difficult for clinicians to publish case reports about interesting and unique patients. Therefore, it is now very difficult to locate patients or families that may be genetically informative. Mechanisms must be developed to improve access of interested scientist to these potentially informative kindreds with inherited disorders. Improved access to such patients will expedite and improve the chance that linkage analysis can be performed and the responsible defective gene identified. There is also significant interest in identifying modifier genes that may dramatically alter the clinical course and therapeutic options of a patient. A modifier gene is a specific allele that alters the clinical manifestations and progression of a clinical condition. Modifier genes may account for the clinical variability that is sometimes seen between two patients with the same disorder caused by a similar or identical alternation of a disease-causing gene. Identifying modifier genes should assist in defining other genes involved in common pathways or programs. As the human genome project continues to identify the genes involved in many of these pathways, elucidating these developmental pathways may also offer clues to understanding the large number of congenital malformations that affect the gastrointestinal and hepatobiliary systems. Modifier genes have been implicated in several disorders, including Hirschsprung disease, polyposis syndromes, cystic fibrosis, inflammatory bowel disease, alpha-1-antitrypsin deficiency, and hereditary pancreatitis, to name just a few. Because of the complexity and variability of the human genome, the research efforts in the development and investigation thereof are caused by the interaction of several distinct alleles. Recent advancements in linkage analysis programs designed to identify the various loci that contribute to the inheritance of polygenic disorders should prove valuable in the coming years. It is anticipated that the identification of these various loci may assist in clarifying the dramatic clinical and therapeutic heterogeneity that exists within many of these disorders. The recent development of DNA microarray technology is particularly well suited for studying patterns of gene expressions in tissue samples of patients with various clinical disorders. The technology may also be helpful in developing genetic testing of a set of known disease-causing genes. Microarray technology can also be used to define “downstream” targets of disease-causing genes and may help elucidate other potentially defective genes that could account for a similar, yet distinct, clinical disorder. It is also recognized that microarray tools can be used to begin characterizing, and, therefore, classifying, many poorly defined disorders, including those that are currently classified as idiopathic. This advancement will be particularly useful as the function of many genes and their location within specific pathways become increasingly clear. Further studies along these lines may enable the use of such technology in the routine diagnosis of many disorders. The continued advancements in understanding the defective gene responsible for inherited disorders will provide an opportunity to establish genotype–phenotype relationships for the first time. It is generally accepted that the various clinical manifestations of a disorder are multifactorial, and include the specific mutation, modifier alleles, diet, and environmental factors. The overall objective of defining genotype–phenotype correlations would be to begin determining the contribution of each parameter, and to better predict clinical outcome and therapeutic options. By improving genotyping technology, phenotypic heterogeneity will be increasingly appreciated and should allow for the difficult process of teasing apart many of these factors. Focus groups could begin classifying the various clinical manifestations of particular disorders, and should help correlate genotype and phenotypic relationships. The ongoing availability for genetic testing, including the analysis of mutations by reliable and meaningful in vitro assays, will be required to complete these important correlations. Overall, a variety of approaches, ranging from structure function analysis of proteins to in vivo animal model systems, need to be encouraged and supported. Extending these studies further to clinical trial is the long-term goal. The focus groups should develop patient registries that have been shown to be very effective in enhancing the basic and clinical research of various disorders. Among some of the better-established registries are those concerning inherited polyposis and inflammatory bowel disease syndromes. Several large registries have been established that would identify families at risk for the diseases, and provide a mechanism to contact them for further research and clinical follow-up. Focus groups should begin interfacing with existing registries, and assist in the development of new registries for other disorders. Continuous public and private support to define the molecular basis of disorders is encouraged via standard investigator-initiated research proposals. Continued support in this area will provide a pool of well-trained investigators. Research techniques such as genetic mapping and microarray analysis show particular promise. Because many of these disorders are relatively rare, large-scale multi-center collaborative groups are required. Continued support of genetic testing for research purposes of all disorders is strongly encouraged. Support may occur by proposals submitted by single investigators studying a specific disorder, or by large research groups capable of analyzing a variety of disease-causing genes. The funding and development of an international Pediatric Gastroenterology website would serve as a platform to enhance communication between scientists, physicians, and patients and foster the basic and clinical research. The proposed site would also serve as a central point, or conduit, between physicians (or patients) and basic scientists interested in a particular disorder. This structure may also enable patients to volunteer for research protocols. New support is required to foster the development of international focus groups that will, among other things, develop patient registries and DNA repositories. Such registries will expedite analysis of genotype–phenotype correlations and provide access to all pertinent information on the Pediatric Gastroenterology website. Because of the large number of genes that are altered, better genetic screening techniques will need to be developed. Focus groups would also develop core clinical laboratories that would be capable of processing actual tissue samples and perform techniques such as microarray analysis. This arrangement should provide us with better clues into the pathogenesis of many disorders that are currently classified as idiopathic. A planning committee composed of members of the international community should be developed to form a consensus to carry out many of these recommendations. Education of Physicians and Allied Health Care Workers About the Genetics of Gastrointestinal and Hepatobilary Disorders The rapid pace of discoveries in the area of inherited diseases is unprecedented in the field of medicine. All too often, however, many of these breakthroughs and their clinical implications have gone unnoticed by patients and the physicians who care for them. Because of the growing complexities of medical practice, many clinicians are finding it increasingly difficult to remain updated on inherited disorders in their own subspecialty field. A contributing factor may be related to the inexperience that many clinicians have in understanding the methods used in molecular/genetic research. Therefore, the difficulty that many practicing clinicians have in both interpreting the information and deciding its clinical implications is an area that needs to be addressed. Physicians and their patients are particularly interested in easily determining whether genetic testing for specific disorders is available. If genetic testing is an option, learning more about the actual test samples, and how and where to send them, are frequently a difficult and time-consuming exercise for many clinicians. Informed consents are also required for genetic testing, and are usually specific for the requested test. The complexity of this inquiry can understandably be overwhelming, and certainly has discouraged many clinicians from pursuing genetic testing. A simplified method to obtain information about genetic testing currently does not exist, and the working group encourages the use of the previously proposed website to provide this type of information to interested clinicians: not only what tests are available, but also the predictive value of such tests and how to interpret test results. For patients to benefit directly from such discoveries, clinicians must become better informed about genetic testing and its implications in the daily management of patients. The movement of journal articles from the paper format to that of the Internet may improve access of practicing clinicians to this type of research. Several mechanisms to improve gastroenterologists' understanding of genetic disorders and testing are also envisioned. Annual and biannual international symposia and workshops that review and update the genetic breakthroughs to the practicing physician will be a particularly useful mechanism of informing the interested health care workers. Such symposia may be stand-alone conferences, or can be incorporated into the annual meetings of the various Pediatric Gastroenterology societies, including NASPGN, ESPGHAN, APPSPGAN, and LASSPGN. Mechanisms should also be developed that would allow the practicing physician to be notified about significant advancements in the field. Our working group encourages the development of international focus groups that could be sponsored by the World Congress, and could focus on various groups of disorders such as cholestatic liver disease and inflammatory disorders of the gastrointestinal tract. These focus groups could also summarize recent developments on a quarterly basis and the dissemination of the information with penitent references by e-mail to physicians. The Pediatric gastroenterology e-mail group with more than 800 members from 37 countries may facilitate this dissemination. Alternatively, the Journal of Pediatric Gastroenterology and Nutrition may consider designating a quarterly section dedicated to the dissemination of recent significant advances in the field. Pediatric gastroenterologists in training should become familiar with the area of the genetic basis of disease as they proceed through their medical training. The introduction of principles relevant to inherited disorders must be included in the curriculum of fellows in training, and specialty board examinations should be encouraged to test the breadth of the fellows' fund of knowledge in this particular area. Because information provided by the human genome project is clinically relevant, practicing physicians will require ready access to the latest pertinent molecular and clinical science information. The working group supports the use of the proposed international website as a format to provide brief summaries of new information to improve dissemination of information. Several international workshops and symposia are proposed whose focus would be to update clinicians about these critical discoveries, and also serve to enhance contact between physicians and clinical and basic science researchers. Methods of support include contracts, training, and career development awards and sponsored workshops and symposia. Subspecialty boards in Pediatric GI are urged to test physicians on these concepts of the biology and clinical implications of various inherited gastrointestinal and hepatobiliary disorders. Trainees should also be encouraged to enroll in a survey course on molecular genetics. Patient Education About the Benefits and Risks of Genetic Testing With the increasing availability of genetic testing for inherited disorders, patients must be well informed about the overall risks and benefits of testing before performing the test. Among the frequently described benefits of testing is that it may decrease the apparent uncertainty of the diagnosis, and also may modify the patient's therapeutic or surveillance guidelines. Genetic testing has also been suggested to improve patient compliance and is particularly useful for decisions related to family planning. One of the frequently discussed drawbacks of genetic screening is the potential insurance and employment implications that an abnormal test may have for the patient. Important psychological considerations also must be taken into account when performing genetic testing, especially for a disorder that has a delayed onset of clinical presentation. Many of these issues are receiving substantial international attention from policy makers and leaders in the areas of medical ethics and genetics. Family support groups are frequently a useful mechanism of obtaining answers that are beyond the traditional scope of physicians. Such family support groups may more effectively address issues such as lifestyle and educational concerns. The development of family support groups is strongly encouraged and could be located on the proposed Pediatric Gastroenterology website. The working group strongly opposes the use of genetic testing for insurance and employment purposes. We encourage national and international organizations to limit access to genetic test results to only the patient and their physician. This recommendation also applies to testing results obtained from presumed genetic carriers. The working group is against genetic discrimination and support legislative efforts to prevent it. The use of clinical registries to enhance the development of disease-specific family support groups is also encouraged. Groupings also facilitate the organization of private foundations to support research. The Development of Diagnostic Guidelines and Algorithms The availability of genetic testing has altered the diagnostic workup for many disorders. Despite their use in clinical medicine, carefully developed and tested algorithms that evaluate their effectiveness have not been established for most of these tests. At what point in the clinical evaluation of patient with a presumed inherited disorder should available genetic testing be performed? To answer the question, rigorously tested algorithms defining the usefulness and cost-effectiveness of many diagnostic tests must be performed. The clinical utility of a test is determined by the test's success in predicting disease and the availability of effective treatment. In the absence of such algorithms, the diagnostic evaluations for many clinical symptoms various considerably between clinicians, and is frequently based on clinical impressions and experience. Although this approach is very valuable and has been the standard of practice for many years, it will become more difficult with the increasing availability of diagnostic tests. The development of such algorithms and their eventual acceptance into clinical practice should help expedite the clinical evaluation of patients with such disorders. To facilitate the workup of patients with many of these genetic disorders, the working group supports the development of symptom-based diagnostic algorithms. All disorders will be categorized within groups based on predominant symptoms. For hepatobiliary tract disorders, the symptom-based algorithms should include but are not limited to 1) fulminant liver failure, 2) acute and 3) chronic hepatitis, 4) cholestatic jaundice in the newborn, 5) chronic jaundice, and 6) hepatomegaly. Among the gastrointestinal disorders, the algorithms should be established for 7) congenital diarrheas, 8) pancreatitis and pancreatic insufficiency, 9) inflammatory intestinal disorders, 10) chronic diarrhea, 11) failure to thrive, 12) GI bleeding, and 13) chronic vomiting. The categorizing of disorders in a symptom-based format should be especially useful in the daily practice of medicine and may allow for a more efficient assessment and diagnosis of patients, many of whom may have life-threatening disorders. The working group proposes that international focus groups consisting of leaders in these various fields should develop the diagnostic algorithms. The objective of such algorithms will be to provide a logical and cost-effective approach to the evaluation of such patients. An interdisciplinary effort will be necessary that will draw on the expertise of bioinformatics, molecular genetic researchers, and clinicians to better understand this process, and these proposed algorithms must be tested for their true accuracy. Grant support should be sought to assist the development of international focus groups that are interested in research projects whose aim is to define symptom-based diagnosis algorithms. Collaboration and communication between individuals in related yet different fields of research are critical to advancing our knowledge base. Therefore, we must encourage and foster interdisciplinary interactions. Federal and international support that could unite investigators and interested clinicians and encourage interactions between molecular scientist and clinicians. The proposed international Pediatric Gastroenterology website should contain the proposed and established diagnostic algorithms to enhance its availability to all clinicians. The working group supports the establishment of patient registries that would provide means to study the accuracy of such algorithms. The Development of Management Guidelines and Algorithms for Inherited Disorders The long-term objective of clinically applicable bench research is to elucidate the pathogenesis of these various disorders. A more thorough understanding of the pathogenesis of these disorders will eventually lead to more clinical trials. Such clinical trials will be particularly useful in the clinical management of many inherited disorders that have not been very well studied. The difficulty of establishing such management guidelines for these disorders may be related in the uncertainty of the diagnosis. The availability of genetic testing and ongoing research in the area of genotype–phenotype and modifier genes may assist in better understanding the likely clinical outcome of many of these patients. Guidelines that address the clinical surveillance and management schedule of patients with specific disorders and general genotypes may provide for a more rational approach. It will better define goals and patient outcome while understanding that they may vary secondary to specific individual requirements. The working group encourages the establishment of international collaborative focus groups with the specific interest in developing surveillance and management guidelines for these broad groups of disorders. Multi-center collaborations are encouraged. The proposed international Pediatric Gastroenterology website should contain the proposed and established surveillance and management guidelines to enhance its availability to all clinicians. The working group proposes the establishment of further patient registries that can be used to assess the effectiveness of management guidelines.
Introduction: Steroids induce CD remission within 3 months in 58% of adults, but by 1 year only 32% are steroid/surgery free (Gastro 2001;121:255). The use of IFX may have changed patients’ outcomes to steroids. PURPOSE: To determine children’s responses to steroids begun within 30 days of CD diagnosis (dx) and their need for IFX during the 1st year post-dx. Methods: Since January 2002, 18 US/Canadian sites prospectively enrolled newly diagnosed children with IBD in an observational registry. All were managed according to the dictates of their physicians, not standard protocols. The database was searched for children with CD followed for 1 yr who received po/iv steroids within 30 days after dx. Data on use of steroids, immunomodulatory agents (IA), IFX and surgery were prospectively compiled. Children were considered to have a complete response if steroids were successfully stopped by 3 months without requiring IFX or surgery. A prolonged response was defined as no steroids, IFX or surgery in the next 3 quarters (9 months). Results: 47 children (mean age 11.5 yrs, 30 male, PCDAI at dx 32+/−16) started steroids within 30 days of dx. 32 (68%) were on concomitant IA, including 20 who began IA in the 1st month. By 3 months after dx, 29 (62%) had a complete response and another 4 (9%) stopped steroid after adding IFX. Half of these responders also received IA. A prolonged response was seen in 21 (64% of initial responders, 45% of total population), but 11 required additional courses of steroids or IFX and 1 required surgery. Among the 14 subjects not off steroids by 3 months, 9 received steroids in the Quarter 2, 3 in the Quarter 3 and 2 throughout the year. Seven of the 14 were only weaned off steroids after starting IFX, and 1 failed IFX and required surgery. Overall, 16 (34%) subjects received IFX in the year and 18 (38%) required steroids (8), IFX (7) or both (3) in the 4th quarter of observation. Conclusion: 70% of children with CD receiving steroids within 30 days of dx can be weaned off steroids by 3 months, although at times only by adding IFX. While 77% of the cohort is off steroids at 1 year, 21% remain on IFX and 4% have undergone surgery despite widespread use of concomitant IA. Frequency and duration of steroid use is in large measure determined by when IFX is started. While steroid dependence can be decreased by use of IFX, studies are needed to see if IFX leads to better long term outcome in children with CD.
colorectal surgeons in RI and 11 in MA agreed to refer patients.Practice billing data were queried to capture missed referrals.RESULTS: 237 newly diagnosed CD patients and 274 newly diagnosed UC/IC patients were identified between January 1, 2008 and December 31, 2009.103 of 237 CD patients and 77 of 274 UC/IC patients enrolled in OSCCAR.Medical therapy during the first year is summarized in tables 1 & 2. 5-ASA was the mainstay of therapy for UC, and a high rate of 5-ASA use was observed in CD.Immunomodulator use was much higher in pediatric compared to adult patients (both CD and UC).CD patients were more likely to be on an immunomodulator or anti-TNF agent compared with UC patients.A substantial percentage of patients were started on anti-TNF therapy early after diagnosis.CONCLUSION: Different patterns of medication usage are seen in adult and pediatric patients, as well as in UC and CD.More than half of patients were exposed to steroids in the first year after diagnosis.A large portion of CD patients were on 5-ASA despite the lack of evidence supporting its use for this indication.Long term follow-up will yield insight into prescribing patterns and clinical effectiveness of various IBD therapies.
Phenotypically, disorders of intestinal epithelial transport demonstrate similar symptoms irrespective of the specific molecular basis of the defect in absorption. For some, clinical tests are available that may yield clues to the specific diagnosis. These are discussed in this chapter. Lactose malabsorption may occur whenever the level of small intestinal lactase is compromised either as a consequence of genetically regulated reductions in the expression of lactase enzyme or secondary to small intestinal injury. Of all the disorders of congenital carbohydrate absorption, the altered cellular events associated with sucrase–isomaltase deficiency have been best characterized. Cystic fibrosis is the most commonly occurring lethal genetic disorder in the world, and is associated predominantly with pulmonary and pancreatic disease but may affect multiple organs. With modern treatment programs, most affected people survive to adulthood. Effects on extrapulmonary organs, including the intestine, are variable.
Biliary atresia (BA) is the end result of a destructive, inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis and obliteration of the biliary tract with the development of biliary cirrhosis. It is the commonest cause of chronic cholestasis in infants and children, and therefore is the most frequent indication for liver transplantation in this age group. The disease occurs worldwide, affecting an estimated 1 in 8,000 to 12,000 live births. At present, there is no specific therapy for BA; however, sequential surgical therapy begins with creation of a hepatoportoenterostomy (HPE); in those with end-stage liver disease, liver transplantation is indicated. Since most candidates are young children of small size, there is a shortage of size-matched donors for liver transplantation. At present, an increased awareness to ensure early diagnosis and development of methods to prevent progressive fibrosis are needed. These considerations are dependent on detailed studies of the pathogenesis of BA. Recent studies have focused on normal and altered bile duct morphogenesis and the role of various factors (infectious or toxic agents and metabolic insults) in isolation or in combination with a genetic or immunologic susceptibility in the etiology of BA.
