Epidemiologic and family studies indicate that cholesterol gallstone formation is in part genetically determined. The major contribution to our current understanding of gallstone genes derives from animal studies, particularly cross-breeding experiments in inbred mouse strains that differ in genetic susceptibility to cholesterol gallstone formation (quantitative trait loci mapping). In this review we summarize how the combined use of genomic strategies and phenotypic studies in inbred mice has proven to be a powerful means of dissecting the complex pathophysiology of this common disease. We present a "gallstone map" for the mouse, consisting of all genetic loci that have been identified to confer gallstone susceptibility as well as putative candidate genes. Translation of the genetic loci and genes between mouse and human predicts chromosomal regions in the human genome that are likely to harbor gallstone genes. Both the number and the precise understanding of gallstone genes are expected to further increase with rapid progress of the genome projects, and multiple new targets for early diagnosis and prevention of gallstone disease should become possible.

The major challenge currently facing liver transplantation is the performance of a greater number of liver transplants, which has been fueled by the large and growing disparity between the increasing number of qualified patients listed for transplantation and the relatively static number of available cadaver donor organs. In the past 2 years, approximately 4500 liver transplants have been performed annually, with 1-year survival rates in the 85%-90% range, while the waiting list has expanded as of November 2000 to more than 16,000 patients, resulting in an increasing death rate among listed patients. In the short term, there will continue to be a major focus on more effective use of available cadaver donor organs to balance the competing principles of justice (patients with most urgent need for transplant and lower probability of posttransplant survival) and medical utility (patients with less urgent need for transplant and higher odds of postoperative survival). Over the long term, there will be an increasing application of novel approaches to liver replacement including cadaver split liver transplantation and adult living donor liver transplantation and possibly, in the more distant future, xenotransplantation and hepatocyte transplantation. The treatment, and ideally the prevention, of recurrent disease after liver transplantation, particularly chronic hepatitis C-the most common indication for transplantation-is a major priority to optimize the use of liver grafts. Finally, improved immunosuppressive strategies, including movement toward minimal immunosuppression and steroid withdrawal and the development of safer and more effective drugs, is another important factor that has the potential to increase the success of liver transplantation.

HH should be distinguished from the other syndromes of iron overload. Many patients with HH have abnormal serum iron values before the development of any significant symptoms or clinical findings, and liver biopsy is less important in these patients. HFE mutation analysis has strengthened our ability to diagnose HH accurately and is useful in family studies. HFE mutations may play a contributory role in some patients with PCT, NASH, or chronic HCV. Generalized population screening for HH may someday become a reality and lead to the identification and treatment of more patients before they have tissue damage or increased morbidity. With the identification of the HFE gene, we are beginning to unravel many of the mysteries of both normal iron absorption and the disorder of iron metabolism found in patients with HH.

Recurrent acute pancreatitis represents a challenging clinical problem associated with significant morbidity, impairment in quality of life, and expense. If unchecked, recurrent episodes of acute pancreatitis may lead to chronic pancreatitis. In this work we have combined the opinion of experts in pancreatology and an extensive review of the literature to develop a logical algorithm that facilitates the stepwise identification and elimination of inciting factors using current technology. The approach taken in recurrent acute pancreatitis is clearly dependent on adequate and appropriate evaluation and treatment of the patient with an initial episode of acute pancreatitis. Future advances in the treatment of these patients will almost certainly depend on improved imaging modalities, prospective clinical trials assessing the efficacy of endoscopic and surgical intervention, a better understanding of mutations and pathophysiologic mechanisms responsible for recurrent acute pancreatitis, and the development of novel, effective preventive and therapeutic strategies.

The utilization of recent advances in molecular and genomic technologies and progress in pancreatic imaging techniques provided remarkable insight into genetic, environmental, immunologic, and pathobiological factors leading to chronic pancreatitis. Translation of these advances into clinical practice demands a reassessment of current approaches to diagnosis, classification, and staging. We conclude that an adequate pancreatic biopsy must be the gold standard against which all diagnostic approaches are judged. Although computed tomography remains the initial test of choice for the diagnosis of chronic pancreatitis, the roles of endoscopic retrograde pancreatography, endoscopic ultrasonography, and magnetic resonance imaging are considered. Once chronic pancreatitis is diagnosed, proper classification becomes important. Major predisposing risk factors to chronic pancreatitis may be categorized as either (1) toxic-metabolic, (2) idiopathic, (3) genetic, (4) autoimmune, (5) recurrent and severe acute pancreatitis, or (6) obstructive (TIGAR-O system). After classification, staging of pancreatic function, injury, and fibrosis becomes the next major concern. Further research is needed to determine the clinical and natural history of chronic pancreatitis developing in the context of various risk factors. New methods are needed for early diagnosis of chronic pancreatitis, and new therapies are needed to determine whether interventions will delay or prevent the progression of the irreversible damage characterizing end-stage chronic pancreatitis.

The incidence of obesity (especially childhood obesity) and its associated health-related problems have reached epidemic proportions in the United States. Recent investigations suggest that the causes of obesity involve a complex interplay of genetic, environmental, psychobehavioral, endocrine, metabolic, cultural, and socioeconomic factors. Several genes and their protein products, such as leptin, may be particularly important in appetite and metabolic control, although the genetics of human obesity appear to involve multiple genes and metabolic pathways that require further elucidation. Severe obesity is frequently associated with significant comorbid medical conditions, including coronary artery disease, hypertension, type II diabetes mellitus, gallstones, nonalcoholic steatohepatitis, pulmonary hypertension, and sleep apnea. Long-term reduction of significant excess weight in these patients may improve or resolve many of these obesity-related health problems, although convincing evidence of long-term benefit is lacking. Available treatments of obesity range from diet, exercise, behavioral modification, and pharmacotherapy to surgery, with varying risks and efficacy. Nonsurgical modalities, although less invasive, achieve only relatively short-term and limited weight loss in most patients. Currently, surgical therapy is the most effective modality in terms of extent and duration of weight reduction in selected patients with acceptable operative risks. The most widely performed surgical procedure, Roux-en-Y gastric bypass, achieves permanent (followed up for more than 14 years) and significant weight loss (more than 50% of excess body weight) in more than 90% of patients.

Irritable bowel syndrome (IBS) is the most common disorder diagnosed by gastroenterologists and one of the more common ones encountered in general practice. The overall prevalence rate is similar (approximately 10%) in most industrialized countries; the illness has a large economic impact on health care use and indirect costs, chiefly through absenteeism. IBS is a biopsychosocial disorder in which 3 major mechanisms interact: psychosocial factors, altered motility, and/or heightened sensory function of the intestine. Subtle inflammatory changes suggest a role for inflammation, especially after infectious enteritis, but this has not yet resulted in changes in the approach to patient treatment. Treatment of patients is based on positive diagnosis of the symptom complex, limited exclusion of underlying organic disease, and institution of a therapeutic trial. If patient symptoms are intractable, further investigations are needed to exclude specific motility or other disorders. Symptoms fluctuate over time; treatment is often restricted to times when patients experience symptoms. Symptomatic treatment includes supplementing fiber to achieve a total intake of up to 30 g in those with constipation, those taking loperamide or other opioids for diarrhea, and those taking low-dose antidepressants or infrequently using antispasmodics for pain. Older conventional therapies do not address pain in IBS. Behavioral psychotherapy and hypnotherapy are also being evaluated. Novel approaches include alosetron; a 5-HT(3) antagonist, tegaserod, a partial 5-HT(4) agonist, kappa-opioid agonists, and neurokinin antagonists to address the remaining challenging symptoms of pain, constipation, and bloating. Understanding the brain-gut axis is key to the eventual development of effective therapies for IBS.

Celiac disease (CD) is a syndrome characterized by damage of the small intestinal mucosa caused by the gliadin fraction of wheat gluten and similar alcohol-soluble proteins (prolamines) of barley and rye in genetically susceptible subjects. The presence of gluten in these subjects leads to self-perpetuating mucosal damage, whereas elimination of gluten results in full mucosal recovery. The clinical manifestations of CD are protean in nature and vary markedly with the age of the patient, the duration and extent of disease, and the presence of extraintestinal pathologic conditions. In addition to the classical gastrointestinal form, a variety of other clinical manifestations of the disease have been described, including atypical and asymptomatic forms. Therefore, diagnosis of CD is extremely challenging and relies on a sensitive and specific algorithm that allows the identification of different manifestations of the disease. Serologic tests developed in the last decade provide a noninvasive tool to screen both individuals at risk for the disease and the general population. However, the current gold standard for the diagnosis of CD remains histologic confirmation of the intestinal damage in serologically positive individuals. The keystone treatment of CD patients is a lifelong elimination diet in which food products containing gluten are avoided.