The origins of hepatobiliary and gastrointestinal physiology

Each year as I complete my attending responsibilities on our in-patient liver service, I am increasingly impressed with how little our students, residents and fellows know about the basic physiologic processes that underlie the management of the decompensated cirrhotic patient. The reasons for this state of affairs are several. Today’s medical school curricula no long have the luxury to provide much information concerning organ physiology, as they focus increasingly on subjects that include cellular and molecular biology, immunobiology, child and adolescent development, genetics and the biological basis of behavior, areas of emphasis that were hardly conceivable when those of us of the older generations were in medical school. Indeed few medical schools teach classical physiology today as their departments of physiology have long since transitioned into Departments of Cellular and Molecular Physiology often combined with traditional Departments of Pharmacology. Chairpersons of these basic science departments are themselves trained in the molecular era and so they tend to direct courses to the background they come from. Indeed, at Yale Medical School, the only opportunity medical students get to learn the pathophysiology of digestive disease, is in a tightly packed 2 week period in the second year. It is little wonder then that few if any residents come on to our in-patient service with an understanding of the basic pathophysiologic processes that lead to the decompensated cirrhotic, or the reasons behind the choice, dose and means of administration of diuretics for patients with ascites, or the precipitants of hepatic encephalopathy and why tap water enemas are an effective means for rapid treatment. Their rotations through our in-patient liver service hopefully offer them the opportunity to learn some of these as well as other important principals that lie behind the algorithms in therapeutic guidelines. Indeed, understanding that portal hypertension leads to splanchnic and systemic release of nitric oxide and other humoral mediators helps to explain why systemic blood pressure is low in the cirrhotic patient and why their kidneys are vasoconstricted resulting in a reduction in glomerular filtration. With this background one can better appreciate the rationale for albumin replacement in the face of bacterial peritonitis or large volume paracentesis and the role of volume replacement and midodrine in the cirrhotic with acute kidney injury. When you understand that the major source of circulating ammonia is urea and that urea freely diffuses across the gut epithelium and is broken down by bacterial urease in the colon to NH3 and C02, the importance of ridding the colon of stool Is more readily apparent. While these examples serve to underscore why a better understanding of hepatobiliary and gastroenterology organ physiology and pathophysiology can enhance the medical skills of our students and residents, a similar lack of a basic physiologic background also impacts the ability of our fellows not only to be effective physicians and teachers but it also affects their choice of subjects for research. This is because postdoctoral research projects have increasingly focused on molecular events, signal transduction pathways and genetic aspects that are far afield from the classical experiments that have formed the foundations of our discipline. These concerns are also shared by our renal colleagues and have led the American Society of Nephrology to endorse the concept that “A solid grounding in renal physiology and its history can only enhance the perspective of new renal investigators, and such knowledge will enrich the subsequent teaching moment with new medical students and trainees in medicine.” (1) To this end, in 2008, a 1-wk course was established at the Mt Desert Island Biological Laboratory (MDIBL) in Maine to reconnect renal trainees with the origins of kidney physiology and a systems approach to mechanisms of homeostasis in electrolyte disorders. This course has been held annually in September and accommodates ~ 30–36 postdoctoral fellows, usually in their second year of fellowship. The course consists of 6 1 ½ day modules and covers subjects such as water homeostasis, salt homeostasis and secretion, collecting duct sodium balance, and proximal tubular function. Fellows carry out classic physiologic experiments using well described models such as the shark rectal gland, toad urinary bladder and Xenopus oocytes interspersed with modern cellular and molecular techniques. (see ref 1). Based on the success of the renal course, a similar course, “The Origins of Hepatobiliary and Gastrointestinal Physiology” will be offered at MDIBL for liver and gastroenterology fellows in both adult, pediatric and surgical training programs in the second week of September 2015. This course has been endorsed by both the American Association for the Study of Liver Disease and the American Gastroenterology Association. The course is designed to remind fellows of some of the early work that provides the foundation for modern science in this field and to help them prepare for their role as PIs and teachers irrespective of the area of research that they may or may not follow. It is intended to provide liver and GI trainees with hands on research education in the fundamental concepts of digestive organ physiology by exposing them to classical experiments that form the basic foundation of Hepatology and Gastroenterology. Scientific understanding of the mechanisms of secretion and absorption in the liver and gastrointestinal tissues has progressed over the past 50 years from studies in the whole animal or man, to isolated tissues, cells, membranes and subcellular organelles, to descriptions of the role of individual molecules and regulatory pathways. This remarkable progress has led to an in-depth understanding of the mechanisms of bile formation, bile acid synthesis and metabolism, gastric and intestinal secretory mechanisms and the enterohepatic circulation, with much of this understood now at the molecular level. However, these remarkable advances have resulted in unintended consequences since the narrow focus of GI and Liver fellows today on single molecules and regulatory pathways is affecting the ability of many of these future young investigators to pursue the most significant scientific questions. At the same time they are finding it difficult to understand how their research findings relate to the overall physiology of the liver and intestine or to their patient’s problems when they are attending physicians and involved with teaching on the wards. This apparent disconnect between their research and their clinical experience is having the negative effect of discouraging many would be trainees from pursuing a career as an academic hepatologist or gastroenterologist and particularly in working at the bench. This course, “The Origins of Hepatobiliary and Gastrointestinal Physiology” has been initiated to help counteract this problem and to enable Liver and GI fellows to obtain a stronger background in the fundamentals of liver and intestinal physiology in order to stimulate their interest and kindle excitement in the significant questions that remain to be answered in this field. The course is organized around 5 modules: 1) Hepatobiliary secretion; 2) Physiologic imaging in live cells and tissues; 3) Enterohepatic Circulation; 4) Mechanisms of Intestinal Secretion; and 5) Gastric Secretion. Interspersed within each module, and reinforced by a daily didactic curriculum for Bioinformatics, and genomics that will equip the student with modern day molecular computer based technologies. Each of the modules are equipped with detailed syllabi and run in consecutive two-day rotations (Monday–Tuesday, Wednesday–Thursday and Friday–Saturday). The first day of each rotation involves intensive experimental work while the second day involves analysis and presentation of results to the entire group. While each fellow will participate in only 3 of the modules, all will be exposed to the entire curriculum. Rotations will also involve case studies in Responsible Conduct of Research, Lectures in Animal Care and IACUC regulations, how to write a grant and grant opportunities and how to prepare manuscripts for publication. All hands on experiments will be performed with well described animal models from marine or amphibian sources. These include experimental studies of biliary excretion in isolated perfused skate livers and hepatocyte cultures; calcium signaling and studies of signal transduction using isolated skate hepatocytes; classic studies of bile salt enterohepatic circulation using intestinal gut sacs from skate and hagfish; mechanism of intestinal chloride secretion using the isolated perfused rectal gland and studies of intestinal secretion using the frog stomach. Simultaneously the fellows will be exposed to the molecular basis of the physiologic processes they are studying and will utilize bioinformatics and genetic approaches to further elucidate their clinical significance. Each module will be led by an international leader in the field.