The origins of hepatobiliary and gastrointestinal physiology
Authors: James L. Boyer
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Each year as I complete my attending responsibilities on our inpatient 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 patient with decompensated cirrhosis. The reasons for this state of affairs are several. Today's medical school curricula no longer 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, 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 to our inpatient service with an understanding of the basic pathophysiologic processes that lead to decompensated cirrhosis; 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 inpatient liver service hopefully offer them the opportunity to learn some of these as well as other important principles 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 patient with cirrhosis and why the 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 patient with cirrhosis 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 CO2, 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 gastroenterologic organ physiology and pathophysiology can enhance the medical skills of our students and residents, a similar lack of a basic physiologic background also impacts not only the ability of our fellows to be effective physicians and teachers but also 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‐week course was established at the Mt. Desert Island Biological Laboratory 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 approximately 30‐36 postdoctoral fellows, usually in their second year of fellowship. The course consists of six 1.5‐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.1Figure 1: Aerial view of the Mt. Desert Island Biological Laboratory's lower campus.Based on the success of the renal course, a similar course, The Origins of Hepatobiliary and Gastrointestinal Physiology, will be offered at the Mt. Desert Island Biological Laboratory (Fig. 1) for liver and gastroenterology fellows in adult, and 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 principal investigators and teachers irrespective of the area of research that they may or may not follow. It is intended to provide liver and gastrointestinal 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 human to studies in 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 gastrointestinal 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 patients' 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 gastrointestinal 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 five 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, the course will equip the student with modern‐day molecular computer‐based technologies. Each of the modules is equipped with detailed syllabi and run in consecutive 2‐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 three 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 Institutional Animal Care and Use Committee 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. The course is open to enrollment, with second‐year postdoctoral digestive disease fellows in liver, gastrointestinal, pediatric, and surgical training grants given preference. Residents and postdoctoral Ph.D.s are also welcome to apply, pending space availability. Interested persons and program directors should contact the Mt. Desert Island Biological Laboratory website for details of course content and instructions for applications: https://mdibl.org/course/origins‐of‐hepatobiliary‐and‐gastrointestinal‐physiology/.