James P. Nolan

The role of intestinal endotoxin in liver injury: A long and evolving history

From the mid‐1950s, it was observed that liver injury by a variety of toxins greatly sensitized the host to the effects of administered lipopolysaccharide. In the nutritional cirrhosis of choline deficiency, and in acute toxic injury as well, the need for the presence of enteric endotoxin was demonstrated. The universality of this association was striking for almost all agents associated with liver injury. In addition, the presence of endotoxemia in human liver disease was documented in the 1970s, when the hypothesis was first proposed, and correlated with the severity of the disease. Despite imposing evidence of the critical role of enteric endotoxin in liver injury, it did not excite much interest in investigators until the 1980s. With the ability to study effects of alcohol in newer delivery systems, and an increased understanding of the role of Kupffer cells in the process, the original hypothesis has been accepted. This historical review details the progress of this novel concept of disease initiation and suggests future directions to bring potential therapies to the bedside. (HEPATOLOGY 2010.)

Endotoxin and the liver. I. Toxicity in rats with choline deficient fatty livers.

Summary Because previous reports have demonstrated that intestinal bacterial suppression retards the development of cirrhosis in rats on choline deficient diets, the sensitivity of these animals to the lethal and sublethal effects of E. coli lipopolysaccharide was studied. Rats with fatty livers of choline deficiency had a marked reduction in the LD 50 to endotoxin. In addition, serum transaminase levels of these animals were raised by doses of the endotoxin that were too small to affect the enzyme levels in controls. It is suggested that rats on a choline-deficient cirrhotogenic diet, experience tissue necrosis from amounts of endotoxin that are ordinarily rendered harmless.

Internal Medicine in the Current Health Care Environment: A Need for Reaffirmation

Managed care has revolutionized the delivery of health care in the United States. Because of its ability to curb the increasing costs of health care, managed care has been eagerly embraced by employers and federal and state governments. According to all projections, managed care will continue to prosper in the United States. It has already dramatically changed the traditional roles of the general internist and the internist-subspecialist. As managed care systems increasingly demand a high volume of cost-effective encounters, does the traditional relationship between internist and patient still have a role? Some might argue that the detailed, thoughtful, and sometimes even ponderous workup of the internist is becoming obsolete in the current health care marketplace, but others would counter that the forces that drive managed care make the role of the internist even more central in health care delivery for adults. Indeed, although internists must practice more economically and selectively now than in the past, they must also be among the leaders in medicine who insist that the first priority of health care delivery is to maximize the quality of health care rather than to minimize its cost. The new order in health care delivery raises major obstacles to the continued primacy of internal medicine in the care of patients with acute and chronic illness. One challenge for internists is to show managed care organizations how internists provide more appropriate and more effective care to adults than do family physicians. At a time when the health care system views physicians as providers and patients as clients, many managed care companies believe that the breadth of family medicine suits their needs better than the depth of internal medicine. If family medicine poses an external challenge to the role of internal medicine in providing medical care to adults, the managed care delivery system threatens to fragment relationships within internal medicine itself. Thus, as more of the referral base of internal medicine subspecialists becomes eroded by health maintenance organizations, the issue of when and how subspecialists should be involved in care has been pushed to the forefront. The traditional role of the general internist has been further fragmented by the introduction of the hospitalist, who assumes the responsibility of providing inpatient care in the interest of clinical efficiency and cost-effectiveness. Replacing the primary caregiver-the general internist-at a time when the patient is most vulnerable is again a threat to the role of the internist as the principal physician for adult patients in all settings. Historical Perspective To consider the future of internal medicine, it is useful to look at how the specialty has developed over the past century [1, 2]. The term internal medicine was introduced in the 1880s in Germany to describe a discipline that had special scientific knowledge of organ pathophysiology, a knowledge that remains central to the discipline today. In the United States, internal medicine initially developed as a consultative specialty with a strong biomedical focus. The identity of internal medicine was more firmly established when the American Board of Internal Medicine was created and certification as a specialist became possible. After World War II, internal medicine as a whole and its subspecialties in particular grew exponentially, fueled in part by the availability of generous funding from the National Institutes of Health for biomedical research. Despite the trend toward subspecialty medicine during the period from 1950 to 1970, most trainees who were not heading for academic positions practiced internal medicine as a comprehensive specialty, often with additional training in an organ-based specialty but without subspecialty certification. In the early 1970s, some academic centers began forming divisions of general internal medicine within their departments of medicine, perhaps partially as a response to the new specialty of family medicine. At this time, a gifted group of young Turks formed an organization for academic general internists that is now called the Society for General Internal Medicine. The Society had a new approach to teaching the skills of generalism and used clinical epidemiology, informatics, ethics, health services research, and the emerging techniques of the decision sciences to define their research base. These generalists carried on the proud tradition of internal medicine as the first specialty to commit to the development of knowledge in the diagnosis and treatment of various diseases. Perhaps even more important have been their contributions to the development of innovative educational programs for medical students and residents and their emphasis on the preventive and psychosocial aspects of clinical practice. Because of the louder voice of generalists in departments of internal medicine, the number of trainees who choose general medicine as a career has increased to the extent that most physicians who are seeking specialist training are entering this discipline (Whitcomb M, Association of American Medical Colleges. Personal communication). Divisions of general medicine have grown in almost all departments of medicine, populating themselves with enthusiastic role models, including generalist internists who now occupy faculty chairs at distinguished research universities. The academic internists persuasively argue that complicated medical problems rarely fit neatly into the expertise of a single subspecialty and that referrals to multiple subspecialists may contribute to fragmentation of care. Continuity and integration of care are the core of internal medicine and bolster the specialty in its role as the comprehensive adult medical specialty. Thus, in the past century, internal medicine has moved from the Oslerian model of an elite consultative specialty to one with strengths in both general and subspecialty medicine. Internists continue to constitute a majority of specialists in adult medicine, and their numbers continue to grow even as the marketplace changes. A similar recognition of the need for general internists to coordinate adult care has occurred in the European Union countries. The European Committee on Medical Specialties [3] recently approved an obligatory base of internal medicine training to be completed in preparation for medical subspecialization. In contrast to internal medicine, family medicine has its roots in general practice and has established standards for generalist physicians, whose practice includes medicine, pediatrics, surgery, and obstetrics. State legislatures provided the impetus for the development of the discipline of family medicine in many medical schools. The legislatures appropriately identified family physicians as the principal answer to workforce needs in underserved, particularly rural, areas. Although state medical schools now have departments of family medicine, some private, research-intensive medical schools and academic centers have largely ignored the specialty of family practice, believing that the biomedical basis of internal medicine and pediatrics is ideal for the development of knowledge about disease and its treatment. Conflicts between Internists and Family Physicians At a time when the complementary nature of family medicine and internal medicine should be emphasized and appreciated, an increasingly adversarial relationship between the two disciplines is arising in the tightly managed, time-constrained world of insurance-dominated practice. Managed care, with its emphasis on a high volume of 10- to 15-minute encounters, works against the very core of what makes internal medicine the productive and intellectually stimulating discipline it has been over the past century. In general, family physicians are not trained as extensively as internists in the diagnosis and treatment of the complex medical problems associated with aging and chronic illness. Family physicians should not be expected to fill this role. However, in the world of managed care, the skills of the internist may not be differentiated from those of the family physician. Equally important in a cost-dominated environment is the need for managed care organizations to recognize the value that is added when internists serve as primary care physicians. Elderly patients and chronically ill patients with multiple problems comprise an increasing market segment. In any managed care plan, 75% of enrolled adults consider themselves healthy and require only preventive therapies, obstetric-gynecologic services, and episodic care for acute, self-limited problems. Of the remaining 25%, about half are the worried well; the rest are patients with serious, progressive, or chronic problems (Woll D, Cigna Health Plans. Personal communication). An internist, by training and by clinical approach, is the physician best equipped to render the most efficient and effective care for patients with chronic diseases. The health care decisions that patients make arise from their perceived needs. Healthy young adults with families often find that family physicians meet their expectations, whereas elderly patients and patients with multisystem, chronic illnesses often believe that general internists can best meet their health care needs. Faced with a serious medical problem, however, most patients seek a physician who can provide the most expert care and who has the ability to address their concerns. It can be argued that internists have always filled this role and that they continue to be better able to function across the continuum of primary care to tertiary care than are family physicians. Some managed care organizations seem to believe that family physicians provide a broader spectrum of care to adults and children and are more facile in procedural skills than general internists. Indeed, family physicians often feel comfortable performing such procedures even though thei

The Fever of Sarcoidosis

Excerpt Judging from the literature, it would appear that fever is not a significant feature of sarcoidosis except in cases with erythema nodosum or uveoparotitis. Indeed, no mention is made of thi...

The clearance capacity of the canine liver for a portal vein endotoxin infusion

The capacity of the livers of anesthetized dogs to clear a portal vein infusion of Escherichia coli 026 endotoxin was evaluated. Appearance of the endotoxin in arterial blood was quantitated by immunoradiometric assay. Various hemodynamic and metabolic parameters were monitored throughout the infusion to corroborate the development of systemic endotoxemia. Significant amounts of E. coli 026 endotoxin were detected in arterial blood after infusion of 240 micrograms endotoxin. As expected, systemic endotoxemia was associated with decreased cardiac index, mean arterial blood pressure, heart rate, and splanchnic (portal vein) blood flow. Changes in plasma levels of glucose, insulin, and glucagon and in the pancreatic outputs of insulin and glucagon did not occur before the development of severe hypotension and the termination of the study. It was concluded that the liver clearance capacity for endotoxin in the dog is 0.72 microgram/gm liver/hour and that severe hemodynamic alterations develop in this animal model before changes in carbohydrate balance.

United We Stand

In recent decades, departments of medicine have grown enormously. More recently, however, there have been suggestions that certain subspecialties (that is, cardiology and oncology) reconfigure as categorical disease centers with an eventual weakening of ties to departments of medicine. Recent trends in health care make such a change undesirable. More and more, general internists will direct and coordinate the care of patients, and fragmentation of departments of medicine will make this task more difficult. The need to practice and teach cost-effective medicine and analyze patterns of care will require a closer working relationship between general internists and specialists. To accomplish these goals, a unified, rather than a fragmented, department of medicine is required. At the very time when internal medicine and its subspecialties are being asked to act in unison to cope with a rapidly changing health care environment, one increasingly hears of efforts to fragment internal medicine. At some institutions, separate categorical centers (for example, cardiology and oncology) are being formed, often with separate hospital beds, training programs, and finances. The role of a department of medicine as the home for internal medicine and its sub-specialties is being questioned. In this editorial, we examine the implications of fragmentation and conclude that it would be an unwise course for internal medicine. In every academic medical center, one can find faculty who wistfully recall earlier days, when departments of medicine were administered by a single departmental secretary, the faculty all had contiguous offices, and departmental budgets were a small fraction of todays. Integration was easier then. In recent decades, however, centripetal forces have grown. Departments of medicine have been transformed because of the dramatic growth of subspecialty medicine, which followed the development of new knowledge leading to improved ways of caring for patients. Departments of medicine have grown to become the largest in most medical schools, whether measured in space, faculty numbers, hospital beds, or budget. This growth was based on achievement and is well earned. It was, however, made possible by generous funding for patient care and research, which could foster such aggressive growth. The current economic climate threatens to stall this momentum and has created new tensions within departments of medicine. Constrained reimbursement for clinical activities has now for the first time limited the growth of even successful elements of the department. Reductions in clinical revenues have placed economic pressures on departments of medicine by calling attention to wide differences in clinical earnings among procedural and nonprocedural divisions and raising questions about the support of less wealthy elements of the department by the more financially successful elements. At the same time, centers and institutes that were developed to accommodate highly specialized programs sequester resources that formerly were shared across the department. These programs often require flexible approaches to governance, academic appointments, assignment of space, and the utilization of revenues. Many institutions have dealt successfully with these challenges, but others have found them a source of unrest. The impetus to change the traditional organization of departments of medicine comes most strongly from categorical or disease- or system-related programs, such as those in cardiovascular disease, oncology, and gastroenterology. For the past few years certain division chiefs of cardiology have had growing interest in separating from departments of medicine and establishing their own departments. They have argued that this would enhance training in their subspecialty and that their faculty have had disproportionately greater responsibilities with insufficient recognition of their contributions. However, another important issue is income, a portion of which is reallocated by the department to support teaching as well as less financially viable divisions. Whatever the merits of these adjustments, the rapid introduction of managed care threatens to turn this situation completely around rapidly. With health system reform, there will probably be more generalists, fewer patients referred to specialists, as well as a lower level of reimbursement for their services. Experience in Los Angeles and Minneapolis, which have large managed care systems, supports this prediction. The future will require integrated clinical arrangements involving faculty not only in departments of medicine but also other clinical departments. The relationship with the academic center hospital will be interactive, flexible, and respectful of all of the constituents needs. Precisely these considerations, in our opinion, make the unity of departments of medicine more critical than ever. Clinical Care Fundamental changes in health care reimbursement have forced changes in the way medicine is practiced. The pressure by third-party insurers to provide comprehensive and coordinated medical services for their subscribers demands that generalists, subspecialists, and hospitals be organized in an efficient and cooperative fashion. It will be less likely, in the years ahead, that an individual patient can directly and independently choose individual subspecialty physicians. Rather, primary care physicians will be called on to coordinate care, direct subspecialty referrals, and remain the stable link in a complex system. An organizational structure such as a department of medicine has the breadth and strength needed to balance these competing needs and requirements, which will only become more complex in the years ahead. Multidisciplinary, disease-oriented programs and centers that offer new opportunities for innovative, specialized care compete successfully for patients and attract and retain outstanding physicians who can provide state-of-the-art care. Most successful medical centers have developed such multidisciplinary programs. It would be an error, however, to fundamentally reorganize the structure of departments of medicine to accommodate these specific programs. No one can predict with certainty changing rates of diseases, technologic advances, or the interdependence of subspecialties brought about by new approaches to care. For example, consider how clinical practice and reimbursement have been altered by changing medical practice. The changing economics of renal dialysis, the reassessment of the role of biliary lithotripsy, or the advent of laparoscopic surgery are examples of changing areas of clinical practice that have had major effects. Technologically advanced subspecialty programs would be severely compromised without the participation of nonprocedural disciplines. It is precisely the depth and diversity of departments of medicine that promote the needed integration and coordination. It would be unwise to risk overdependence on a limited number of subspecialty programs and centers at the expense of the broader clinical expertise traditionally included in departments of medicine. Research Research used to be carried out successfully along traditional subspecialty lines, without much need for other kinds of scholars. Now research requires the participation of scholars in many disciplines. For example, investigation into the causes of inflammatory bowel disease involves specialists in infectious disease, immunology, and genetics, in addition to gastroenterologists. Departments of medicine can accommodate cross-disciplinary research, which would be more difficult to accomplish in multiple, smaller administrative units. It is also desirable to have research programs that represent the full range of clinically relevant perspectives, from molecular biology to health services research. This can best be fostered in departments of medicine because of their breadth and diversity. As noted by Braunwald [1], this critical evaluation of health care practices is more likely to be carried out in the intellectual environment of a department of medicine than in a more narrowly focused disease-oriented center. Teaching As patterns of care become more complex, teaching physicians becomes more challenging. The Balkanization of care along strict subspecialty lines is as undesirable for education as it is for patient care and research. With increasing specialization, the traditional core of knowledge and skill for all internists is being questioned but is, in reality, more critical than ever [2]. First, internal medicine training is necessary to provide the generalists America needs. Second, a basic understanding of internal medicine as a whole is an essential foundation for subspecialists. As the information base of medicine expands, the training period for subspecialists may need to be extended. It is therefore incumbent on medical educators to continually refine training programs that will preserve the essential components of internal medicine training for those destined to receive further subspecialty training. Third, as clinical medicine changes, understanding the interplay between general and subspecialty medicine is essential. With limited financial resources for medical care there will be pressure for physicians to be more cost-effective in ordering diagnostic tests and consultations and this requires excellent communication, mutual knowledge, and colleagueship among generalists and the subspecialists. We must be able to teach students, housestaff, and fellows these concepts. These complex teaching missions are a major responsibility of departments of medicine. The rapidly changing environment, competing demands for general and subspecialty care and training, and economic pressures make the unity of departments of medicine more essential than ever. The challenge of modern departments of medicine is to provide a setting where the balanced ecology of medicine can be preserved. If the

Tinkering or Real Reform? The Choice Is Ours

Excerpt Internal medicine has been in a dynamic process of change throughout this century (1). Much of the ferment has resulted from new knowledge about disease causes and treatments, development o...

ACTIVISM IN ACADEMIC INTERNAL MEDICINE

Excerpt In a past issue of this journal, the Association of Professors of Medicine (APM) was identified as an organization with the power to effect change because it has the authority, responsibil...