Pathophysiology and Diagnosis Inflammation and Extent of Disease

Left-sided UC describes colonic inflammation that begins distal to the splenic flexure and extends in a generally uniform pattern to the anal canal margin. Ulcerative proctitis involves the last 15 to 20 cm of colon and always involves the junction of the anal canal and the rectum. It is often taught that left-sided UC is an extension of ulcerative proctitis. This is probably not true. The area of most severe inflammation in left-sided UC is the sigmoid colon. The rectum often is less inflamed, and may appear nearly normal. Prior to the advent of flexible endoscopy, the explanation for less active inflammation in the rectum was that the "rectal sparing" was due to topical rectal therapy. As new drugs have become available, it is clear that the rectum has less inflammation than the sig-moid colon. The other interesting observation that arose during the numerous drug studies evaluating the response to therapy in left-sided UC was that there is often a cecal patch of inflammation in an otherwise normal right colon. The skip lesions of left-sided UC support a unique pathophysiology that we do not fully understand. Ulcerative proctitis differs from left-sided UC because the intense inflammation does begin at the anal margin and extend for a short distance prox-imally. The distinction between these two disorders helps explain the different clinical courses of these two entities.

Inflammation involving only part of the colon is a curious phenomenon. The mysterious line of demarcation of disease has yet to be explained. Physiologic differences exist between the right and left sides of the colon with the dominant luminal substrate for oxidative phosphorylation being glutamine in the right colon and butyrate in the left colon. In addition, there are differences in the distribution of inflammatory cells in the right and left colon, which may provide insight into the abrupt cessation of inflammation at the line of disease demarcation. We histologically evaluated the "line of demarcation" in an attempt to understand the aggressive and protective balance occurring at the inflammatory interface. Much to our surprise, there were numerous mast cells on the normal side of the line of demarcation and in the terminal ileum of patients with well-defined left-sided UC. Evolving understanding of the role of the mast cells in UC suggests that the mast cells may be providing a degree of protection rather than active inflammation. Until recently, the homeostatic role of mast cells has been ignored because they have always been given a pathobiologic role in human physiology. The interaction between the mast cell and the eosinophil has important implications for IBD. The inflammatory response is dependent on eosinophilic chemoattractant factor released by the mast cell. The mast cell also modulates the effect of eosinophil function and engulfs major basic protein, which limits tissue injury.

From a practical perspective, the advent of videoen-doscopy permits frequent assessment of the degree of mucosal inflammation and response to therapy as well as providing an opportunity to histologically evaluate a biopsy of the mucosa. Endoscopic examination is essential to the management of UC because it permits the assessment of the severity and extent of mucosal inflammation. Biopsies are easily obtainable and play an important role in distinguishing the severity and nature of the inflammation. In left-sided UC, the laboratory evaluation is often normal and the only method to assess disease severity is history, physical examination, and videoendoscopy with biopsy. During the initial evaluation, laboratory assessment is essential in order to exclude a treatable infectious cause of colitis and to assess the immunologic pressure on the patient in terms of inflammation and metabolic home-ostasis. Stool studies for enteric pathogens, parasites, Clostridium difficile, leukocytes, eosinophils, and Charcot-

Layden crystals, provide support for idiopathic colonic inflammation as well as directing management.

Importance Of Histology

During the initial stage of evaluation, mucosal biopsies should be obtained to determine the chronicity of disease and to exclude other causes of colitis. The principle alternative diagnosis that needs to be considered in the first attack of UC is acute self-limiting colitis (ASLC). The endoscopic appearance is indistinguishable from idiopathic UC, but the microscopic changes are more acute and the mucosal atrophy and the crypt changes of chronic colitis (crypt branching) are absent. ASLC may last for several months, but the long term prognosis is excellent with no chronic disease issues that need to be considered. For the consultant, it is often impossible to reconstruct the initial illness. Long term remission following an acute attack raises the possibility of ASLC and supports a trial period of management without maintenance therapy. C. difficile may masquerade as chronic colitis or may cause relapse of symptomatic disease. The characteristic "explosive volcano" seen microscopically is a useful histologic marker of this infectious colitis. All patients with distinct ulceration of the rectum require biopsies to exclude solitary rectal ulcer syndrome (SRUS), which has a pathognomonic histologic picture of disrupted submucosal muscle fibers. SRUS is an ischemic lesion that does not respond to the immunosup-pressive treatment offered for IBD and requires special attention to the physiology of defecation to prevent the internal prolapse of rectal mucosal into the anal canal. There is a separate chapter on this topic (Chapter 89, "Rectal Prolapse, Rectal Intussusception and Solitary Rectal Ulcer Syndrome").


A second issue regarding the histopathology of IBD has emerged over the past few years. In the 1950s, the eosinophil was recognized as a dominant cell in the microscopic picture of IBD. Because it was believed the function of the eosinophil was limited to parasitic infections and allergy, considerable research focused on identifying either of these problems as the etiology of IBD. Parasitic infections were easily dismissed, but it took over a decade to eliminate definitively the allergic etiology of IBD. The eosinophil, which had captured the interest of pathologists studying IBD, subsequently was declared to be a surrogate marker for inflammation. In the 1990s, the homeostatic role of eosinophils began to be understood. An extended pathobiologic role of eosinophil function emerged during the national epidemic of the "tryptophan-eosinophilic-myalgia syndrome" in which eosinophils caused extensive tissue injury unrelated to parasites or allergies. Tissue resident mast cells release eosinophilic chemoattractant factor to recruit eosinophils to the tissue from the circulation. Once recruited, a variety of events need to occur to activate the eosinophils, one of which is the presence of Intracellular Adhesion Molecule (ICAM-1), which not only traffics the eosinophils to the inflammatory site, but also is required for eosinophils activation. The importance of eosinophils in the activation of disease may be determined by examination of the biopsy or by stool studies. In the biopsy, the number of eosinophils gives an estimation of the intensity of the inflammatory response, but the presence of eosinophils in crypt abscesses or mucosal migration of eosinophils indicates sufficient immunologic pressure to force the eosinophils into the intestinal lumen. These histologic findings identify activated eosinophils. Eosinophils in the stool indicate migration of eosinophils. Charcot-Layden crystals, which are related to the intracellular products of the eosinophil, reflect probable eosinophil-induced tissue injury and suggest the need for aggressive treatment of the increased number of eosinophils.

51 Ways to Reduce Allergies

51 Ways to Reduce Allergies

Do you hate the spring? Do you run at the site of a dog or cat? Do you carry around tissues wherever you go? Youre not alone. 51 Ways to Reduce Allergies can help. Find all these tips and more Start putting those tissues away. Get Your Copy Of 51 Ways to Reduce Allergies Today.

Get My Free Ebook

Post a comment