Management of patient with chronic diarrhea syndrome Management of patient with constipation

 

1.Main syndromes and symptoms of the bowel diseases.

DIARRHEA

DEFINITION

Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, stool weight exceeding 200 g/d can generally be considered diarrheal. Because of the fundamental importance of duration to diagnostic considerations, diarrhea may be further defined as acute if <2 weeks, persistent if 2 to 4 weeks, and chronic if >4 weeks in duration.

Two common conditions, usually associated with the passage of stool totaling <200 g/d, must be distinguished from diarrhea, as diagnostic and therapeutic algorithms differ. Pseudodiarrhea, or the frequent passage of small volumes of stool, often is associated with rectal urgency and accompanies the irritable bowel syndrome or anorectal disorders like proctitis. Fecal incontinence is the involuntary discharge of rectal contents and is most often caused by neuromuscular disorders or structural anorectal problems. Diarrhea and urgency, especially if severe, may aggravate or cause incontinence. Pseudodiarrhea and fecal incontinence occur at prevalence rates comparable to or higher than that of chronic diarrhea and should always be considered in patients complaining of “diarrhea.” A careful history and physical examination generally allow these conditions to be discriminated from true diarrhea.

ACUTE DIARRHEA

More than 90% of cases of acute diarrhea are caused by infectious agents; these cases are often accompanied by vomiting, fever, and abdominal pain. The remaining 10% or so are caused by medications, toxic ingestions, ischemia, and other conditions.

Other Causes.  Side effects from medications are probably the most commooninfectious cause of acute diarrhea, and etiology may be suggested by a temporal association between use and symptom onset. Although innumerable medications may produce diarrhea, some of the more frequently incriminated include antibiotics, cardiac antidysrhythmics, antihypertensives, nonsteroidal anti-inflammatory drugs, certain antidepressants, chemotherapeutic agents, bronchodilators, antacids, and laxatives. Occlusive or nonocclusive ischemic collitis typically occurs in persons older than 50 years of age, often presents as acute lower abdominal pain preceding watery, then bloody diarrhea, and generally results in acute inflammatory changes in the sigmoid or left colon while sparing the rectum. Acute diarrhea may accompany colonic diverticulitis and graft-versus-host disease. Acute diarrhea, often associated with systemic compromise, can follow ingestion of toxins including organophosphate insecticides, amanita and other mushrooms, arsenic, and preformed environmental toxins in seafoods, like ciguatera and scombroid. The conditions causing chronic diarrhea can also be confused with acute diarrhea early in their course. This confusion may occur with inflammatory bowel disease and some of the other inflammatory chronic diarrheas that may have an abrupt rather than insidious onset and exhibit features that mimic infection.

CHRONIC DIARRHEA

Diarrhea lasting more than 4 weeks warrants evaluation to exclude serious underlying pathology. In contrast to acute diarrhea, most of the many causes of chronic diarrhea are noninfectious. The classification of chronic diarrhea by pathophysiologic mechanism facilitates a rational approach to management (Table 1).

 

 

Secretory Causes. Secretory diarrheas are due to derangements in fluid and electrolyte transport across the enterocolic mucosa. They are characterized clinically by watery, large-volume fecal outputs that are typically painless and persist with fasting. Because there is no malabsorbed solute, stool osmolality is accounted for by normal endogenous electrolytes with no fecal osmotic gap.

Medications. Side effects from regular ingestion of drugs and toxins are the most common secretory causes of chronic diarrhea.

Bowel resection, mucosal disease, or enterocolic fistula. These conditions may result in a secretory-type diarrhea because of inadequate surface for resorption of secreted fluids and electrolytes. Unlike other secretory diarrheas, this subset of conditions tends to worsen with eating. With disease (e.g., Crohn’s ileitis) or resection of <100 cm of terminal ileum, dihydroxy bile acids may escape absorption and stimulate colonic secretion (cholorrheic diarrhea). This mechanism may contribute to so-called idiopathic secretory diarrhea, in which bile acids are functionally malabsorbed from a normal-appearing terminal ileum. Partial bowel obstruction, ostomy stricture, or fecal impaction may paradoxically lead to increased fecal output due to hypersecretion.

Osmotic Causes. Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw enough fluid lumenward to exceed the resorptive capacity of the colon. Fecal water output increases in proportion to such a solute load. Osmotic diarrhea characteristically ceases with fasting or with discontinued oral intake of the offending agent.

Osmotic laxatives. Ingestion of magnesium-containing antacids, health supplements, or laxatives may induce osmotic diarrhea typified by a stool osmotic gap: 2([Na] + [K]) <<290 mosm/kg. Anionic laxatives containing sulfates or phosphates produce osmotic diarrhea without an osmotic gap, as sodium accompanies the anionic solutes; direct measurement of stool sulfates and phosphates may be necessary to confirm the cause of diarrhea.

Carbohydrate malabsorption. Carbohydrate malabsorption due to acquired or congenital defects in brush-border disaccharidases and other enzymes leads to osmotic diarrhea with a low pH. One of the most common causes of chronic diarrhea in adults is lactase deficiency, which affects three-fourths of non- Steatorrheal Causes. Fat malabsorption may lead to greasy, foul-smelling, difficult-to-flush diarrhea often associated with weight loss and nutritional deficiencies due to concomitant malabsorption of amino acids and vitamins. Increased fecal output is caused by the osmotic effects of fatty acids, especially after bacterial hydroxylation, and, to a lesser extent, by the burden of neutral fat. Quantitatively, steatorrhea is defined as stool fat exceeding the normal 7 g/d; daily fecal fat averages 15 to 25 g with small intestinal diseases and often exceeds 40 g with pancreatic exocrine insufficiency. Intraluminal maldigestion, mucosal malabsorption, or lymphatic obstruction may produce steatorrhea.

Intraluminal maldigestion. This condition most commonly results from pancreatic exocrine insufficiency, which occurs when >90% of pancreatic secretory function is lost. Chronic pancreatitis, usually a sequela of ethanol abuse, most frequently causes pancreatic insufficiency. Other causes include cystic fibrosis, pancreatic duct obstruction, and rarely, somatostatinoma. Bacterial overgrowth in the small intestine may deconjugate bile acids and alter micelle formation that impair fat digestion; it occurs with stasis from a blind-loop, small bowel diverticulum, or dysmotility and is especially likely in the elderly. Finally, cirrhosis or biliary obstruction may lead to mild steatorrhea due to deficient intraluminal bile acid concentration.

Mucosal Malabsorption. Mucosal malabsorption occurs from a variety of enteropathies, but most prototypically and perhaps most commonly from celiac sprue. This gluten-sensitive enteropathy characterized by villous atrophy and crypt hyperplasia in the proximal small bowel often presents with fatty diarrhea associated with multiple nutritional deficiencies of varying severity and affects all ages. Tropical sprue may produce a similar histologic and clinical syndrome, but it occurs in residents of or travelers to tropical climates; its often abrupt onset and response to antibiotics suggest an infectious etiology. Whipple’s disease, due to the actinomycete Treponema whippleii and histiocytic infiltration of the small bowel mucosa, is a less common cause of steatorrhea that most typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopathy, and extreme fatigue and may affect the central nervous system and endocardium.

Inflammatory Causes. Inflammatory diarrheas are generally accompanied by pain, fever, bleeding, or other manifestations of inflammation. The mechanism of diarrhea may not only be exudation but, depending on lesion site, may include fat malabsorption, disrupted fluid/electrolyte absorption, and hypersecretion or hypermotility from release of cytokines and other inflammatory mediators. The unifying feature on stool analysis is the presence of leukocytes or leukocyte-derived proteins such as calprotectin.

Idiopathic inflammatory bowel disease  The illnesses in this category, which include Crohn’s disease and chronic ulcerative colitis, are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to fulminant and life threatening. They may be associated with uveitis, polyarthralgias, cholestatic liver disease (primary sclerosing cholangitis), and various skin lesions (erythema nodosum, pyoderma gangrenosum). Microscopic colitis, including collagenous colitis, is an increasingly recognized cause of chronic watery diarrhea; biopsy of a normal appearing colorectum is required for histologic diagnosis.

Eosinophilic gastroenteritis  Eosinophil infiltration of the mucosa, muscularis, or serosa at any level of the gastrointestinal tract may cause diarrhea, pain, vomiting, or ascites. Affected patients often have an atopic history, Charcot-Leyden crystals due to extruded eosinophil contents may be seen on microscopic inspection of stool, and peripheral eosinophilia is present in 50 to 75% of patients. While hypersensitivity to certain foods occurs in adults, true food allergy causing chronic diarrhea is rare.

Other Causes  Chronic inflammatory diarrhea may be caused by radiation enterocolitis, chronic graft-versus-host disease, Behcet’s syndrome, and Cronkite-Canada syndrome, among others.

Dysmotile Causes  Rapid transit may accompany many diarrheas as a secondary or contributing phenomenon, but primary dysmotility is an unusual etiology of true diarrhea. Stool features often suggest a secretory diarrhea, but mild steatorrhea up to 14 g of fat per day can be produced by maldigestion from rapid transit alone. Hyperthyroidism, carcinoid syndrome, and certain drugs (e.g., prostaglandins, prokinetic agents) may produce hypermotility with resultant diarrhea. Primary visceral neuromyopathies or idiopathic acquired intestinal pseudo-obstruction may lead to stasis with secondary bacterial overgrowth causing diarrhea. Diabetic diarrhea, often accompanied by peripheral and generalized autonomic neuropathies, may occur in part because of intestinal dysmotility.

The exceedingly common irritable bowel syndrome (10% point prevalence, 1 to 2% per year incidence) is characterized by disturbed intestinal and colonic motor and sensory responses to various stimuli. Symptoms of stool frequency typically cease at night, alternate with periods of constipation, are accompanied by abdominal pain relieved with defecation, and rarely result in weight loss or true diarrhea.

CONSTIPATION

DEFINITION

Constipation is a common complaint in clinical practice and usually refers to persistent, difficult, infrequent, or seemingly incomplete defecation. Because of the wide range of normal bowel habits, constipation is difficult to define precisely. Most persons have at least three bowel movements per week; however, stool frequency alone is not a sufficient criterion for the diagnosis of constipation because many constipated patients describe a normal frequency of defecation but subjective complaints of excessive straining, hard stools, lower abdominal fullness, and a sense of incomplete evacuation. The individual patient’s symptoms must be analyzed in detail to ascertain what is meant by “constipation” or “difficulty” with defecation.

Stool form and consistency are well correlated with the time elapsed from the preceding defecation. Hard, pellety stools occur with slow transit, while loose watery stools are associated with rapid transit. Small, pellety stools are more difficult to expel than large ones.

The perception of hard stools or excessive straining is more difficult to assess objectively, and the need for enemas or digital disimpaction is a clinically useful way to corroborate the patient’s perceptions of difficult defecation.

Psychosocial factors may also be important. A person whose parents attached great importance to daily defecation will become greatly concerned when he or she misses a daily bowel movement; some children withhold stool to gain attention; and some adults are simply too busy or too embarrassed to interrupt.

2. Criteria for diagnosis of the colitis.

2.1. nonulcerative.

2.2. ulcerative.

2.3. irritable bowel syndrome.

2.1 INFECTIOUS DISEASE

Infections of the small intestines and colon can mimic CD or UC. They may be bacterial, fungal, viral, or protozoal in origin. Campylobacter colitis can mimic the endoscopic appearance of severe UC and can cause a relapse of established UC. Salmonella can cause watery or bloody diarrhea, nausea, and vomiting. Shigellosis causes watery diarrhea, abdominal pain, and fever followed by rectal tenesmus and by the passage of blood and mucus per rectum. All three are usually self-limited but 1% of patients infected with Salmonella become asymptomatic carriers. Yersinia enterocolitica infection occurs mainly in the terminal ileum and causes mucosal ulceration, neutrophil invasion, and thickening of the ileal wall. Other bacterial infections that may mimic IBD include C. difficile, which presents with watery diarrhea, tenesmus, nausea, and vomiting, and Escherichia coli, three categories of which can cause colitis. These are enterohemorrhagic, enteroinvasive, and enteroadherent E. coli, all of which can cause bloody diarrhea and abdominal tenderness. Diagnosis of bacterial colitis is made by sending stool specimens for bacterial culture and C. difficile toxin analysis. Gonorrhea, Chlamydia, and syphilis can also cause proctitis

Gastrointestinal involvement with mycobacterial infection occurs primarily in the immunosuppressed patient but may occur in patients with normal immunity. Distal ileal and cecal involvement predominates and patients present with symptoms of small bowel obstruction and a tender abdominal mass. The diagnosis is made most directly by colonoscopy with biopsy and culture. Mycobacterium avium intracellulare complex infection occurs in advanced stages of HIV infection and in other profoundly immunocompromised states, and usually manifests as a systemic infection with diarrhea, abdominal pain, weight loss, fever, and malabsorption. Diagnosis is established by acid-fast smear and culture of mucosal biopsies.

Although most of the patients with viral colitis are immunosuppressed, cytomegalovirus (CMV) and herpes simplex proctitis may occur in immunocompetent individuals. CMV occurs most commonly in the esophagus, colon, and rectum, but may also involve the small intestine. Symptoms include abdominal pain, bloody diarrhea, fever, and weight loss. With severe disease, necrosis and perforation can occur. Diagnosis is made by identification of intranuclear inclusions in mucosal cells on biopsy. Herpes simplex infection of the gastrointestinal tract is limited to the oropharynx, anorectum, and perianal areas. Symptoms include anorectal pain, tenesmus, constipation, inguinal adenopathy, difficulty with urinary voiding, and sacral paresthesias. Diagnosis is made by rectal biopsy. HIV itself can cause diarrhea, nausea, vomiting, and anorexia. Small intestinal biopsies show partial villus atrophy; small bowel bacterial overgrowth and fat malabsorption may also be noted.

Protozoan parasites include Isospora belli, which can cause a self-limited infection in healthy hosts but causes a chronic profuse, watery diarrhea and weight loss in AIDS patients. Entamoeba histolytica or related species infect about 10% of the world’s population; symptoms include abdominal pain, tenesmus, frequent loose stool containing blood and mucus, and abdominal tenderness. Colonoscopy reveals focal punctate ulcers with normal intervening mucosa; diagnosis is made by biopsy or serum amebic antibodies. Fulminant amebic colitis is rare but has a mortality rate of >50%.

Other parasitic infections that may mimic IBD include hookworm (Necator americanus), whipworm (Trichuris trichiura), and Strongyloides stercoralis. In severely immunocompromised patients Candida or Aspergillus can be identified in the submucosa. Disseminated histoplasmosis can involve the ileocecal area.

2.2. ULCERATIVE COLITIS: MACROSCOPIC FEATURES

UC is a mucosal disease that usually involves the rectum and extends proximally to involve all or part of the colon. Approximately 40 to 50% of patients have disease limited to the rectum and rectosigmoid, 30 to 40% have disease extending beyond the sigmoid but not involving the whole colon, and 20% have a total colitis. Proximal spread occurs in continuity without areas of uninvolved mucosa. When the whole colon is involved, the inflammation extends 1 to 2 cm into the terminal ileum in 10 to 20% of patients. This is called backwash ileitis and has little clinical significance. Although variations in macroscopic activity may suggest skip areas, biopsies from normal-appearing mucosa are usually abnormal. Thus, it is important to obtain multiple biopsies from apparently uninvolved mucosa, whether proximal or distal, during endoscopy.

With mild inflammation, the mucosa is erythematous and has a fine granular surface that looks like sandpaper. In more severe disease, the mucosa is hemorrhagic, edematous, and ulcerated. In long-standing disease, inflammatory polyps (pseudopolyps) may be present as a result of epithelial regeneration. The mucosa may appear normal in remission but in patients with many years of disease it appears atrophic and featureless and the entire colon becomes narrowed and foreshortened. Patients with fulminant disease can develop a toxic colitis or a toxic megacolon where the bowel wall becomes very thin and the mucosa is severely ulcerated, which may lead to perforation.

ULCERATIVE COLITIS: MICROSCOPIC FEATURES

Histologic findings correlate well with the endoscopic appearance and clinical course of UC. The process is limited to the mucosa and superficial submucosa with deeper layers unaffected except in fulminant disease. In UC, two major histologic features are indicative of chronicity and help distinguish it from infectious or acute self-limited colitis. First, the crypt architecture of the colon is distorted; crypts may be bifid and reduced iumber, often with a gap between the crypt bases and the muscularis mucosae. Second, some patients have basal plasma cells and multiple basal lymphoid aggregates. Mucosal vascular congestion with edema and focal hemorrhage, and an inflammatory cell infiltrate of neutrophils, lymphocytes, plasma cells, and macrophages may be present. The neutrophils invade the epithelium, usually in the crypts, and give rise to cryptitis and, ultimately, to crypt abscesses. The cryptitis is associated with mucus discharge from goblet cells and increased epithelial cell turnover. Histologically, this results in goblet cell depletion. Other chronic changes that are sometimes seen are neuronal hypertrophy and fibromuscular hyperplasia of the muscularis mucosae.

Chronic Ulcerative Colitis

These photos are from a total colectomy done for clinically severe, intractable chronic ulcerative colitis (CUC). The photo above shows a veritable shag carpet of inflammatory pseudopolyps. Yes, this does look an awful lot like a case of familial adenomatous polyposis, but microscopically there was no adenomatous or otherwise dysplastic change anywhere in the whole colon.

The photo below may look like bacon frying in a cast iron skillet, but it’s actually a closeup of three longitudinal sections through the colon wall. For each section, the serosa/adventitial connective tissue is shown as bright yellow lumps on the bottom. Right above is the ribbon-like muscularis propria, unbesmirched and indifferent to the devastation that has made an inflammatory ruin of the mucosa and submucosa above it.

The photo below shows a slightly closer view of a longitudinal section through the colon wall. This demonstrates not only the angry red mucosa but also the tendency for the inflamed tissue to throw itself up into inflammatory pseudopolyps.

These photos were taken with a Minolta X-370 and a Rokkor 100mm bellows lens, on Kodak Elite daylight film, ISO 100, with a blue filter to compensate for tungsten illumination. The tissue was formalin-fixed, but the nice red coloration of the inflamed tissue was recovered by soaking the specimen overnight in 70% alcohol before shooting.

CLINICAL PRESENTATION

ULCERATIVE COLITIS

Signs and Symptoms  The major symptoms of UC are diarrhea, rectal bleeding, tenesmus, passage of mucus, and crampy abdominal pain. The severity of symptoms correlates with the extent of disease. Although UC can present acutely, symptoms usually have been present for weeks to months. Occasionally, diarrhea and bleeding are so intermittent and mild that the patient does not seek medical attention.

Patients with proctitis usually pass fresh blood or blood-stained mucus, either mixed with stool or streaked onto the surface of a normal or hard stool. They also have tenesmus, or urgency with a feeling of incomplete evacuation. They rarely have abdominal pain. With proctitis or proctosigmoiditis, proximal transit slows, which may account for the constipation that is commonly seen in patients with distal disease.

When the disease extends beyond the rectum, blood is usually mixed with stool, or grossly bloody diarrhea may be noted. Colonic motility is altered by inflammation with rapid transit through the inflamed intestine. When the disease is severe, patients pass a liquid stool containing blood, pus, and fecal matter. Diarrhea is ofteocturnal and/or postprandial. Although severe pain is not a prominent symptom, some patients with active disease may experience vague lower abdominal discomfort or mild central abdominal cramping. Severe cramping and abdominal pain can occur in association with severe attacks of the disease. Other symptoms in moderate to severe disease include anorexia, nausea, vomiting, fever, and weight loss.

Physical signs of proctitis include a tender anal canal and blood on rectal exam. With more extensive disease, patients have tenderness to palpation directly over the colon. Patients with a toxic colitis have severe pain and bleeding, and those with megacolon have hepatic tympany. Both may have signs of peritonitis if a perforation has occurred. The classification of disease activity is shown in Table 2.

 

 

Laboratory, Endoscopic, and Radiographic Features  Active disease can be associated with a rise in acute phase reactants (C-reactive protein, orosomucoid levels), platelet count, erythrocyte sedimentation rate (ESR) and a decrease in hemoglobin. In severely ill patients, the serum albumin level will fall rather quickly. Leukocytosis may be present but is not a specific indicator of disease activity. Proctitis or proctosigmoiditis rarely causes a rise in C-reactive protein. Diagnosis relies upon the patient’s history; clinical symptoms, negative stool examination for bacteria, Clostridium difficile toxin, and ova and parasites; sigmoidoscopic appearance; and histology of rectal or colonic biopsy specimens

 

 

Ulcerative Colitis

 

Ulcerative Colitis

 

Ulcerative Colitis

 

Ulcerative Colitis

 

Ulcerative Colitis

 

 

Ulcerative Colitis

 

Sigmoidoscopy is used to assess disease activity and is often performed before treatment. Histologic features change more slowly than clinical features but can also be used to grade disease activity (Table 3).

 

Patients with a severe attack of UC should have a plain, supine film of the abdomen. In the presence of severe disease, the margin of the colon becomes edematous and irregular. Colonic thickening and toxic dilation can both be seen on a plain radiograph.

The earliest radiologic change of UC seen on single-contrast barium enema is a fine mucosal granularity. With increasing severity, the mucosa becomes thickened and superficial ulcers are seen. Deep ulcerations can appear as “collar-button” ulcers, which indicate that the ulceration has penetrated the mucosa. Haustral folds may be normal in mild disease, but as activity progresses they become edematous and thickened. Loss of haustration can occur, especially in patients with long-standing disease. In addition, the colon becomes shortened and narrowed. Polyps in the colon may be postinflammatory polyps or pseudopolyps, adenomatous polyps, or carcinoma.

Computed tomography (CT) scanning is not as helpful as endoscopy and barium enema in making the diagnosis of UC, but typical findings include mild mural thickening (<1.5 cm), inhomogeneous wall density, absence of small bowel thickening, increased perirectal and presacral fat, target appearance of the rectum, and adenopathy.

Video: ulcerative colitis

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) disorder characterized by altered bowel habits and abdominal pain in the absence of detectable structural abnormalities. No clear diagnostic markers exist for IBS, so all definitions of the disease are based on the clinical presentation. The Rome criteria for the diagnosis of IBS are summarized in Table 1. IBS is one of the most common conditions encountered in clinical practice but one of the least well understood. Until recently, many physicians did not consider IBS to be a disease at all; they viewed it as nothing more than a somatic manifestation of psychological stress. With the availability of better techniques to study colonic and GI motility and visceral sensory function, along with the development of newer concepts about the importance of the brain in regulating gut function, significant progress has been made toward a better understanding of the pathogenesis of IBS. Improved methods of treatment may result from these insights.

 

CLINICAL FEATURES

IBS is a disorder of young people, with most new cases presenting before age 45. However, some reports suggest that the elderly are troubled by IBS symptoms up to 92% as often as middle-aged persons. Indeed, many of the diagnoses of “painful diverticular disease” given the elderly patients may represent IBS. Women are diagnosed with IBS two to three times as often as men and make up 80% of the population with severe IBS. Patients with IBS may fall into two broad clinical groups. Most commonly, patients have abdominal pain associated with altered bowel habits that include constipation, diarrhea, or both. In the second group, patients have painless diarrhea. This latter group accounts for <20% of patients with IBS; their condition may be a separate entity but is generally considered a variant of IBS.

Abdominal Pain  Abdominal pain in IBS is highly variable in intensity and location. Pain in IBS is localized to the hypogastrum in 25%, the right side in 20%, to the left side in 20%, and the epigastrum in 10% of patients. Pain is frequently episodic and crampy but may be superimposed on a background of constant ache. Pain may be mild enough to be ignored or it may interfere with daily activities. Despite this, malnutrition due to inadequate caloric intake is exceedingly rare with IBS. Sleep deprivation is also unusual because abdominal pain is almost uniformly present only during waking hours. Pain is often exacerbated by eating or emotional stress and relieved by passage of flatus or stools.

Altered Bowel Habits  Alteration in bowel habits is the most consistent clinical feature in IBS. Symptoms usually begin in adult life. The most common pattern is constipation alternating with diarrhea, usually with one of these symptoms predominating. At first, constipation may be episodic, but eventually it becomes continuous and increasingly intractable to treatment with laxatives. Stools are usually hard with narrowed caliber, possibly reflecting excessive dehydration caused by prolonged colonic retention and spasm. Most patients also experience a sense of incomplete evacuation, thus leading to repeated attempts at defecation in a short time span. Patients whose predominant symptom is constipation may have weeks or months of constipation interrupted with brief periods of diarrhea. In other patients, diarrhea may be the predominant symptom.

Gas and Flatulence  Patients with IBS frequently complain of abdominal distention and increased belching or flatulence, all of which they attribute to increased gas. Although some patients with these symptoms actually may have a larger amount of gas, quantitative measurements reveal that most patients who complain of increased gas generate no more than a normal amount of intestinal gas.

Upper Gastrointestinal Symptoms  Between 25 and 50% of patients with IBS complain of dyspepsia, heartburn, nausea, and vomiting. This suggests that areas of the gut other than the colon may be involved. Prolonged ambulant recordings of small bowel motility in patients with IBS show a high incidence of abnormalities in the small bowel during the waking period; nocturnal motor patterns are no different from those of healthy controls. A characteristic finding is the frequent occurrence of episodes of clustered contractions recurring at 0- to 9-min intervals. These episodes have a mean duration of 46 min and are often associated with transient abdominal pain and discomfort. A similar pattern has been observed in patients with IBS by the application of psychological stressors and by intravenous neostigmine. In addition, temporary abolition of migrating motor complexes is observed in IBS patients under mental stress.

3. Criteria for diagnosis of the Cronh’s disease and Whipple’s disease.

 

CROHN’S DISEASE: MACROSCOPIC       FEATURES

CD can affect any part ofthe gastrointestinal tract from the mouth to the anus. CD is segmental, with skip areas in the midst of diseased intestine. Perirectal fistulas, fissures, abscesses, and anal stenosis are present in one-third of patients with CD, particularly those with colonic involvement. CD may also involve the liver and the pancreas.

Unlike UC, CD is a transmural process. Endoscopically, aphthous or small superficial ulcerations characterize mild disease; in more active disease, stellate ulcerations fuse longitudinally and transversely to demarcate islands of mucosa that frequently are histologically normal. This “cobblestone” appearance is characteristic of CD, both endoscopically and by barium radiography. As in UC, pseudopolyps can form in CD.

Active CD is characterized by focal inflammation and formation of fistula tracts, which resolve by fibrosis and stricturing of the bowel. The bowel wall thickens and becomes narrowed and fibrotic, leading to chronic, recurrent bowel obstructions. Projections of thickened mesentery encase the bowel (“creeping fat”) and serosal and mesenteric inflammation promote adhesions and fistula formation.

CROHN’S DISEASE: MICROSCOPIC FEATURES

The earliest lesions are aphthoid ulcerations and focal crypt abscesses with loose aggregations of macrophages, which form noncaseating granulomas in all layers of the bowel wall from mucosa to serosa. Granulomas can be seen in lymph nodes, mesentery, peritoneum, liver, and pancreas. Although granulomas are a pathognomonic feature of CD, only half of cases reveal granulomas on surgical or endoscopic biopsy specimens. Other histologic features of CD include submucosal or subserosal lymphoid aggregates, particularly away from areas of ulceration, gross and microscopic skip areas, and transmural inflammation that is accompanied by fissures that penetrate deeply into the bowel wall and sometimes form fistulous tracts or local abscesses.

CLINICAL PRESENTATION. CROHN’S DISEASE. Signs and Symptoms  Although CD usually presents as acute or chronic bowel inflammation, the inflammatory process evolves toward one of two patterns of disease: a fibrostenotic-obstructing pattern or a penetrating-fistulous pattern, each with different treatments and prognoses. The site of disease influences the clinical manifestations.

Ileocolitis  Because the most common site of inflammation is the terminal ileum, the usual presentation of ileocolitis is a chronic history of recurrent episodes of right lower quadrant pain and diarrhea. Sometimes the initial presentation mimics acute appendicitis with pronounced right lower quadrant pain, a palpable mass, fever, and leukocytosis. Only at laparotomy, when the appendix is found to be normal, is the ileitis discovered. Pain is usually colicky; it precedes and is relieved by defecation. A low-grade fever is usually noted. High-spiking fever suggests intraabdominal abscess formation. Weight loss is commonѕtypically 10 to 20% of body weight-and develops as a consequence of diarrhea, anorexia, and fear of eating.

 

 

An inflammatory mass may be palpated in the right lower quadrant of the abdomen. The mass is composed of inflamed bowel, adherent and indurated mesentery, and enlarged abdominal lymph nodes. Extension of the mass can cause obstruction of the right ureter or bladder inflammation, manifested by dysuria and fever. Edema, bowel wall thickening, and fibrosis of the bowel wall within the mass account for the radiographic “string sign” of a narrowed intestinal lumen.

 

Bowel obstruction may take several forms. In the early stages of the disease, bowel wall edema and spasm produce intermittent obstructive manifestations and increasing symptoms of postprandial pain. Over several years, this persistent inflammation gradually progresses to fibrostenotic narrowing and stricture. Diarrhea will decrease and eventually lead to chronic bowel obstruction and obstipation. Acute episodes of obstruction occur as well, precipitated by bowel inflammation and spasm or sometimes by impaction of undigested food. These episodes usually resolve with intravenous fluids and gastric decompression.

Severe inflammation of the ileocecal region may lead to localized wall thinning, with microperforation and fistula formation to the adjacent bowel, the skin, the urinary bladder, or to an abscess cavity in the mesentery. Enterovesical fistulas typically present as dysuria or recurrent bladder infections or less commonly as pneumaturia or fecaluria. Enterocutaneous fistulas follow tissue planes of least resistance, usually draining through abdominal surgical scars. Enterovaginal fistulas are rare and present as dyspareunia or as a feculent or foul-smelling, often painful vaginal discharge. They are unlikely to develop without a prior hysterectomy.

Diarrhea is characteristic of active disease; its causes include: (1) bacterial overgrowth in obstructive stasis or fistulization, (2) bile-acid malabsorption due to a diseased or resected terminal ileum, (3) intestinal inflammation with decreased water absorption and increased secretion of electrolytes.

Colitis and Perianal Disease  Patients with colitis present with low-grade fevers, malaise, diarrhea, crampy abdominal pain, and sometimes hematochezia. Gross bleeding due to deep colonic ulceration is not as common as in UC and appears in about half of patients with exclusively colonic disease. Only 1 to 2% bleed massively. Pain is caused by passage of fecal material through narrowed and inflamed segments of large bowel. Decreased rectal compliance is another cause for diarrhea in Crohn’s colitis patients. Toxic megacolon has been associated with severe inflammation and short-duration disease.

Perianal disease affects about one-third of patients with Crohn’s colitis and is manifested by incontinence, large hemorrhoidal tags, anal strictures, anorectal fistulae, and perirectal abscesses. Not all patients with perianal fistula will have endoscopic evidence of colonic inflammation.

Gastroduodenal Disease  Symptoms and signs of upper gastrointestinal tract disease include nausea, vomiting, and epigastric pain. Patients usually have a H. pylori-negative gastritis..

Laboratory, Endoscopic, and Radiographic Features  Laboratory abnormalities include elevated sedimentation rate and C-reactive protein. In more severe disease, findings include hypoalbuminemia, anemia, and leukocytosis.

Endoscopic features of CD include rectal sparing, aphthous ulcerations, fistulas, and skip lesions. Endoscopy is useful for biopsy of mass lesions or strictures, or for visualization of filling defects seen on barium enema. Colonoscopy allows examination and biopsy of the terminal ileum, and upper endoscopy is useful in diagnosing gastroduodenal involvement in patients with upper tract symptoms. Ileal or colonic strictures may be dilated with balloons introduced through the colonoscope. Endoscopic appearance correlates poorly with clinical remission; thus, repeated endoscopy is not used to monitor the inflammation.

In CD early radiographic findings in the small bowel include thickened folds and aphthous ulcerations. “Cobblestoning” from longitudinal and transverse ulcerations most frequently involves the small bowel. In more advanced disease, strictures, fistulas, inflammatory masses, and abscesses may be detected. The earliest macroscopic findings of colonic CD are aphthous ulcers. These small ulcers are often multiple and separated by normal intervening mucosa. As more severe disease develops, aphthous ulcers become enlarged, deeper, and occasionally connected to one another, forming longitudinal stellate, serpiginous, and linear ulcers.

CT findings include mural thickening >2 cm, homogeneous wall density, mural thickening of small bowel, mesenteric fat stranding, perianal disease, and adenopathy. CT scanning can help identify abscesses, fistulas, and sinus tracts. Magnetic resonance imaging (MRI) may prove superior for demonstrating pelvic lesions such as ischiorectal abscesses.

WHIPPLE’S DISEASE

Whipple’s disease is a chronic multisystem disease associated with diarrhea, steatorrhea, weight loss, arthralgia, and central nervous system and cardiac problems that is caused by the bacteria Tropheryma whippelii. Until the identification of T. whippelii by polymerase chain reaction during the past decade, the hallmark of Whipple’s disease had been the presence of PAS-positive macrophages in the small intestine and other organs with evidence of disease. Long before the establishment of T. whippelii as the causative agent of Whipple’s disease, gram-positive bacilli had been identified both within and outside of macrophages.

Clinical Presentation  The onset of Whipple’s disease is insidious and is characterized by diarrhea, steatorrhea, abdominal pain, weight loss, migratory large-joint arthropathy, and fever as well as ophthalmologic and central nervous system symptoms. The development of dementia is a relatively late symptom and is an extremely poor prognostic sign, especially in patients who relapse following the induction of a remission with antibiotics. For unexplained reasons, the disease occurs primarily in middle-aged (50-year-old) Caucasian men. The steatorrhea in these patients is generally believed secondary to both small-intestinal mucosal injury and lymphatic obstruction secondary to the increased number of PAS-positive macrophages in the lamina propria of the small intestine.

Diagnosis. The diagnosis of Whipple’s disease is suggested by a multisystem disease in a 50-year-old Caucasian male with diarrhea and steatorrhea. Obtaining tissue biopsies from the small intestine and/or other organs that may be involved (e.g., liver, lymph nodes, heart, eyes, central nervous system, or synovial membranes), based on the patient’s symptoms, is the primary approach to establish the diagnosis of Whipple’s disease. The presence of PAS-positive macrophages containing the characteristic small (0.25 ґ 1 to 2 um) bacilli is suggestive of this diagnosis. However, Whipple’s disease can be confused with the PAS-positive macrophages containing M. avian complex, which may be a cause of diarrhea in AIDS. The presence of the T. whippelii bacillus outside of macrophages is a more important indicator of active disease than their presence within the macrophages. T. whippelii has now been successfully grown in culture.

6. Criteria for diagnosis of the tumours of the colon.

COLORECTAL CANCER

POLYPS AND MOLECULAR PATHOGENESIS

Most colorectal cancers, regardless of etiology, arise from adenomatous polyps. A polyp is a grossly visible protrusion from the mucosal surface and may be classified pathologically as a nonneoplastic hamartoma (juvenile polyp), a hyperplastic mucosal proliferation (hyperplastic polyp), or an adenomatous polyp. Only adenomas are clearly premalignant, and only a minority of such lesions ever develop into cancer. Population-screening studies and autopsy surveys have revealed that adenomatous polyps may be found in the colons of >30% of middle-aged or elderly people; however <1% of polyps ever become malignant. Most polyps produce no symptoms and remain clinically undetected. Occult blood in the stool may be found in <5% of patients with such lesions.

Clinically, the probability of an adenomatous polyp becoming a cancer depends on the gross appearance of the lesion, its histologic features, and its size. Adenomatous polyps may be pedunculated (stalked) or sessile (flat-based). Cancers develop more frequently in sessile polyps. Histologically, adenomatous polyps may be tubular, villous (i.e., papillary), or tubulovillous. Villous adenomas, most of which are sessile, become malignant more than three times as often as tubular adenomas. The likelihood that any polypoid lesion in the large bowel contains invasive cancer is related to the size of the polyp, being negligible (<2%) in lesions <1.5 cm, intermediate (2 to 10%) in lesions 1.5 to 2.5 cm in size, and substantial (10%) in lesions >2.5 cm.

Following the detection of an adenomatous polyp, the entire large bowel should be visualized endoscopically or radiographically, since synchronous lesions are present in about one-third of cases. Colonoscopy should then be repeated periodically, even in the absence of a previously documented malignancy, since such patients have a 30 to 50% probability of developing another adenoma and are at a higher-than-average risk for developing a colorectal carcinoma. Adenomatous polyps are thought to require >5 years of growth before becoming clinically significant; colonoscopy need not be carried out more frequently than every 3 years.

Polyposis Coli  Polyposis coli (familial polyposis of the colon) is a rare condition characterized by the appearance of thousands of adenomatous polyps throughout the large bowel. It is transmitted as an autosomal dominant trait; the occasional patients with no family history probably developed the condition due to a spontaneous mutation. Polyposis coli is associated with a deletion in the long arm of chromosome 5 (including the APC gene) in both neoplastic (somatic mutation) and normal (germline mutation) cells. The loss of this genetic material (i.e., allelic loss) results in the absence of tumor suppressor genes whose protein products would normally inhibit neoplastic growth. The presence of soft tissue and bony tumors, congenital hypertrophy of the retinal pigment epithelium, mesenteric desmoid tumors, and of ampullary cancers in addition to the colonic polyps characterizes a subset of polyposis coli known as Gardner‘s syndrome. The appearance of malignant tumors of the central nervous system accompanying polyposis coli defines Turcot’s syndrome. The colonic polyps in all these conditions are rarely present before puberty but are generally evident in affected individuals by age 25. If the polyposis is not treated surgically, colorectal cancer will develop in almost all patients before age 40. Polyposis coli results from a defect in the colonic mucosa leading to an abnormal proliferative pattern and an impaired DNA repair following exposure to radiation or ultraviolet light. Once the multiple polyps that constitute polyposis coli are detected, patients should undergo a total colectomy. The ileoanal anastomotic technique allows removal of the entire bowel while retaining the anal sphincter; this appears to be the best treatment. Medical therapy with nonsteroidal anti-inflammatory drugs such as sulindac and cyclooxygenase-2 inhibitors such as celecoxib decreases the number and size of polyps in patients with polyposis coli; however, this effect on polyps is only temporary. Colectomy remains the primary therapy. The offspring of patients with polyposis coli, who often are prepubertal when the diagnosis is made in the parent, have a 50% risk for the development of this premalignant disorder and should be carefully screened by annual flexible sigmoidoscopy until age 35. Proctosigmoidoscopy is a sufficient screening procedure because polyps tend to be evenly distributed from cecum to anus, making more invasive and expensive techniques such as colonoscopy or barium enema unnecessary. Testing for occult blood in the stool is an inadequate screening maneuver. An alternative method for identifying carriers is testing DNA from peripheral blood mononuclear cells for the presence of a mutated APC gene. The detection of such a germline mutation can lead to a definitive diagnosis before the development of polyps.

Hereditary Nonpolyposis Colon Cancer  Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is another autosomal dominant trait. It is characterized by the presence of three or more relatives with histologically documented colorectal cancer, one of whom is a first-degree relative of the other two; one or more cases of colorectal cancer diagnosed before age 50 in the family; and colorectal cancer involving at least two generations. In contrast to polyposis coli, HNPCC is associated with an unusually high frequency of cancer arising in the proximal large bowel. The median age for the appearance of an adenocarcinoma is <50 years, 10 to 15 years younger than the median age for the general population. Despite having a poorly differentiated histologic appearance, the proximal colon tumors in HNPCC have a better prognosis than sporadic tumors from patients of similar age. Families with HNPCC often include individuals with multiple primary cancers; the association of colorectal cancer with either ovarian or endometrial carcinomas is especially strong in women. It has been recommended that members of such families undergo biennial colonoscopy beginning at age 25 years, with intermittent pelvic ultrasonography and endometrial biopsy offered for potentially afflicted women; such a screening strategy has not yet been validated. HNPCC is associated with germline mutations of several genes, particularly hMSH2 on chromosome 2 and hMLH1 on chromosome 3. These mutations lead to errors in DNA replication and are thought to result in DNA instability because of defective repair of DNA mismatches, resulting in abnormal cell growth and tumor development. Testing tumor cells for “microsatellite instability” (sequence changes reflecting defective mismatch repair) in patients under age 50 with colorectal cancer and a positive family history for colorectal or endometrial cancer may identify probands with HNPCC.

SCREENING

Most programs directed at the early detection of colorectal cancers have focused on digital rectal examinations and fecal occult blood testing. The digital examination should be part of any routine physical evaluation in adults older than age 40, serving as a screening test for prostate cancer in men, a component of the pelvic examination in women, and an inexpensive maneuver for the detection of masses in the rectum. The development of the Hemoccult test has greatly facilitated the detection of occult fecal blood. Unfortunately, even when performed optimally, the Hemoccult test has major limitations as a screening technique. About 50% of patients with documented colorectal cancers have a negative fecal Hemoccult test, consistent with the intermittent bleeding pattern of these tumors. When random cohorts of asymptomatic persons have been tested, 2 to 4% have Hemoccult-positive stools. Colorectal cancers have been found in <10% of these “test-positive” cases, with benign polyps being detected in an additional 20 to 30%. Thus, a colorectal neoplasm will not be found in most asymptomatic individuals with occult blood in their stool. Nonetheless, persons found to have Hemoccult-positive stool routinely undergo further medical evaluation, including sigmoidoscopy, barium enema, and/or colonoscopy-procedures that are not only uncomfortable and expensive but also associated with a small risk for significant complications. The added cost of these studies would appear justifiable if the small number of patients found to have occult neoplasms because of Hemoccult screening could be shown to have an improved prognosis and prolonged survival. Prospectively controlled trials addressing this issue have been performed. One of these studies, conducted at the University of Minnesota and involving >46,000 participants, reported a statistically significant reduction in mortality from colorectal cancer for individuals undergoing annual screening. However, this benefit only emerged after >13 years of follow-up and was extremely expensive to achieve, since all positive tests (most of which were false-positive) were followed by colonoscopy. Moreover, these colonoscopic examinations may have represented “chance selection” for more effective endoscopic screening and may also have provided the opportunity for cancer prevention through the removal of potentially premalignant adenomatous polyps.

Screening techniques for large-bowel cancer in asymptomatic persons remain unsatisfactory. Recommendations from governmental and private agencies are conflicting. Compliance with any screening strategy within the general population is poor. At present, the American Cancer Society suggests annual digital rectal examinations beginning at age 40, annual fecal Hemoccult screening beginning at age 50, and sigmoidoscopy (preferably flexible) every 3 to 5 years beginning at age 50 for asymptomatic individuals having no colorectal cancer risk factors. The use of colonscopy or double-contrast barium enemas for screening have not yet been systematically examined.

CLINICAL FEATURES

Symptoms vary with the anatomic location of the tumor. Since stool is relatively liquid as it passes through the ileocecal valve into the right colon, cancers arising in the cecum and ascending colon may become quite large, without resulting in any obstructive symptoms or noticeable alterations in bowel habits. Lesions of the right colon commonly ulcerate, leading to chronic, insidious blood loss without a change in the appearance of the stool. Consequently, patients with tumors of the ascending colon often present with symptoms such as fatigue, palpitations, and even angina pectoris and are found to have a hypochromic, microcytic anemia indicative of iron deficiency. Since the cancer may bleed intermittently, a random fecal occult blood test may be negative. As a result, the unexplained presence of iron-deficiency anemia in any adult (with the possible exception of a premenopausal, multiparous woman) mandates a thorough endoscopic and/or radiographic visualization of the entire large bowel.

Since stool becomes more concentrated as it passes into the transverse and descending colon, tumors arising there tend to impede the passage of stool, resulting in the development of abdominal cramping, occasional obstruction, and even perforation. Radiographs of the abdomen often reveal characteristic annular, constricting lesions (“apple-core” or “napkin-ring”).

Cancers arising in the rectosigmoid are often associated with hematochezia, tenesmus, and narrowing of the caliber of stool; anemia is an infrequent finding. While these symptoms may lead patients and their physicians to suspect the presence of hemorrhoids, the development of rectal bleeding and/or altered bowel habits demands a prompt digital rectal examination and proctosigmoidoscopy.

Staging, Prognostic Factors, and Patterns of Spread  The prognosis for individuals having colorectal cancer is related to the depth of tumor penetration into the bowel wall and the presence of both regional lymph node involvement and distant metastases. These variables are incorporated into the staging system introduced by Dukes and applied to a TNM classification method, in which T represents the depth of tumor penetration, N the presence of lymph node involvement, and M the presence or absence of distant metastases. Superficial lesions that do not penetrate into the muscularis or involve regional lymph nodes are designated as stage A (T1N0M0) disease; tumors that penetrate more deeply but have not spread to lymph nodes are stage B disease [subclassified as stage B1 (T2N0M0) if lesions are restricted to the muscularis and as stage B2 (T3N0M0) if lesions involve or penetrate the serosa]; regional lymph node involvement defines stage C (TxN1M0) disease; and metastatic spread to sites such as liver, lung, or bone indicates stage D (TxNxM1) disease. Unless gross evidence of metastatic disease is present, disease stage cannot be determined accurately before surgical resection and pathologic analysis of the operative specimens. It is not clear whether the detection of nodal metastases by special immunohistochemical molecular techniques has the same prognostic implications as disease detected by routine light microscopy.

Cancers of the large bowel generally spread to regional lymph nodes or to the liver via the portal venous circulation. The liver represents the most frequent visceral site of metastatic dissemination; it is the initial site of distant spread in one-third of recurring colorectal cancers and is involved in more than two-thirds of such patients at the time of death. In general, colorectal cancer rarely metastasizes to the lungs, supraclavicular lymph nodes, bone, or brain without prior spread to the liver. A major exception to this rule occurs in patients having primary tumors in the distal rectum, from which tumor cells may spread through the paravertebral venous plexus, escaping the portal venous system and thereby reaching the lungs or supraclavicular lymph nodes without hepatic involvement. The median survival after the detection of distant metastases is 6 to 9 months (hepatomegaly, abnormal liver chemistries) to 24 to 30 months (small liver nodule initially identified by elevated CEA level and subsequent CT scan).

7. Criteria for diagnosis of the congenital enthesopathies

Congenital defects in ion absorption. Rarely, these defects cause watery diarrhea from birth and include defective Cl-/HCO3- exchange (congenital chloridorrhea) with alkalosis and defective Na+/H+ exchange with acidosis. Some hormone deficiencies may be associated with watery diarrhea, such as occurs with adrenocortical insufficiency (Addison’s disease) that may be accompanied by hyperpigmentation.

Mucosal Malabsorption. Mucosal malabsorption occurs from a variety of enteropathies, but most prototypically and perhaps most commonly from celiac sprue. This gluten-sensitive enteropathy characterized by villous atrophy and crypt hyperplasia in the proximal small bowel often presents with fatty diarrhea associated with multiple nutritional deficiencies of varying severity and affects all ages. Tropical sprue may produce a similar histologic and clinical syndrome, but it occurs in residents of or travelers to tropical climates; its often abrupt onset and response to antibiotics suggest an infectious etiology. Whipple’s disease, due to the actinomycete Treponema whippleii and histiocytic infiltration of the small bowel mucosa, is a less common cause of steatorrhea that most typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopathy, and extreme fatigue and may affect the central nervous system and endocardium. A similar clinical and histologic picture results from Mycobacterium avium intracellulare infection in patients with AIDS. Abetalipoproteinemia is a rare defect of chylomicron formation and fat malabsorption in children associated with acanthocytic erythrocytes, ataxia, and retinitis pigmentosa. Several other conditions may cause mucosal malabsorption including infections, especially with protozoa like Giardia, numerous medications (e.g., colchicine, cholestyramine, neomycin), and chronic ischemia.

8. Ischaemia of the alimentary tract.

DISORDERS OF THE MESENTERIC CIRCULATION

Ischemia of the intestine is the end result of interruption or reduction of its blood supply. However, the clinical manifestations of intestinal ischemia range from mild chronic symptoms to a catastrophic acute episode, depending on the vascular supply involved, the extent of the occlusion or ischemia, and the rapidity of the process. The clinician should be aware of the spectrum of clinical manifestations. The gut derives its arterial blood supply from the celiac axis and the superior and inferior mesenteric arteries. The small intestine is supplied by the celiac and superior mesenteric arteries, the colon by branches of the superior and inferior mesenteric arteries. A rich network of anastomotic vessels and the possible development of collateral circulation determine the clinical picture of acute or chronic intestinal arterial insufficiency.

 

 

 

 

MESENTERIC ISCHEMIA AND INFARCTION

 

 

Superior mesenteric ischaemia

                                   Acute intestinal ischemia

 

Acute intestinal ischemia may be classified as occlusive or nonocclusive. Occlusion accounts for about 75% of acute intestinal ischemia and may result from an arterial thrombus (one-third of arterial occlusions) or embolus (two-thirds of arterial occlusions) of the celiac or superior mesenteric arteries, or from venous occlusion (<5% of occlusions) in the same distribution. Arterial embolus occurs most commonly in patients with chronic or recurrent atrial fibrillation, artificial heart valves, or valvular heart disease; arterial thrombosis is usually associated with extensive atherosclerosis or low cardiac output. Venous occlusion is rare; it is occasionally seen in women taking oral contraceptives. Approximately one-fourth of patients with mesenteric ischemia have no definite occlusion of a major vessel, a condition referred to as nonocclusive ischemia. The exact cause of nonocclusive disease is obscure; systemic arterial hypotension, cardiac arrhythmias, prolonged heart failure, digitalis therapy, dehydration, and endotoxemia can be contributing factors.

The major clinical feature of acute mesenteric ischemia is severe abdominal pain, often colicky and periumbilical at the onset, later becoming diffuse and constant. Vomiting, anorexia, diarrhea, and constipation are also frequent but of little diagnostic help. Examination of the abdomen may reveal tenderness and distention. Bowel sounds are ofteormal even in the face of severe infarction. Some patients have a surprisingly normal abdominal examination in spite of severe pain. Mild gastrointestinal bleeding is often detected by examination of stool for occult blood; gross hemorrhage is unusual except in ischemic colitis. Leukocytosis is often present. Late in the course of the disease (24 to 72 h), gangrene of the bowel occurs with diffuse peritonitis, sepsis, and shock. Abdominal plain films in patients with mesenteric ischemia may reveal air-fluid levels and distention. Barium study of the small intestine reveals nonspecific dilation, poor motility, and evidence of thick mucosal folds (“thumbprinting”).

Acute mesenteric ischemia is a grave condition with a high morbidity and mortality. Patients suspected of having acute arterial embolus should undergo immediate celiac and mesenteric angiography to localize the embolus, followed by embolectomy. Restoration of normal circulation may allow complete recovery if performed before irreversible necrosis or gangrene has occurred. Unfortunately, infarction and transmural necrosis are frequently found at surgery, necessitating resection. Arterial or venous thrombosis is not generally amenable to surgical removal of the thrombus, and resection of the affected bowel is required. Similarly, patients with nonocclusive ischemia are not candidates for corrective vascular surgery (as major vessels are patent). These individuals often have extensive necrosis of the small or large intestine because of the widespread nature of the ischemic event. The decision to operate when mesenteric ischemia is suspected is often difficult, because the typical patient is a poor surgical risk owing to advanced age, dehydration, sepsis, and other serious medical conditions.

Chronic arterial insufficiency may precede acute vascular insufficiency, producing so-called abdominal angina. As in angina pectoris, the pain of chronic mesenteric insufficiency occurs under conditions of increased demand for splanchnic blood flow. The patient complains of intermittent dull or cramping midabdominal pain 15 to 30 min after a meal, lasting for several hours postprandially. Significant weight loss due to decreased food intake may be present. Chronic intestinal ischemia also may produce mucosal damage and malabsorption, which in turn aggravates the weight loss. Since abdominal angina may progress to bowel infarction, arteriographic studies should be performed to confirm the diagnosis in those patients who are candidates for abdominal vascular surgery. The only definitive treatment is vascular surgery or balloon angioplasty to remove the thrombus or the construction of bypass arterial grafts to the ischemic bowel.

A number of systemic conditions are associated with vasculitis of the large and small arteries supplying the intestine. Most often these disorders can be recognized by the associated extraintestinal manifestations, as in polyarteritis nodosa, lupus erythematosus, dermatomyositis, Henoch-Schonlein purpura (allergic vasculitis), and rheumatoid vasculitis. When larger arteries are involved, as in polyarteritis nodosa, the picture of acute intestinal infarction is similar to that of embolic or atherosclerotic vascular occlusion. Often the involvement of smaller vessels leads to areas of intramural hemorrhage and edema resulting in abdominal pain, variable degrees of intestinal obstruction, and bleeding. Barium enema may show “thumbprinting” and “spiculation” due to localized edema, hemorrhage, and ulceration. In many instances, treatment of the underlying disorder may lead to regression of symptoms. If signs of an acute abdomen develop, surgical exploration is usually indicated.

Intramural small-intestinal hemorrhage may occur with vasculitis, trauma, or impaired coagulation, especially in patients receiving anticoagulants. The clinical and radiologic features resemble those seen with vasculitis and local mucosal hemorrhage.

ISCHEMIC COLITIS

Ischemia of the colon most often affects the elderly because of their greater frequency of vascular disease. Ischemic colitis is almost always nonocclusive. Shunting of blood away from the mucosa may contribute to this condition, but the mechanism of ischemia is not known.

The clinical picture depends on the degree of ischemia and its rate of development. In acute fulminant ischemic colitis, the major manifestations are severe lower abdominal pain, rectal bleeding, and hypotension. Dilation of the colon and physical signs of peritonitis are seen in severe cases. Abdominal films may reveal thumbprinting from submucosal hemorrhage and edema. Barium enema is hazardous in the acute situation because of the risk of perforation. Sigmoidoscopy or colonoscopy may detect ulcerations, friability, and bulging folds from submucosal hemorrhage. Angiography is not helpful in the management of patients with presumed ischemic colitis because a remediable occlusive lesion is very rarely found. Surgical resection may be required in some patients with fulminant ischemic colitis to remove gangrenous bowel; others with lesser degrees of ischemia may respond to conservative medical management.

Subacute ischemic colitis is the most common clinical variant of ischemic colonic disease. It produces lesser degrees of pain and bleeding, often occurring over several days or weeks. The left colon may be involved, but the rectum is usually spared because of the collateral blood supply, a feature distinguishing it from acute ulcerative colitis. Barium enema reveals edema, cobblestoning, thumbprinting, and occasionally superficial ulceration. Angiography is not indicated because almost all cases are nonocclusive. Occasionally, stricture formation may follow a bout of ischemic colitis or may present de novo without a history of antecedent pain or bloody diarrhea. Most cases of nonocclusive ischemic colitis resolve in 2 to 4 weeks and do not recur. Surgery is not required except for obstruction secondary to postischemic stricture.

9. Treatment of the bowel diseases.

Tropical sprue TREATMENT

Broad-spectrum antibiotics and folic acid are most often curative, especially if the patient leaves the tropical area and does not return. Tetracycline should be used for up to 6 months and may be associated with improvement within 1 to 2 weeks. Folic acid alone will induce a hematologic remission as well as improvement in appetite, weight gain, and some morphologic changes in small intestinal biopsy. Because of the presence of marked folate deficiency, folic acid is most often given together with antibiotics.

TREATMENT

5-ASA Agents  The mainstay of therapy for mild to moderate UC and CD colitis is sulfasalazine and the other 5-ASA agents. Sulfasalazine was originally developed to deliver both antibacterial (sulfapyridine) and anti-inflammatory (5-aminosalicylic acid, 5-ASA) therapy into the connective tissues of joints and the colonic mucosa. The molecular structure provides a convenient delivery system to the colon by allowing the intact molecule to pass through the small intestine after only partial absorption, and to be broken down in the colon by bacterial azo reductases that cleave the azo bond linking the sulfa and 5-ASA moieties. Sulfasalazine is effective in inducing and maintaining remission in mild to moderate UC and CD ileocolitis and colitis, but its high rate of side effects limits its use. Although sulfasalazine is more effective at higher doses, at 6 or 8 g/d up to 30% of patients experience allergic reactions or intolerable side effects such as headache, anorexia, nausea, and vomiting that are attributable to the sulfapyridine moiety. Hypersensitivity reactions, independent of sulfapyridine levels, include rash, fever, hepatitis, agranulocytosis, hypersensitivity pneumonitis, pancreatitis, worsening of colitis, and reversible sperm abnormalities. Sulfasalazine can also impair folate absorption and patients should be supplemented with folic acid.

Newer sulfa-free aminosalicylate preparations deliver increased amounts of the pharmacologically active ingredient of sulfasalazine (5-ASA, mesalamine) to the site of active bowel disease while limiting systemic toxicity. 5-ASA may function through inhibition of NF-kB activity. Sulfa-free aminosalicylate formulations include alternative azo-bonded carriers, 5-ASA dimers, pH-dependent tablets, and continuous-release preparations. Each has the same efficacy as sulfasalazine when equimolar concentrations are used. Olsalazine is composed of two 5-ASA radicals linked by an azo bond which is split in the colon by bacterial reduction and two 5-ASA molecules are released. Olsalazine is similar in effectiveness to sulfasalazine in treating CD and UC, but up to 17% of patients experience non-bloody diarrhea caused by increased secretion of fluid in the small bowel. Balsalazide contains an azo bond binding mesalamine to the carrier molecule 4-amino benzoyl b alanine; it is effective in the colon. Claversal is an enteric-coated form of 5-ASA that consists of mesalamine surrounded by an acrylic-based polymer resin and a cellulose coating that releases mesalamine at pH > 6.0, a level that is present from the mid-jejunum continuously to the distal colon.

The most commonly used drugs besides sulfasalazine in the United States are Asacol and Pentasa. Asacol is also an enteric-coated form of mesalamine, but it has a slightly different release pattern, with 5-ASA liberated at pH > 7.0. The disintegration of Asacol is variable with complete break-up of the tablet occurring in many different parts of the gut ranging from the small intestine to the splenic flexure; it has increased gastric residence when taken with a meal. Asacol is used to induce and maintain remission in UC and in CD ileitis, ileocolitis, and colitis. Appropriate doses of Asacol and the other 5-ASA compounds are shown in Table 287-6. Some 50 to 75% of patients with mild to moderate UC and CD improve when treated with 2 g/d of 5-ASA; the dose response continues up to at least 4.8 g/d. Doses of 1.5-4 g/d maintain remission in 50 to 75% of patients with UC and CD.

 

 

 

 

Nutritional Therapies  Dietary antigens may act as stimuli of the mucosal immune response. Patients with active CD respond to bowel rest, along with total enteral or total parenteral nutrition (TPN). Bowel rest and TPN are as effective as glucocorticoids for inducing remission of active CD but are not as effective as maintenance therapy. Enteral nutrition in the form of elemental or peptide-based preparations are also as effective as glucocorticiods or TPN, but these diets are not palatable. Enteral diets may provide the small intestine with nutrients vital to cell growth and do not have the complications of TPN. In contrast to CD, active UC is not effectively treated with either elemental diets or TPN.

Surgical Therapy

Ulcerative Colitis  Nearly half of patients with extensive chronic UC undergo surgery within the first 10 years of their illness. Morbidity is about 20% in elective, 30% for urgent, and 40% for emergency proctocolectomy. The risks are primarily hemorrhage, contamination and sepsis, and neural injury. Although single-stage total proctocolectomy with ileostomy has been the operation of choice, newer operations maintain continence while surgically removing the involved rectal mucosa.

The IPAA is the most frequent continence-preserving operation performed. Because UC is a mucosal disease, the rectal mucosa can be dissected out and removed down to the dentate line of the anus or about 2 cm proximal to it. The ileum is fashioned into a pouch that serves as a neorectum. This ileal pouch is then sutured circumferentially to the anus in an end-to-end fashion. If performed carefully, this operation preserves the anal sphincter and maintains continence. The overall operative morbidity is 10%, with the major complication being bowel obstruction. Pouch failure necessitating conversion to permanent ileostomy occurs in 5 to 10% of patients. Some inflamed rectal mucosa is usually left behind, and thus endoscopic surveillance is necessary. Primary dysplasia of the ileal mucosa of the pouch has occurred rarely.

Patients with IPAAs usually have about six to eight bowel movements a day. On validated quality of life indices, they report better performance in sports and sexual activities than ileostomy patients. The most frequent late complication of IPAA is pouchitis in about one-third of patients with UC. This syndrome consists of increased stool frequency, watery stools, cramping, urgency, nocturnal leakage of stool, arthralgias, malaise, and fever. Although it usually responds to antibiotics, in 3% of patients it is refractory and requires pouch take-down.

Crohn’s Disease  Most patients with CD require at least one operation in their lifetime. The need for surgery is related to duration of disease and the site of involvement. Patients with small bowel disease have an 80% chance of requiring surgery. Those with colitis alone have a 50% chance.

TREATMENT

The treatment for Whipple’s disease is prolonged use of antibiotics. At the present time the drug of choice is double-strength trimethoprim/sulfamethoxazole for approximately 1 year. PAS-positive macrophages can persist following successful treatment, and the presence of bacilli outside of macrophages is indicative of persistent infection or an early sign of recurrence. Recurrence of disease activity, especially with dementia, is an extremely poor prognostic sign and requires an antibiotic that crosses the blood-brain barrier. If trimethoprim/sulfamethoxazole is not tolerated, chloramphenicol is an appropriate second choice.

MANAGEMENT OF DYSPLASIA AND CANCER

If high grade dysplasia (HGD) is encountered on colonoscopic surveillance, the usual treatment for UC is colectomy and for CD is either colectomy or segmental resection. If low grade dysplasia (LGD) is found, the management is controversial. Many investigators recommend immediate colectomy, but some repeat the colonoscopy in 1 to 6 months and search for recurrent dysplasia.  Polyps in chronic colitis can be removed endoscopically provided that biopsies of the surrounding mucosa are free of dysplasia.

IBD patients are also at greater risk for other malignancies. Patients with CD may have an increased risk of developing non-Hodgkin’s lymphoma and squamous cell carcinoma of the skin. Although CD patients have a twelvefold increased risk of developing small bowel cancer, this type of carcinoma is extremely rare.

 

Whipple disease

Whipple’s disease is a rare infectious disorder that can affect many areas of the body, including the gastrointestinal and central nervous systems. Caused by the bacteria Tropheryma whipplei, it is typically diagnosed from malabsorption symptoms such as diarrhea and weight loss. If the central nervous system is infected, Whipple’s disease can cause impairment of mental faculties and lead to dementia . It can be treated successfully with antibiotic therapy, but up to a third of patients suffer relapse.

Description

Whipple’s disease, also known as intestinal lipodystrophy, was first reported in 1907 by George Hoyt Whipple (1878–1976). An autopsy on a thirty-seven year old male missionary revealed a granular accumulation of fatty acids in the walls of the small intestine and lymph nodes.

Historically, Whipple’s disease has been considered an gastro-intestinal disorder, however, in the 1960s it was realized that other organs could be involved, with or without intestinal infection. It is now considered a systemic infection with a wide range of possible symptoms.

Demographics

The disorder typically affects middle-aged men of European descent. Most cases have been reported in America  and Europe. Many texts suggest the disorder affects eight times as many males as females, although there is some evidence to suggest the rate in females is rising.

The disease is extremely rare and no reliable estimate of incidence is known. Farmers and other rural people are most often diagnosed with Whipple’s disease, but as yet, no specific environmental factors have been linked to the disorder.

 

Causes and symptoms

The bacterium that causes Whipple’s disease was only successfully cultured in 1997. Tropheryma whipplei belongs to the high G+C phylum of gram-positive bacteria, and its genome was sequenced in 2003.

Whipple’s disease has traditionally been regarded as a malabsorption disease of the small intestine, but in most cases the first symptoms are arthritic joints, which can precede the malabsorption symptoms of Whipple’s disease by many years. Commonly, the disease progresses to the small intestine. Symptoms then include diarrhea, anemia, weight loss, and there is often fat present in the stool, all due to the bacteria disrupting absorption of fat and nutrients. If untreated, other malabsorption problems, such as reductions in the levels of calcium and magnesium, may result. Fever and night sweats are common, as well as general weakness. There are many further possible symptoms depending on the organs affected.

In cases where the central nervous system is affected, there may be a decrease in intellectual abilities, insomnia, hearing loss or tinnitus (ringing in the ears), and uncontrolled muscle movements (ataxia ) or eye movements. If untreated, the disorder can lead to dementia and progressive brain cell death, leading to coma and death over a period of months to years.

Common signs and symptoms
Gastrointestinal signs and symptoms are common in Whipple’s disease and may include:

• Diarrhea

• Abdominal cramping and pain, which may worsen after meals

• Weight loss, associated with the malabsorption of nutrients

Other frequent signs and symptoms associated with Whipple’s disease include:

• Inflamed joints, particularly your ankles, knees and wrists

• Fatigue

• Weakness

• Anemia

Less common signs and symptoms
In some cases, signs and symptoms of Whipple’s disease may include:

• Fever

• Cough

• Enlarged lymph nodes

• Skin darkening (hyperpigmentation) in areas exposed to the sun and in scars

• Chest pain

• Enlarged spleen

Neurological signs and symptoms may include:

• Difficulty walking

• Visual impairment, including lack of control of eye movements

• Seizures

• Confusion

• Memory loss

Symptoms tend to develop slowly over a period of many years in most people with this disease. In some cases, some symptoms, such as joint pain and weight loss, develop years before the gastrointestinal symptoms that lead to diagnosis.

Diagnosis of Whipple’s disease is difficult, and is commonly suspected only if the patient presents with malabsorption symptoms. Then, a small-bowel biopsy can be made to locate the presence of the bacteria and confirm the diagnosis. However, symptoms can vary greatly depending on the areas of the body that are affected, and up to a third of sufferers do not present with malabsorption ailments.

Whipple disease is a systemic disease most likely caused by a gram-positive bacterium, Tropheryma whippelii. Although the first descriptions of the disorder described a malabsorbsion syndrome with small intestine involvement, the disease also affects the joints, CNS, and cardiovascular system. Because fewer than 1000 reported cases have been described, clinical experience with this disorder is sparse.

The clinical manifestations of the disease are believed to be caused by infiltration of the various body tissues by T whippelii. The patient’s immune system reacts by incorporating the organisms into tissue macrophages.

These macrophages can be easily observed infiltrating the tissues using conventional light microscopy. The macrophages are easily observed when periodic acid-Schiff stain is used for the histologic sections. However, positive periodic acid-Schiff–stained macrophages infiltrating body tissues are not pathognomonic for Whipple disease. These microphages also can be detected in infection due to Mycobacterium avium intracellulare, cryptococcosis, or other parasitic organisms (usually observed in patients who are immunosuppressed with HIV disease). Stains for fungal organisms and acid-fast bacilli are helpful in ruling out Whipple disease.

Diagnostic electron microscopy reveals coccobacillary bodies that represent the T whippelii organism. This is diagnostic because a positive polymerase chain reaction (PCR) for T whippelii will be present in the affected tissue.

The malabsorption observed in the small bowel that is associated with this condition is believed to be secondary to the disruption of normal villous function due to infiltration of the lamina propria of the small bowel. Patients with arthralgias have been found to have the organism in the synovial tissues. The organisms have been detected in the heart valves of patients with cardiac Whipple disease^.and in the CNS of patients with neurologic disease. Rarely, the organism can be detected in the lungs of affected patients. In short, although Whipple disease represents a systemic condition, only a few organ systems of the body are affected overtly.

• The classic presentation of Whipple disease is that of a wasting illness characterized by arthralgias, arthritis, fever, and diarrhea.

• Lymphadenopathy may be present.

• If Whipple disease affects the small intestine, steatorrhea often is present.

• Approximately 90% of patients with Whipple disease present with weight loss, and 70% of patients with Whipple disease complain of either diarrhea or arthralgias.

• Occult GI bleeding can be found in 80% of patients of Whipple disease, but frank hematochezia is uncommon.

• Cardiac involvement occurs in approximately 30% of cases.

•  

·  Swelling of the joints may occur, but frankly deforming arthritis is quite rare. Sacroileitis, pancarpal narrowing, and cervical epiphyseal fusion has been described in selected patients.

·  Patients with Whipple disease may have any of the physical findings associated with malabsorption. These findings are nonspecific but include the following:

• Cachexia

• Distended abdomen

• Glossitis

• Perlèche (angular cheilitis)

• Chvostek or Trousseau sign (secondary to hypocalcemia)

• Gingivitis and parafollicular hemorrhages (secondary to vitamin C deficiency)

• Night blindness (secondary to vitamin A deficiency)

• Visible peristalsis with borborygmi

• Hyperpigmentation around the orbital and malar areas of the face (occasionally)

·  When the CNS is involved, patients may demonstrate signs of frontal release (as seen with dementia), meningoencephalitis, or ataxia and clonus (if the cerebellum is affected). One review noted that supranuclear ophthalmoplegia and cerebellar ataxia were two of the most commoeurologic findings

• Basic laboratory studies that suggest the presence of malabsorption may be useful screening tests, as follows:

• Sudan stain of stool

• Serum carotene

• Serum albumin

• Prothrombin time

• The definitive test for the presence of malabsorption is the 72-hour fecal fat determination.

• Abnormalities in any of these laboratory test results suggest that malabsorption is present, but they are not specific for Whipple disease.

• Imaging studies, such as a CT scan and a small-bowel series, may suggest the presence of malabsorption, but these imaging studies are not specific for Whipple disease.

• Brain MRI may demonstrate T1, T2, and fluid-attenuated inversion recovery abnormalities in the cerebellar peduncles, vermis, medulla, and foci of enhancement in the subcortical white matter, but these abnormalities are not pathognomonic for Whipple disease.

No tests are specific for diagnosis except determining the presence of T whippelii DNA through PCR.

• This test is not available universally. PCR currently is performed only at a few centers, including the Mayo Clinic and Stanford University.

• Availability and cost are prohibitive to obtaining this test. Check for availability with the medical laboratory and for cost approval with each hospital or office laboratory used by the practice.

• IgG antibody for T whippelii should not be used diagnostically, as up to 70% of control subjects demonstrate the antibody. IgM antibody is more specific but not easily available.

Biopsy of the appropriate tissue is essential for establishing a diagnosis.

• These tissues may include small bowel, brain, endocardial, and synovial.

• Biopsies of tissue samples from the small bowel show expanded villi containing macrophages staining positive with periodic acid-Schiff stain. This finding leads to electron microscopy and then DNA testing for T whippelii.

Treatment

Treatment of Whipple’s disease is with antibiotics, either alone or in combination, which can destroy the bacteria causing the infection.

Treatment is long term, generally lasting a year or two, in an effort to destroy the bacteria.  But relief from symptoms typically comes much quicker, often within the first week or two. Most people with no brain or nervous system complications recover completely after a full course of antibiotics.

When choosing antibiotics, doctors often select those that not only wipe out infections of the intestinal tract but also cross the blood-brain barrier — a layer of tissue around your brain — in order to eliminate bacteria that may have entered your brain and central nervous system.

Because of the lengthy use of antibiotics, your doctor will need to monitor your condition for development of resistance to the drugs. If you relapse during treatment, your doctor may change your antibiotics.

Treatment for standard cases
In most cases, Whipple’s disease therapy begins with 14 days of intravenous (IV) ceftriaxone (Rocephin). Following that initial therapy, you’ll likely take an oral course of sulfamethoxazole-trimethoprim, or SMX- TMP, (Bactrim, Septra), for one to two years. A shorter duration of antibiotic treatment may lead to a relapse.

Possible side effects of ceftriaxone and SMX- TMP include mild diarrhea, nausea and vomiting.

Treatment for severe cases
If you have neurologic symptoms, you may be started immediately on a 12- to 18-month course of oral doxycycline (Vibramycin) combined with the antimalarial drug hydroxychloroquine (Plaquenil). You’ll also be given long-term antibiotics that can enter the cerebrospinal fluid and brain, such as TMP-SMX.

Possible side effects of doxycycline include loss of appetite, nausea, vomiting and sensitivity to sunlight. Hydroxychloroquine may cause loss of appetite, diarrhea, headache, stomach cramps and dizziness.

Symptom relief
Your symptoms should improve within one to two weeks of starting antibiotic treatment and go away entirely within about one month.

But even though symptoms improve quickly, further laboratory tests may reveal presence of the bacteria for two or more years after you begin taking antibiotics. Follow-up testing will help your doctor determine when you can stop taking antibiotics. Regular monitoring can also indicate development of resistance to a particular drug, often reflected in a lack of improvement of your symptoms.

Even after successful treatment, Whipple’s disease can recur. Doctors usually advise regular checkups. If you’ve experienced a recurrence, you’ll need to repeat antibiotic therapy.

Taking supplements
Because of the nutrient-absorption difficulties associated with Whipple’s disease, your doctor may recommend taking vitamin and mineral supplements to ensure adequate nutrition. Your body may require additional vitamin D, folic acid, calcium, iron and magnesium.

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Charles M. WienerAnthony S. Fauci

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Edited by C. J. Hawkey, Jaime Bosch, Joel E. Richter, Guadalupe Garcia-Tsao, Francis K. L. Chan. – Chicester : John Wiley and Sons Ltd, 2012. – 1272 p.

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