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Primary sclerosing cholangitis (PSC) has been suggested as a risk factor for the development of colorectal cancer in ulcerative colitis (UC); however, previous studies of this association have been limited by small numbers of patients with PSC or have been performed retrospectively. This study prospectively evaluates the risk and natural history of colonic tumorigenesis in patients with PSC and UC and compares it with patients with UC without PSC.Twenty patients with PSC and UC and 25 control patients with UC were followed prospectively by colonoscopic surveillance using extensive mucosal biopsy sampling. All control patients with UC had disease extending beyond the sigmoid colon ofor = 8 years' duration; patients with PSC and UC were studied regardless of disease duration.Forty-five percent (9 of 20) of the patients with PSC and UC had dysplasia compared with 16% (4 of 25) of the control patients with UC (Por = 0.002). Prior liver transplantation did not affect the risk of colonic dysplasia. The time course for progression to dysplasia was similar between the patients with PSC and UC and the patients with UC; however, the patients with PSC and UC were five times more likely to develop dysplasia.Patients with PSC and UC represent a subset of patients with UC who are at markedly increased risk for colonic neoplasia and who need close colonoscopic surveillance with extensive biopsy sampling.

To determine whether or not flow-cytometric evidence of aneuploidy and increased G2/tetraploid fractions predispose to neoplastic progression in Barrett's esophagus, 62 patients with Barrett's esophagus were evaluated prospectively for a mean interval of 34 months. Nine of 13 patients who showed aneuploid or increased G2/tetraploid populations in their initial flow-cytometric analysis developed high-grade dysplasia or adenocarcinoma during follow-up, none of the 49 patients without these abnormalities progressed to high-grade dysplasia or cancer ( P

A normal or mildly abnormal fundal gland histology and its well-documented enlarged parietal cell mass. The critical evaluation of gastric biopsy published in this journal 30 years ago was uncertain regarding clinicopathologic correlations in gastritis. Although the two H. pylori gastritides other than DAG involve both antrum and body and become progressively abnormal discovery of the etiologic importance of Helicobacter pylori has greatly advanced our understanding of the pathogenwith time. In DAG, the fundal glands of the body do not become progressively more abnormal with the passage of esis of gastritis, several unsolved problems remain. A critical question is which histological patterns of H. pytime. More than 50 years ago, Robert Hebbel meticulously documented the differences in gastric mucosal hislori–induced gastritis are associated with different types of ulcer and cancer? tology in patients with duodenal compared with gastric ulcer. Most subsequent studies have confirmed Hebbel’s This viewpoint will mainly address the variations in the histological patterns of H. pylori gastritis and their findings, but none are as extensive and well controlled as his classic description. The patterns of H. pylori gastriassociated diseases. Much of the data are not of the quality or quantity to justify final conclusions. Nevertheless, crittis are well described in a preliminary endoscopic study that is outstanding because of the extensive biopsy samical reevaluation may be worth undertaking now because of some new studies relating H. pylori to various types pling and the suitability of the controls. H. pylori–DAG is the pattern of which I am most confident because I of gastritis. Also, there are some observations in the older literature that merit reconsideration. I now believe that have been able to recognize it on blinded review of gastric biopsy specimens in 92% of 311 patients with endoscopithere is evidence for three kinds of HP gastritis: the first associated with duodenal ulcer, the second with gastric cally proven duodenal ulcers. The pangastritis involving the whole stomach, now ulcer and gastric cancer, and the third with neither ulcers nor usually with symptoms. known to be caused by H. pylori, was well described by Correa and Stemmerman and Hayashi. It is referred to The gastritis pattern associated with duodenal ulcer can probably be recognized relatively easily by examining by the acronym MAG for multifocal atrophic gastritis. I three large, well-placed endoscopic biopsy specimens believe that MAG should be subdivided and would be (two from the lesser curvature of the antrum and one better replaced by two new acronyms representing diffrom the mid–greater curvature of the gastric body). The ferent clinicopathologic subsets: nonulcer pangastritis acronym for this type of gastritis is DAG for diffuse (NUP), found in usually asymptomatic H. pylori–infected antral-predominant gastritis. Inflammation of the pyloric individuals without ulcers, and progressive intestinalized glands of the antrum is diffuse and will be of similar pangastritis (PIP), found in patients with non–nonsteroiseverity in both antral biopsy specimens. Although focal dal anti-inflammatory drug (non-NSAID) gastric ulcers intestinal metaplasia may be present in the antrum of and distal gastric cancers. 10%–20% patients with duodenal ulcer, it is less severe The acronym NUP is proposed for the type of gastritis and far less extensive than that seen in patients with seen in more than 90% of usually asymptomatic individgastric ulcer. On the other hand, inflammation of the uals infected with H. pylori who do not have an ulcer. fundal glands is mild or absent in DAG despite histologiThis entity has not been studied extensively because it cally demonstrable H. pylori infection. Intestinal metais difficult to justify endoscopy with extensive biopsy in plasia of the fundal glands is never seen in DAG. Beasymptomatic individuals. However, it has been well cause extensive intestinal metaplasia is the most accepted Abbreviations used in this paper: DAG, diffuse antral-predominant possible precursor of distal gastric cancer, it is not surgastritis; MAG, multifocal atrophic gastritis; NUP, nonulcer pangasprising that the gastric cancer risk is low in patients tritis; PIP, progressive intestinalized pangastritis. with duodenal ulcer disease. Similarly, increased acid q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00 secretion in duodenal ulcer is to be expected with its

Background & Aims: The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of >8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified. Methods: A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma. Results: After direct sequencing of exon 13 and flanking regions of human MSH2 , a germline T to C substitution was shown at the −6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) ( P ≤ 0.04) and in 7 of 80 healthy adult blood donors (9%) ( P ≤ 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it. Conclusions: An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.

The value of endoscopic surveillance biopsy for dysplasia and carcinoma in patients with Barrett's esophagus is controversial. One reason is that the available histologic criteria are not adequate to separate patients with lesser degrees of dysplasia or predysplastic changes who are at increased risk for carcinoma and therefore require more frequent surveillance from those patients who are not at increased risk. We used flow cytometry and histology to evaluate 317 biopsy specimens from 64 consecutive patients who were in a cancer surveillance program for Barrett's esophagus and 3 additional patients with adenocarcinoma in Barrett's esophagus. Specimens from 10 patients had aneuploid cells; 9 of these had dysplasia or carcinoma, or both, but 1 patient had only specialized metaplastic epithelium. Twenty specimens ahd G2/tetraploid fractions greater than 6%; all 20 came from patients who had cancer or dysplasia, or were indefinite for dysplasia. All patients with dysplasia or adenocarcinoma had evidence of genomic instability (aneuploidy) or abnormalities of mucosal proliferation by flow cytometry, even when the dysplasia was focal or difficult to recognize histologically. In a small subset of patients with specialized metaplastic epithelium whose specimens were histologically negative or indefinite for dysplasia, the mucosa had aneuploid cell populations or proliferative abnormalities that were otherwise found only in dysplasia or carcinoma. Additional study may prove that this subset of patients merits more frequent endoscopic biopsy surveillance because of an increased risk for developing carcinoma. Because the abnormalities we have detected by flow cytometry correlate well with the conventional histologic diagnoses of dysplasia and carcinoma, they may prove to be a valuable objective adjunct in the diagnosis of dysplasia and carcinoma in Barrett's esophagus.

Gastric acid secretion in response to a protein meal and to exogenously administered synthetic human gastrin 17-I was measured in patients with Barrett's esophagus, patients with uncomplicated gastroesophageal reflux, and normal age- and sex-matched controls. Acid secretion, both basally and in response to gastrin 17-I, was significantly greater in patients with Barrett's esophagus compared to normal individuals without reflux. Basal gastrin levels and meal-stimulated levels of the hormone were similar among all three groups. Sensitivity to gastrin, expressed as the concentration causing half-maximal acid secretion, was also similar among the study groups. It is speculated that elevated basal acid production in Barrett's esophagus may contribute to the pathogenesis of the disorder.

Seven of 8 patients with hypogammaglobulinemia and gastrointestinal symptoms were infected with Giardia lamblia. This parasite was not detected by multiple stool examinations in 4 of the 7 infected patients but was diagnosed correctly by small intestinal biopsy. Abnormalities of the small intestinal mucosa were found in all 8 patients. Two patients had nodular lymphoid hyperplasia and 3 the flat lesion of hypogammaglobulinemic sprue. The remaining 3 patients had mixed lesions; that is, the lesions varied both in severity of the villus abnormality and in the frequency of lymphoid nodules. All patients lacked plasma cells in the lamina propria. Because of the variation in the severity of the small intestinal abnormalities within individual patients, multiple small bowel biopsies were needed to evaluate the effects of treatment on mucosal morphology. After eradication of Giardia lamblia in 7 patients, the abnormalities in villus structure returned towards normal in all. No change occurred after a course of metronidazole (Flagyl) in the 1 patient who had a severe intestinal lesion but no evidence of giardiasis. Four patients with steatorrhea and giardiasis gained weight and their fecal fat excretion returned to normal. Diarrhea disappeared after treatment in the remaining 3 patients.

Steatorrhea in small intestinal stasis syndrome is often attributed to defective luminal micelle formation secondary to deconjugation of bile salts by excessive numbers of bacteria. The intestinal mucosa is usually presumed to be normal. The pathogenesis of steatorrhea was investigated in 3 patients with stasis syndrome of differing etiologies: (1) multiple jejunal diverticula; (2) scleroderma; and (3) idiopathic intestinal pseudo-obstruction. Although bacterial overgrowth and some deconjugation of bile salts was demonstrated in all 3 of these patients, normal amounts of free fatty acids were solubilized in the aqueous phase of jejunal contents aspirated during a fat meal, indicating normal jejunal micelle formation by the remaining conjugated bile salts. When a sufficient number of jejunal biopsies were taken, patchy abnormalities were revealed by light microscopy in all 3 patients. This histological appearance varied widely in each patient from little or no abnormalities in villus architecture, to severe lesions with virtual absence of villi. Electron microscopy revealed far more extensive intestinal abnormalities than had been suspected by light microscopy. Several defects in mucosal fat absorption were demonstrated by electron microscopic examination of jejunal biopsies taken during a fat meal: (1) decreased numbers of fat particles in absorptive cells; (1) decreased numbers of absorptive cells participating in fat absorption; and (3) impaired transport of chylomicrons out of the absorptive cells into the lamina propria. After antibiotic treatment fat absorption improved by fat balance and there was electron microscopic evidence of chylomicron transport out of the absorptive cells. Nevertheless, other abnormalities by light and electron microscopy remained unchanged after antibiotics. Although the etiology of the jejunal mucosal lesions in these 3 patients remains unclear, our studies suggest that absorptive cell dysfunction rather than defective micelle formation is an important factor in the pathogenesis of their steatorrhea.

This is a prospective study of the pathogenesis of a violent gastrointestinal reaction to soy protein in an infant. Within 24 hr of changing this 6-week-old infant's formula to soy milk, he developed sequentially: fever, leukocytosis, cyanosis, vomiting, massive blood-tinged mucoid diarrhea, dehydration, and metabolic acidosis. All symptoms disappeared after discontinuing soy milk. At 6 and 10 months the patient was given a single test feeding of soy milk formula and soy protein isolate respectively. All symptoms recurred promptly. The previously normal jejunal mucosa became acutely inflamed and flat (villi disappeared). The patient recovered completely within 48 hr and villi regenerated within 4 days. Soy lecithin, gluten, and cow's milk neither produced symptoms nor altered intestinal structure. Total hemolytic complement did not change after soy milk exposure nor did circulating eosinophils increase, despite leukocytosis with shift to the left. This is the first documentation of a reversible flat jejunal lesion caused by feeding soy protein to a susceptible infant.

A 23-year-old man with eosinophilic gastroenteritis was studied over a 2½-year period to determine the possible etiologic role of specific foods in his illness. Because of the extremely patchy nature of the gastrointestinal lesion a total of 303 gastrointestinal suction biopsies were obtained so that our experiments could be adequately evaluated. Before treatment, while eating a normal diet, he experienced nausea, vomiting, and abdominal pain postprandially. Peripheral eosinophilia, steatorrhea, hypoalbuminemia, and enteric blood loss were also demonstrated. Subsequently, protein-losing enteropathy was documented. Patchy infiltration of eosinophilic leukocytes was evident in the lamina propria and submucosa of the stomach and proximal small bowel. The degree of infiltration varied unpredictably from biopsy to biopsy even when the same general area was sampled at the same time. Similarly, villous architecture varied from normal to complete loss of villi; variable abnormalities of the surface epithelium were also evident. These villous and epithelial abnormalities had not been described previously in eosinophilic gastroenteritis. Although skin tests were positive to a number of foods, the results of these tests correlated poorly with symptomatology. On a diet free of animal protein, dramatic clinical improvement occurred initially, although peripheral eosinophilia persisted and symptoms eventually recurred despite continuation of the elimination diet. Marked clinical improvement followed corticosteroid therapy on two occasions. The severity and distribution of the intestinal morphologic abnormalities did not clearly relate to the patient’s clinical status. Oral challenges with soybean and steak, which had produced symptoms by history, also produced symptoms; however, blind review of intestinal biopsies taken during these challenges showed no significant changes either in villous architecture or in the degree of intestinal infiltration with eosinophilic leukocytes. Perfusion of a segment of small intestine with pureed steak and repeated steak ingestion failed to produce significant histological changes in the proximal small bowel. We conclude that eosinophilic gastroenteritis is not a simple reversible allergic reaction to specific foods. Rather we believe it to be a self-perpetuating process which may be symptomatically aggravated by different foods. Thus elimination diets have no long term role in the treatment of this disease and many patients may require prolonged treatment with corticosteroids to remain well. Institution of more rational therapy must await discovery of the cause of eosinophilic gastroenteritis.

Solitary rectal ulcer syndrome (SRUS) is sufficiently uncommon that the clinician or general pathologist may lack familiarity with the disorder and may confuse it with other inflammatory bowel diseases. To evaluate the role of collagen staining in facilitating the differential diagnosis of SRUS, an initial open review was undertaken on 1672 consecutive patients whose 4780 colorectal biopsies were stained with HE with added saffron to demonstrate collagen. Excess mucosal collagen was present in 39 (2.3%) of these patients. Twenty patients with a diffuse excess of mucosal collagen in biopsies from rectal ulcer margins or from otherwise abnormal rectal mucosa had SRUS; in the remaining 19 patients, excess mucosal collagen was focal (seven ischemic colitis, five collagenous colitis, three adenocarcinoma, and four chronic idiopathic ulcerative colitis). Diffuse excess mucosal collagen never was seen in idiopathic inflammatory bowel disease (128 Crohn's colitis and 446 ulcerative colitis). Blinded reviews then were performed on rectal biopsies from 33 patients with a variety of diagnoses (14 SRUS and 19 controls). Diffuse excess collagen by saffron staining was consistently observed in SRUS but was absent in all 19 controls. Additional blinded reviews were carried out because the collagen staining pattern in ischemic colitis, although focal, could potentially be confused with SRUS. It was possible to differentiate these two diseases blindly from one another by using additional histologic criteria (14 SRUS and 12 ischemic colitis). We conclude that the demonstration of a diffuse excess of mucosal collagen in rectal biopsies facilitates the diagnosis of SRUS and differentiates it from idiopathic ulcerative colitis and Crohn's disease, with which SRUS is often confused, and other inflammatory bowl diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphologic and physiologic experiments in rodents have demonstrated differences between jejunal and ileal fat absorption. Compared with the rat jejunum, absorbed lipid particles within rat ileal absorptive cells are larger and exit at a slower rate. To evaluate the relevance of these observations to humans, we studied jejunal and ileal ultrastructure in 3 volunteers, each of whom had an intact small intestine and an ileostomy postcolectomy for ulcerative colitis. Proximal jejunal biopsy specimens were obtained via a hydraulic tube after an overnight fast and again after a 20-min intrajejunal lipid infusion. On a separate day, terminal ileal biopsy specimens were taken via the stoma with a small steerable suction biopsy tube after an overnight fast and again after a 20-min intraileal infusion of the same lipid mixture. One volunteer underwent biopsy after a 60-min ileal infusion of a digested meal of higher lipid content. Electron microscopy of fasting human jejunal absorptive cells revealed obvious smooth endoplasmic reticulum in the extreme apical region beneath the terminal web; very low density lipoprotein particles were observed within smooth endoplasmic reticulum and Golgi cisternae. In contrast, fasting human ileal absorptive cells contained less apical smooth endoplasmic reticulum and fewer or no very low density lipoprotein particles. After the 20-min infusion of lower-lipid content, human jejunal and ileal absorptive cells were indistinguishable because they contained fat particles of the same size and number within smooth endoplasmic reticulum, Golgi cisternae, and extracellular spaces. After the 60-min ileal infusion of higher-lipid content, human ileal absorptive cells appeared to be the same as those of the human jejunum after similar lipid infusions. Our observations of the ultrastructural similarity in human jejunal and ileal absorptive cells after lipid infusions contrasts with those in rodents and may reflect species-specific differences in mechanisms of fat absorption.

The nature of the gastrointestinal absorptive defect for triglyceride in three subjects with abetalipoproteinemia has been investigated by studying peroral biopsies of the gastrointestinal mucosa. The following conclusions were reached. 1) In confirmation of other studies, the abnormal vacuoles within the duodenal absorptive cells of these individuals were lipophilic. 2) On chemical analysis there was significantly more mucosal lipid than found in normal fasting specimens, and almost the entire increase was due to triglyceride. 3) This excess mucosal lipid was reduced by a low fat diet, but even after 34 days on such a diet there was still an excess of lipophilic material near the villus tip and increased quantities of total lipid and triglyceride when compared with material from normal subjects similarly treated. 4) Although there are demonstrable qualitative changes in mucosal and plasma lipids after an acute fat load, they are not quantitatively as great as in normal individuals. Fat balance studies and the qualitative changes in plasma and tissue lipids that do occur after more extended periods on different types of dietary fat do indicate that a considerable percentage of the dietary fat is assimilated. The route by which it is absorbed remains to be clarified.

Summary Esophagogastroduodenoscopy has proved to be the most accurate method of diagnosing disease of the upper gastrointestinal tract. Endoscopic technics already are being employed for the treatment of gastric polyps. Experimental work on endoscopic treatment of upper gastrointestinal bleeding is under way in several medical centers. A variety of methods are being tested: laser photocoagulation, suture clip placement and the use of biocompatible tissue glues. Endoscopic retrograde cholangiopancreatography now is established as a useful technic in the diagnosis of biliary tract disease. Its diagnostic usefulness in the pancreas is confined to certain diseases in which it is desirable to determine the need for operative intervention. The initial success of endoscopic papillotomy and stone extraction promises further future therapeutic uses for ERCP. Colonoscopy may well prove to be the most useful of the gastrointestinal endoscopic methods. It is particularly helpful in diagnosing colonic cancer, in determining the source of occult colonic bleeding and in providing information regarding idiopathic colonic inflammatory disease. The success of polypectomy indicates the possibility of substituting endoscopic treatment for invasive surgery. Laparoscopy in conscious patients is a well-established technic that is useful in gastroenterology, hepatology, oncology and gynecology. Its usefulness has long been appreciated in other countries and the method merits wide use in the United States. Endoscopy is a rapidly changing and evolving field. This monograph has attempted to outline the current state of the art, but many changes are expected in the next 5–10 years.

Excerpt INTRODUCTION The rarity of duodenal sarcoma has been repeatedly stressed by various authors,2, 3, 5, 9, 13, 14, 21, 26and the literature consists primarily of single case reports.2, 6, 11, ...

Summary In order to investigate systematically the possible relationship between celiac disease and idiopathic sprue, 230 suction biopsies of the duodenum and proximal jejunum were taken from 26 patients with celiac disease, 16 patients with idiopathic sprue, and 73 controls (3 months to 77 years old). The controls consisted of normals, patients with other types of malabsorption, and persons with situations which might theoretically cause an intestinal mucosal abnormality. A small diameter, highly flexible instrument was developed which enabled biopsies to be taken with equal facility from infants and adults. The absorptive surface of the fresh, unsectioned specimen was studied microscopically during fixation. The controls were covered with delicate villi, each of which contained numerous villous capillaries, whereas the abnormal specimens were more or less bald and had a disorganized, sparse vasculature. These findings were confirmed by the appearance of the tissue sections. The most constant diagnostic feature was the reduction in epithelial surface, with varying degrees of blunting or loss of villi. Infiltration of the lamina propria with round cells and abnormalities of the epithelial cells at the luminal surface were frequent but not invariable findings. Perfectly oriented serial sections were evaluated histologically by three observers independently and without clinical foreknowledge. A fourth observer evaluated them by a quantitative technique. This histologic interpretation and obj ective quantitativn agreed with the proved clinical diagnosis in every instance. The appearance of the proximal intestinal abnormality in celiac disease and idiopathic sprue is identical. The celiac-sprue lesion is apparently specific for it was not found in any of the controls. The normalcy of the ileal mucosa was demonstrated in 1 adult celiac patient and 1 idiopathic sprue patient, despite the fact that the proximal j ej unal biopsies in both cases were severely abnormal. The characteristic lesion in the duodenum and proximal jejunum in celiac disease and idiopathic sprue is probably pathognomonic.