GASTROENTEROLOGY. Official Publication of the American Gastroenterological Association

Size: px

Start display at page:

Download "GASTROENTEROLOGY. Official Publication of the American Gastroenterological Association"

Anna Welch
5 years ago
Views:

1 GASTROENTEROLOGY Official Publication of the American Gastroenterological COPYRIGHT 1975 THE WILLIAMS & WILKINS CO. Vol 68 March 1975 Number 3 ALIMENTARY TRACT STRUCfURE OF THE GASTRIC MUCOSA IN ACUTE INFECTIOUS NONBACTERIAL GASTROENTERITIS LAWRENCE WIDERLITE, M.D., JERRY S. TRIER, M.D., NEIL R. BLACKLOW, M.D., AND DAVID S. SCHREIBER, M.D. Departments of Medicine, Boston University Medical Center, Peter Bent Brigham Hospital, and Harvard Medical School, Boston, Massachusetts It is now well documented that a characteristic mucosal lesion of the proximal small intestine is present in acute nonbacterial gastroenteritis. To determine whether a gastric mucosal lesion also accompanies this illness, stool filtrate containing Norwalk agent was given orally to 15 volunteers after base line biopsies of gastric fundal and/or antral mucosa had been obtained. Gastric fundal and/or antral biopsies were then obtained serially between 24 and 168 hr after administration of the inoculum. Nine volunteers developed symptoms of gastroenteritis. Gastric biopsies from those with normal base line fundal and/or antral biopsies remained normal during and after clinical illness. Those volunteers who had mild to moderate gastritis in their base line biopsies showed persistence but no progression of the lesion during illness. In 4 of the volunteers who became ill, intestinal biopsies were available and sho,!"ed the typical gastroenteritis lesion. These results indicate that acute infectious nonbacterial gastroenteritis induced by Norwalk agent is not associated with a histologically detectable gastric mucosal lesion. Acute infectious nonbacterial gastroenteritis, a usually self-limited but often incapacitating illness, is second only to acute upper respiratory disease as the most Received July 10, Accepted September 11, Address requests for reprints to: Dr Jerry S. Trier, Peter Bent Brigham Hospital, 721 Huntington Ave nue, Boston, Massachachusetts Supported by Contract DADA C 2071 from the United States Army Medical Research and Devel opment Command, and by Grants AM 17537, AM05005, R ~ O Oand 5 3GM , from the National Institutes of Health. 425 common illness in the United States. 1 Recent studies suggest that viruses may be the etiological agents responsible for this transmissible form of gastroenteritis in man. 2 " In addition, a characteristic morphological lesion of the small intestines. 6 has recently been described in gastroenteritis caused by one such putative virus, the Norwalk agent. Mucosal inflammation, villous shortening, crypt hypertrophy, ab- The authors wish to acknowledge the expert tech nical assistance of Elaine Markezin and Pamela C. Moxey.

2 426 WIDERLITE ET AL. Vol. 68, No. 3 sorptive cell damage, and increased epithelial cell mitosis characterize this intestinal lesion. 6,6 To determine whether a gastric mucosal lesion accompanies the intestinal lesion, we describe in this report the morphology of gastric fundal and gastric antral biopsies obtained serially from 15 volunteers who ingested an inoculum known to contain Norwalk agent and known to be capable of causing acute infectious non bacterial gastroenteritis. Materials and Methods Volunteers Fifteen normal adult male volunteers between 36 and 45 years of age were studied. All had normal physical examinations, complete blood counts, urinalyses, liver function studies, chest X-rays, and electrocardiograms. None had known gastrointestinal or liver disease. Hepatitis-associated antigen was absent in the serum as determined by the counterimmunoelectrophoresis method. 7 Volunteers were hospitalized in strict isolation in the Boston University Clinical Research Center at Boston City Hospital. Written informed consent was obtained from all volunteers for administration of the Norwalk agent, as well as for all other aspects of the study, including gastric and small intestinal biopsies. All studies were approved by committees on human experimentation at Boston University School of Medicine. Peter Bent Brigham Hospital, and the Department of the Army. Inoculum The inoculum containing Norwalk agent was a fecal filtrate prepared after two serial human passages of the agents and was free of detectable microbial agents or enterotoxins by safety test techniques previously described. 8 Volunteers were given orally 2 g of sodium bicarbonate followed by 3 ml of stool filtrate diluted in 30 ml of water after an overnight fast. Fasting was continued for 3 additional hr. Criteria for Illness All specimens of stool and vomitus were examined by one of us (N. R. B.). The presence or absence of nausea, vomiting, anorexia, malaise, abdominal cramps, headache, myalgia, fever, and the number and character of all stools were recorded for all volunteers. Clinical illness was defined as the development of vomiting and/or diarrhea (unformed stool) or both, when accompanied by other signs and symptoms. All decisions regarding the presence or absence of clinical illness in volunteers were made by one of us (N. R. B.) without foreknowledge of the biopsy findings. Biopsy Studies Peroral gastric and small intestinal biopsies were obtained with a multipurpose biopsy tube after an overnight fast. 9 Gastric biopsies were obtained from the greater curvature of the fundus or from the distal antrum under fluoroscopic control. Several biopsies were usually obtained from each site studied in any given volunteer at each time interval. Base line gastric biopsies were done in all volunteers before the Norwalk agent was administered. Additional gastric biopsies were then obtained serially, 24 to 168 hr after administration of the inoculum. Intestinal biopsies were obtained under fluoroscopic control from the duodenojejunal junction from 6 of the same group of volunteers before and 24 to 168 hr after administration of the inoculum. Biopsies were oriented on nylon mesh, fixed in Bouin's solution, embedded in paraffin, serially sectioned at 6 J.I., and stained with hematoxylin and eosin, as described previously. 5 A total of 148 gastric and 34 small intestinal biopsies were available for study. Biopsies were coded, randomized, and evaluated by two observers without foreknowledge of their source. In the instances in which interpretations varied, biopsies were rexamined jointly by three observers and disagreements were resolved before the slides were decoded. Gastric biopsies were classified as normal, or as showing evidence of gastritis. Those showing gastritis were further classified as showing a minimal, mild, or moderate lesion using the following criteria: Minimal. Increased infiltration of lamina propria with predominately mononuclear cells, and, in some cases, a few neutrophiles between adjacent gastric pits, no increase in the cellularity of the lamina propria between gastric glands, and normal surface cell morphology. Mild. Increased infiltration of the lamina propria with both mononuclear cells and with neutrophiles between adjacent gastric glands, as well as between pits, no change in surface cell morphology, and no inflammatory exudate within gastric pits or glands. Moderate. More extensive infiltration of the lamina propria with mononuclear cells and neutrophiles between gastric pits and glands, presence of inflammatory exudate in gastric pits and/or glands (pit or gland abscesses), and

3 March 1975 GASTRIC M UCOSA IN ACUTE GASTROENTERITIS 427 patchy abnormalities of surface cell structure, such as loss of nuclear polarity and decreased cell height. Small intestinal biopsies were judged as abnormal if they had features previously noted in acute infectious non bacterial gastroenteritis. 5 Results Clinical evidence of gastroenteritis with diarrhea and/or nausea and vomiting developed in 9 of 15 volunteers within 36 hr after administration of Norwalk agent; the other 6 volunteers remained asymptomatic after administration of Norwalk agent. Gastrointestinal symptoms in individual ill patients are detailed in table 1. The histological features of available gastric and intestinal biopsies from the 9 volunteers who developed clinical symptoms of acute infectious nonbacterial gastroenteritis and summarized in table 1. Both gastric antral and fundal biopsies were obtained from 3 of these volunteers, gastric fundal but no antral biopsies were obtained from 3, and gastric antral but no fundal biopsies were obtained from the other 3 volunteers. Of the 6 volunteers with gastroenteritis in whom gastric fundal biopsies were done, 3 had normal base line biopsies. Multiple fundal biopsies obtained during illness and during the immediate recovery period remained normal in these individuals (fig. 1, A and B). In the other 3, fundal gastritis was noted in the base line biopsies, but its histological severity did not change during the clinical illness or during the recovery period (table 1). Of the 6 volunteers with gastroenteritis in whom gastric antral biopsies were done, 1 had normal base line biopsies and multiple normal biopsies during illness and during the immediate recovery period (fig. 2, A and B). In another volunteer with clinical evidence of gastroenteritis, multiple antral biopsies obtained during acute illness were normal, but no base line or recovery antral biopsies were available (table 1). Antral gastritis was noted in base line biopsies from the other 4 volunteers, but multiple biopsies obtained during acute illness and during the immediate recovery period showed no change in the histological severity of the antral gastritis. Intestinal biopsies were obtained in 4 of the volunteers who developed symptoms of gastroenteritis. In all 4, the intestinal lesion typical of gastroenteritis was observed in biopsies obtained 24 to 48 hr after administration of the Norwalk agent (figs. lc and 2C), confirming the clinical evidence that these individuals had gastroenteritis. The intestinal mucosal changes included villous shortening, crypt hypertrophy, infiltration of the lamina propria with neutrophiles and increased numbers TABLE 1. Summary of biopsy findings and symptoms in volunteers with clinical evidence of illness' Gastric biopsies Intestinal biopsies Symptoms' Volun teer Biopsy site Base line hr hr Base line hr biopsy after after biopsy after inocul urn Nausea Vomiting Diarrhea inoculum inoculum 1 Fundus N N N Antrum N N N N Enteritis Fundus N N N Antrum ND N ND N Enteritis Fundus Antrum ND ND Fundus N N N N D ND Fundus ND ND Fundus ND ND Antrum N Enteritis Antrum N Enteritis Antrum ND ND N, normal mucosa; ND, not done; +, minimal gastritis, 2+, mild gastritis; 3+, moderate gastritis; see "Methods" section for classification criteria. +, present; --, absent.

In the 6 volunteers who developed no symptoms of gastroenteritis after ingestion of Norwalk agent, multiple gastric biopsies obtained 24 to 168 hr after Norwalk agent were histologically unchanged

4 428 WIDERLITE ET AL. Vol. 68, No.3 of mononuclear cells, patchy vacuolization of the cytoplasm and decreased height of some villous absorptive cells, and increased number of mitoses in the intestinal crypts. In the 6 volunteers who developed no symptoms of gastroenteritis after ingestion of Norwalk agent, multiple gastric biopsies obtained 24 to 168 hr after Norwalk agent were histologically unchanged from base line biopsies. Gastric fundal biopsies were available from all 6 of these volunteers and gastric antral biopsies were available from 2. Intestinal biopsies done in 2 of these volunteers before and after administration of Norwalk agent were entirely normal. Discussion Our findings indicate that gastric fundal and gastric antral mucosa show no evidence of histological change in patients who develop gastroenteritis after ingestion of Norwalk agent. In all 9 volunteers who developed symptomatic gastroenteritis, gastric mucosal biopsies obtained during and after illness did not differ significantly histologically from biopsies obtained from the same individuals prior to ingestion of Norwalk agent. That gastroenteritis was indeed present was confirmed by intestinal biopsies which showed the characteristic lesion associated with acute infectious nonbacterial gastroenteritis 5, 6 in 4 of these volunteers. Thus, the term "gastroenteritis" may be a misnomer, at least in regard to available morphological evidence, and the disease might more rationally be called acute infectious nonbacterial "enteritis" until clear cut evidence of gastric involvement is available in this disease. The absence of a gastric mucosal lesion FIG. 1. Light micrographs of gastric fundal biopsies and an intestinal biopsy from volunteer 2. The base line fundal biopsy (A) obtained before ingestion of Norwalk agent is normal. The fundal biopsy obtained during clinical illness after ingestion of Norwalk agent (B) is also normal. The intestinal biopsy ( C) obtained at the same time as gastric biopsy (B) srows a typical intestinal gastroenteritis lesion with shortened villi, hypertrophied crypts, and increased cellularity of the lamina propria (hematoxylin ani eoxin; x 1(0),

remain asymptomatic after ingesting Norwalk agent,5 as well as after ingesting another putative virus, the Hawaii agent.

5 March 1975 GASTRIC MUCOSA IN ACUTE GASTROENTERITIS 429 in Norwalk agent-induced gastroenteritis was somewhat unexpected. A clear-cut mucosal lesion of the small intestine regularly accompanies clinical gastroenteritis caused by Norwalk agent, 5, 6 and this lesion has even been found in some, but not all, volunteers who remain asymptomatic after ingesting Norwalk agent,5 as well as after ingesting another putative virus, the Hawaii agent.l0 Many of the patients with symptomatic acute infectious nonbacterial gastroenteritis have symptoms which suggest gastric involvement, such as nausea and vomiting. In this study, all 3 patients with normal fundal biopsies and both patients with normal antral biopsies during illness had such symptoms (table 1). Moreover, it is not uncommon during acute illness to have patients vomit the remains of a meal eaten as long as 16 hr earlier, suggesting some degree of gastric retention. It may be that there is impaired gastric motor function in patients with Norwalk agent-induced disease in the absence of a histologically detectable gastric mucosal lesion. Clearly, studies of gastric and small intestinal motor function would be of interest in this disease. It has been suggested that histological evidence of gastritis may occur in individuals who have no gastrointestinal symptoms. 11 In an autopsy series of patients without known gastrointestinal symptoms, some degree of antral gastritis was present in 66% and fundal gastritis in 49% of patients. 12 Similar results have been reported in several biopsy series. 13, 14 In a recent biopsy study, antral gastritis was noted in 84% and fundal gastritis in 50% of alcoholics who had abstained for 4 to 8 weeks prior to biopsy.15 Most of our volunteers also had a history of heavy alcohol FIG. 2. Light micrographs of gastric antral biopsies and an intestinal biopsy from volunteer 1. The base line antral biopsy (A) obtained before ingestion of Norwalk agent is normal. The antral biopsy obtained during clinical illness after ingestion of Norwalk agent (B) is also normal. The intestinal biopsy (C) obtained at the same time as gastric biopsy (B) shows a typical intestinal gastroenteritis lesion with shortened villi, hypertrophied crypts, and increased cellularity of the lamina propria (hematoxylin and eosin; x 100).

6 430 WlDERLlTE ET AL. Vol. 68, No.3 consumption in the recent past but had no alcohol intake for a least 1 month before study. Antral gastritis was present in 56% and fundal gastritis in 27% of the base line biopsies in our group of patients. Since all our volunteers were asymptomatic prior to ingestion of Norwalk agent, our findings provide additional evidence that significant histological evidence of fundal and antral gastritis may be present in the absence of clinical symptoms. REFERENCES 1. Dingle JH, Badger GF, Feller AE, et al: A study of illness in a group of Cleveland families. I. Plan of study and certain general observations. Am J Hyg 58:16-30, Blacklow NR, Dolin R, Fedson DS, et al: Acute infectious nonbacterial gastroenteritis: etiology and pathogenesis. Ann Intern Med 76: , Kapikian AZ, Wyatt RG, Dolin R, et al : Visualization by immune electron microscopy of a 27 -nm particle associated with acute infectious non-bacterial gastroenteritis. J Virol 10: , Bishop R, Davidson GB, Holmes IH, et al: Virus particles in epithelial cells of duodenal mucosa from children with acute non bacterial gastroenteritis. Lancet 2: , Schreiber DS, Blacklow NR, Trier JS: The mucosal lesion of the proximal small intestine in acute infectious non bacterial gastroenteritis. N Engl J Med 288: , Agus SG, Dolin R, Wyatt RG et al: Acute infectious nonbacterial gastroenteritis: intestinal histopathology. Ann Intern Med 79:18-25, Gocke DJ, Howe C: Rapid Detection of Australia antigen by counter-immunoelectrophoresis. J Immunol 104: , Dolin R, Blacklow NR, DuPont H, et al: Transmission of acute infectious nonbacterial gastroenteritis to volunteers by oral administration of stool filtrates. J Infect Dis 123: , Brandborg LL, Rubin CE, Quinton WE: A multipurpose instrument for suction biopsy of the esophagus, stomach, small bowel, and colon. Gastroenterology 37: 1-16, Schreiber DS, Blacklow NR, Trier JS: The small intestinal lesion induced by Hawaii Agent acute infectious non bacterial gastroenteritis. J Infect Dis 129: , MacDonald WC, Rubin CE: Gastric biopsy-a critical evaluation. Gastroenterology 53: , Hebbel R: The topography of chronic gastritis in otherwise normal stomachs. Am J Pat hoi 25: , Joske RA, Finckh ES, Wood IJ: Gastric Biopsy. Q J Med 24: , Ylvisaker RS, Carey JB Sr, Myhre J, et al: Biopsy studies of the gastric mucosa. Gastroenterology 28:88-102, Dinoso VP, Chey WY, Braverman SP, et al: Gastric secretion and gastric mucosal morphology In chronic alcoholics. Arch Intern Med 103: , 1972

Gastroenteritis and viral infections

Gastroenteritis and viral infections A Large number of viruses are found in the human gut; these include some that are associated with gastroenteritis Rotaviruses Adenoviruses 40/41 Caliciviruses Norwalk-like