Biomedical subjects
J H Yardley
Publications and source records attributed to J H Yardley.
Increased HLA A1 and diminished HLA A3 in lymphocytic colitis compared to controls and patients with collagenous colitis.
Lymphocytic colitis is a newly described chronic diarrheal disorder. Although its etiology is unknown, the possibility has been raised that autoimmunity may play a role in both lymphocytic and collagenous colitis, a similar clinicopathologic illness. The frequencies of HLA class I and class II antigens were examined in 24 white patients with lymphocytic colitis and in 47 white patients with collagenous colitis. Frequencies in these two disorders were compared to control white populations and to each other. An increased frequency of HLA-A1 was noted in 16 of 24 lymphocytic colitis patients (66.6%) compared with 1089 of 3942 controls (27.6%) (P less than 0.005; relative risk 5.2). Furthermore, HLA-A3 was found in decreased frequency in lymphocytic colitis patients: 0 of 24 (0%) compared with 1017 of 3942 controls (25.8%) (P less than 0.05; relative risk 0.0). Collagenous colitis patients had no significant deviation from control frequencies of HLA antigens. In lymphocytic colitis, there was no significant increase in B8 or DR3 antigens, which are found in linkage disequilibrium with A1 and associated with many autoimmune diseases. Moreover, the frequency of autoimmune-associated class I HLA antigens was not increased in lymphocytic colitis. Statistically significant differences existed between lymphocytic and collagenous colitis in HLA-A1, A3, Bw6, and B7 antigen frequencies. The HLA patterns noted previously in other gastrointestinal disorders, including ulcerative colitis and Crohn's disease, were not apparent in lymphocytic or collagenous colitis. HLA typing provides further evidence that lymphocytic colitis is a distinct form of chronic intestinal inflammatory disease associated with HLA class I phenotypes.
Grading and classification of chronic gastritis: one American response to the Sydney system.
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Association of gastric hypoacidity with opportunistic enteric infections in patients with AIDS.
To determine the relation and possible significance of gastric hypoaciditity to chronic diarrhea in AIDS, patients with and without chronic (greater than 1 month) diarrhea underwent fasting gastric juice pH measurement and microbiologic study and upper and lower endoscopy with biopsy. All 8 patients with diarrhea and high gastric pH (greater than 3; mean, 6.1 +/- 1.0) had gastric bacterial overgrowth (greater than 10(4) bacteria/mL) along with opportunistic enteropathogens in the duodenum or rectosigmoid, but only 1 of 6 patients with diarrhea and gastric pH in the normal range (less than or equal to 3; mean, 1.9 +/- 0.7) had overgrowth or an opportunistic enteropathogen. By contrast, all but 1 of 9 controls (AIDS patients without diarrhea) had normal fasting gastric pH (mean, 2.9 +/- 1.5). Overall, the presence of gastric hypoacidity was associated with identification of opportunistic enteropathogens (P = .035). Thus, gastric hypoacidity is associated with quantitative bacterial overgrowth and opportunistic enteric infections and may be etiologically important in the pathophysiology of the chronic diarrhea seen in some AIDS patients.
AIDS enteropathy: occult enteric infections and duodenal mucosal alterations in chronic diarrhea.
OBJECTIVE: To investigate occult enteric infections and morphologic changes in the small intestine in patients with advanced human immunodeficiency virus (HIV) infection and chronic diarrhea of undefined cause. DESIGN: Case-control study. SETTING: Referral-based clinic and hospital in tertiary care center. PATIENTS: Twenty-two patients with advanced HIV infection (19 with the acquired immunodeficiency syndrome [AIDS], 3 with AIDS-related complex) with chronic diarrhea, selected because of previously negative stool evaluations for bacterial or parasitic pathogens, were compared with 13 patients with advanced HIV infection (9 with AIDS, 4 with AIDS-related complex) without diarrhea by analysis of endoscopic biopsies using light and electron microscopy, viral culture, and morphometric studies. Both groups were convenience samples and had at least 7 months follow-up. MEASUREMENTS AND MAIN RESULTS: Eleven of twenty-two patients with HIV infection and chronic diarrhea but only 1 of 13 patients without diarrhea showed occult enteric pathogens (that is, undetected by routine studies) after extensive evaluation of duodenal and colorectal biopsies. Mycobacterium avium-intracellulare and microsporidia were the most common occult agents in study patients with diarrhea (5 each). Patients with diarrhea and occult enteric infections had greater weight loss (mean, 14.3 kg compared with 6.2 kg; P less than 0.05) and shorter survival (1 of 11 compared with 8 of 11 still alive; P less than 0.004) than those with diarrhea but no identified pathogens (defined as "AIDS enteropathy"). Duodenal morphometry showed decreased villus-to-crypt ratios because of villus atrophy and crypt elongation in HIV-infected patients both with and without diarrhea compared with normal controls (P less than 0.001 for each). All three groups showed comparable frequencies of epithelial mitoses. CONCLUSIONS: Further endoscopic biopsy evaluation of patients with AIDS who had unexplained chronic diarrhea showed an occult infectious cause in half of the cases. However, altered villus and crypt architecture in advanced HIV infection was independent of the presence of diarrhea or enteric infection and therefore did not correlate with AIDS enteropathy. Subnormal epithelial proliferation in response to injury could be a factor, but the underlying cause of the architectural changes remains obscure. We suggest that T-cell dysfunction may play a role.
Prominent mononuclear cell infiltrate is characteristic of herpes esophagitis.
Diagnosis of herpes esophagitis is often difficult since the characteristic nuclear inclusions and/or multinucleate giant cells of herpes virus infection may be absent in endoscopic biopsy specimens. We have noted aggregates of large mononuclear cells with convoluted nuclei adjacent to infected epithelium in the exudates of herpetic esophagitis, and postulate that this is a characteristic inflammatory response to the virus. To test this hypothesis, we reviewed biopsies from 22 cases of ulcerative herpetic esophagitis and from 44 control cases of nonherpetic esophageal ulcers (including nine cases of candidal and five cases of bacterial esophagitis) that contained a quantifiable amount of exudate. The estimated percentage of mononuclear cells present in the specimens was ranked independently by two reviewers using coded photomicrographs of exudate. Wilcoxon's rank sum analysis demonstrated significant correlation between presence of herpes and increased mononuclear cells (P less than .0001). Only one of the 22 herpes cases did not show a prominent mononuclear cell infiltrate. Immunoperoxidase studies performed on Hollande-Bouin's-fixed paraffin-embedded material from 11 herpes cases showed strong staining of the mononuclear cells for KP-1 (CD68), indicating that the majority of these cells are macrophages. These findings suggest strongly that aggregates of macrophages are characteristic of the inflammatory response in ulcerative herpetic esophagitis. The presence of these mononuclear cells in a biopsy specimen that initially does not show herpetic inclusions warrants additional studies to rule out herpes virus infection.
Collagenous colitis in setting of nonsteroidal antiinflammatory drugs and antibiotics.
Collagenous colitis is a clinicopathologic syndrome characterized by chronic watery diarrhea and a mucosal inflammatory process with increased subepithelial collagen band on colonic biopsy. This disorder occurs primarily in females, and the etiology is unknown. We report the atypical presentation of collagenous colitis in two older-aged men following prolonged use of nonsteroidal antiinflammatory agents and short-term use of antibiotics. Although one patient had colonic pseudomembranes, neither patient had microbiological evidence of C. difficile toxin or infection. A variety of medications were initially given to these patients without resolution of diarrhea. Only after the diagnosis of collagenous colitis was made and antiinflammatory drugs directed at the colitis given did the diarrhea abate. These cases illustrate an unusual presentation of collagenous colitis with possible implications for pathogenesis.
Enhancement of human intestinal mast cell mediator release in active ulcerative colitis.
To further define the role of mast cells in the idiopathic inflammatory bowel diseases, mediator release from intestinal mast cells derived from actively inflamed and relatively quiescent areas of ulcerative colitis was studied. It was hypothesized that mast cells in the actively diseased segments would indicate involvement in the disease process by releasing a different profile of mediators than cells in uninflammed tissue. Mast cell-containing suspensions derived from matched segments of 12 ulcerative colitis specimens were compared for responsiveness to the mast cell stimulus goat anti-human immunoglobulin E. Supernatants from challenged cells were analyzed for levels of three mast cell mediators, histamine, prostaglandin D2, and the sulfidopeptide leukotriene C. Mast cells from the actively involved areas released significantly greater amounts of histamine, prostaglandin D2, and sulfidopeptide leukotriene. The difference in histamine release was not a result of greater stores of histamine in the active tissue cells, because the total histamine content of the mast cells from the active areas was not significantly greater. The enhanced release of both preformed and newly generated mediators indicates activation of those cells in the course of the disease and points to the mast cell contribution to the inflammatory process in these disorders.
Collagenous, "microscopic," lymphocytic, and other gentler and more subtle forms of colitis.
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Pitfalls in the diagnosis of collagenous colitis: experience with 75 cases from a registry of collagenous colitis at the Johns Hopkins Hospital.
Collagenous colitis is a relatively rare disorder presenting mainly in middle-aged women as watery diarrhea. Endoscopic and radiographic studies of the colon are usually normal, and diagnosis must be made by biopsy. The characteristic biopsy findings are a combination of increased mucosal inflammation (collagenous colitis) as well as subepithelial collagenous thickening. The mucosal inflammatory changes include increased lamina propria plasma cells, prominent intraepithelial lymphocytes, and in some cases, numerous eosinophils. The collagenous thickening has qualitative as well as quantitative differences from normal, and may be highlighted by Masson trichrome stains. Simply quantitating the thickness of a subepithelial collagen layer is neither adequate nor necessary for the diagnosis of collagenous colitis. Major problems in diagnosing collagenous colitis arise from focusing solely on the subepithelial region without attention to inflammatory changes. For example, tangential sectioning of normal colon results in an artifactually thickened basement membrane, and such cases have been wrongly interpreted as collagenous colitis. If biopsies lack the characteristic inflammatory pattern, a tangentially cut thick basement membrane should be ignored. The key to correct diagnosis of collagenous colitis is analyzing the summation of various inflammatory changes plus subepithelial collagenization, rather than focusing on any single feature in isolation.
Reversal by antrectomy of endocrine cell hyperplasia in the gastric body in pernicious anemia: a morphometric study.
Multifocal gastric carcinoid tumors occasionally develop in patients with pernicious anemia, associated with hyperplasia of endocrine cells in the atrophic and metaplastic gastric body mucosa. This constellation of findings probably requires a trophic drive from hypergastrinemia associated with antral G cell hyperplasia, a consequence of achlorhydria in these patients. We report a case in which antrectomy was performed on such a patient in order to abrogate the trophic stimulus. Antrectomy was followed by resolution of hypergastrinemia and a decrease in the size of polyps endoscopically. Nine months later, the gastric remnant was resected. Using morphometric techniques, endocrine cells in the initial antrectomy specimen (which included body mucosa at the resection line) were compared with those in the subsequently removed gastric body. Antrectomy resulted in striking decreases in number (137 versus 34/mm2; P = 0.0001) and size (93 versus 56 microns2; P = 0.0001) of endocrine cells of body mucosa. The findings suggest that antrectomy may be useful in the management of endocrine cell hyperplasia, and possibly also associated carcinoid tumors, in pernicious anemia.
Antireticulin antibodies in collagenous and lymphocytic (microscopic) colitis.
Serum antireticulin antibodies (ARAs) are often present in patients with dermatitis herpetiformis and celiac disease (CD), especially before instituting a gluten-free diet. In both collagenous colitis (CC) and lymphocytic (microscopic) colitis (LC) the colorectal mucosa shows surface epithelial damage with intraepithelial lymphocytes that is strikingly comparable to the small intestinal findings in CD. Also, CD may show subepithelial collagen deposition resembling that seen in CC. Because of these similarities, ARAs were measured in sera from patients with biopsy-proven CC and LC and compared with sera tested from CD patients. Antibody binding to reticulin was detected in frozen sections of rat liver and kidney by indirect immunofluorescent techniques. Whereas five of 14 CD patients (35.7%) had ARAs, only one of 29 CC patients (3.4%) (P = 0.010 versus CD) and none of 17 LC patients (0%) (P = 0.012 versus CD) had ARAs. The positive CC patient had IgA ARA titers of 1:20 noted in two sera taken 2 mo apart. The five positive CD patients had IgA ARA titers ranging from 1:20 to 1:320. The rare presence of ARAs noted in collagenous colitis and lymphocytic colitis was similar to its occurrence in normals, whereas the frequency of ARAs found in celiac disease (35.7%) was within the range reported for that disorder. Therefore, ARAs do not appear to be associated with CC or LC despite the morphologic similarities to CD.
Pathology of chronic gastritis and duodenitis.
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Lymphocytic enterocolitis in patients with 'refractory sprue'.
We describe a patient with refractory sprue with malabsorption, a flat small-bowel biopsy specimen unresponsive to a gluten-free diet, and colonic biopsy specimens consistent with lymphocytic (microscopic) colitis. To investigate further the relation between celiac disease and lymphocytic or collagenous colitis (a similar and possibly related entity), we examined colorectal and small-bowel biopsy specimens in patients indexed histologically as having celiac disease who have been seen at The Johns Hopkins Hospital since 1958. Of 135 indexed patients, 21 had colorectal biopsies. Colorectal biopsy specimens were abnormal in 7 of the 21 patients. Four patients had biopsy specimens resembling lymphocytic colitis, 2 patients had acute colitis, and another patient had both lymphocytic and acute colitis. No patients had collagenous colitis. Three of the patients with lymphocytic colitis and celiac-like changes of the small bowel never responded to a gluten-free diet and may represent a distinctive panintestinal disease for which the term "lymphocytic enterocolitis" with malabsorption is proposed.
Taxol toxicity. Epithelial necrosis in the gastrointestinal tract associated with polymerized microtubule accumulation and mitotic arrest.
Taxol, an antineoplastic agent with a novel mechanism of action, is currently undergoing Phase I trials at The Johns Hopkins Hospital, Baltimore. The authors recently observed striking mitotic arrest associated with epithelial necrosis and ulceration in an esophageal biopsy specimen. The biopsy specimen was taken from a patient who received taxol the day before endoscopy. Review of our autopsy files revealed four other cases in which taxol had been administered. Sections of esophagus, stomach, small intestine, colon, liver, skin, bone marrow, and testes were examined for evidence of mitotic arrest. Mitotic arrest was seen in the two patients who underwent autopsy who received taxol less than 11 days before death, whereas the two autopsy patients who received taxol more than 2 weeks before death did not show these changes. Although mitotic arrest was most prominent in the esophagus, it was also found in the stomach, small intestine, colon, liver, and bone marrow. The mitotic arrest was associated with bundling of intermediate filaments and appeared to be secondary to accumulation of polymerized microtubules. These results suggest that taxol induces a transient mitotic arrest associated with cell necrosis.
Lymphocytic (microscopic) colitis. Clinicopathologic study of 18 patients and comparison to collagenous colitis.
Lymphocytic colitis, formerly called microscopic colitis, is a clinicopathologic syndrome with chronic watery diarrhea and diffuse mucosal inflammatory changes with prominent intraepithelial lymphocytes. The 18 lymphocytic colitis patients studied presented with chronic watery diarrhea at a mean age of 53.8 +/- 17 years (+/- 1 SD). Roentgenographic, endoscopic, and culture data were not diagnostic. In patients tested, there was a high prevalence of arthritis (82%) and autoantibodies (50%) but no increase in frequency of histocompatibility antigens associated with well-defined autoimmune disease (DR3, B8). Lymphocytic colitis patients were compared to 21 patients with collagenous colitis. Similarities included age, symptomatology, and nondiagnostic radiographic and endoscopic studies. However, the sex distribution was statistically different, with an equal male-to-female ratio in lymphocytic colitis and female predominance (80%) in collagenous colitis. Other differences included dissimilar histocompatibility phenotypes and collagen band on biopsies of collagenous but not lymphocytic colitis. These findings suggest that lymphocytic and collagenous colitis may be related yet distinct disorders.
Three cases of gastric spirochetelike organisms.
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Lymphocytic ("microscopic") colitis: a comparative histopathologic study with particular reference to collagenous colitis.
Lymphocytic colitis, previously termed "microscopic colitis", is a clinicopathologic syndrome of watery diarrhea, grossly normal colonoscopy, and mucosal inflammatory changes. Since lymphocytic colitis is a new, incompletely characterized entity, a histopathologic study was performed to compare lymphocytic colitis (n = 16), collagenous colitis (n = 17), idiopathic inflammatory bowel disease (n = 16), acute colitis (n = 16), and histologically normal colon (n = 12). The study was a blinded semiquantitative analysis of histologic features in the surface epithelium, lamina propria, and crypts. The most distinctive feature of lymphocytic colitis was increased intraepithelial lymphocytes, particularly in the surface epithelium (P = .0001 v idiopathic inflammatory bowel disease, acute colitis, and normal colon). Other prominent features of lymphocytic colitis included surface epithelial damage (P less than .005 v idiopathic inflammatory bowel disease and normal colon), increased lamina propria chronic inflammation (P less than .01 v normal), and minimal crypt distortion or active cryptitis. There were striking similarities between lymphocytic colitis and collagenous colitis, but subepithelial collagen thickening was seen only in collagenous colitis. Idiopathic inflammatory bowel disease showed prominent crypt distortion and greater active inflammation, in addition to minimal intraepithelial lymphocytes. Acute colitis occasionally demonstrated prominent surface epithelial damage, but was otherwise dissimilar from lymphocytic colitis. We reached the following conclusions: (1) the entity "microscopic colitis" shows characteristic histopathology including prominent lymphocytic infiltration of epithelium, and thus, a more appropriate designation is lymphocytic colitis; (2) although lymphocytic colitis closely resembles collagenous colitis, each entity is distinct on biopsy; and (3) lymphocytic colitis is readily distinguishable from idiopathic inflammatory bowel disease, acute forms of colitis, and normal colorectum.