Thymoglobulin induction decreases rejection in solitary pancreas transplantation.

BACKGROUND: Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. METHODS: Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. RESULTS: The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. CONCLUSIONS: Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.

Development of autoimmune hepatitis in the setting of long-standing primary biliary cirrhosis.

Primary biliary cirrhosis and autoimmune hepatitis, the most common autoimmune liver diseases in adults, are frequently easily differentiated by a combination of clinical, biochemical, and histological features along with the presence of highly sensitive and characteristic serum autoantibodies. Patients presenting with "overlapping" features of both conditions simultaneously are not uncommon. However, patients who switch over time from one disease to another have remained largely unrecognized. We report here two cases from the spectrum of autoimmune liver disease, patients who had well-defined primary biliary cirrhosis for a number of years and then developed the classic picture of superimposed autoimmune hepatitis. The importance of its recognition and the appropriate management modifications are discussed.

Autoimmune hepatitis with incidental histologic features of bile duct injury.

Bile duct changes are atypical of autoimmune hepatitis. Our aims were to assess the frequency and significance of these changes in classical disease. Liver biopsy specimens were reviewed under code from 84 patients who satisfied international scoring criteria for autoimmune hepatitis, and the findings were correlated with clinical features and outcome. Twenty patients (24%) had biliary changes, including 6 with destructive cholangitis, 4 with ductopenia, and 10 with nondestructive cholangitis. Patients with and without bile duct changes had similar laboratory findings. Diagnostic scores for autoimmune hepatitis were lower in patients with bile duct changes (16.6 +/- 0.6 vs. 19.1 +/- 0.2, P <.0001). The frequencies of scores sufficient for a definite (80% vs. 97%, P =.03) or probable diagnosis (20% vs. 3%, P =.03) were also less in this group. Patients with destructive cholangitis and/or ductopenia responded as well to therapy as patients with nondestructive cholangitis, and outcomes in each group were similar to those of patients without biliary changes. We concluded that biliary changes can occur in classic autoimmune hepatitis, and they are not associated with distinctive clinical features or treatment response. They may be coincidental findings associated with classic disease or weak expressions of a variant syndrome. In the absence of a cholestatic clinical syndrome, they do not compel a different management strategy.

Recurrent autoimmune hepatitis after orthotopic liver transplantation.

To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.

Hepatic localization of endothelin-1 in patients with idiopathic portal hypertension and cirrhosis of the liver.

Endothelin-1 (ET-1) may mediate increased resistance to hepatic sinusoidal blood flow. We evaluated the hepatic distribution of ET-1 in patients with idiopathic portal hypertension (IPH), in which liver architecture may be normal, and in patients with cirrhosis, in which distortion of hepatic sinusoidal architecture is prominent. Immunohistochemistry and in situ hybridization were used to localize ET-1 in hepatic tissue of patients with IPH and cirrhosis. ET-1 was measured in plasma from a peripheral vein, the hepatic vein, and the portal vein of patients with cirrhosis of the liver and controls. On immunohistochemistry and in situ hybridization, ET-1 was localized to periportal hepatocytes and sinusoidal cells in patients with IPH and cirrhosis. Minimal positive staining for ET-1 was observed in control livers. Plasma ET-1 levels were significantly greater in patients with cirrhosis than in controls. In patients with cirrhosis, ET-1 was greater in the hepatic vein compared with the portal vein. However, the level of plasma ET-1 in patients with cirrhosis did not correlate with either the presence of ascites or portacaval pressure gradient. We conclude that in IPH, ET-1 is localized to sites in which it can modulate intrahepatic resistance. In late stages of cirrhosis, ET-1 may not modulate resistance. We speculate that vascular resistance in late stages of cirrhosis probably results from distortion of hepatic architecture.

Autoimmune cholangitis within the spectrum of autoimmune liver disease.

Autoimmune cholangitis is an idiopathic disorder with mixed hepatocellular and cholestatic findings. Our goal was to characterize the disease prospectively by application of uniform diagnostic criteria. Twenty patients were identified and compared with 242 patients with conventional forms of autoimmune liver disease. Patients with autoimmune cholangitis were distinguished from type 1 autoimmune hepatitis (AIH) by lower serum levels of aspartate transaminase (AST), gamma-globulin, and immunoglobulin G; higher serum levels of alkaline phosphatase; and lower frequencies of autoantibodies. They were distinguished from primary biliary cirrhosis (PBC) by higher serum levels of AST and bilirubin, lower serum concentrations of immunoglobulin M, and greater occurrence of autoantibodies. Their female predominance, lower serum alkaline phosphatase levels, higher frequency of autoantibodies, and absence of inflammatory bowel disease differentiated them from primary sclerosing cholangitis (PSC). Laboratory findings ranged widely and did not characterize individual patients. HLA risk factors were similar to those of type 1 AIH and PBC, and different from those of PSC. Treatment responses to corticosteroids or ursodeoxycholic acid were poor. Composite histological patterns resembled mainly PBC or PSC. We conclude that autoimmune cholangitis diagnosed by prospective analysis cannot be assimilated into a single, conventional, diagnostic category. It may represent variant forms of diverse conditions, a transition stage, or a separate entity with varying manifestations.

The importance of clinicopathological correlation in the diagnosis of inflammatory conditions of the colon: histological patterns with clinical implications.

Histological reaction patterns within the colon are not disease-specific but reflect mechanisms of injury and duration of disease. By correlating these patterns with known causes of colonic inflammation, we provide guidelines to enhance the diagnostic value of colonoscopic samples. Normal histological features are reviewed, and the sequence of inflammation and repair is used as the basis for appreciating pathological deviations. The common histological patterns of acute colitis with and without features of pseudomembranous or ischemic colitis and the morphological features of chronic colitis with and without crypt destruction are collated with clinical and endoscopic features to emphasize the importance of dialogue between the pathologist and gastroenterologist. Less common patterns, including eosinophilic colitis, graft-versus-host disease, chronic mucosal prolapse, portal hypertensive colopathy, and nonspecific or idiopathic ulcer, illustrate variations in the basic reaction patterns. Difficulties in differential diagnosis are underscored, and biopsy strategies are suggested.

Clinical and pathologic correlation of 84 mucinous cystic neoplasms of the pancreas: can one reliably differentiate benign from malignant (or premalignant) neoplasms?

OBJECTIVE: To determine whether the long-term behavior of cystic mucinous neoplasms of the pancreas could be predicted using a novel, precisely defined classification of benign mucinous cystadenomas, noninvasive proliferative cystic mucinous neoplasms, and invasive mucinous cystadenocarcinomas. The primary interest was to obtain long-term follow-up after complete resection to determine the recurrence rates based on this objective classification. BACKGROUND: Current understanding is that all cystic mucinous neoplasms of the pancreas are potentially malignant and that mucinous cystadenomas, when completely removed, are biologically benign. Cystadenocarcinomas are thought to be less aggressively malignant than ordinary ductal adenocarcinoma, but reported recurrence rates vary widely and are unpredictable. METHODS: All patients who underwent "curative" resection for cystic mucinous neoplasms at Mayo Clinic Rochester from 1940 to 1997 were identified. All available pathology slides, gross specimens, and clinical records were reviewed, eliminating patients with inadequate documentation. Neoplasms were reclassified as mucinous cystadenomas, noninvasive proliferative mucinous cystic neoplasms, or invasive cystadenocarcinomas based on specific histologic criteria. RESULTS: Of 84 patients (70 women, 14 men) with cystic mucinous neoplasms of the pancreas, 54 were classified as cystadenomas, 23 as noninvasive proliferative cystic mucinous neoplasms, and only 7 as cystadenocarcinomas. Recurrent disease developed in none of the 77 patients without invasion, but 5 of the 6 patients surviving resection for cystadenocarcinomas died of recurrent cystadenocarcinoma within 5 years. CONCLUSIONS: When the neoplasm is completely resected and subjected to adequate histopathologic examination based on these objective criteria, absence of tissue invasion predicts a curative operation and detailed follow-up may be unnecessary. In contrast, a histologic diagnosis of invasive cystadenocarcinoma portends a dismal prognosis, similar to that of typical ductal adenocarcinoma of the pancreas.

Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial.

To evaluate the efficacy of ursodeoxycholic acid as adjunctive therapy in type 1 autoimmune hepatitis, 37 patients who had experienced treatment failure, repeated relapse, or incomplete response were randomized to ursodeoxycholic acid (13-15 mg/kg daily) or placebo for 6 months in addition to their usual corticosteroid schedule. Serum aspartate transaminase (70% vs. 31%, P =.04) and alkaline phosphatase (47% vs. 7%, P =.02) levels improved more commonly in the 21 patients randomized to ursodeoxycholic acid. Mean serum levels, however, were similar before and after the treatment period. The frequency of dose reduction or corticosteroid withdrawal was comparable in both groups (29% versus 31%, P >.9), and clinical improvement (48% vs. 44%, P >.9) or its absence (52% vs. 56%, P >.9) occurred as commonly in patients receiving ursodeoxycholic acid or placebo. The modified histological activity score (3.5 +/- 0.8 vs. 3. 5 +/- 0.9) and the modified fibrosis score (2.4 +/- 0.4 vs. 2.4 +/- 0.4) were similar before and after treatment with ursodeoxycholic acid and no different than after placebo therapy. We conclude that ursodeoxycholic acid can improve certain laboratory tests in problematic patients with type 1 autoimmune hepatitis when administered adjunctively for 6 months. Short-term therapy, however, does not facilitate reduction in the dose of corticosteroids or its withdrawal, affect clinical outcome, or reduce histological activity.

Host- and disease-specific factors affecting steatosis in chronic hepatitis C.

BACKGROUND/AIM: Steatosis is commonly present in chronic hepatitis C. Our aim was to evaluate host- and disease-specific factors associated with its occurrence. METHODS: Histologic findings in 60 patients were correlated with body mass index, human leukocyte antigens, and other conventional parameters. Comparisons were made with 41 patients who had nonalcoholic steatohepatitis and 18 patients who had chronic hepatitis B. RESULTS: Patients with chronic hepatitis C and steatosis had lower serum concentrations of gamma-globulin (p=0.01) and immunoglobulin G (p=0.05) than their counterparts without steatosis, and they had a lower frequency of antinuclear antibodies (19% versus 52%, p=0.01). They also had a higher mean body mass index (p=0.002) and a greater frequency of risk factors for steatosis (70% versus 34%, p=0.009). These risk factors, however, occurred more commonly in patients with nonalcoholic steatosis (p=0.007). Furthermore, fat deposition occurred more often in chronic hepatitis C than in chronic hepatitis B (52% versus 22%, p=0.03), despite comparable metabolic findings. The degree of steatosis in chronic hepatitis C was not associated with individual metabolic features. CONCLUSIONS: Steatosis in chronic hepatitis C is mainly a viral effect, and host-dependent metabolic factors may potentiate the manifestation. Fat deposition is associated with less immunoreactivity and it may connote a distinctive pathogenic mechanism.

GB virus-C infection in type 1 autoimmune hepatitis.

OBJECTIVE: To assess the frequency and significance of GB virus-C infection in type 1 autoimmune hepatitis. MATERIAL AND METHODS: Serum specimens from 94 patients with type 1 autoimmune hepatitis were tested for GB virus-C RNA by reverse transcription and polymerase chain reaction. Serum samples from 50 normal subjects were also assessed. RESULTS: Three of the 94 specimens from patients with autoimmune hepatitis were positive for GB virus-C RNA in comparison with none of the 50 control samples (3% versus 0%; P = 0.5). Two patients were seropositive after variceal hemorrhage and blood transfusion, including one patient who clearly acquired the infection in this fashion. One patient had no epidemiologic basis for his seropositivity. Viremia was prolonged in all infected patients (mean duration, 69 +/- 23 months; range, 36 to 113); however, no clinical features suggested a concurrent viral infection, and mortality was similar to that among the uninfected counterparts (33% versus 8%; P = 0.2). Liver transplantation was more common in the infected patients (67% versus 9%; P = 0.03), but the duration of disease was also longer in these patients (277 +/- 29 months versus 106 +/- 9 months; P = 0.0008). Clinical features and immediate responses to corticosteroid therapy were similar in both groups. CONCLUSION: GB virus-C RNA is found infrequently in type 1 autoimmune hepatitis, and GB virus-C is unlikely to be an important etiologic agent or prognostic determinant.

Bacterial and parasitic cholangitis.

Bacterial cholangitis is a clinically defined syndrome caused by the regurgitation of infected bile into the circulation. The pathogenic mechanism is unclear, and systemic sepsis may not occur. Prerequisite conditions are the presence of microorganisms in the bile and increased biliary pressure. Bacteria that commonly cause cholangitis are Escherichia coli, Klebsiella, Enterococcus, Enterobacter, Pseudomonas, and anaerobes. Although most infections are polymicrobial, this situation may not always prevail. Successful treatment depends on relieving biliary obstruction and administering antibiotics effective against bacteria in the circulation and the bile. The causes of biliary obstruction that predispose to bacterial cholangitis are myriad. Common conditions include biliary stones and benign strictures. In many parts of the world, biliary parasites are an important factor. Biliary parasites cause necrosis, inflammation, fibrosis, strictures, and cholangiectasis of the bile ducts by several mechanisms: (1) as a direct result of the irritating chemical composition of the parasite, parasitic secretions, or eggs; (2) physical obstruction of the bile ducts; (3) induction of formation of biliary stones; and (4) introduction of bacteria into the biliary system during migration from the duodenum. Therefore, bacterial cholangitis has an important and frequently dominant role in the pathogenesis and clinical course of biliary disease due to these parasitic infestations. Common biliary parasites include the nematode Ascaris lumbricoides, the trematodes Opisthorchis viverrini and felineus, Clonorchis sinensis, and Fasciola hepatica, and the cestodes Echinococcus granulosus and multilocularis. The epidemiologic, pathologic, and clinical manifestations of these parasitic infestations are reviewed.

Acute hepatitis E by a new isolate acquired in the United States.

OBJECTIVE: To report the first case of acute hepatitis E by a novel isolate acquired in the United States and confirmed by nucleotide sequencing. MATERIAL AND METHODS: We describe the clinical manifestations and the results of associated laboratory studies in a man who was found to have acute hepatitis E infection. RESULTS: A 62-year-old man was hospitalized because of fever, abdominal pain, and jaundice. After an initial evaluation did not provide a cause, his serum was found to be positive for IgG anti-hepatitis E virus (HEV) by three antibody assays. Serum was also positive for HEV RNA by reverse transcriptase polymerase chain reaction (PCR). Sequencing results from the PCR products demonstrated substantial differences at the nucleotide level between this strain and the known Mexican and Burmese strains. CONCLUSION: On the basis of this initial report, HEV should be considered an etiologic agent in patients with acute non-ABC hepatitis in the United States.

Histological findings in chronic hepatitis C with autoimmune features.

To evaluate the histological findings in patients with chronic hepatitis C and autoimmune features, liver tissue specimens from 60 patients were graded under code for individual features and composite patterns that denoted autoimmune, viral, combined autoimmune and viral, and nondiscriminative changes. Portal, interface, and acinar hepatitis in any combination with plasma cell infiltration connoted an autoimmune pattern that was associated with higher serum levels of gamma-globulin (2.4 +/- 0.2 g/dL vs. 1.7 +/- 0.1 g/dL; P = .0003) and immunoglobulin G (2,211 +/- 227 mg/dL vs. 1,508 +/- 83 mg/dL; P = .001) than patients with other patterns. Patients with the autoimmune pattern also had a greater frequency of cirrhosis (43% vs. 8%; P = .003), higher mean Knodell score (13.2 +/- 0.9 vs. 6.8 +/- 0.9; P < .0001), and a greater occurrence of high-titer smooth muscle antibodies (SMA) (13% vs. 0%; P = .05) than patients with other histological findings. HLA DR3 also occurred more frequently in these individuals than in other patients (48% vs. 15%; P = .01) and normal subjects (43% vs. 16%; P = .01). Patients with nondiscriminative patterns and interface hepatitis had clinical findings similar to those with autoimmune patterns, except for a lower mean serum level of gamma-globulin. We conclude that the composite histological pattern that resembles autoimmune hepatitis is associated with greater immunoreactivity, inflammatory activity, and disease severity than other patterns. Interface hepatitis may be the most important histological finding associated with these clinical manifestations.

Pervasive occult gastrointestinal bleeding in an Alaska native population with prevalent iron deficiency. Role of Helicobacter pylori gastritis.

OBJECTIVE: To confirm prevalent iron deficiency among Yupik Eskimos living in Alaska and to explore the frequency of and potential lesions accounting for occult gastrointestinal bleeding. DESIGN: Descriptive survey. SETTING: Rural Arctic community. SUBJECTS: A total of 140 adult volunteers from 3 villages in the Yukon-Kuskokwim Delta region of western Alaska. MAIN OUTCOME MEASURES: Daily iron intake, hematologic and biochemical indexes of iron status, fecal hemoglobin levels, stool parasites, and endoscopic findings. RESULTS: While dietary iron intake by Yupiks was similar to that of a reference population, iron deficiency prevalence was increased 13-fold in Yupik men and 4-fold in Yupik women. Fecal hemoglobin levels were elevated in 90% of subjects contrasted with only 4% of a reference group; median levels were 5.9 and 0.5 mg of hemoglobin per gram of stool, respectively. Among 70 Yupik subjects with elevated fecal hemoglobin levels who had endoscopy performed, 68 (97%) had an abnormal gastric appearance consisting of erythema, mucosal thickening, diffuse mucosal hemorrhages, erosions, or ulcerations. Gastric biopsies revealed chronic active gastritis with associated Helicobacter pylori in 68 (99%) of 69. No other hemorrhagic gastrointestinal disease was detected. CONCLUSIONS: Based on this study sample, occult gastrointestinal bleeding appears to be pervasive in the Yupik population and likely underlies the prevalent iron deficiency. An atypical hemorrhagic gastritis associated with H pylori infection is present almost universally and may represent the bleeding source.

Barrett's esophagus, high-grade dysplasia, and early adenocarcinoma: a pathological study.

OBJECTIVES: In Barrett's esophagus, early adenocarcinomas are often missed on endoscopic biopsy. We therefore examined the distribution and extent of dysplasia and carcinoma in the resected esophagus for comparison with the preoperative biopsy findings. METHODS: Patients whose endoscopy showed Barrett's esophagus but no visible cancer had four-quadrant esophageal biopsies taken every 2 cm. After resection for high-grade dysplasia or early adenocarcinoma, the esophagus was mapped histologically. RESULTS: Nineteen patients had surgery for high-grade dysplasia; two of them (10.5%) had adenocarcinoma in the resected esophagus. Eleven patients had resection after a biopsy diagnosis of adenocarcinoma or suspicion of adenocarcinoma. Esophagectomy mapping confirmed carcinoma in only five of them. Median surface areas were: total Barrett's esophagus 32 sq cm, low-grade dysplasia 13 sq cm, high-grade dysplasia 1.3 sq cm, adenocarcinoma (seven cases) 1.1 sq cm. CONCLUSIONS: Areas of high-grade dysplasia and microscopic carcinoma in Barrett's esophagus are often small. Biopsy differentiation between these lesions is difficult. A systematic endoscopic biopsy protocol will reduce the chance of missing early malignancy in Barrett's esophagus.

Bismuth carbomer foam enemas for active chronic pouchitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Bismuth carbomer liquid enemas are equivalent to mesalamine enemas for active distal ulcerative colitis. AIMS: In this study, the efficacy and safety of bismuth carbomer foam enemas for active chronic pouchitis was determined in a placebo-controlled trial. PATIENTS: Forty adult patients with active chronic pouchitis were randomly assigned into either concurrent therapy for pouchitis or no concurrent therapy. Topical corticosteroids and mesalamine were withdrawn prior to the study. METHODS: Patients received either bismuth carbomer (270 mg elemental bismuth) (n = 20) or placebo (n = 20) foam enemas for 3 weeks. Clinical assessment was performed at baseline and at 3 weeks using the pouchitis disease activity index score which incorporates symptoms, endoscopy and histology. Serum bismuth concentrations were determined by atomic absorption spectrophotometry. RESULTS: At 3 weeks nine of 20 patients (45%) in both the bismuth and placebo groups had improved. Ten patients discontinued prematurely because of worse diarrhoea (three in each group) or abdominal cramping after enema use (one from the bismuth group and three from the placebo group). No other side-effects were noted. Serum bismuth concentrations were negligible in all patients. CONCLUSIONS: Bismuth carbomer foam enemas (270 mg bismuth) nightly for 3 weeks are safe but not efficacious for active chronic pouchitis.

Validation of scoring system for diagnosis of autoimmune hepatitis.

To assess the validity of a scoring system developed by the International Autoimmune Hepatitis Group for the definite diagnosis of autoimmune hepatitis, 119 patients with autoimmune hepatitis by standard clinical criteria and 131 patients with other chronic liver diseases were evaluated. Each patient was graded on 35 items in 13 clinical categories. Ninety-seven patients diagnosed as having autoimmune hepatitis by conventional criteria (82%) had a definite diagnosis by the scoring system and 22 patients (18%) had a probable diagnosis. Of these patients, those with definite diagnoses had significant clinical differences from those with probable diagnoses. Only two patients with other chronic liver disease (2%) had scores sufficient for a definite diagnosis of autoimmune hepatitis. Probable diagnoses, however, were common in other conditions (33%). Failure to adequately downgrade for cholestatic features contributed to these uncertain diagnoses. Scoring for treatment response downgraded the diagnosis in 17 of 93 patients with a definite diagnosis before therapy (18%) and upgraded the diagnosis in 6 of 14 others (43%). We conclude that the scoring system is specific for the definite diagnosis of autoimmune hepatitis, and it complements standard clinical criteria by establishing the strength of the diagnosis and defining distinctive subgroups within the diagnostic category. Refinements are necessary to reduce the frequency of probable diagnoses. Diagnoses at presentation can be commonly modified by scoring treatment response.

Genetic predispositions for immunological features in chronic liver diseases other than autoimmune hepatitis.

BACKGROUND/AIMS: Human leukocyte antigens DR3 and DR4 influence susceptibility for type 1 autoimmune hepatitis and affect its immunological manifestations. We aimed to determine if autoimmune features in patients with chronic liver diseases other than autoimmune hepatitis are associated with these same antigens. METHODS: One hundred and seventy-eight patients were evaluated. Class II typing was performed by restriction fragment length polymorphism in all patients and 80 normal subjects. RESULTS: One or more autoantibodies, including antinuclear antibodies (28%), smooth muscle antibodies (8%), thyroid antibodies (18%) and antimitochondrial antibodies (13%), were found in 92 patients (52%). Concurrent clinical diseases of an immunological nature were recognized in 53 patients (30%). Patients with antinuclear antibodies had a higher frequency of the A1-B8-DR3 haplotype than patients without these antibodies (27% versus 12%, p = 0.04) and patients with concurrent immunological diseases had a higher frequency of HLA DR4 than patients without this antigen (51% versus 26%, p = 0.003). Patients with antinuclear antibodies were more commonly DR3 positive than normals (35% versus 16%, p = 0.03) and patients with concurrent immunological diseases were more commonly HLA DR4 positive than normals (51% versus 30%, p = 0.02). CONCLUSIONS: We conclude that the clinical expression of antinuclear antibodies is associated with the A1-B8-DR3 haplotype and the presence of concurrent immunological diseases is related to the DR4 antigen. These clinical manifestations have a genetic basis that is not disease-specific.

Immunolocalization of transforming growth factor-alpha in normal and diseased human gastric mucosa.

Roles for transforming growth factor-alpha (TGF alpha) in the stomach include cell migration and proliferation, inhibition of acid secretion, and cytoprotection. The authors have previously shown increased TGF alpha expression in rat gastric mucosa in response to acute gastric injury. They also have shown that TGF alpha immunoreactivity is increased in the gastric mucosa of four patients with Ménétrier's disease. To further characterize TGF alpha immunoreactivity in human gastric mucosa, the authors have performed immunohistochemical analysis with an anti-TGF alpha monoclonal antibody on human gastric biopsies (n = 25) showing either normal (n = 8), mild reactive/reparative change in common conditions with or without associated gastritis (n = 13), and exaggerated mucosal change in proliferative conditions (Ménétrier's disease, hypertrophic lymphocytic gastritis, and hyperplastic polyps) (n = 17). All normal biopsies showed a predictable pattern of TGF alpha immunostaining, with significant positivity found only in foveolar cells at the luminal surface and parietal cells, sparing foveolar cells in the gastric pits, mucous neck cells and chief cells of the gastric glands. Three patients with mild foveolar hyperplasia without associated inflammation did not deviate from the normal pattern except in foci of reactive epithelial change. Ten of 11 patients with chronic active gastritis, in addition to this normal staining pattern, demonstrated significant immunoreactivity in deeper foveolar cells and mucous neck cells showing reactive epithelial changes, defined as the presence of nuclear enlargement and nucleolar prominence with or without mucin depletion. Three cases of ulceration with associated reactive epithelial changes also showed increased immunoreactivity. Furthermore, five cases of Ménétrier's disease with massive foveolar hyperplasia and minimal inflammation (MFH) and six cases with hypertrophic lymphocytic gastritis (HLG) have been studied, and both show full-thickness TGF alpha immunoreactivity restricted to the gastric epithelium. This pattern of staining is indistinguishable from that observed in two cases of hyperplastic polyps but differs significantly from that observed in cases of mild foveolar hyperplasia. These results further define patterns of TGF alpha immunostaining in normal, reactive/reparative and exaggerated proliferative human gastric biopsies, confirm participation of TGF alpha in the response to gastric mucosal injury, and provide additional support for a possible role for TGF alpha in the pathogenesis of proliferative gastric disorders including Ménétrier's disease, hypertrophic lymphocytic gastritis, and hyperplastic gastric polyps.