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Autoimmune hepatitis (AIH) may have an atypical serum alkaline phosphatase elevation, antimitochondrial antibodies, histologic features of bile duct injury/loss, or cholangiographic findings of focal biliary strictures and dilations. These manifestations characterize the overlap syndromes. Patients can be classified as having AIH with features of primary biliary cholangitis, primary sclerosing cholangitis, or a cholestatic syndrome. The gold standard of diagnosis is clinical judgment. Histologic evaluation is a major diagnostic component. Treatment is based on algorithms; outcomes vary depending on the predominant disease component. Combination therapy has been the principal recommendation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The purpose of this study was to explore rehabilitation professionals' knowledge regarding signs and symptoms, prevention, and intervention of fetal alcohol spectrum disorders (FASD). Participants were 111 rehabilitation practitioners (e.g., occupational therapy, physical therapy, and speech-language pathology practitioners) recruited through email using a quantitative online survey design with purposive, snowball sampling. Results showed the majority of participants' demonstrated accurate knowledge of the signs and symptoms of FASD. Since professionals who received formal education on FASD reported significantly higher feelings of preparedness to identify children with FASD and manage/coordinate intervention plans, this study suggests rehabilitation professionals may be better prepared to treat individuals with FASD if they participate in formal training.

Background: One-third of US adults, 86 million people, have prediabetes. Two-thirds of adults are overweight or obese and at risk for diabetes. Effective and affordable interventions are needed that can reach these 86 million, and others at high risk, to reduce their progression to diagnosed diabetes., Objective: The aim was to evaluate the effectiveness of a fully automated algorithm-driven behavioral intervention for diabetes prevention, Alive-PD, delivered via the Web, Internet, mobile phone, and automated phone calls., Methods: Alive-PD provided tailored behavioral support for improvements in physical activity, eating habits, and factors such as weight loss, stress, and sleep. Weekly emails suggested small-step goals and linked to an individual Web page with tools for tracking, coaching, social support through virtual teams, competition, and health information. A mobile phone app and automated phone calls provided further support. The trial randomly assigned 339 persons to the Alive-PD intervention (n=163) or a 6-month wait-list usual-care control group (n=176). Participants were eligible if either fasting glucose or glycated hemoglobin A1c (HbA1c) was in the prediabetic range. Primary outcome measures were changes in fasting glucose and HbA1c at 6 months. Secondary outcome measures included clinic-measured changes in body weight, body mass index (BMI), waist circumference, triglyceride/high-density lipoprotein cholesterol (TG/HDL) ratio, and Framingham diabetes risk score. Analysis was by intention-to-treat., Results: Participants' mean age was 55 (SD 8.9) years, mean BMI was 31.2 (SD 4.4) kg/m(2), and 68.7% (233/339) were male. Mean fasting glucose was in the prediabetic range (mean 109.9, SD 8.4 mg/dL), whereas the mean HbA1c was 5.6% (SD 0.3), in the normal range. In intention-to-treat analyses, Alive-PD participants achieved significantly greater reductions than controls in fasting glucose (mean -7.36 mg/dL, 95% CI -7.85 to -6.87 vs mean -2.19, 95% CI -2.64 to -1.73, P<.001), HbA1c (mean -0.26%, 95% CI -0.27 to -0.24 vs mean -0.18%, 95% CI -0.19 to -0.16, P<.001), and body weight (mean -3.26 kg, 95% CI -3.26 to -3.25 vs mean -1.26 kg, 95% CI -1.27 to -1.26, P<.001). Reductions in BMI, waist circumference, and TG/HDL were also significantly greater in Alive-PD participants than in the control group. At 6 months, the Alive-PD group reduced their Framingham 8-year diabetes risk from 16% to 11%, significantly more than the control group (P<.001). Participation and retention was good; intervention participants interacted with the program a median of 17 (IQR 14) of 24 weeks and 71.1% (116/163) were still interacting with the program in month 6., Conclusions: Alive-PD improved glycemic control, body weight, BMI, waist circumference, TG/HDL ratio, and diabetes risk. As a fully automated system, the program has high potential for scalability and could potentially reach many of the 86 million US adults who have prediabetes as well as other at-risk groups., Trial Registration: Clinicaltrials.gov NCT01479062; https://clinicaltrials.gov/ct2/show/NCT01479062 (Archived by WebCite at http://www.webcitation.org/6bt4V20NR).

Objective: Hepatocellular carcinoma (HCC) is an uncommon but serious occurrence in autoimmune hepatitis. Our objective was to determine predictors for this neoplasm to improve screening strategies., Methods: Two hundred twenty-seven patients underwent hepatic ultrasonography and serum alpha fetoprotein determinations at 6-12-month intervals., Results: Nine patients developed HCC (4%), and each had cirrhosis > or =73 months prior to the malignancy (mean, 110 +/- 7 months). By univariate Cox analysis, features at accession associated with a higher risk of HCC were: male gender (Hazard Ratio [HR] 7.0, 95% Confidence Interval [CI] 1.87-26.1, P= 0.004), history of blood transfusion (HR 5.6, 95% CI 1.51-21.1, P= 0.01), thrombocytopenia (HR 7.3, 95% CI 1.89-28.3, P= 0.004), ascites (HR 23.8, 95% CI 4.65-121.8, P= 0.0001), esophageal varices (HR 7.9, 95% CI 1.96-31.8, P= 0.004), and any sign of portal hypertension (HR 19.1, 95% CI 3.91-93.3, P= 0.0003). Features after accession associated with a higher risk of malignancy were: treatment for > or =3 yr (HR 7.6, 95% CI 1.25-18.2, P= 0.02), worsening laboratory tests during corticosteroid therapy (HR 7.6, 95% CI 1.81-32.1, P= 0.006), and cirrhosis for > or =10 yr (HR 8.4, 95% CI 1.69-41.9, P= 0.009)., Conclusions: Male gender, features of portal hypertension, history of blood transfusions, immunosuppressive treatment for > or =3 yr, treatment failure, and cirrhosis of > or =10 yr duration identify patients at risk for HCC. These risk factors should focus screening in autoimmune hepatitis.

Our goal was to determine if HLA DRB1*13 is associated with autoimmune hepatitis in North American patients. Two hundred and ten adults with definite type 1 autoimmune hepatitis were typed by DNA-based techniques, and the frequency of HLA DRB1*13 in patients without DRB1*03 and DRB1*04 was compared to that in 396 patients with eight other chronic liver diseases and 102 normal individuals. HLA DRB1*13 occurred more commonly in the autoimmune patients who lacked DRB1*03 and DRB1*04 than normal subjects who were similarly restricted (56% vs. 27%, P = 0.007). The frequency of HLA DRB1*13 was higher in autoimmune patients without DRB1*03 and DRB1*04 than in patients with other chronic liver diseases who were similarly restricted (59% vs. 32%, P = 0.01). Only patients with primary sclerosing cholangitis had a comparable occurrence of HLA DRB1*13. In conclusion, HLA DRB1*13 may be a genetic risk factor for some white North American patients with type 1 autoimmune hepatitis.

Unlabelled: Autoimmune hepatitis may fail to respond to corticosteroid therapy, but the frequency and bases for this outcome are uncertain. We aimed to determine the frequency and nature of treatment failure in patients with type 1 autoimmune hepatitis, define features associated with its occurrence, and assess if the model for end-stage liver disease can predict this outcome. Patients failing conventional corticosteroid regimens were compared to patients who responded to similar regimens. Fourteen of 214 patients (7%) failed corticosteroid treatment. Patients who failed therapy were younger (33 +/- 3 years versus 48 +/- 1 years, P = 0.0008), had higher serum levels of bilirubin at accession (4.1 +/- 0.9 mg/dL versus 2.3 +/- 0.2 mg/dL, P = 0.02), presented acutely more frequently (43% versus 14%, P = 0.01), and had a higher frequency of HLA (human leukocyte antigen) DRB1*03 (93% versus 53%, P = 0.004) than did patients who achieved remission. An alternative disease (fatty liver disease) emerged in only 1 patient who failed therapy (7%). Scores determined by the model of end-stage liver disease at presentation of patients who failed treatment were higher than those of who achieved remission (16 +/- 1 versus 10 +/- 0.3 points, P < 0.0001), and score greater than 12 points had greater sensitivity (97%) and specificity (68%) for treatment failure than did HLA DRB1*03 or other features., Conclusion: Onset at an early age, acute presentation, hyperbilirubinemia, and presence of HLA DRB1*03 characterize patients who fail corticosteroid treatment. The model for end-stage liver disease may be a useful instrument for identifying patients prone to this outcome.

The histologic assessment of acute and chronic liver disease is based on an accurate description of the pattern of injury within the tissue specimen. Interpretation of the injury pattern requires review of the associated clinical and laboratory features. The morphologic interpretation achieves relevance only if it satisfactorily explains the clinical syndrome. Clinical characterization of the liver disease as having a hepatitic or cholestatic nature is useful in focusing the histologic assessment. The principal histologic patterns have hepatitic, steatotic, biliary, granulomatous, vascular, and metabolic designations, and mixed clinical and histologic patterns are possible. The goal of this review is to optimize the yield from the liver biopsy examination by indicating the importance of a systematic analysis of the tissue specimen and the crucial need for correlating the clinical and histologic patterns of liver injury. Meaningful histologic interpretations reflect the collaborative effort of the pathologist and the clinical physician. Neoplastic changes typically are cytologic transformations rather than injury patterns, and they are not discussed here.

Background and Aims: Drug-related side effects are considered the major consequences of relapse and re-treatment in patients with autoimmune hepatitis. Our goals were to determine whether relapse is associated with disease progression and whether treatment end points can be refined., Methods: The outcomes of 132 patients with definite type 1 autoimmune hepatitis who had been treated comparably until remission were assessed retrospectively after drug withdrawal., Results: Patients who had relapsed repeatedly after initial treatment withdrawal developed cirrhosis more commonly than patients who sustained remission (18/48 vs 1/22, P=0.004), and those who relapsed once (18/48 vs 2/21, P=0.02). Hepatic death or the need for liver transplantation was also more frequent in the patients who had multiple relapses than those who sustained remission (13/64 vs 0/30, P=0.008) and those who relapsed once (13/64 vs 1/38, P=0.02). Patients who sustained their remission had a higher frequency of normal laboratory indices at drug withdrawal than patients who relapsed (88% vs 46%, P=0.003). Adverse outcomes after relapse did not distinguish patients until after 5 years of observation., Conclusions: Multiple relapses are associated with a poorer prognosis than sustained remission or single relapse episodes. Initial treatment to resolution of laboratory abnormalities may afford the greatest opportunity to prevent relapse.

Objective: Relapse of autoimmune hepatitis may reflect incomplete suppression of disease activity prior to corticosteroid withdrawal, and liver tissue examination prior to the termination of therapy may be insufficient to predict subsequent course. Our goal was to refine treatment end point criteria so as to reduce the frequency of relapse after drug withdrawal., Methods: One hundred thirty-two patients with definite type 1 autoimmune hepatitis who fulfilled clinical, laboratory, and histological criteria for remission were evaluated. The degree of laboratory improvement at the termination of treatment was correlated with subsequent clinical course in patients who had improved to normal or near-normal histological findings during corticosteroid therapy., Results: Serum aspartate aminotransferase (AST) levels at the end of treatment were higher in patients who subsequently relapsed than in those who sustained remission (32 +/- 2 U/L vs 25 +/- 2 U/L, P= 0.04). Serum gamma-globulin (1.4 +/- 0.1 g/dL vs 1.2 +/- 0.1 g/dL, P=0.03) and immunoglobulin G (IgG) (1,416 +/- 55 mg/dL vs 1,079 +/- 57 mg/dL, P=0.001) levels were also higher in these patients prior to termination of therapy. The frequencies of abnormal serum AST (40%vs 13%, P=0.008), gamma-globulin (25%vs 3%, P=0.009), and IgG levels (36%vs 4%, P=0.001) at treatment withdrawal were also greater in the patients who subsequently relapsed., Conclusions: Patients who are treated to normal serum AST, gamma-globulin, and IgG levels have a lower frequency of relapse than others despite comparable histological findings.

Background: HLA DRB1*03-DRB1*04 combines both susceptibility factors for type-1 autoimmune hepatitis., Aims: Determine whether this phenotype is a risk factor for autoimmune hepatitis in white North American patients, assess its associations with clinical features and treatment outcome, and determine whether alleles within this phenotype affect prognosis., Methods: One hundred and ninety-eight patients with type 1 autoimmune hepatitis and 102 normal adults were evaluated. HLA typing was performed by DNA-based techniques., Results: Twenty-eight patients had HLA DRB1*03-DRB1*04, and the frequency was higher than in normal subjects (14% vs 4%, OR 4.0%, 95% CI 1.4-11.8, P = 0.01). Patients with DRB1*03-DRB1*04 relapsed less frequently than patients with DRB1*03 (1.3 +/- 0.3 vs 2.1 +/- 0.2, P = 0.04), but they otherwise had outcomes similar to patients with other phenotypes. Patients with DRB1*03-DRB1*04 who had 3-4 alleles encoding lysine at position DRbeta71 within the class II molecule of the major histocompatibility complex developed cirrhosis more commonly (75% vs 9%, P = 0.05) and had a higher frequency of hepatic-related death or liver transplantation (40% vs 0%, P = 0.04) than patients with fewer alleles., Conclusions: HLA DRB1*03-DRB1*04 is a risk factor for type-1 autoimmune hepatitis, and its impact on outcome relates to the diversity of DRB1*04 alleles that encode a critical motif.

Aims: To determine the clinical phenotype and outcome of patients with definite type 1 autoimmune hepatitis, who lack human leukocyte antigen (HLA) DR3 and DR4, and to assess the importance of HLA DR7 and DR13., Methods: Two hundred and seven adult patients were typed for DR3, DR4, DR7, and DR13 by DNA-based techniques. One hundred and two blood donors constituted a normal population., Results: Twenty-six patients lacked DR3 and DR4 (13%). Treatment failure occurred more commonly in these individuals than in the 68 patients with DR4 (20% vs. 3%, P = 0.03), and relapse after drug withdrawal was less frequent than in the 84 patients with DR3 (55% vs. 87%, P = 0.03). HLA DR13 occurred more often than in those with DR3 (54% vs. 15%, P = 0.0002) or DR4 (54% vs. 12%, P = 0.00005), and it was more frequent than in normal adults (54% vs. 22%, P = 0.003), including those without DR3 or DR4 (54% vs. 27%, P = 0.03). HLA DR7 was not associated with susceptibility or outcome., Conclusions: White North American patients who lack DR3 and DR4 respond differently to corticosteroid treatment than patients with classical HLA phenotypes. HLA DR13 is common in these adult patients, and it may affect treatment outcome.

Objectives: Determine the frequency, clinical phenotype, and prognostic implications of antibodies against cyclic citrullinated peptides in patients with type 1 autoimmune hepatitis., Methods: Three hundred and ninety-five serum samples from 179 patients were tested by enzyme-linked immunosorbent assay, and findings correlated with clinical and histological features, frequency of HLA DR3 and DR4, and treatment outcome., Results: Twenty patients (11%) had antibodies against cyclic citrullinated peptides. Seropositivity was associated with a higher frequency of rheumatoid arthritis (RA) (25 vs. 0%, P < 0.001). Patients with antibodies against cyclic citrullinated peptides also had a significantly greater occurrence of histological cirrhosis at presentation (47 vs. 20%, P = 0.01) and death from hepatic failure than seronegative patients (25 vs. 9%, P = 0.04). Cirrhosis at presentation occurred more commonly in the patients with antibodies against cyclic citrullinated peptides and RA than in the other patients (100 vs. 21%, P = 0.005)., Conclusions: Antibodies against cyclic citrullinated peptides occur in a subgroup of patients with type 1 autoimmune hepatitis who have a greater occurrence of cirrhosis at presentation and death from hepatic failure. Their presence with RA at accession characterizes a subgroup with cirrhosis.

Thiopurine methyltransferase deficiency has been associated with intolerance to azathioprine. Our goals were to assess the frequency of enzyme deficiency in autoimmune hepatitis and correlate deficiency states with azathioprine intolerance. Eighty-six patients receiving azathioprine (50-150 mg daily) were evaluated for enzyme activity and azathioprine-related complications. Their findings were compared to 89 similarly treated but untested patients. Thirteen patients (15%) had low thiopurine methyltransferase levels (11.4+/- 0.9 U/ml RBC; range, 3.5-14.9 U/ml RBC). Azathioprine intolerance occurred as commonly in patients with normal or above normal enzyme levels as in patients with below normal levels (12% versus 15%, p = 0.7). Patients treated without enzyme testing had the same frequency of complications (9% versus 13%, p = 0.5) as tested patients. We conclude that routine screening of blood thiopurine methyltransferase levels has a low yield for identifying individual patients at risk for azathioprine toxicity during conventional low dose therapy for autoimmune hepatitis.

Autoimmune hepatitis is classically a disease of young women. Our aims were to determine its occurrence, clinical phenotype, and outcome in elderly patients and contrast findings to young adults. Two-hundred-and-five white North American adults with definite type 1 autoimmune hepatitis were grouped according to age at presentation and the groups compared. Forty-seven patients (23%) were aged > or = 60 years (median age, 68 years), and 31 patients (15%) were aged < or = 30 years (median age, 25 years). The patients > or = 60 years had a higher frequency of cirrhosis at presentation than the patients < or = 30 years (33% versus 10%, P = .03). They also had thyroid or rheumatic diseases more commonly (42% vs. 13%, P = .006). HLA DR3 occurred more frequently in the patients < or = 30 years than in those > or = 60 years (58% vs. 23%, P = .004), and HLA DR4 occurred more often in the patients > or = 60 years (47% vs. 13%, P = .003). Patients aged > or = 60 years failed corticosteroid treatment less commonly than those aged < or = 30 years (5% vs. 24%, P = .03). Autoimmune hepatitis occurred in patients aged 18-30 years (15%), 31-39 years (15%), 40-49 years (21%), 50-59 years (25%), and > or = 60 years (23%). Differences in age distribution, HLA frequencies, and treatment outcome occurred after age > or = 40 years. In conclusion, elderly patients have a greater frequency of cirrhosis at presentation and HLA DR4 than patients < or = 30 years, and they have a lower occurrence of treatment failure. Transitions in clinical and genetic phenotypes occur after age > or = 40 years. Genetic susceptibilities may favor etiologic factors that are age-related.

Goal: To assess the outcomes of empiric therapy with mycophenolate mofetil in patients with autoimmune hepatitis., Background: Mycophenolate mofetil is a purine antagonist that selectively inhibits immunocyte proliferation, and its empiric use in autoimmune hepatitis has been stimulated by small clinical experiences., Study: Eight patients received mycophenolate mofetil (0.5-3 g daily) for 19 +/- 7 months as frontline therapy or after adverse responses to conventional corticosteroid treatment. Seventeen patients who had been treated with high-dose corticosteroid regimens after treatment failure constituted a historical comparison population., Results: Five of the 8 patients receiving mycophenolate mofetil and all 17 patients who had been treated with the conventional corticosteroid regimens for treatment failure responded to therapy. The frequency of response (62% vs. 100%, P = 0.02) was lower during longer intervals of treatment (19 +/- 7 months vs. 6 +/- 1 months, P = 0.02) in the patients receiving mycophenolate mofetil. None receiving mycophenolate mofetil resolved their laboratory abnormalities, whereas 6 patients in the comparison group improved to normal tests (0% vs. 35%, P = 0.1). Histologic resolution did not occur in 4 patients sampled during treatment, and successive specimens in 2 patients showed progressive fibrosis. Corticosteroids could not be withdrawn in the patients treated with mycophenolate mofetil, whereas discontinuation was possible in 7 patients in the comparison group (0% vs. 41%, P = 0.06)., Conclusions: Mycophenolate mofetil did not induce laboratory resolution, prevent progressive fibrosis, or allow corticosteroid withdrawal. Clinical trials are needed to evaluate its role and target population.

New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The assessment of new front-line and salvage therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic criteria and treatment regimens for children required codification, and pharmacokinetic studies were encouraged to develop optimal dosing schedules based on therapeutic ranges. Collaborative efforts were proposed to help understand racial, geographical, and genetic factors affecting outcome and to establish definitions and therapies for variant syndromes and graft dysfunction after transplantation. The development of experimental animal models was deemed essential for the study of site-specific molecular interventions, and gene therapy was endorsed as a means of bolstering reparative processes. In conclusion, evolving pharmacological and technical advances promise to improve the treatment of autoimmune hepatitis, and investigations of these advances are timely, feasible, and necessary.

Background: Bile duct injury is not a feature of classical autoimmune hepatitis (AIH), but it has been described in variant forms of the disease., Aims: Our goals were to assess the similarity of AIH with bile duct injury to classical disease and to evaluate the possibility of concurrent primary biliary cirrhosis (PBC)., Methods: Fifteen patients with bile duct injury were compared with 151 patients with classical AIH. Patterns of nuclear immunofluorescence and the frequency and nature of autoantibodies associated with AIH and PBC were determined., Results: Patients with bile duct injury had the same nuclear-staining patterns, frequency and nature of autoantibodies, and genetic risk factors as the comparison group. Features specific for PBC, including the multiple nuclear dot pattern of immunofluorescence and antibodies to the M2 antigens, Sp100 and nuclear pore complex antigen, gp210, did not distinguish them from classical disease. Remission and treatment failure occurred with similar frequencies in both groups., Conclusions: Patients with AIH and bile duct injury lack features of PBC, and they respond as well to corticosteroid therapy as patients with classical disease. Background bile duct changes should not alter the diagnosis or treatment of AIH., (Copyright Blackwell Munksgaard 2004)

Hepatic fibrosis and cirrhosis are possible consequences of corticosteroid-treated autoimmune hepatitis. Our aims were to determine the frequency of progressive fibrosis and the factors associated with this progression. Two hundred seventy-seven liver tissue specimens that had been obtained from 73 patients were interpreted in batch under code by a single pathologist. Fibrosis scores and histological activity indices were determined using the Ishak scoring system, and worsening fibrosis scores were correlated with clinical features, laboratory findings, and treatment responses. Fibrosis scores increased (2.3 +/- 0.4 points to 4.2 +/- 0.4 points; P <.0001) in 18 patients (25%) during 79 +/- 13 months. Only five patients (7%) developed cirrhosis, and 55 patients (75%) had stable (16 patients) or decreased (39 patients) fibrosis scores. Human leukocyte antigen (HLA) DR3/DR4 occurred more frequently in patients with progressive fibrosis than others (23% vs. 2%; P =.03). Patients with progressive fibrosis had higher histological activity indices at last follow-up than patients with stable or reduced fibrosis (3.2 +/- 0.7 vs. 1.7 +/- 0.2; P =.01), and these indices worsened more commonly during therapy (17% vs. 2%, P =.04). Relapse, treatment failure, and incomplete response did not affect progression of fibrosis. In conclusion, fibrosis progresses in only a minority of patients during corticosteroid therapy. Progression is associated with HLA DR3/DR4 and worsening histological activity. Exacerbations or persistence of disease activity does not increase disease progression after treatment has been instituted.

Background/aims: Reduction in hepatic fibrosis and reversibility of cirrhosis has been described in chronic liver disease. Our goal was to determine changes in fibrosis and the frequency of histological cirrhosis in corticosteroid-treated autoimmune hepatitis (AIH)., Methods: Three hundred twenty-five liver specimens from 87 treated patients were reviewed in batch under code by one pathologist and graded by the Ishak method., Results: Fibrosis scores improved (3.4+/-0.2 versus 2.6+/-0.2, P=0.0002) during 63+/-6 months, and histological activity indices decreased concurrently (6.8+/-0.5 versus 2.1+/-0.2, P<0.0001). Fibrosis scores improved in 46 patients (53%) during 57+/-7 months and did not progress in 23 patients during 62+/-12 months. The fibrosis score improved more commonly in patients who had improvement in the histological activity indices than in others (61 versus 32%, P=0.02), and the frequency of histological cirrhosis decreased from 16% (14 patients) to 11% (10 patients)., Conclusions: Fibrosis commonly improves or does not progress during corticosteroid therapy of AIH, and histological cirrhosis may disappear. Improvements in fibrosis are associated with suppression of inflammatory activity. Improvement or prevention of fibrosis may be a common but unheralded advantage of corticosteroid therapy.

Unlabelled: Relapse of type 1 autoimmune hepatitis after drug withdrawal may relate to incomplete histological improvement during corticosteroid therapy and/or persistence of pathogenic mechanisms., Aim: Determine the histological features prior to drug withdrawal that are associated with relapse in patients satisfying pre-established clinical, laboratory, and histological criteria for remission and relapsing after corticosteroid withdrawal., Methods: One hundred liver tissue samples obtained immediately prior to corticosteroid withdrawal from 88 patients who had previously satisfied criteria for histological remission were reviewed retrospectively., Results: Histological findings in the patients who relapsed were similar to those in the patients who sustained remission in regard to histological activity index (1.7 +/- 0.1 versus 1.6 +/- 0.2, P = 0.6), fibrosis score (2.6 +/- 0.3 versus 2.3 +/- 0.4, P = 0.5), and frequencies of interface hepatitis (36% versus 20%, P = 0.2), cirrhosis (21% versus 17%, P = 0.8), and normal or near normal tissue (9% versus 7%, P > 0.9). Only the presence of portal plasma cells was associated with relapse (31% versus 7%, P = 0.01). The positive predictability of portal plasma cell infiltration for relapse was 92%, but its sensitivity was only 31%., Conclusions: Portal plasma cell infiltration is predictive of relapse after drug withdrawal in tissue specimens already satisfying criteria for remission. Portal plasma cell infiltration may be indicative of an active antibody-dependent pathogenic mechanism. Its low sensitivity for relapse indicates the need for other complementary predictors of outcome.

The diagnosis of autoimmune hepatitis requires a constellation of clinical, laboratory, and histologic features that exclude other conditions and support the syndrome. Interface hepatitis is the histologic hallmark of the disease, and it may be associated with panacinar hepatitis with or without bridging necrosis or multiacinar necrosis. The liver tissue examination at accession supports the diagnosis and assesses disease severity. It can also suggest the diagnosis in patients with atypical presentations, including those with an acute onset or cryptogenic disease. The liver tissue examination during therapy defines end points of treatment (remission) and evaluates unexpected outcomes (treatment failure, incomplete response). Manifestations of bile duct injury are incompatible with the classic diagnosis of autoimmune hepatitis, and they may be coincidental findings of no or uncertain clinical significance or weak expressions of a variant form. Histologic features of autoimmune hepatitis may intermix with those of PBC, PSC, and chronic hepatitis C infection, or they may occur in autoimmune cholangitis or cryptogenic chronic hepatitis. Conditions in which the histologic findings suggest the overlap of two disorders or are insufficient for designation as classic disease constitute the variant syndromes.

Autoimmune hepatitis commonly relapses after corticosteroid therapy, and long-term management strategies have been proposed based on the premise that repeated relapses after drug withdrawal are inevitable. Our goal was to determine the frequency that remission can be sustained after its induction and termination of therapy. A total of 107 patients who had entered remission on conventional regimens were assessed for sustained remission after initial treatment and after relapse and re-treatment. Re-treatment strategies included conventional regimens and long-term maintenance schedules. Twenty-two patients (21%) achieved a sustained remission after initial treatment, and 24 of 85 patients who relapsed and were re-treated (28%) had a similar outcome. The probability of a sustained remission was 47% after 10 years of follow-up. Patients who sustained remission after initial therapy were distinguished only by a lower serum gamma-globulin level at entry. Conventional re-treatment schedules after relapse were able to induce a sustained remission more commonly then long-term maintenance schedules (59% vs. 12%, P =.00002). In conclusion, patients who respond to initial corticosteroid therapy can achieve a sustained remission after treatment withdrawal or after relapse and re-treatment. All patients are candidates for this outcome, and withdrawal of medication, even during maintenance schedules, is necessary to assess its likelihood.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background & Aims: In contrast to the dramatic decrease in the overall incidence of gastric cancer, there has been a reported increase in the incidence of cases located in the gastric cardia. The aim of this study was to identify changes in site- and histology-specific incidence rates of gastric adenocarcinoma during a 50-year period., Methods: The Rochester Epidemiology Project medical records linkage system was used to identify all cases of gastric adenocarcinoma among residents of Olmsted County, Minnesota, between 1941 and 1990 (n = 342). Each patient's complete (inpatient and outpatient) medical records were reviewed and tumor location determined from pathological, surgical, endoscopic, and radiological reports. All available histological specimens (n = 246) were reviewed independently., Results: The overall incidence of gastric cancer decreased from 48.8 per 100,000 person-years in the 1940s to 11.6 per 100,000 in the 1980s, whereas the incidence of adenocarcinoma of the cardia did not change significantly during the 50-year period. The incidence of adenocarcinoma of the esophagogastric junction increased from 0.0 to 1.9 per 100,000 person-years, but the number of cases was small., Conclusions: The incidence of adenocarcinoma of the gastric cardia has not increased in this population. The reported increase in cardia cancer in other populations may be due to an increasing incidence of adenocarcinoma of the esophagogastric junction.

Background & Aims: Barrett's esophagus is associated with adenocarcinoma of the esophagus. The aim of this study was to find the prevalence of Barrett's esophagus in patients with adenocarcinoma of the esophagogastric junction., Methods: Consecutive, freshly resected surgical esophagogastrectomy specimens were examined, and multiple histological sections were made around the tumor periphery. Barrett's esophagus was defined as specialized columnar epithelium above the esophagogastric junction. Tumors centered < or = 2 cm from the junction were defined as junction cancers., Results: Barrett's esophagus was found in 9 of 9 (100%) esophageal adenocarcinomas compared with 0 of 8 (0%) squamous carcinoma controls (P < 0.001). Ten of 24 (42%) junction adenocarcinomas had a Barrett's esophagus. A Barrett's esophagus was found in 8 of 12 (67%) junction cancers < or = 6 cm in length but only 2 of 12 (17%) larger tumors (P < 0.05). Barrett's esophagus was significantly associated with junction tumors < 6 cm compared with squamous carcinoma controls (P < 0.02). In 5 specimens with junction cancer, the length of Barrett's esophagus was < 3 cm, and in 5 specimens it was > or = 3 cm. Specialized epithelium was often found below the esophagogastric junction in controls., Conclusions: Adenocarcinomas of the esophagogastric junction are associated with short and long segments of Barrett's esophagus. Larger cancers probably overgrow and conceal the underlying specialized columnar epithelium from which they arise.