Histological Hepatitis Research Articles

Analysis of autoimmune hepatitis with acute presentation in the early stage of illness.

There is no gold standard for making the diagnosis of autoimmune hepatitis (AIH), and the diagnosis of acute onset AIH (A-AIH) is most challenging. A-AIH sometimes develops into acute liver failure with poor prognosis if the diagnosis is delayed. Therefore, it is most important for the better prognosis to diagnose non-severe A-AIH early and treat appropriately. However, features in the early stage of A-AIH are unclear. We examined initial characteristics of non-severe A-AIH in detail and tried to find novel clinical features for the early diagnosis. Clinical, biochemical, immunological, radiological, and histological features of 71 patients (54 women, mean age 57.9±14.3years) with non-severe A-AIH admitted to community hospitals between 2001 and 2022 were analyzed retrospectively. Forty-six had no symptom on onset and liver injuries were discovered by regular medical checkups. The mean duration from onset to consultation was 25.0±29.3days. Liver histology showed acute hepatitis in 59% and chronic hepatitis in 41%. Patients with symptoms revealed more male sex (P=0.039), higher alanine aminotransferase (P<0.001), higher total bilirubin (P<0.001), and higher rate of histological acute hepatitis (P=0.0013) than those without symptoms significantly. Male sex, presence of symptoms on onset, occurrence of jaundice in the course, and histological acute hepatitis were correlated. Sixty-five percent of non-severe A-AIH patients were asymptomatic on onset, suggesting that A-AIH would develop insidiously and present a longer clinical course than that reported. Male patients more often revealed true acute hepatitis clinically, biochemically, and histologically than female ones.

A291 ANA-NEGATIVE AUTOIMMUNE HEPATITIS IN A 30-YEAR-OLD FEMALE: A DIAGNOSTIC CHALLENGE

Abstract Background Autoimmune Hepatitis (AIH) is a chronic liver condition arising from the immune system's attack on liver cells. Its diagnosis is typically supported by the presence of autoantibodies, notably ANA. However, cases have been identified where AIH occurs in the absence of these conventional serologic markers. Prior studies have reported that ANA-negative AIH patients showed more acute presentations and higher frequencies of histologic acute hepatitis compared to those with positive autoimmune serology. As such, ANA-negative subset of patients presents a diagnostic challenge but highlights the evolving understanding of autoimmune processes in liver diseases. Aims To detail the clinical presentation, investigative measures, and treatment approach in a an otherwise healthy 30-year-old female diagnosed with ANA-negative autoimmune hepatitis. Methods The diagnostic approach included clinical symptomatology, biochemical tests, imaging via abdominal ultrasound, and histopathological evidence from an ultrasound-guided liver biopsy Results The patient presented initially with epigastric pain, jaundice, and pruritus over two weeks. Blood tests revealed acute hepatitis: ALT at 2723 U/L[JA1] , AST at 1428 U/L, and hyperbilirubinemia at 503 μmol/L, with GGT and ALP remaining normal. An abdominal ultrasound presented a typical liver morphology and biliary system. Initial autoimmune liver disease panels, including ANA, and viral hepatitis screenings, returned negative results. Furthermore, the patient's medication and drug history provided no additional clues for drug-induced aetiologies. For more conclusive diagnostics, an US-guided liver biopsy was performed during the admission revealing moderate acute hepatitis characterized by both interface hepatitis and lobular inflammation, prompting the suspicion for ANA-negative AIH. Initiating prednisone treatment (40 mg daily) based on clinical and biopsy evidence led to a significant reduction in liver enzymes and bilirubin. By the time of her discharge, her primary residual symptoms were mildly controlled jaundice and pruritus. She was transitioned to a tapering dose of prednisone, and Azathioprine was later added to her regimen. Subsequent close follow up revealed complete resolution of her symptoms. Notably, a 7-month follow-up unveiled a previously undetected AIH marker: ASMA with a titre of 1:80. Conclusions ANA-negative AIH, as showcased in this case, emphasizes the importance of a thorough and iterative diagnostic approach. Traditional serological markers may not always be present, necessitating reliance on a combination of clinical presentations and histopathology. Regular follow-ups and periodic re-evaluations are essential. This approach is crucial for pinpointing the diagnosis, guiding effective therapeutic interventions, and ultimately ensuring positive outcomes for patients navigating complex autoimmune liver conditions. Funding Agencies None

Non-invasive markers of inflammation in alcohol-associated liver disease: A scoping review.

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts.

Serum Amino Acids Imbalance in Canine Chronic Hepatitis: Results in 16 Dogs.

Simple SummaryHuman chronic liver disease is reported to be associated with alterations in amino acids metabolism, with a decrease in serum branched-chain amino acids and an increase in aromatic amino acids. A decreased Fischer ratio (branched to aromatic amino acids ratio) has showed prognostic significance and is a therapeutic target in human cirrhosis. In dogs, few studies have been performed, and the Fischer ratio seems to be reduced in animals with congenital portosystemic shunts. The aim of this study was to evaluate serum amino acids in dogs with chronic hepatic inflammation compared with healthy dogs. The serum amino acids in dogs with chronic hepatitis were also evaluated in relation to their histological severity. Eighteen amino acidic metabolites were measured using the leftover serum samples of 16 dogs with histological chronic hepatitis and 25 healthy dogs. Several amino acid concentrations were significantly different between dogs diagnosed with chronic hepatitis and healthy controls. In human medicine, aromatic amino acids seem to increase during chronic hepatitis, whereas isoleucine decreases. The Fischer ratio was significantly reduced if higher grades of fibrosis were present. Even if total serum proteins did not significantly differ between groups, we observed qualitative imbalances in serum amino acids among dogs presenting with chronic hepatitis.In humans, chronic liver disease may cause alterations in amino acids (AAs) metabolism, with serum branched-chain AAs (BCAAs) decreasing and aromatic AAs (AAAs) increasing. A reduced Fischer ratio (BCAAs/AAAs) has been found to be associated with hepatic fibrosis and is useful for assessing prognosis in human patients. In veterinary medicine, few studies have been performed, and in contrast to human patients, dogs with different kinds of hepatopathy tend to show both increased AAAs and BCAAs. In dogs, the association between histological scores and serum AAs has not been previously investigated. The aim of this study was to evaluate serum AAs in dogs with chronic hepatitis (CH) compared with a healthy control group (C) and, among CH dogs, in relation to their histological fibrosis and necroinflammatory activity scores. Leftover serum samples of 16 dogs with histological CH and 25 healthy dogs were employed. Serum AAs were measured by high performance liquid chromatography. Proline and the AAAs phenylalaine and tyrosine progressively increased with the histological severity. In contrast, cysteine, tryptophan and BCAA isoleucine progressively reduced. Lysine and the BCAAs leucine and valine showed a non-linear trend with the histological findings. The BCAAs/AAAs ratio was significatively reduced if higher grades of liver fibrosis were present.

A small animal model of chronic hepatitis E infection using immunocompromised rats

Background & AimsHEV variants such as swine genotypes within Paslahepevirus species balayani (HEV-A) and rat HEV (Rocahepevirus ratti; HEV-C1) cause chronic hepatitis E in immunocompromised individuals. There are few reliable and accessible small animal models that accurately reflect chronic HEV infection. We aimed to develop an immunocompromised rat model of chronic hepatitis E infection.MethodsIn this animal model infection study, rats were immunosuppressed with a drug combination (prednisolone, tacrolimus, and mycophenolate mofetil) commonly taken by transplant recipients. Rats were challenged with human- and rat-derived HEV-C1 strains or a human-derived HEV-A strain. Viral load, liver function, liver histology, humoural, and cellular immune responses were monitored.ResultsA high-dose (HD) immunosuppressive regimen consistently prolonged human- and rat-derived HEV-C1 infection in rats (up to 12 weeks post infection) compared with transient infections in low-dose (LD) immunosuppressant-treated and immunocompetent (IC) rats. Mean HEV-C1 viral loads in stool, serum, and liver tissue were higher in HD regimen-treated rats than in LD or IC rats (p <0.05). Alanine aminotransferase elevation was observed in chronically infected rats, which was consistent with histological hepatitis and HEV-C1 antigen expression in liver tissue. None (0/6) of the HD regimen-treated, 5/6 LD regimen-treated, and 6/6 IC rats developed antibodies to HEV-C1 in species-specific immunoblots. Reversal of immunosuppression was associated with clearance of viraemia and restoration of HEV-C1-specific humoural and cellular immune responses in HD regimen-treated rats, mimicking patterns in treated patients with chronic hepatitis E. Viral load suppression was observed with i.p. ribavirin treatment. HD regimen-treated rats remained unsusceptible to HEV-A infection.ConclusionsWe developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients.Lay summaryConvenient small animal models are required for the study of chronic hepatitis E in humans. We developed an animal model of chronic hepatitis E by suppressing immune responses of rats with drugs commonly taken by humans as organ transplant rejection prophylaxis. This model closely mimicked features of chronic hepatitis E in humans.

Diagnostic Approach to Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic liver disease caused by unknown etiology, characterized by elevated liver enzyme, hypergammaglobulinemia, circulating autoantibodies, and histological interface hepatitis. As untreated AIH often leads to decompensated cirrhosis and even death, prompt and timely diagnosis is essential. However, about 1/3 of patients with AIH have cirrhosis at diagnosis. On the other hand, new onset acute or acute exacerbation of previous undiagnosed AIH can be presented as acute hepatitis. Thus, any patients with acute or chronic liver disease with hypergammagloblinemia without other cause should be considered to evaluate circulating non-organ specific autoantibodies for diagnosis of AIH. In case of suspected AIH, liver biopsy should be considered to evaluate its histological characteristics including interface hepatitis, plasma cell infiltration, emperipolesis, and rosettes. When the diagnosis is made, prompt treatment with prednisolone followed by combined azathioprine should be considered to improve its prognosis.

Increasing incidence of acute autoimmune hepatitis: a nationwide survey in Japan

The Japanese diagnostic guidelines for autoimmune hepatitis (AIH) were proposed in 2014. This study aimed to determine the trends and characteristics of AIH based on a Japanese nationwide survey. Data for 796 patients who were newly diagnosed with AIH from 2014 to 2017 were collected from January to March, 2019 from 54 hospitals throughout Japan. Clinical characteristics, including treatment, were compared with those reported in a prior 2015 survey. The population had a median age of 63 years at diagnosis, and the male to female ratio was 1:5.3. The numbers of women was significantly lower in this survey than in the 2015 survey. Moreover, the incidence of AIH with histological acute hepatitis increased significantly from 11.0 to 21.7%. The changes in the laboratory findings, such as in transaminase and immunoglobulin G levels and antinuclear antibody titers, as well as in prednisolone treatment, reflected an increasing incidence of acute AIH. The clinical characteristics of AIH changed rapidly, in parallel with the increasing incidence of acute AIH. The elucidation and diagnosis of AIH with acute hepatitis are important in the management of AIH.

Des-gamma-carboxy prothrombin affects the survival of HCC patients with marginal liver function and curative treatment: ACRoS1402.

Considering the initial treatment of hepatocellular carcinoma (HCC), the best prognostic index for Child-Pugh classes B and C (CP-BC) patients has not been yet established. This study aimed to elucidate the risk factors for disease-free survival (DFS) and overall survival (OS) in multicenter patients with a poor liver functional reserve after curative treatment. Between April 2000 and April 2014, 212 CP-BC patients who received treatment in five high-volume centers in Japan were included in this study. CP-B and C patients were 206 and 6, respectively. Cox proportional hazard regression analyses for DFS and OS were performed to estimate the risk factors. The mean observation time was 1132days. Mean Child-Pugh score and indocyanine green retention rate at 15min were 7.5 and 31.5%, respectively. Histological chronic hepatitis and liver cirrhosis were observed in 20% and 74% patients, respectively. In the multivariate analysis, the risk factors for DFS were des-gamma-carboxy prothrombin (DCP) [hazard ratio (HR), 1.6; P = 0.012] and treatment without liver transplantation. Moreover, DCP was identified as an independent risk factor for OS (HR, 1.7; P = 0.01). Tumor size, number, tumor thrombus, Milan criteria, liver cirrhosis, and treatment without liver transplantation were not identified as risk factors for OS. The 5-year OS in patients with high serum DCP levels (< 90mAU/mL) was significantly better than that in those with low serum DCP levels (P = 0.003). Serum DCP value before treatment predicted both DFS and OS in CP-BC patients with HCC.

Presence of Serum Antinuclear Antibodies Does Not Impact Long-Term Outcomes in Nonalcoholic Fatty Liver Disease.

We investigated the longitudinal impact of antinuclear antibody (ANA) on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD). ANA were found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH) or developed AIH after a mean follow-up of 106±50 months. Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellula carcinoma, cardiovascular events, extrahepatic malignancy, and overall survival were similar to ANA-negative. Once AIH has been ruled out, the long-term outcomes and survival are unaffected by the presence of ANA in patients with NAFLD.

Morphological and ultrasound features of liver fibrosis in children with autoimmune hepatitis

Aim. To study the ultrasound peculiarities of the liver parenchyma stiffness in children with autoimmune hepatitis by shear wave elastography comparing with the results of liver biopsy morphological investigation.Materials and methods. 40 children with autoimmune hepatitis were examined during the period of 2015–2018. All children were provided with a complex of laboratory tests according to the protocol, shear wave elastography of the liver and a puncture biopsy of the liver. The disease activity was ranged with the histological index of activity (IHA) according to Knodellby the results of a morphological study of liver biopsy and biochemical parameters (alanine aminotransferase, total bilirubin,gamma globulin, immunoglobulin G). The stage of the disease was estimated by the METAVIR histological index (HIS) andsemi-quantitative elastography of the parenchyma shift wave. A comparison of the relationship between the histological activityof hepatitis and the parameters of the liver stiffness has been made. The changes in 23 children with hypertension wereinvestigated in dynamics of liver stiffness (after 6 and 12 months of treatment).Result. A progressive fibrosis was diagnosed in 72.5 % (n = 29) (METAVIR F2) (χ2 = 16.2; P 0.05). Conclusions. In 50 % of children with autoimmune hepatitis, the stage of fibrosis, which was determined by the method of elastography before treatment, corresponded to the data of the morphological study of liver biopsy. The activity of hepatitis affects the liver parenchyma stiffness, with the decrease of inflammatory process activity this index also decreases. The conducted research showed that in the process of treatment (anti-fibrotic and immunosuppressive therapy), after 6 and 12 months, the parameters of liver parenchyma severity decrease significantly (P < 0.05).

Prediction of histologic alcoholic hepatitis based on clinical presentation limits the need for liver biopsy.

The clinical presentation of alcoholic hepatitis (AH) can be mimicked by other alcoholic liver diseases. The aim of this study was to identify clinical features that predict AH on liver biopsy. Biopsies from patients hospitalized for presumed severe AH were used to identify a derivation cohort (101 patients) and validation cohort (71 patients). Using histologic scores for hepatocyte ballooning, Mallory‐Denk bodies, and lobular inflammation, 95 patient biopsies (55%) were classified as definite AH, 55 (32%) as possible AH, and 22 (13%) as no AH. Survival was similar among the groups, but mortality was significantly increased for patients with fatty change ≤50% on initial liver biopsy. An analysis limited to uninfected patients with definite AH or no AH in the derivation cohort identified a greater leukocyte count at admission and radiographic evidence of liver surface nodularity as independent predictors of definite AH on biopsy (P < 0.05). In the derivation cohort, the leukocyte count thresholds for ensuring 100% specificity for diagnosing definite AH were 10 × 109/L if the liver surface was nodular and 14 × 109/L if the liver surface was smooth, with a sensitivity of 76% and an area under the receiver operator characteristic curve of 0.88. In the validation cohort, these thresholds had a specificity of 86%, a sensitivity of 59%, and an area under the receiver operator characteristic curve of 0.72. Conclusion: The combination of an elevated leukocyte count and a nodular liver surface in the absence of active infection retrospectively identified patients with a high likelihood of histologic AH for whom liver biopsy may not be necessary. For patients with suspected severe AH who do not fulfill these criteria, liver biopsy is important to exclude other variants of alcoholic liver disease. (Hepatology Communications 2017;1:1070–1084)

Comprehensive Study of Multiple Stages Progressing to Nonalcoholic Steatohepatitis with Subsequent Fibrosis in SD Rats.

Because of the absence of the time course of histological nonalcoholic fatty hepatitis with subsequent fibrotic progression, the effective approaches available for controlling the onset and progression of non-alcoholic steatohepatitis (NASH) remain limited. Therefore, we detected the serum and liver tissue related lipid metabolism disorder, liver pathology and relative molecular makers alteration dynamically in a high fat-sucrose diet during different time points. High fat-sucrose diet significantly increased the serum lipid level on day 10. The excess lipid accumulation in liver was referred to as simple steatosis after the feeding of a high fat-sucrose diet for 20 days. The high fat-sucrose diet induced a hepatic inflammation response on day 30. Similarly, hepatic fibrosis was also initiated on day 30 and gradually formed from the 30th to the 50th day. Oxidative stress may be related with the process from NASH to liver fibrosis. Insulin resistance was involved in the progression from hepatic steatosis to NASH with hepatic fibrosis from the 20th to the 50th day. In conclusion, we established a high fat-sucrose diet induced nonalcoholic fatty hepatitis with liver fibrosis rat model, which presented the time course of histological nonalcoholic steatohepatitis and the initiation and progression change of characteristic molecular makers in the process from steatosis to hepatic fibrosis.

Dysfunction of IKZF1/MYC/MDIG axis contributes to liver cancer progression through regulating H3K9me3/p21 activity

MDIG is known to be overexpressed in many types of human cancers and has demonstrated predictive power in the prognosis of cancer, although the functions and mechanisms of MDIG in liver cancer, especially in hepatocellular carcinoma (HCC), are still unknown. In this study, we report that MDIG and MYC were negatively regulated by IKZF1. MDIG overexpression substantially promoted HCC cell proliferation, cell migration and spreading, whereas knockdown of MDIG would reverse above-mentioned effect. MDIG effects on tumour cell growth were further demonstrated in a tumour xenograft model. Moreover, MDIG had effects on the level of p21(CIP1/WAF1) via H3K9me3 expression in HCC. MDIG was also found to be closely related to the sorafenib resistance of HCC cells in vitro. Clinically, we found that MDIG was frequently overexpressed in human HCCs (69.7%; n=155) and was significantly associated with histological grade and hepatitis B virus infection. Our findings indicate that MDIG plays an important role in HCC progression via MDIG/H3K9me3/p21(CIP1/WAF1) signalling and serves as a potential therapeutic target.

Serum Anti-programmed Cell Death-1 Antibody as a Novel Biomarker for Type 1 Autoimmune Hepatitis

Introduction: Autoimmune hepatitis (AIH) is a progressive, autoimmune liver disease characterized by histological interface hepatitis, hypergammaglobulinemia, and circulating autoantibodies. However, the diagnosis is made based on the scoring systems because of the lack of specific diagnostic markers for AIH. Recently, the association of the dysfunction of programmed cell death (PD)-1 expressed on activated lymphocytes with the pathogenesis of autoimmune hepatitis (AIH) has been speculated. This study aimed to investigate the association of serum anti-PD-1 antibodies with clinical characteristics of type 1 AIH. Methods: Serum samples before the initiation of prednisolone treatment were obtained from 143 type 1 AIH patients, 97 patients with drug-induced liver injury (DILI), 21 patients with IgG4-related disease (IgG4-RD), and 62 healthy volunteers. Serum levels of anti-PD-1 antibodies were measured by the indirect ELISA. The cutoff level was represented by a mean absorbance + 2 standard deviations in healthy volunteers. Results: Prevalence of serum anti-PD-1 antibodies was 47% in type 1 AIH patients, 7% in DILI patients, 0% in IgG4-RD patients, and 3% in healthy volunteers. In type 1 AIH patients, serum levels of anti-PD-1 antibodies were correlated with serum bilirubin levels (P = 0.014) and prothrombin activities (P = 0.006). Positivity for serum anti-PD-1 antibodies was associated with the later normalization of serum ALT levels after the initiation of prednisolone treatment and the disease relapse. A cumulative incidence of the normalization of serum ALT levels at 3 months from the initiation of prednisolone treatment was 74% in the patients positive for serum anti-PD-1 antibodies and 95% in those negative for serum anti-PD-1 antibodies. A cumulative incidence of the disease relapse at 2 years from the normalization of serum ALT levels was 34% in the patients positive for serum anti-PD-1 antibodies and 20% in those negative for serum anti-PD-1 antibodies. Conclusion: Serum levels of anti-PD-1 antibodies would be useful for the diagnosis of type 1 AIH. In addition, serum levels of anti-PD-1 antibodies reflect the disease severity, response to corticosteroid treatment and the disease relapse in type 1 AIH.

Pathohistological and immunohistochemical features of chronic viral hepatitis b progression

Aim. The paper contains the results of a comprehensive study of pathohistological and immunohistochemical liver biopsies of 50 patients with chronic hepatitis B in relation to clinical and biochemical parameters to improve the most significant microscopic criteria of chronic hepatitis B progression in liver trepanobioptates of the patients.Methods and results. It has been established that most accurate definition of the degree of viral infection of hepatocytes in the liver trepanobioptates of the patients with chronic viral hepatitis B could be made by the immunohistochemical detection of HBsAg and HBsAg, dull glasslike hepatocytes revealed by microscopy not fully reflect the degree of hepatocytes’ infection.Conclusion. The presence of direct, high correlation between the number of infected hepatocytes with HBsAg and histological hepatitis activity index gives reason to use immunohistochemical labelling of HBsAg on the early stages of diagnostics in order to predict the possible progression of chronic viral hepatitis B in patients with normal level of transaminase.

First-line response-adapted treatment with the combination of bendamustine and rituximab in patients with mucosa-associated lymphoid tissue lymphoma (MALT2008-01): a multicentre, single-arm, phase 2 trial

No standard first-line systemic treatment for mucosa-associated lymphoid tissue (MALT) lymphoma is available. In a phase 2 study we aimed to assess the safety and activity of a response-adapted combination of bendamustine plus rituximab as upfront treatment for this type of lymphoma. In a multicentre, single-arm, non-randomised, phase 2 trial, we enrolled patients with MALT lymphoma at any site and stage and treated them with bendamustine (90 mg/m(2) on days 1 and 2) plus rituximab (375 mg/m(2) on day 1), every 4 weeks. Inclusion criteria were measurable or evaluable disease, age 18-85 years, and unequivocal active lymphoma; we also enrolled patients with MALT lymphoma arising in the stomach after failure of Helicobacter pylori eradication and primary cutaneous cases after failure of local therapies. Exclusion criteria included evidence of histological transformation, CNS involvement, and active hepatitis B or C virus or HIV infection. After three cycles, patients achieving complete response received one additional cycle (total four cycles) and those achieving partial response received three additional cycles (total six cycles). The primary endpoint was 2-year event-free survival. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01015248. 60 patients from 19 centres in Spain were enrolled between May 27, 2009, and May 23, 2011, and received treatment; 57 patients were evaluable for the primary endpoint. Only 14 (25%) patients needed more than four cycles of treatment. After a median follow-up of 43 months (IQR 37-51), median event-free survival was not reached. Event-free survival at 2 years was 93% (95% CI 84-97) and at 4 years was 88% (95% CI 74-95). The most frequently observed grade 3-4 adverse events were haematological: lymphopenia in 20 (33%) patients, neutropenia in 12 (20%) patients, and leucopenia in three (5%) patients. Grade 3-4 febrile neutropenia or infections were reported in three (5%) and four (7%) patients, respectively. This response-adapted schedule of bendamustine plus rituximab appears to be an active and well tolerated first-line treatment for patients with MALT lymphoma. Grupo Español de Linfomas/Trasplante de Médula Ósea (GELTAMO), Mundipharma Spain, and Roche Pharma Spain.

White cell count and platelet count associate with histological alcoholic hepatitis in jaundiced harmful drinkers

BackgroundPatients with suspected alcoholic hepatitis and a Discriminant Function ≥32 underwent liver biopsy to confirm the diagnosis. Of these (n = 58), 43 had histological features of alcoholic hepatitis and 15 (25%) did not.We aimed to determine the laboratory features that differentiated those patients with a histological diagnosis of alcoholic hepatitis from those without, and assess potential clinical utility.MethodsLaboratory investigations at presentation for each of the histologically confirmed cases of alcoholic hepatitis (n = 43) were compared to those without (n = 15) to determine whether there were differences between the two groups. Univariate analysis was by Mann Whitney U Test and Multivariate analysis was by a stepwise approach.ResultsWhite cell count (16.2 ± 10.5 v 6.9 ± 3.5 (× 109/L); p = 0.0001) and platelet count (178 ± 81 v 98.4 ± 43 (× 109/L); p = 0.0005) were higher in the patients with histological features of alcoholic hepatitis than in those without. The area under the ROC curve for AH diagnosis was estimated to be 0.83 (0.73, 0.94) and 0.81 (0.69, 0.93) for white cell count and platelet count respectively.ConclusionsClinicians cannot accurately differentiate patients with or without alcoholic hepatitis without liver biopsy. This is critically important when deciding on specific therapies such as corticosteroids or when interpreting data from future trials in which biopsy is not mandated. In situations where liver biopsy is unsuitable or unavailable the white cell and platelet counts can be used to determine the likelihood of histological alcoholic hepatitis and guide treatment.

Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection

The relationship between vitamin D status and response to antiviral therapy and liver histology in hepatitis C virus genotype 1 (HCV-1) infection remains unclear, with studies to date yielding inconsistent results and failing to use reference assay methodology. We therefore analyzed pre-treatment 25-hydroxyvitamin D [25(OH)D] level, using reference liquid chromatography-tandem mass spectrometry methodology, in a cohort of treatment-naïve patients with HCV-1 to evaluate the association between vitamin D status, virologic response, and liver histology. 274 patients, with pre-treatment liver biopsy and up to 48 weeks of pegylated interferon alfa-2a plus ribavirin therapy, were tested for serum 25(OH)D level. Predictors of sustained virologic response (SVR), and variables associated with fibrosis stage, activity grade and 25(OH)D status were identified using multivariate analysis. Mean 25(OH)D level was 79.6 nmol/L, with a prevalence of 25(OH)D <75 nmol/L and <50 nmol/L of 48% and 16%, respectively. Season, race and geographic latitude were independent predictors of 25(OH)D status, while vitamin D deficiency was more prevalent in those with high activity grade (21% vs. 11%; p=0.03). Mean 25(OH)D level was lower (76.6 vs. 84.7 nmol/L; p=0.03) and 25(OH)D <75 nmol/L more prevalent (53% vs. 40%; p=0.03) in patients with an SVR, but no association between 25(OH)D status and SVR was found in multivariate analysis. Mean 25(OH)D level did not vary between fibrosis stage or activity grade. Baseline 25(OH)D level is not independently associated with SVR or fibrosis stage in HCV-1, but vitamin D deficiency is associated with high activity grade.

Prognosis of autoimmune hepatitis showing acute presentation

The number of patients with autoimmune hepatitis (AIH) showing acute presentation has increased. This study aimed to assess their prognosis. A survey of AIH patients by sending questionnaires was performed, and 96 patients showing acute presentation were investigated. The median age was 58 years and 78 patients (81%) were female. Eighty-four patients (88%) were positive for antinuclear antibody and/or anti-smooth muscle antibody. The median serum immunoglobulin G level was 2252 mg/dL. Twenty-five patients (26%) showed histological acute hepatitis. As initial treatment, 88 patients (92%) were treated with corticosteroid, and 28 of them received pulse steroid treatment. Overall, 11 patients (11%) reached fatal outcomes (nine death and two liver transplantation). Patients with histological acute hepatitis showed higher serum bilirubin levels, lower prothrombin activities and higher prothrombin time-international normalized ratios (PT-INR) and reached fatal outcomes more frequently. With a multivariate logistic regression analysis, prothrombin activity and PT-INR at presentation was associated with fatal outcomes. Nine of 13 patients (69%) showing prothrombin activity of 40% or lower at presentation and nine of 19 patients (47%) showing PT-INR of 1.5 or higher reached fatal outcomes. Furthermore, of 13 patients showing prothrombin activity of 40% or lower and/or PT-INR of 1.5 or higher at presentation who were treated with pulse steroid treatment, four (31%) died from infectious disease. Prothrombin activity and PT-INR are prognostic factors for AIH showing acute presentation. Physicians should pay attention to the development of infectious disease when pulse steroid treatment is performed.

Visceral adiposity index is not a predictor of liver histology in patients with non-alcoholic fatty liver disease

Visceral adiposity is associated with hepatic steatosis, inflammation, and fibrosis in non-alcoholic fatty liver disease (NAFLD). The visceral adiposity index (VAI), a novel marker of visceral fat distribution and dysfunction, has been correlated with histology in hepatitis C. We assessed the ability of VAI to predict disease severity in NAFLD and hence its role as a non-invasive marker of liver damage. We examined 190 adults with biopsy-proven NAFLD and 129 controls. All had anthropometric and metabolic profiling. VAI was calculated using waist circumference (WC), body mass index, triglycerides, and HDL-cholesterol. Abdominal fat was quantified by magnetic resonance imaging (MRI) in 38 patients. On multivariate analysis, NAFLD diagnosis and fasting glucose were independently associated with VAI (p <0.05). VAI increased across control, steatosis, and NASH groups (1.5, 2.3, and 3.2, respectively; p=0.000), however, this association was no stronger than the increase in WC across groups (r=0.452 vs. 0.540 respectively, p <0.001). VAI was not associated with steatosis, lobular inflammation or fibrosis, but WC was associated with fibrosis (p=0.01). VAI and WC correlated with an increasing number of metabolic syndrome components (r=0.623 vs. 0.614, p <0.001) and with metabolic syndrome diagnosis (r=0.559 vs. 0.509, p <0.001). VAI only modestly correlated with visceral fat on MRI (r=0.39, p <0.05) compared to WC (r=0.52, p <0.01). In NAFLD, VAI is not associated with steatosis, inflammation or fibrosis. VAI is no more powerful than WC in discriminating steatosis from steatohepatitis, reflecting limitations of the formula with what is known about the pathogenesis of NAFLD.