Histological Liver Disease Research Articles

1412-P: Preexisting Nonalcoholic Steatohepatitis Attenuates Improvement of Adipose Tissue OXPHOS Capacity after Weight-Loss Surgery

Impaired adipose tissue (AT) function closely associates with obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) . Mitochondrial oxidative phosphorylation (OXPHOS) capacity of AT improves after weight loss surgery. However, it is not clear if the improvement is affected by the presence of NAFLD before surgery. We examined 52 severely obese people exhibiting no histological liver disease (OBE_CON) , simple steatosis (OBE_NAFL) or steatohepatitis (OBE_NASH) before (0 weeks) , 12 and 52 weeks after bariatric surgery. Whole-body insulin sensitivity was measured by hyperinsulinemic euglycemic clamps. OXPHOS capacity of subcutaneous AT was assessed by high-resolution respirometry. Transcript levels of TNFα in AT were quantified by RT-PCR. Before surgery, OBE_NASH presented with lower insulin sensitivity and higher HbA1c compared to OBE_CON and OBE_NAFL (all p<0.05) whereas OXPHOS capacity in AT was comparable between the groups. Maximum coupled respiration declined at week 12 by 17% from week 0 in OBE_CON only (p<0.05) . From 12 to 52 weeks, AT maximum coupled respiration markedly increased by 82 and 49% in OBE_CON and OBE_NAFL (both p<0.001) but only by 28% in OBE_NASH (p=0.05; maximum coupled OXPHOS at week 52: OBE_CON vs. OBE_NASH p<0.05) . The changes in AT maximum coupled respiration from 12 to 52 weeks correlated negatively with changes in AT TNFα levels in OBE_CON (β=-0.83, p<0.001) and negatively with changes in systemic C-reactive protein levels in OBE_NASH (β=-0.34, p<0.05) . Maximal noncoupled OXPHOS yielded similar changes and correlations. In conclusion, in severe obesity, weight loss-related improvements in AT OXPHOS capacity may be mediated to a great extent by reduced AT inflammation in people without liver disease; however, with pre-surgery manifestation of NASH and worsening of metabolic control, residual systemic subclinical inflammation may attenuate the improvement of AT OXPHOS capacity after bariatric surgery. Disclosure S.Kahl: None. G.Heilmann: None. I.Esposito: None. M.Schlensak: None. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. K.Strassburger: None. S.Gancheva: None. N.Saatmann: None. C.Granata: None. C.Herder: Research Support; Sanofi. K.Pafili: None. J.Puetzer-furmanczak: None. T.Sarabhai: None. Funding German Federal Ministry of Health; Ministry of Culture and Science of the State North Rhine-Westphalia;German Federal Ministry of Education and Research;European Funds for Regional Development (EFRE-0400191) ;EUREKA Eurostars-2 (E!113230DIA-PEP) ;German Science Foundation (CRC/SFB1116/2 B12; RTG/GRK 2576 vivid, Project 3) ;Schmutzler Stiftung

PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease.

BACKGROUNDNonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide, with significant morbidity associated with nonalcoholic steatohepatitis (NASH). Genome-wide association studies demonstrated that the variants rs738409 C/G in the PNPLA3 and rs58542926 C/T in the TM6SF2 genes are determinants of inter-individual and ethnicity-related differences in hepatic fat content and NAFLD progression.AIMTo investigate PNPLA3 and TM6SF2 genotype frequency and their association with NAFLD development and progression in Brazilian patients.METHODSThis cross-sectional case-control study enrolled 285 individuals from the Gastroenterology and Hepatology clinics at a university hospital in Brazil. The case patients (n = 148) were confirmed to have NAFLD by the identification of hepatic steatosis on ultrasonography and exclusion of other causes of liver disease. According to the clinical protocol, patients underwent liver biopsy when at high risk for NASH and/or advanced fibrosis (n = 65). Steatohepatitis was confirmed in 54 patients. Individuals who did not have biopsy indication or NASH on histology were considered to have simple steatosis (n = 94). The control group (n = 137) was selected among patients that attended the Intestinal Disease clinic and was composed of subjects without abnormalities on abdominal ultrasonography and normal liver biochemical tests. All individuals underwent PNPLA3 and TM6SF2 genotype analysis. RESULTSPNPLA3 CC, CG and GG genotype frequencies were 37%, 44% and 19%, respectively, in NAFLD patients and were 58%, 31% and 10% in controls (P < 0.001). In a model adjusted for gender, age, body mass index and type 2 diabetes mellitus, the G allele increased the chance of NAFLD (OR = 1.69, 95%CI: 1.21-2.36, P = 0.002) and NASH (OR = 3.50, 95%CI: 1.84-6.64, P < 0.001). The chance of NASH was even higher with GG homozygosis (OR = 5.53, 95%CI: 2.04-14.92, P = 0.001). No association was found between G allele and the features of metabolic syndrome. In histological assessment, PNPLA3 genotype was not associated with steatosis grade, although GG homozygosis increased the chance of significant NASH activity (OR = 17.11, 95%CI: 1.87-156.25, P = 0.01) and fibrosis (OR = 7.42, 95%CI: 1.55-34.47, P = 0.01) in the same adjusted model. TM6SF2 CC, CT and TT genotype frequencies were 83%, 15% and 0.7%, respectively, in NAFLD patients and were 84%, 16% and 0.7% in controls (P = 0.78). The T allele presence was not associated with NAFLD or NASH, and was not associated with histological features.CONCLUSIONPNPLA3 may be involved in susceptibility and progression of NAFLD and NASH in the Brazilian population. More advanced histological liver disease was associated with the G allele. The TM6SF2 genetic variants were not associated with NAFLD susceptibility and progressive histological forms in the population studied, but further studies are required to confirm these findings.

Association of novel markers of liver disease with neonatal liver disease in premature baboons, Papio sp.

Parenteral Nutrition (PN) Associated Liver Disease (PNALD) affects up to 60% of neonates; however, techniques for diagnosing and monitoring disease progression remain limited. The neonatal baboon model may provide a unique opportunity to identify serologic markers associated with this disease. The purpose of this study was to investigate if Hyaluronic Acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP1), Amino-terminal Propeptide of Type-III Collagen (PIIINP) and Enhanced Liver Fibrosis (ELF) score associate with histological liver disease in neonatal baboons exposed to PN. Preterm baboons delivered via c-section at 67% gestation received PN for 14 days with or without Intralipid (PRT+IL, PRT-IL, respectively) or were sacrificed after birth (PRTCTR). Term baboons were sacrificed after birth (TERMCTR) or survived 14 days (TERM+14d). Serum HA, TIMP1, and PIIINP concentrations were measured by ELISA. A blinded pathologist assigned liver histological scores following necropsy. HA increased 9.1-fold, TIMP1 increased 2.2-fold, and ELF score increased 1.4-fold in PRT-IL compared to PRTCTR. ALT, AST, and GGT were within normal limits and did not vary between groups. A trend towards increased fibrosis was found in PRT-IL baboons. Microvesicular hepatocyte steatosis and Kupffer cell hypertrophy were elevated in PRT-IL vs PRTCTR. HA and TIMP1 were significantly elevated in preterm baboons with early histological findings of liver disease evidenced by hepatic steatosis, Kupffer cell hypertrophy and a trend towards fibrosis whereas traditional markers of liver disease remained normal. These novel markers could potentially be utilized for monitoring early hepatic injury in neonates.

Interferon-α plus ribavirin yields 98 % sustained virologic response in children aged 1-5 years with iatrogenic chronic hepatitis C.

The clinical features and efficacies of antivirals for children with hepatitis C virus (HCV) infections that are acquired through different transmission routines are poorly understood worldwide. This study investigated the clinical characteristics of children who were infected via iatrogenic means and analyzed the efficacy of antiviral therapy in children with chronic hepatitis C (CHC). In total, 256 children with HCV infections aged 1 to 5 years were enrolled and surveyed. Interferon-α plus ribavirin was administered to 162 children with CHC for 24 or 48 weeks. The sustained virologic response (SVR) at 24 weeks post-treatment was determined. The median duration of infection was 11.5 (range 6-24) months. The median age was 2.7 years, and 64.5 % of the subjects were male. Ninety-three children (36.3 %, 93/256) exhibited spontaneous resolution of the HCV infection. The remaining 163 (63.7 %) were HCV RNA-positive and had HCV genotypes 1b and 2a, which were identified in 42 and 58 %, respectively, of the 133 tested children. Liver biopsies were performed in all HCV RNA-detectable children. A total of 23.9 % cases exhibited grade 2 activity, and 30.1 % exhibited stage 2/3 liver fibrosis. The serum HCV RNA levels were positively correlated with the aminotransferases. Of the 162 treated CHC children, 158 (97.5 %) achieved SVR. The side effects were mild, and 158 (97.5 %) of the treated patients tolerated the treatment well. This study revealed that histological liver disease can be present within 6-24 months of acquiring an HCV infection in children aged 1-5 years. Interferon-α plus ribavirin therapy is a highly effective and cost-effective means of managing children with early-stage chronic HCV infection.

Clinical Predictors of Recurrent Non-Alcoholic Steatohepatitis Following Liver Transplantation for Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is expected to become the leading US indication for liver transplant (LT) in the near future. NAFLD after LT has been described in case series, heterogenous populations, and single center experiences. No study to date has described histologic recurrent non-alcoholic fatty liver disease (rNAFLD) and non-alcoholic steatohepatitis (rNASH) in LT patients undergoing annual per protocol liver biopsies. The aim of this study was to determine rNAFLD and rNASH rates and their predictive risk factors. Methods: Cohort study of deceased donor LT recipients at a single center from 4/2005-6/2012. Patients with a diagnosis of NAFLD and cryptogenic cirrhosis suspected to be NAFLD were included. Patients underwent per protocol annual liver biopsies up to 5 years from LT. Donor and recipient characteristics were explored as possible risk factors for rNAFLD and rNASH. rNASH was defined as the presence of NASH using the NASH-CRN Histologic Scoring System. General estimating equation with binomial distribution was used to analyze the repeated liver biopsies. Results: 76 patients with cirrhosis due to NAFLD underwent LT. 63 had ≥1 planned liver biopsy. 88.9% had documented NAFLD pre-LT. 11.1% were cryptogenic but clinical suspicion of NAFLD was documented. There were 173 annual protocol biopsies in this analysis: 105 biopsies from 42 patients showed rNAFLD, 17 biopsies from 11 patients showed rNASH. The cumulative rate of rNAFLD and rNASH was 66.6% and 17.5%, respectively. In multivariable analysis, risk factors for rNASH were donor BMI (p=0.0001), recipient pre-LT coronary artery disease (p=0.01), and number of years after LT (p<0.0001). Donor characteristics not predictive of rNASH include ischemic time and cause of death. Recipient characteristics not predictive of rNASH include gender, age, race, weight, BMI, immunosuppression, allograft rejection, diabetes, hepatocellular carcinoma, combined liver kidney transplant, hypertension, cholesterol, triglycerides, or HgbA1C%. Conclusion: Our study confirms high rates of rNAFLD and rNASH following LT and establishes possible risk factors for recurrence. This data supports the development of larger trials to better understand the impact of rNASH on long term LT outcomes and to explore treatments/interventions to prevent rNASH.

Risk factors for hepatic decompensation in patients with primary biliary cirrhosis

To examine the clinical features and analyze prognostic factors in a prospective study of primary biliary cirrhosis (PBC) patients. From 1995 to 2010, PBC patients without hepatic decompensation seen at the Peking Union Medical College Hospital were enrolled. Clinical signs and manifestations (pruritus, persistent fatigue, jaundice and pain in the right hypochondrium), laboratory parameters (auto-antibodies for autoimmune hepatic disease, biliary and hepatic enzymes, immunoglobulin, bilirubin, and albumin) and imaging findings were recorded at entry and at specific time points during follow-up. Cox regression and Kaplan-Meier analyses, respectively, assessed the risk factors for hepatic decompensation and survival. Two hundred and sixty-two PBC patients were enrolled with a median follow-up of 75.2 mo (range, 21-201 mo). The 240 patients were aged 51.5 ± 10.2 years at diagnosis and 91.6% were female. Two hundred and forty-five (93.5%) were seropositive for anti-mitochondrial antibodies. At presentation, 170 patients (64.9%) were symptomatic, while 96 patients (36.6%) had extra-hepatic autoimmune disease. During the follow-up period, 62 (23.7%) patients developed hepatic decompensation of whom four underwent liver transplantation and 17 died. The cumulative survival rate and median survival time were 83.9% and 181.7 mo, respectively. Cox regression analysis revealed that an incomplete ursodeoxycholic acid (UDCA) response or inconsistent treatment [P < 0.001; hazard risk (HR) 95%CI = 2.423-7.541], anti-centromere antibodies (ACA) positivity (P < 0.001; HR 95%CI = 2.516-7.137), alanine aminotransferase ratio (AAR) elevations (P < 0.001; HR 95%CI = 1.357-2.678), and histological advanced liver disease (P = 0.006; HR 95%CI = 1.481-10.847) were predictors of hepatic decompensation. The clinical features and survival of PBC in China are consistent with those described in Western countries. Incomplete UDCA response or inconsistent treatment, ACA positivity, AAR elevations, and advanced histological stage are predictors of decompensation.

Study of hepatic histomorphology in HBeAg+ and HBeAg− patients with CHB: Experience from Bangladesh

ObjectiveTo compare Knodell and HAI scores in patients with wild type and pre-core/core promoter mutant CHB to see if there is any difference in severity of liver injury between these two types of HBV. MethodsWe did percutaneous liver biopsies of 155 CHB patients. Of them 102 (65.8%) were infected wild type HBV and the rest 53 (34.2%) were infected with pre-core/core promoter mutant CHB. Results11/53 (20.8%) patients with pre-core/core promoter mutant CHB had moderate to severe CH (HAI score 8-18). In contrast, moderate to severe CH was seen in 19/102 (18.6%) patients with wild type CHB. Fibrosis score was >2 in 15/53 (28.3%) pre-core/core promoter mutant CHB as opposed to 20/102 (19.6%) patients with wild type CHB. ConclusionsThe study shows that pre-core/core promoter mutant HBV produces more severe histological liver disease compared to wild type HBV.

8.0 Antiretroviral therapy in specific populations

8.0 Antiretroviral therapy in specific populations

YKL‐40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C

The aim of this study was to explore the association of a functional YKL-40 promoter polymorphism (rs4950928) with baseline disease stage, response to antiviral therapy and risk of liver disease progression in a group of patients with chronic hepatitis C (CHC). YKL-40 promoter polymorphisms were determined in 456 Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial patients with bridging fibrosis or cirrhosis entering a prerandomization lead-in peginterferon/ribavirin 24-week treatment phase and in 462 patients followed for a mean of 3.8 years after randomization to maintenance peginterferon or observation. Mean patient age was 49.5 years, 70.4% were men and 71.2% were Caucasian. The 17% frequency of the YKL-40 minor allele (T) was similar to that reported in the general population. YKL-40 genotype was associated significantly with baseline serum YKL-40 levels but was not associated with the likelihood of a virological response following 24-48 weeks of peginterferon/ribavirin therapy. Serum YKL-40 levels remained significantly lower during follow-up in the randomized TT homozygotes compared with CT heterozygotes and CC homozygotes (P < 0.001). Despite this association, YKL-40 genotype was not associated with the risk of clinical or histological liver disease progression. A reduced frequency of the protective YKL-40 promoter polymorphism was not observed in the HALT-C Trial patient population. The absence of an association between YKL-40 promoter polymorphisms and baseline liver disease severity as well as with the risk of liver disease progression over time suggests that this polymorphism is not associated with disease progression in CHC patients with established fibrosis.

Pathology of the Liver in Copper Overload

Copper accumulation in the liver is associated with cellular and apoptotic injury. Wilson disease is the most well-characterized disorder of disordered copper metabolism. Other less-common disorders include Indian childhood cirrhosis, endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. The histopathologic spectrum of the liver in Wilson disease is extremely variable and overlaps among the different entities, though this review will focus on the pathology of Wilson disease. The findings lack specificity, although characteristic findings are observed. Unlike other disorders of copper overload, the pathologic changes are typically sequential, ranging from little or no significant findings to cirrhosis with or without widespread hepatocellular damage. Steatosis and glycogenated nuclei are frequent. Staining of copper is an unreliable method of diagnosis of Wilson disease, whether there are minimal histologic abnormalities or chronic liver disease. Copper and copper-associated protein accumulation may also be seen in chronic biliary obstructive processes.

Changes in ELF Score During Treatment With Pegylated Interferon and Silymarin Are Associated With Progression of Histological Liver Disease in Non-Responder Patients With Chronic Hepatitis C

Introduction Liver biopsy remains the reference standard for monitoring changes in liver fibrosis resulting from antifibrotic therapy. While non-invasive serum markers have been validated in the detection of fibrosis in patients with chronic liver disease, their utility in tracking changes in fibrosis is not established. Methods 70 previous non-responders to pegylated interferon and ribavirin (40 male, 30 female, age range 24–67, mean 48.7) were recruited from five centres. Patients were randomised to receive pegylated interferon with or without silymarin as an antifibrotic therapy for 24 months. All patients underwent a liver biopsy and ELF tests (HA, P3NP, TIMP-1) prior to and after treatment (month 0 and 24) and area under receiver operating characteristic curves plotted. ELF tests were also taken during treatment (month 12). Changes in histological fibrosis stages before and after therapy (0–24 months) were compared with changes in ELF scores before and during therapy (0–12 months). Results ELF test results correlated well with liver histology with AUROC of 0.832 and 0.830 (F0-1 vs F2-6), 0.847 and 0.802 (F0-2 vs F3-6), 0.811 and 0.858 (F0-3 vs F4-6), 0.868 and 0.891 (F0-4 vs F5-6) pretreatment and post-treatment respectively. Following treatment, the absolute change in Ishak score ranged from −4 to +4, mean −0.027, SD 1.51 with 21 patients with increased and 24 with decreased fibrosis. At month 12 the changes in ELF score ranged from −1.02 to 2.85, mean 0.5911, SD 0.834. The change of ELF between 0 and 12 months was found to correlate with the absolute change of Ishak fibrosis stage on biopsy before and after treatment (R=0.315, p=0.004). Conclusion ELF testing performed well when compared with liver biopsy prior to and after treatment. A significant association was observed between change of ELF test at 12 months during therapy and histological change after 24 months of therapy. This suggests that a change in ELF score during therapy may predict changes in histology over a longer period. If confirmed, this may permit the refinement of ‘response guided therapy’ by identifying those patients who will benefit from both continued and prolonged treatment.

Changes in elf score during treatment with pegylated interferon and silymarin are associated with progression of histological liver disease in non-responder patients with chronic hepatitis C

IntroductionLiver biopsy remains the reference standard for monitoring changes in liver fibrosis resulting from antifibrotic therapy. While non-invasive serum markers have been validated in the detection of fibrosis in patients...

Development and Progression of Portal Hypertensive Gastropathy in Patients With Chronic Hepatitis C

The objective of this study was to determine the incidence and risk factors associated with new-onset and worsening portal hypertensive gastropathy (PHG) in patients with chronic hepatitis C (CHC). A total of 831 CHC patients with bridging fibrosis or cirrhosis at the time of entry were prospectively monitored for clinical and histological liver disease progression while receiving either low-dose peginterferon α2a or no antiviral therapy in the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial. Upper endoscopy with grading of PHG was performed at baseline and at year 4 of the study. The presence and severity of PHG were determined using the NIEC (New Italian Endoscopy Conference) criteria, and worsening PHG was defined as a score increase of ≥1 point. During a median follow-up of 3.85 years, 50% of 514 subjects without PHG developed new-onset PHG, whereas 26% of 317 patients with baseline PHG had worsening PHG. Independent predictors of new-onset PHG included higher alkaline phosphatase and being diabetic, whereas predictors of worsening PHG were Caucasian race, lower albumin, as well as higher serum aspartate transaminase/alanine transaminase ratio and homeostatic model assessment levels. New-onset and worsening PHG were significantly associated with clinical and histological progression. They were also associated with new-onset and worsening gastroesophageal varices. New-onset and worsening PHG develop at a rate of 12.9% per year and 6.7% per year, respectively, in non-responder CHC patients with advanced fibrosis. If confirmed in other studies, endoscopic surveillance for PHG may need to be tailored to individual patient risk factors.

A survey of chronic hepatitis B patient management practices in the European Union

The current study sought to evaluate the characteristics of chronic hepatitis B virus (HBV) infection and current management practices in the European Union by surveying physician and patient records. A detailed survey of physician practices and management of patients with CHB was conducted between July and October 2006 in France, Germany, Italy and Spain. A total of 200 physicians participated in the survey, and data were collected from 2023 patients with chronic HBV infection. Most patients were men (69%), who had hepatitis B e antigen (HBeAg)-negative disease (64%), and demonstrated evidence of significant disease [53%; moderate fibrosis (35%), compensated cirrhosis (14%), or decompensated cirrhosis (4%)]. Among the 1665 HBV-monoinfected patients surveyed, 1184 (71%) were currently receiving treatment for chronic HBV infection. At treatment initiation, 70% of HBeAg-positive patients had both pretreatment serum HBV DNA levels <or=9 log(10) copies/mL and alanine aminotransferase (ALT) levels >or=2 x the upper limit of normal (ULN), and 81% of HBeAg-negative patients had HBV DNA levels of <or=7 log(10) copies/mL. Among untreated patients, HBV DNA levels <or=5 log(10,) ALT levels <2 x ULN, and mild or no liver fibrosis were present in 48% and 84% of HBeAg-positive and HBeAg-negative patients, respectively. In conclusion, the majority of European patients with CHB surveyed were HBeAg negative, Caucasian, men, and presented with significant histologic liver disease. At treatment initiation, most HBeAg-positive patients had pretreatment serum HBV DNA levels <or=9 log(10) copies/mL and ALT levels >or=2 x ULN, while the HBeAg-negative patients had HBV DNA levels <or=7 log(10) copies/mL.

HBV-DNA Levels in HBsAg-positive Blood Donors and its Relationship With Liver Histology

The clinical meaning of viremia, especially at low levels, in chronic hepatitis B virus (HBV)-infected patients remains unknown. The objective of the present study was to determine serum HBV-DNA levels and its relationship with liver histology in HBsAg-positive blood donors. A cross-sectional study was conducted on 78 blood donors, with alanine aminotransferase (ALT) and HBeAg evaluation and quantitative determination of HBV-DNA by polymerase chain reaction (Amplicor, HBV Monitor, Roche; lower limit of sensitivity 1,000 copies/mL). Liver biopsy was obtained from all patients with detectable viremia irrespective of ALT and HBV-DNA levels. Among 78 blood donors, serum HBV-DNA was detected in 47 (60%) patients; 39 (83%) were males; mean age 37.6+/-10.4 years; 31 (66%) were HBeAg-negative, and ALT was elevated in 26 (55%). The median of HBV-DNA levels was 24,000 copies/mL and 31 (40%) subjects had no detectable serum HBV-DNA. Although the histologic lesions were mild in the majority of patients, HBV-DNA levels were significantly higher in patients with chronic hepatitis or cirrhosis when compared with patients without histologic liver disease (25,260,000 vs. 9480 copies/mL; P<0.001). There was a significant correlation between HBV-DNA levels and necroinflammatory score (r=0.59) and fibrosis (r=0.50); however, in the subset of HBeAg-negative patients with HBV-DNA levels below 30,000 copies/mL, 25% presented histologic disease related to HBV. Most HBsAg-positive blood donors show low viral load. There is a significant association between viral replication and liver damage; however, low HBV-DNA levels do not exclude the presence of histologic disease.

Precore/Core Promoter Mutant Hepatitis B Virus Produces More Severe Histologic Liver Disease than Wild Type Hepatitis B Virus

Introduction: The aim of this study is to compare Knodell and HAI scores in patients with wild type and precore/core promoter mutant CHB to see if there is any difference in severity of liver injury between these two types of HBV. Methods: We did percutaneous liver biopsies of 155 CHB patients. 102 (65.8%) of them were infected wild type HBV and the rest 53 (34.2%) were infected with precore/core promoter mutant CHB. Results: 11/53 (20.8%) patients with precore/core promoter mutant CHB had moderate to severe CH (HAI score 8–18). In contrast, moderate to severe CH was seen in 19/102 (18.6%) patients with wild type CHB. Fibrosis score was >2 in 15/53 (28.3%) precore/core promoter mutant CHB as opposed to 20/102 (19.6%) patients with wild type CHB. Conclusion: The study shows that precore/core promoter mutant HBV produces more severe histologic liver disease compared to wild type HBV.

Liver Patology in Patients with Hematological Malignancies.

BACKGROUND: Morphologic study shows liver patology in about 90% patients with hematology malignancies. Among causes of liver pathology are tumor infiltration, endogenous intoxication that follows malignancy progression, as well as cytostatic agents use. Hepatic damage of infectious etiology: bacterial, fungal and viral very often occurred due to immunosuppression and neutropenia. Besides, chronic liver diseases such as chronic viral hepatitis may contribute to toxic damage effects of antitumor drugs. Thus, there are many factors involved in liver lesions development in these patients. It is known that treatment approaches should be different depend on kind of liver lesion. Definitive identification of liver lesion etiology and mechanism can be done by liver morphological examination. At the same time morphological examination often cannot be performed in these patients because of high risk of complications. Therefore study of liver structural changes and searching of clinical criteria that associated with different pathways of liver lesions in lymphprolifirative disorders and acute leukemia are very important. Objective was to study liver lesions in lymphprolifirative disorders and acute leukemia on base of comparing clinical data with morphological examination results.PATIENTS AND METHODS: Examinated 60 patients (male/female - 39/21): 33 - with lymphoproliferative disorders (non-Hodgkin's lymphoma - 20, multiple myeloma - 5, Hodgkin's lymphoma - 4, hairy cell leukaemia - 2, solitare myeloma - 1, Waldenstrom's macroglobulinemia - 1) and 27 - with acuten leukemia (lymphoblastic leukemia/non-lymphoblastic leukemia - 11/16). The mean age was 49,7 yr (range 18 – 77). All patients received conventional chemotherapy. Liver function tests and main disease were studied. Presence chronic liver, hepatobiliary and pancreas diseases, alcoholic liver diseases were take into account. Were studied to evaluate histological features in all patients. Statistical analyses were calculated with statistical program SPSS, Version 10.0.RESULTS: Tumor infiltration liver was revealed in 44 (73%) patients. 22 (37%) patients have demonstrated chronic viral hepatitis (HBV-infection - 5, HCV-infection - 2), alcoholic liver diseases - 5, chronic calculous and noncalculous cholecystitis - 9, chronic pancreatitis - 7. Seven patients was observed a combination of two diseases. A multifactor analysis has determined clinical syndromes that associated with tumor infiltration of liver in lymphprolifirative disorders and acute leukemia: hepatomegaly (p = 0.04, OR = 4.7, 95% CI 1.0 – 22.0), splenomegaly (p = 0.005, OR = 11.1, 95% CI 2.1 – 59.2), hemorrhagic syndrome (p = 0.02, OR = 7.5, 95% CI 1.3 – 42.3). One-sided analyses has indicated that tumor infiltration of liver is correlated with tumor intoxication (OR = 5.0, 95% CI 1.2 – 21.3), hepatocellular cholestasis (OR = 3.0, 95% CI 1.0 – 22.7), thrombocytopenia (OR = 3.4, 95% CI 1.0 – 12.4).Multifactor analysis (logistic regression model) has revealed that presence of chronic liver diseases, is associated with elevation in serum aminotransferases (p < 0.001, OR = 11.8, 95% CI 3.4 – 41.1). HBV, HCV infection and alcoholic liver diseases were related to a more severe histological liver disease (p = 0.02, OR = 20.8, 95% CI 1.6 – 271.7).Morphological examination indicates on severe structural hepatic changes. Combination of destructive changes of microcirculation and hepatocytes dystrophy/necrosis is evidenced about strong endogenous intoxication.

Steatosis in chronic hepatitis C: Relationship to the virus and host risk factors

Steatosis occurs frequently in hepatitis C. However, the mechanisms leading to this lesion are still unknown, and the role of steatosis in the progression of the disease remains controversial. The aim of the present paper was to determine the prevalence of steatosis in hepatitis C and its association with hepatitis C virus (HCV) genotype, viral load and the presence of risk factors for steatosis, and to analyze the association between steatosis and the intensity of liver disease. Patients infected with HCV who underwent liver biopsy were included. Patients coinfected with hepatitis B virus and/or human immunodeficiency virus and those previously treated for hepatitis C were excluded. The following risk factors for steatosis were investigated: obesity (body mass index [BMI] > 25 kg/m(2)), diabetes mellitus, hyperlipidemia, alcoholism, and use of potential steatosis-inducing drugs. Histological analysis evaluated the presence of steatosis, the degree of periportal activity and staging. Patients with and without steatosis were compared regarding demographic, epidemiological, laboratory and histological characteristics. Logistic regression analysis was applied to identify variables that were independently associated with the presence of steatosis. Ninety patients (55 men, 35 women) with a mean age of 45 +/- 13 years were included. The prevalence of steatosis was 67%. Variables that remained independently associated with steatosis were age, female gender, obesity and genotype 3. The prevalence of steatosis in hepatitis C was high. Risk factors usually related to steatosis such as age, female gender and obesity, as well as genotype 3, were independently associated with the presence of steatosis. Steatosis was not independently associated with the intensity of histological liver disease.

Erythrocyte concentrations of metabolites or cumulative doses of 6‐mercaptopurine and methotrexate do not predict liver changes in children treated for acute lymphoblastic leukemia

During therapy consisting of 6MP and MTX, metabolites accumulate in the erythrocytes. The erythrocyte levels of metabolites reflect the intensity of therapy. Whether they are associated with hepatotoxicity manifested as histological liver changes is not known. We studied the association of the metabolites and cumulative doses of 6MP and MTX with histological liver disease. Serial measurements of E-TGN, E-MTX, and ALT during maintenance therapy were performed and cumulative doses of 6MP and MTX were calculated as g/m2 in 16 children with ALL. Each subject underwent a percutaneous liver biopsy at the end of therapy to screen for histological liver disease. No differences in E-TGN, E-MTX, or cumulative doses of 6MP or MTX were detected in the children with ALL with liver fibrosis compared to those without fibrosis, or in the children with less liver fatty change compared to those with more fatty change. Serum median ALT levels correlated significantly positively with cumulative doses of 6MP during therapy (rS = 0.527, P = 0.036), but not with cumulative doses of MTX, or E-TGN, or E-MTX. Erythrocyte levels of the metabolites or the cumulative doses of 6MP and MTX do not predict histological liver disease in children treated for ALL.

The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection

In the era of antiretroviral therapy (ART), liver disease has emerged as an important cause of death among persons with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. The objective of this study was to estimate the burden of liver disease and evaluate determinants of liver fibrosis and necroinflammatory activity among HIV/HCV coinfected patients receiving ART. We studied 112 randomly selected and 98 referred HCV-infected patients undergoing care in the Johns Hopkins University HIV clinic. Liver disease was characterized clinically and histologically. Of the 210 individuals studied--64% of whom had received ART within 2 years of liver disease assessment--33% had no fibrosis (F0), and 26% had bridging fibrosis or cirrhosis (> or =F3). The median necroinflammatory activity score was 3 (range, 0-9 of 18). ART was not associated with fibrosis; however, significantly less hepatic necroinflammatory activity was observed among persons who had received highly active antiretroviral therapy longer (P = .02) and more effectively (defined by HIV RNA suppression; P < .01). Twelve percent of individuals had previous ART-associated liver enzyme elevations (grades 3-4), but liver fibrosis was not more severe if the liver enzyme elevation resolved. On the other hand, liver fibrosis was more severe in persons with persistent liver enzyme elevations (grades 1-4). In conclusion, despite widespread exposure to ART and documented instances of ART-related hepatitis, we found no evidence that ART caused serious histological liver disease. Recognition of bridging fibrosis and cirrhosis in some but not most patients underscores the importance of identifying and treating liver disease in HIV/HCV coinfected persons.