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Significant advances have been made in the field of liver-directed gene therapy. Many diseases are potential targets for gene therapy, including diseases that have exclusive liver involvement and those with systemic manifestations as a result of defective protein synthesis from the liver. Examples are Crigler-Najjar syndrome type 1, α-antitrypsin deficiency and haemophilia A and B. Strategies for gene delivery include the use of viral and nonviral vectors. In addition to previously developed viral vectors, such as retroviruses, adenoviruses and adeno-associated viruses, new viral vectors such as lentiviruses are being investigated extensively. Nonviral vectors for gene delivery include liposomes and receptor-mediated gene therapy. A strategy to correct gene defects has been developed using chimaeric RNA/DNA oligonucleotides, and methods to inhibit aberrant or deleterious gene expression using ribozymes, antisense oligonucleotides and dominant-negative gene products are being developed. However, more research focusing on more efficient gene expression and safety will be required before gene therapy can be routinely applicable. [ABSTRACT FROM AUTHOR]

Background/Objectives: Patients with Non-Alcoholic Fatty Liver Disease (NAFLD) are reported to have an increased risk of developing severe infections, leading to hospitalizations with sepsis. However, data regarding the impact of comorbid NAFLD on in-hospital outcomes of patients with sepsis is scarce. Methods: This nationwide retrospective observational study using discharge data from the National Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), and Agency for Healthcare Research and Quality included 21,057,911 adult patients who were admitted to hospitals in the United States between 2000 and 2019 with a primary discharge diagnosis of sepsis. These patients were categorized according to the presence or absence of comorbid NAFLD. The twenty-year trend of nationwide NAFLD prevalence among sepsis inpatients was elucidated. Multivariable logistic regression analysis was used to analyze NAFLD's impact on sepsis outcomes. Results : In the twenty-year study period, the prevalence of NALFD among sepsis inpatients trended up from 1.2% in 2000 to 4.2% in 2019. Similar trends were observed in regional analysis. While overall sepsis mortality decreased, comorbid NAFLD in sepsis patients was consistently associated with a higher adjusted in-hospital all-cause mortality rate (adjusted odds ratio (OR), 1.19; 95% confidence interval (CI), 1.07-1.32), higher odds of developing septic shock, and higher likelihood of development of multi-organ dysfunction. Conclusions : Comorbid NAFLD in the stage of NASH or cirrhosis is associated with higher in-hospital all-cause mortality and worse clinical outcomes in sepsis inpatients. Addressing this rising epidemic will be of paramount importance to improve sepsis in-hospital outcomes.

Introduction: Mailed fecal immunochemical testing (mFIT), in-clinic FIT (cFIT), and colonoscopy are believed to reach distinct patient populations. This study aims to evaluate this belief., Methods: Sociodemographic, clinical, and social determinants of health (SDOH) characteristics of 201 patients completing mFIT, 203 patients completing cFIT, and 74 patients completing colonoscopy at a Northeastern United States Veterans Affairs center from August 2023 to January 2024 were compared using descriptive statistics, χ2, and ANOVA tests., Results: Patients completing mFIT (P=0.003) and cFIT (P=0.001) were older than those completing colonoscopy. mFIT patients had more private health insurance as compared with cFIT (P<0.0001) patients. Patients completing colonoscopy had higher average disability ratings as compared with cFIT patients (P<0.0001). mFIT (P<0.0001) and colonoscopy (P<0.0001) patients had more time elapsed since their last primary care visit as compared with cFIT patients. mFIT patients had lower rates of mental health disorders as compared with colonoscopy (P<0.0001) and cFIT (P<0.0001) patients. cFIT patients had higher rates of past stool test use as compared with mFIT (P<0.0001) and colonoscopy (P<0.0001) patients. mFIT patients had lower rates of past colonoscopy completion as compared with cFIT (P<0.0001) and colonoscopy (P<0.0001) patients. There were no significant differences in SDOH domains among patients completing each of the screening methods., Conclusion: While each of the screening methods reaches a different patient population, mFIT does not reach a substantially more vulnerable population compared with cFIT and colonoscopy, highlighting the need for improvements in mFIT outreach., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The prevalence of steatotic liver disease (SLD) among patients with rheumatoid arthritis (RA) remains largely unknown., Aims: To investigate the prevalence of SLD and liver fibrosis among patients with RA., Methods: We utilized data from the United States (US)-based National Health and Nutrition Examination Survey (NHANES) 2017-2020 cycle. After applying established sample weights, we estimated the age-adjusted prevalence of SLD and its subclassifications (CAP ≥ 285 dB/m), high-risk NASH (FAST score) and liver fibrosis (LSM) among participants with self-reported RA. Multivariable logistic regression was performed to identify independent risk factors for metabolic dysfunction associated SLD (MASLD), high-risk NASH and fibrosis, respectively, among participants with RA. We present adjusted odds ratios (aORs) and 95% confidence intervals (CIs)., Results: Age-adjusted prevalence of MASLD among US adults with RA was 34.91% (95% CI: 24.02-47.65%). We also found that the age-adjusted prevalence of high-risk NASH (FAST score > 0.35) and significant fibrosis (LSM > 8.6 kPa) was 12.97% (95% CI: 6.89-23.07%) and 10.35% (95% CI: 5.55-18.48%), respectively. BMI ≥ 30 kg/m 2 , (aOR 6.23; 95% CI: 1.95-19.88), diabetes (aOR 5.90; 95% CI: 1.94-17.94), and dyslipidemia (aOR 2.83; 95% CI: 1.12-7.11) were independently associated with higher odds of MASLD among participants with RA. Diabetes (aOR 19.34; 95% CI: 4.69-79.70) was also independently associated with high-risk NASH., Conclusions: The prevalence of MASLD, high-risk NASH, and liver fibrosis among patients with RA is equal or higher than the general population. Future studies of large cohorts are needed to substantiate the role of systemic inflammation in the pathophysiology of MASLD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nonalcoholic fatty liver disease (NAFLD) is a growing public health concern worldwide. Early detection and management of modifiable risk factors are critical to mitigating its impact. This study aimed to investigate the prevalence and risk factors of NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis among lean adults in the United States (US), using the latest National Health and Nutrition Examination Survey (NHANES) dataset from 2017-2020., Methods: Using controlled attenuation parameter scores of ≥285 dB/m, we assessed the age-adjusted prevalence of lean NAFLD. To determine the age-adjusted prevalence of high-risk NASH and significant fibrosis, we used the FibroScan-aspartate aminotransferase (FAST) score (cutoffs 0.35 and 0.67) and vibration-controlled transient elastography (liver stiffness measurement ≥8 kPa). Multivariate logistic regression was used to identify potential risk factors., Results: We found the age-adjusted prevalence of lean NAFLD to be 6.30%. Among lean US adults, the age-adjusted prevalence of high-risk NASH and significant fibrosis was 1.29% and 4.35%, respectively. Older age and metabolic comorbidities, such as hypertension, diabetes, and dyslipidemia were associated with NAFLD and its complications., Conclusion: These findings suggest that the prevalence of NAFLD is of concern among lean individuals, particularly those aged 40 and older with metabolic comorbidities, while a targeted approach to screening and risk stratification for hepatic fibrosis upon lean NAFLD diagnosis is warranted., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. The association between prior hepatitis B virus (HBV), hepatitis A virus (HAV), hepatitis E virus (HEV) infection and NAFLD remains unclear. We utilized the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and performed multivariable logistic regression analyses to examine the association of prior HBV, HAV and HEV infection with NAFLD, as well as high risk non-alcoholic steatohepatitis (NASH) and liver fibrosis. Our analysis included 2565 participants with available anti-HBc serology results, 1480 unvaccinated participants with anti-HAV results, and 2561 participants with anti-HEV results. Among participants with NAFLD, the age-adjusted prevalence of prior HBV, HAV and HEV infection was 3.48%, 32.08% and 7.45%, respectively. Prior infection with HBV, HAV and HEV was not associated with NAFLD (cut-off 285 dB/m) [aOR: 0.99 (95% CI, 0.77-1.29), 1.29 (95% CI, 0.95-1.75), and 0.94 (95% CI, 0.70-1.27), respectively] or high-risk NASH [aOR 0.72 (95% CI, 0.45-1.17), 0.92 (95% CI, 0.55-1.52), and 0.89 (95% CI, 0.41-1.94), respectively]. Participants with anti-HBc and anti-HAV seropositivity were more likely to have significant fibrosis [aOR: 1.53 (95% CI, 1.05-2.23) and 1.69 (95% CI, 1.16-2.47), respectively]. The odds of significant fibrosis are 53%, and 69% greater for participants with prior history of HBV and HAV infection. Healthcare providers should prioritize vaccination efforts and employ a tailored approach to NAFLD in patients with prior viral hepatitis and especially HBV or HAV infection to limit disease-related outcomes., (© 2023 John Wiley & Sons Ltd.)

Importance: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy., Objective: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors., Design, Setting, and Participants: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022., Exposure: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals., Main Outcomes and Measures: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year., Results: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25)., Conclusions and Relevance: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.

Background: Among liver injury causes, few result in marked elevation of liver enzymes to a level > 1,000 international units per liter (IU/L). This review summarizes common etiologies of marked transaminase elevation and associated prognostic factors., Methods: We performed a comprehensive search on PubMed, EMBASE, Cochrane Library, and Google Scholar from inception through December 2022 using MOOSE guidelines for studies reporting frequency of etiologies of marked transaminase elevation. We used a proportion meta-analysis to pool frequencies with corresponding 95% confidence interval (CI). I 2 was used to adjudicate heterogeneity. We used CMA software for statistical analysis., Results: Seven relevant studies (n = 1608 patients) were included. The pooled frequency of ischemic hepatitis was 51% (95% CI 42-60%, I 2  = 91%), viral hepatitis was 13.1% (95% CI 9.7-17.6%, I 2  = 80%), toxins or drug-induced liver injury (DILI) was 13% (95% CI 8-18%, I 2  = 85%), and pancreaticobiliary-related injury was 7.8% (95% CI 4.4-13.6%, I 2  = 89%). Mortality was significantly higher in ischemic hepatitis versus other causes of marked transaminase elevation, with an odds ratio of 21 (95% CI 9.9-44.8, P value < 0.0001, I 2  = 64% Q 11.1)., Discussion: This is the first meta-analysis to examine etiologies of marked transaminase elevation > 1000 IU/L. Liver ischemia is the most common cause, while other causes include DILI or toxins, viral hepatitis, and biliary pathologies. We found biliary pathologies to be the fourth most common cause. This is clinically relevant as it has been traditionally linked to a cholestatic pattern of liver injury. Being aware of this presentation may help prevent delayed or missed diagnoses and unnecessary testing., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Liver disease remains a leading cause of morbidity and mortality among people living with HIV (PLWH). Emerging data suggest that PLWH are at high risk for developing nonalcoholic fatty liver disease (NAFLD). The aim of this review is to examine the current literature and provide an accurate estimate of the prevalence of NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis, and identify potential risk factors for NAFLD in PLWH., Methods: We searched PubMed and Embase databases to identify studies reporting the prevalence of NAFLD and/or fibrosis in PLWH monoinfection. We performed a random effects meta-analysis of proportions to estimate the pooled prevalence of NAFLD, NASH, and fibrosis among PLWH monoinfection. We also examined potential risk factors for NAFLD by comparing characteristics of PLWH monoinfection with and without NAFLD., Results: A total of 43 studies, reporting data for 8230 patients, met our eligibility criteria and were included in the meta-analysis. Based on imaging studies the overall pooled prevalence of NAFLD and moderate liver fibrosis (METAVIR ≥ F2) among PLWH monoinfection was 33.9% (95% confidence interval [CI], 29.67%-38.39%), and 12.00% (95% CI, 10.02%-14.12%), respectively. Based on biopsy studies, prevalence of NASH and significant liver fibrosis (stage ≥F2 on histology) was 48.77% (95% CI, 34.30%-63.34%) and 23.34% (95% CI, 14.98%-32.75%), respectively. Traditional metabolic syndrome and HIV-related factors were associated with NAFLD in PLWH., Conclusions: Our study confirms that the burden of NAFLD, NASH, and fibrosis is high among PLWH monoinfection. Prospective longitudinal studies are needed to delineate NAFLD, NASH, and fibrosis risk factors, and identify early interventions and new therapies for NAFLD in this population., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Goal: We sought to quantify the independent effects of age, sex, and race/ethnicity on risk of colorectal cancer (CRC) and advanced neoplasia (AN) in Veterans., Study: We conducted a retrospective, cross-sectional study of Veterans aged 40 to 80 years who had diagnostic or screening colonoscopy between 2002 and 2009 from 1 of 14 Veterans Affairs Medical Centers. Natural language processing identified the most advanced finding and location (proximal, distal). Logistic regression was used to examine the adjusted, independent effects of age, sex, and race, both overall and in screening and diagnostic subgroups., Results: Among 90,598 Veterans [mean (SD) age 61.7 (9.4) y, 5.2% (n=4673) were women], CRC and AN prevalence was 1.3% (n=1171) and 8.9% (n=8081), respectively. Adjusted CRC risk was higher for diagnostic versus screening colonoscopy [odds ratio (OR)=3.79; 95% confidence interval (CI), 3.19-4.50], increased with age, was numerically (but not statistically) higher for men overall (OR=1.53; 95% CI, 0.97-2.39) and in the screening subgroup (OR=2.24; 95% CI, 0.71-7.05), and was higher overall for Blacks and Hispanics, but not in screening. AN prevalence increased with age, and was present in 9.2% of men and 3.9% of women [adjusted OR=1.90; 95% CI, 1.60-2.25]. AN risk was 11% higher in Blacks than in Whites overall (OR=1.11; 95% CI, 1.04-1.20), was no different in screening, and was lower in Hispanics (OR=0.74; 95% CI, 0.55-0.98). Women had more proximal CRC (63% vs. 39% for men; P=0.03), but there was no difference in proximal AN (38.3% for both genders)., Conclusions: Age and race were associated with AN and CRC prevalence. Blacks had a higher overall prevalence of both CRC and AN, but not among screenings. Men had increased risk for AN, while women had a higher proportion of proximal CRC. These findings may be used to tailor when and how Veterans are screened for CRC., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting over 30% of the United States population. Early patient identification using a simple method is highly desirable., Aim: To create machine learning models for predicting NAFLD in the general United States population., Methods: Using the NHANES 1988-1994. Thirty NAFLD-related factors were included. The dataset was divided into the training (70%) and testing (30%) datasets. Twenty-four machine learning algorithms were applied to the training dataset. The best-performing models and another interpretable model ( i.e. , coarse trees) were tested using the testing dataset., Results: There were 3235 participants ( n = 3235) that met the inclusion criteria. In the training phase, the ensemble of random undersampling (RUS) boosted trees had the highest F1 (0.53). In the testing phase, we compared selective machine learning models and NAFLD indices. Based on F1, the ensemble of RUS boosted trees remained the top performer (accuracy 71.1% and F1 0.56) followed by the fatty liver index (accuracy 68.8% and F1 0.52). A simple model (coarse trees) had an accuracy of 74.9% and an F1 of 0.33., Conclusion: Not every machine learning model is complex. Using a simpler model such as coarse trees, we can create an interpretable model for predicting NAFLD with only two predictors: fasting C-peptide and waist circumference. Although the simpler model does not have the best performance, its simplicity is useful in clinical practice., Competing Interests: Conflict-of-interest statement: No conflict of interest exists., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children and adolescents., Aim: To determine the prevalence and risk factors of steatosis and advanced fibrosis using transient elastography (TE) in the United States' adolescent population., Methods: Using the National Health and Nutrition Examination Survey 2017-2018, adolescent participants aged 13 to 17 years who underwent TE and controlled attenuation parameter (CAP) were included in this study. Forty-one factors associated with liver steatosis and fibrosis were collected. Univariate and multivariate linear regression analysis were used to identify statistically significant predictors., Results: Seven hundred and forty participants met inclusion criteria. Steatosis (S1-S3), based on CAP, and advanced fibrosis (F3-F4), based on TE, were present in 27% and 2.84% of the study population, respectively. Independent predictors of steatosis grade included log of alanine aminotransferase, insulin resistance, waist-to-height ratio, and body mass index. Independent predictors of fibrosis grade included steatosis grade, non-Hispanic black race, smoking history, and systolic blood pressure., Conclusion: This study demonstrated a high prevalence of steatosis in the United States' adolescent population. Almost 3% of United States' adolescents had advanced fibrosis. These findings are concerning because a younger age of onset of NAFLD can lead to an earlier development of severe disease, including steatohepatitis, cirrhosis, and liver decompensation., Competing Interests: Conflict-of-interest statement: The authors declare that there are no any conflicts of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Diabetes mellitus (DM) negatively affects the development and progression of chronic liver diseases (CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Post-transplant infections have been studied widely but data on comparisons of deceased donor liver transplants (DDLT) and living donor liver transplants (LDLT), type and timings of infections, and their relations to outcomes are not explored., Material and Methods: We analysed data from 612 participants of the Adult-to-Adult Living Donor Liver Transplantation Study (A2ALL), a retrospective data set of LDLT and DDLT. We compared the type and timing of the first post-transplant infection in relation to transplant outcomes between the two groups., Results: Out of 611 patients, 24.5% experienced the first post-transplant infection, the majority of which were bacterial (35.3%), followed by fungal (11%) and viral infections (4.2%). There was no significant difference in the rate, type or timing of infection between LDLT and DDLT. Patients with late (> 1 year) first infection were 1.8 times more likely to die (95% CI: 1.12-2.98, p = 0.015) and 9 times more likely to have graft failures (95% CI: 3.26-24.8, p < 0.001). DDLT recipients who experienced bacterial infection had a significantly lower survival rate compared to LDLT recipients ( p < 0.001)., Conclusions: Late infection is associated with lower survival in both DDLT and LDLT. Bacterial infection might be more detrimental for DDLT than LDLT. Late infection should be managed aggressively to improve outcomes.

Background: Approximate 180 million people worldwide are infected with hepatitis C virus (HCV). Historically, vaccination has been the most effective strategy for controlling infections of such major health concern. Therapeutic vaccine strategies for HCV, however, have demonstrated negligible success., Aim: Demonstrate the ability of highly-conserved viral epitopes to overcome the immune dysfunction often associated with chronic HCV infections., Methods: T cells from five chronic, HCV-infected patients were immunophenotyped by flow cytometry. The ex vivo T cell responses to highly-conserved viral epitopes were assessed by ELISpot assay and cytokine bead array analysis., Results: Both HLA-DRB-1- and HLA-A2-restricted viral epitopes induced specific, T H 1-type cytokine production by T cells derived from the patients. Induction occurred despite expression of cell-surface inhibitory molecules and the presence of regulatory T cells., Conclusion: These findings support the potential ability of a broad, multi-epitope-based therapeutic vaccine to elicit virus-specific immune responses in chronic hepatitis C virus-infected patients., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: While traditional risk factors for the development of nonalcoholic fatty liver disease (NAFLD) relate to metabolic syndrome, several Asian studies have suggested a high rate of de novo NAFLD following pancreaticoduodenectomy (PD). The aim of this study is to identify de novo NAFLD after pancreatic surgery and its associated risk factors., Methods: A retrospective cohort of patients at a single center that underwent PD or distal pancreatectomy (DP) over 7 years was identified. Pre- and postoperative contrast-enhanced computed tomography scans of the abdomen were reviewed, including attenuation measurements of the liver, spleen, and muscle. Primary outcomes included hepatic attenuation, liver to muscle ratio (LMR), and liver to spleen ratio (LSR)., Results: Of the 96 patients (mean age 64.3) included, 70% underwent PD, and 30% underwent DP. The mean LMR decreased significantly from 1.81 to 1.66 (p=0.02), noted only in men. No interaction effect with LMR was observed with surgical type, chemotherapy, blood loss, pancreatic enzyme replacement, or transaminases. LMR decreased in 55% of subjects., Conclusions: Increased fatty infiltration, as evidence by decreased LMR, was found among men that underwent PD and DP within a year of surgery. This may be related to weight loss and malabsorption and deserves further investigation.

Background: An accurate system for tracking of colonoscopy quality and surveillance intervals could improve the effectiveness and cost-effectiveness of colorectal cancer (CRC) screening and surveillance. The purpose of this study was to create and test such a system across multiple institutions utilizing natural language processing (NLP)., Methods: From 42,569 colonoscopies with pathology records from 13 centers, we randomly sampled 750 paired reports. We trained (n=250) and tested (n=500) an NLP-based program with 19 measurements that encompass colonoscopy quality measures and surveillance interval determination, using blinded, paired, annotated expert manual review as the reference standard. The remaining 41,819 nonannotated documents were processed through the NLP system without manual review to assess performance consistency. The primary outcome was system accuracy across the 19 measures., Results: A total of 176 (23.5%) documents with 252 (1.8%) discrepant content points resulted from paired annotation. Error rate within the 500 test documents was 31.2% for NLP and 25.4% for the paired annotators (P=0.001). At the content point level within the test set, the error rate was 3.5% for NLP and 1.9% for the paired annotators (P=0.04). When eight vaguely worded documents were removed, 125 of 492 (25.4%) were incorrect by NLP and 104 of 492 (21.1%) by the initial annotator (P=0.07). Rates of pathologic findings calculated from NLP were similar to those calculated by annotation for the majority of measurements. Test set accuracy was 99.6% for CRC, 95% for advanced adenoma, 94.6% for nonadvanced adenoma, 99.8% for advanced sessile serrated polyps, 99.2% for nonadvanced sessile serrated polyps, 96.8% for large hyperplastic polyps, and 96.0% for small hyperplastic polyps. Lesion location showed high accuracy (87.0-99.8%). Accuracy for number of adenomas was 92%., Conclusions: NLP can accurately report adenoma detection rate and the components for determining guideline-adherent colonoscopy surveillance intervals across multiple sites that utilize different methods for reporting colonoscopy findings.

Objective: The purpose of this study was to evaluate the diagnostic accuracy of real-time shear-wave elastography for assessment of liver fibrosis in an unselected patient population, comparing shear-wave elastography measurements obtained at and remote from the site of random liver biopsy., Subjects and Methods: In a prospective study of 50 patients (21 with and 29 without hepatitis C) referred for clinically indicated random liver biopsy for diffuse liver disease, shear-wave elastography measurements were taken from four locations before biopsy: one at the left lobe, two at the right lobe, and one at the biopsy location. The mean, minimum, maximum, and SD of shear-wave elastography were compared with pathologic grading. Steatosis and serum markers were analyzed using multiple logistic regression. Optimized shear-wave elastography thresholds were calculated using AUC analysis., Results: The AUC (95% CI) at the biopsy site, ipsilateral lobe, and contralateral lobe were 0.82 (0.63-1.0), 0.84 (0.67-1.0), and 0.59 (0.19-0.99) in hepatitis C patients; 0.89 (0.75-1.0), 0.88 (0.73-1.0), and 0.93 (0.80-1.0) in nonhepatitis C patients; and 0.85 (0.74-0.96), 0.89 (0.79-0.99), and 0.80 (0.67-0.93) in all patients, respectively. Optimized biopsy site shear-wave elastography values for detecting Metavir score F2 or greater were 1.87 m/s (75% sensitivity and specificity), 2.00 m/s (80% sensitivity and specificity), and 1.89 m/s (76% sensitivity and specificity) in hepatitis C, nonhepatitis C, and all patients, respectively. Steatosis and serum markers were not significant., Conclusion: Real-time shear-wave elastography accurately predicted significant fibrosis (stage ≥ 2) in an unselected patient population with diffuse disease, including patients with and without hepatitis C. Shear-wave elastography best predicts pathologic grading when taken at the biopsy site or ipsilateral lobe in hepatitis C patients. Percentage steatosis was not predictive of shear-wave elastography results.

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States. Effective treatments are available, however adherence to treatment is challenging. Modified directly observed therapy (mDOT) with weekly administration of pegylated interferon might improve adherence and outcomes for patients infected with chronic HCV. The purpose of this study was to compare two treatment protocols and examine predictors of sustained virologic response (SVR). This retrospective review compares HCV treatment outcomes in two outpatient clinics at an urban academic medical center. Gastroenterology fellows provided standard treatment (SC) in one clinic; a nurse practitioner administered weekly pegylated interferon injections weekly in a primary care clinic. All patients received oral ribavirin. Data was extracted from the medical records of all treated patients over a 5-year period. 155 treatment-naïve, chronically infected HCV patients were treated. Ninety-seven patients received mDOT treatment and 58 received standard care. Mean age was 46 years. Genotype 1 represented 59 % of the sample. The mDOT patients were significantly more likely to be younger (44 vs. 50 years), have a history of injection drug use (93.1 vs. 50.0 %), and be HIV-infected (13.5 vs. 2 %) compared to SC patients. The overall SVR rate was 45.2 % and did not differ between the groups in unadjusted analyses (p = 0.95). Genotype was the only predictor of SVR. Patients treated by nurse practitioners trained in HCV care and seen weekly for interferon injections have comparable treatment outcomes to patients treated by specialists.

Aim:   Non-alcoholic steatohepatitis (NASH) is associated with increased hepatic insulin resistance. Ceramides and other toxic sphingolipids promote inflammation, lipotoxicity and insulin resistance; however, the role of ceramides in the pathogenesis of NASH has not been determined. This study characterizes expression of ceramide-related genes in human livers with NASH and examines the effects of weight loss on NASH and pro-ceramide gene expression in liver., Methods:   Liver biopsies were obtained to assess the histopathological status of non-alcoholic fatty liver disease/NASH prior to and following completion of a 1-year course of implementing either lifestyle changes or a standard enrichment protocol designed to encourage weight loss. Liver biopsy samples were used to measure pro-ceramide gene expression by quantitative reverse transcriptase polymerase chain reaction analysis (qRT-PCR), and serum was used to measure ceramide immunoreactivity., Results:   At baseline, serine palmitoyltransferase (SPTLC)2 (P = 0.02) and ceramide synthase (CER)1 (P = 0.001) mRNA transcripts were less abundantly expressed in livers with NASH relative to normal controls. After weight loss (average 9.3%), SPTLC1 (P = 0.005) and uridine diphosphate glucose ceramide glucosyltransferase (UGCG) (P = 0.001) expression significantly declined while CER1 increased (P = 0.001) among subjects randomized to the lifestyle change subgroup. Reductions in calorie and fat consumption were significantly correlated with changes in ceramide-related gene expression. Finally, both net and relative reductions in serum ceramide levels were significantly greater in the lifestyles compared with the standard enrichment (control) protocol group (both P < 0.005)., Conclusion:   NASH is associated with increased insulin resistance and altered ceramide gene expression in liver. Weight loss-mediated reversal of NASH is associated with reduced pro-ceramide gene expression in liver., (© 2011 The Japan Society of Hepatology.)

To examine the efficacy of a cognitive-behavioral intervention (CBT) to prevent depression among methadone maintenance patients undergoing antiviral treatment for hepatitis C (HCV), 29 patients beginning HCV treatment were randomized to CBT or standard care (SC). Study participants did not meet criteria for major depressive disorder at the time of study recruitment. CBT did not result in less depression-related antiviral treatment failure, better adherence to antiviral treatment, or better HCV RNA outcomes. There were no significant treatment group differences on depressive symptoms over time. The CBT group did display a greater and more consistent decline in both BDI-II and HAM-D scores over time (d=.85 on the BDI-II; d=.72 on the HAM-D).

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is strongly associated with insulin resistance. Myotonic dystrophy (DM1) is the most common form of adult-onset muscular dystrophy, and there is a high frequency of insulin resistance due to insulin receptor mRNA splicing defects in muscle tissue. The frequency and predictors of NAFLD in this population have not been described. Thirty-six patients with DM1 were prospectively assessed for the presence of NAFLD and insulin resistance. NAFLD was defined by abnormal liver chemistry tests with ultrasound or pathologic evidence of steatosis in the absence of other liver disease. Abnormal liver chemistry tests were found in 44% of DM1 patients (mean ALT 73 +/- 21 U/L, AST 53 +/- 15 U/L), and 87% were attributable to NAFLD. Clinical predictors of NAFLD included increased insulin resistance by the homeostasis model assessment (HOMA) method (9.5 vs. 4.0 U, P = 0.03), elevated fasting insulin (40.4 vs. 16.1 microIU/ml, P = 0.03), abdominal obesity (98.6 vs. 90.8 cm, P = 0.03), elevated triglycerides (195.7 vs. 136.8 mg/dl, P = 0.02), and elevated total cholesterol (213.6 vs. 180.6 mg/dl, P = 0.02). NAFLD is very common and should be considered in the management of DM1. It is strongly associated with markers of insulin resistance and features of the metabolic syndrome. These findings support the role of peripheral insulin resistance in the pathogenesis of NAFLD.

Unlabelled: Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease that is strongly associated with obesity. Currently, there is no approved therapy for NASH. Weight reduction is typically recommended, but efficacy data are lacking. We performed a randomized controlled trial to examine the effects of lifestyle intervention using a combination of diet, exercise, and behavior modification, with a goal of 7% to 10% weight reduction, on clinical parameters of NASH. The primary outcome measure was the change in NASH histological activity score (NAS) after 48 weeks of intervention. Thirty-one overweight or obese individuals (body mass index [BMI], 25-40 kg/m(2)) with biopsy-proven NASH were randomized in a 2:1 ratio to receive intensive lifestyle intervention (LS) or structured education (control). After 48 weeks of intervention, participants assigned to LS lost an average of 9.3% of their weight versus 0.2% in the control group (P = 0.003). A higher proportion of participants in the LS group had a reduction of NAS of at least 3 points or had posttreatment NAS of 2 or less as compared with the control group (72% versus 30%, P = 0.03). NAS improved significantly in the LS group (from 4.4 to 2.0) in comparison with the control group (from 4.9 to 3.5) (P = 0.05). Percent weight reduction correlated significantly with improvement in NAS (r = 0.497, P = 0.007). Participants who achieved the study weight loss goal (>or=7%), compared with those who lost less than 7%, had significant improvements in steatosis (-1.36 versus -0.41, P < 0.001), lobular inflammation (-0.82 versus -0.24, P = 0.03), ballooning injury (-1.27 versus -0.53, P = 0.03) and NAS (-3.45 versus -1.18, P < 0.001)., Conclusion: Weight reduction achieved through lifestyle intervention leads to improvements in liver histology in NASH.

Objectives: Screening for hepatitis C virus (HCV) infection in individuals at increased risk is currently recommended by most, but not all, health authorities. This study identifies outcomes of individuals diagnosed through a screening program targeting high-risk patients., Methods: Veterans presenting for care in VA facilities are assessed for HCV risk factors by a questionnaire. Those with a risk factor are offered anti-HCV testing. Between October 1998 and May 2004, 25,701 patients were assessed and 8,471 patients had a risk factor for HCV. Patients diagnosed through the screening program were assessed per study protocol., Results: The prevalence of a positive HCV antibody in veterans who identified a risk factor was 7.3% (95% CI 6.6-8.0%). Among those diagnosed through the screening program (N = 260), 47% had chronic hepatitis C. Among patients with chronic HCV, 18% had evidence of advanced liver disease (stage III/IV on biopsy or clinical cirrhosis) while 34% had persistently normal alanine aminotransferase (ALT). Two-thirds of individuals who underwent liver biopsy had minimal or no fibrosis. About half (47%) of the screen-detected patients with chronic HCV were treatment candidates. Forty-four percent were not immediate candidates secondary to medical or psychiatric comorbidities or active substance abuse. Twenty-two patients (8%) had died after a median follow-up of 911 days. Two were liver-related deaths., Conclusion: Screening for hepatitis C in persons at high risk can lead to early identification of individuals at risk for progressive liver disease who may benefit from antiviral therapy and counseling to reduce HCV-related liver injury.

Unlabelled: A pilot study of a 48-week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty-one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end-of-treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 +/- 13 to 70 +/- 39 IU/l), decrease in adiponectin (from 9.7 +/- 9.1 to 5.1 +/- 4.5 microg/ml), worsening insulin sensitivity (HOMA Index: from 2.9 +/- 1.8 to 5.5 +/- 5.4), and increase in total hepatic fat (from 30% +/- 32% to 71% +/- 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 +/- 0.7 to 2.9 +/- 1.1) and steatosis (from 0.9 +/- 0.6 to 2.1 +/- 1.3) but no change in fibrosis (from 1.1 +/- 1.2 to 1.2 +/- 1.3). NASH was again present on liver biopsy in 7 patients., Conclusion: These findings suggest that long-term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects.

Background & Aims: Thiazolidinedione (TZD) therapy improves liver histology in nonalcoholic steatohepatitis (NASH) through a mechanism possibly related to its insulin-sensitizing or anti-inflammatory activity. This study was conducted to assess changes in serum levels of selected adipokines and proinflammatory cytokines and to relate these changes to the improved liver histology resulting from pioglitazone therapy for NASH., Methods: Serum samples from 18 patients with NASH obtained at day 0 and week 48 of therapy during an open-label study of pioglitazone were tested for adiponectin, leptin, interleukin (IL)-1a, IL-6, and tumor necrosis factor (TNF)-alpha levels. Paired liver biopsy specimens were scored (0-4) for steatosis, parenchymal inflammation, cell injury, and fibrosis., Results: Adiponectin levels increased from 3.7 to 10.3 mug/mL at week 48 (P < .01); the levels of the other cytokines were unchanged: TNF-alpha, 9.1 vs 8.8 pg/mL; IL-1a, 3.9 vs 3.4 pg/mL; IL-6, 19.4 vs 13.4 pg/mL; and leptin, 24.8 vs 29.6 ng/mL (P > .05 for all). Pioglitazone therapy was associated with improvements in steatosis (2.5 vs 1.0), parenchymal inflammation (3.3 vs 2.1), cell injury (2.2 vs 0.9), and fibrosis (2.0 vs 1.4). The change in adiponectin level was associated with the improvement in steatosis (P = .03) as well as in a summary NASH activity index score (P = .01). Changes in IL-1, IL-6, TNF-alpha, and leptin levels did not correlate with improvements in the histological features., Conclusions: Improvements in liver histology during TZD therapy may be modulated by an adiponectin-mediated effect on insulin sensitivity and hepatic fatty acid metabolism rather than by changes in proinflammatory cytokines.

Objective: To determine the prevalence and the metabolic characteristics of acanthosis nigricans (AN) in a group of 28 study subjects with biopsy-proven nonalcoholic steatohepatitis (NASH)., Methods: The study participants (15 female and 13 male patients, 20 of whom were white subjects; mean body mass index, 32.7 +/- 5.7 kg/m2; mean age, 45.7 +/- 11.3 years) underwent an oral glucose tolerance test (OGTT), frequently sampled intravenous glucose tolerance test (FSIGT), and fasting metabolic panels. AN status was clinically determined, and fat mass was measured by dual-energy x-ray absorptiometry., Results: All study subjects had insulin resistance (IR), and 15 (54%) had the metabolic syndrome (by Adult Treatment Panel III criteria). Of the 28 patients, 4 (14%) had AN (AN+) and 24 did not (AN-). AN+ subjects had a higher body mass index (37.7 +/- 5.6 versus 31.5 +/- 4.3 kg/m2), fat mass (38.9 +/- 4.0 versus 29.2 +/- 2.3 kg), and leptin levels (17.2 +/- 3.9 versus 9.3 +/- 1.6 ng/mL) (P<0.05). They also had significantly higher indices of insulin secretion: fasting and stimulated insulin and C-peptide levels from OGTT and FSIGT. Metabolic syndrome prevalence was 40% in AN- versus 75% in AN+ subjects (not significantly different). Although the AN+ group had significantly lower fasting and OGTT-derived indices of insulin sensitivity in comparison with the AN- group, their FSIGT indices were similar. Waist circumference (a surrogate of visceral adiposity) and cytokine profiles were similar in the AN+ and AN- groups., Conclusion: AN was not highly prevalent in our study cohort with NASH, despite the high prevalence of IR. Hyperinsulinemia and total adiposity, rather than visceral adiposity and IR, were the indices most predictive of AN. The use of AN as an index of IR in patients with NASH appears to have limited diagnostic value.

Background: A 25-year-old woman of English/Irish background was diagnosed with hemochromatosis. She manifested hypogonadotrophic hypogonadism and congestive heart failure. Although there were abnormal liver function tests, no cirrhosis was present. The patient has been treated intermittently by phlebotomy for 24 years. The aim of this study was to investigate the genetic basis of the patient's iron overload disease., Methods: Genetic analysis was performed by direct sequencing of the genes for hemojuvelin, HFE, hepcidin, ferroportin and transferrin receptor 2., Results and Conclusions: Molecular analysis showed that the patient was homozygous for a previously undescribed mutation of HJV, the gene encoding hemojuvelin. This mutation, nt 81G deletion, causes a frameshift encoding 23 additional irrelevant amino acids and premature termination. No mutations were found in the other hemochromatosis genes, hepcidin, HFE, ferroportin or transferrin receptor 2, which might have contributed to her iron overload., (Copyright 2006 S. Karger AG, Basel.)

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study.

To assess the efficacy and safety of maintenance therapy with ribavirin alone in chronic hepatitis C, 108 patients were treated with the combination of interferon alfa and ribavirin for 24 weeks; those who failed to have a virologic response were offered enrollment in a randomized, double-blind, controlled trial of ribavirin (1,000-1,200 mg daily) versus placebo for the subsequent 48 weeks. Patients were monitored at regular intervals with symptom questionnaires, serum aminotransferase levels, hepatitis C virus (HCV) RNA levels, and complete blood counts and underwent liver biopsy at the completion of therapy. Among 108 patients, 50 were still HCV RNA positive after 24 weeks of treatment, of whom 34 agreed to be randomized to continue either ribavirin monotherapy or placebo. Among 17 patients who received placebo, there was no overall improvement in symptoms, serum alanine aminotransferase (ALT) levels, HCV RNA levels, or hepatic histology. Among the 17 patients who received ribavirin, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels, and hepatic fibrosis scores were not changed significantly from baseline. Responses to ribavirin seemed to be categorical, such that 8 patients (47%) had definite improvement in liver histology. Patients with improved histology had improvements in serum ALT levels both on combination therapy and after switching to ribavirin monotherapy. In conclusion, continuation of ribavirin monotherapy may maintain serum biochemical improvements that occur during interferon-ribavirin combination therapy in some patients and that these improvements are often associated with decreases in necroinflammatory changes in the liver. Whether these improvements will ultimately result in prevention of progression of hepatitis C requires further study.

Aim: To characterize the host response to hepatitis B virus (HBV) infection in human hepatocytes transplanted into immunocompetent rodent rats tolerized by, and transplanted with primary human hepatocytes., Methods: One week after the transplantation, rats were inoculated with HBV, and viral gene expression, replication, and host response was monitored., Results: HBV DNA was detectable in serum for at least 60 days. HBsAg levels rose steadily for 3 weeks post-inoculation and then plateaued at a level of about 0.6 pg/ml. HBV RNA was also found in liver at levels that remained constant through the time course. Immunofluorescence revealed clusters of hepatocytes that stained positive for HBcAg. The presence of HBV covalently closed circular DNA (cccDNA) in liver was demonstrated using nuclease digestion of single-stranded DNA followed by PCR. Serum ALT levels rose and reached a peak level of 180 IU/L on day 18, but remained elevated for 60 days. Histology revealed a progressive predominantly mononuclear lobular hepatitis., Conclusion: These data indicate that human hepatocytes transplanted into rats rendered tolerant to these cells, when infected by HBV, results in biochemical as well as histological evidence of hepatitis that accompanies viral gene expression, and DNA replication.

Background & Aims: CCR5Delta32, a 32-base pair deletion of the CC chemokine receptor (CCR) 5 gene, is associated with slowed human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes. A recent study found a higher than expected frequency of CCR5Delta32/Delta32 in patients with hepatitis C virus infection. The roles of other disease-associated chemokine system polymorphisms have not been evaluated in hepatitis C virus infection., Methods: Six chemokine system polymorphisms (CCR5Delta32, CCR5 promoter 59029-G/A, CCR2 -64I, RANTES [regulated upon activation, normal T cells expressed and secreted] -403 -G/A, and -28 -C/G and stromal derived factor 1 -3'A) were studied in 417 patients with liver diseases (339 with hepatitis C) and 2380 blood donors. The clinical parameters of hepatitis C virus infection were compared between carriers and noncarriers of each genetic variant., Results: The frequency of CCR5Delta32 homozygosity was 0.8% in whites with hepatitis C virus and 1.1% in controls (P = 0.75). The CCR5Delta32 allele was not associated with any of the clinical parameters of hepatitis C virus infection. Hepatitis C virus-seropositive whites with the RANTES -403-A allele were less likely to have severe hepatic inflammation compared with those without (odds ratio, 0.34; P = 0.03). In multivariate analysis, the CCR5 promoter 59029 -A allele was marginally associated with a sustained response to interferon therapy (odds ratio, 3.07; P = 0.048)., Conclusions: In this cohort, the frequency of CCR5Delta32 homozygosity in patients with hepatitis C was similar to controls. The high prevalence of CCR5Delta32 homozygosity in the hepatitis C virus patients of the earlier study likely reflects resistance to human immunodeficiency virus infection in hemophiliacs rather than a susceptibility to hepatitis C virus infection. Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C.

Background & Aims: Fibrosis is the hallmark of hepatic cirrhosis, worsening of which is probably the best surrogate marker for progression of chronic liver disease. We evaluated a large cohort of patients with chronic hepatitis C (CHC) using liver histology to assess the rate and predictors of progression of fibrosis., Methods: The cohort consisted of 123 patients with CHC who underwent 2 liver biopsies 4-212 months (mean, 44 months) apart without intervening treatment. Liver histology was graded using the histology activity index (score, 0-18) and fibrosis staged using a scoring system of 0 (no fibrosis) to 6 (cirrhosis)., Results: Among 123 patients, 48 (39%) showed progression in fibrosis scores, 46 (37%) showed no change, and 29 (24%) showed improvement. Of those with worsening fibrosis, 75% had a 1-point increase and 25% a 2-point or greater increase in scores, and 9% showed progression to cirrhosis. The overall rate of progression was 0.12 fibrosis units per year, a rate that predicts progression to cirrhosis in 50 years if progression was linear. The rate of fibrosis progression was variable, and it was higher among older patients, those with higher serum alanine and aspartate aminotransferase levels, and those with the most extensive periportal necrosis on initial liver biopsy., Conclusions: The best predictors of fibrosis progression in CHC are the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver biopsy. These findings support the recommendation that patients with normal aminotransferase levels and mild liver histology can safely defer treatment.

Interferon therapy of hepatitis C causes a decrease in neutrophil counts, and neutropenia is a common reason for dose adjustment or early discontinuation. However, it is unclear whether neutropenia caused by interferon is associated with an increased rate of infection. In this study, we assessed factors associated and clinical consequences of neutropenia before and during interferon therapy of chronic hepatitis C. A total of 119 patients with chronic hepatitis C treated with the combination of interferon alfa and ribavirin were analyzed. In these studies, neutropenia was not used as an exclusion or dose modification criterion. In multivariate analysis, only black race was associated with baseline neutropenia. During treatment, neutrophil counts decreased by an average of 34%. Among 3 blacks with baseline neutropenia without cirrhosis or splenomegaly, there was little or no decrease in neutrophil counts (despite typical decreases in platelet and lymphocyte counts). Documented or suspected bacterial infections developed in 22 patients (18%), but in no patient with neutropenia. United States population estimates suggest that 76,000 blacks with hepatitis C have neutrophil counts below 1,500 cells/microL and might be denied therapy if this exclusion criterion was generally applied. In conclusion, neutropenia is frequent during treatment of hepatitis C with interferon and ribavirin, but it is not usually associated with infection. Constitutional neutropenia, which is common among blacks, should not exclude patients from therapy with interferon as these patients usually have minimal further decreases in neutrophil counts on therapy and are not excessively prone to bacterial infections.

Aim: To determine whether normal genetically immunocompetent rodent hosts could be manipulated to accept human hepatocyte transplants with long term survival without immunosuppression., Methods: Tolerance towards human hepatocytes was established by injection of primary human hepatocytes or Huh7 human hepatoma cells into the peritoneal cavities of fetal rats. Corresponding cells were subsequently transplanted into newborn rats via intrasplenic injection within 24h after birth., Results: Mixed lymphocyte assays showed that spleen cells from non-tolerized rats were stimulated to proliferate when exposed to human hepatocytes, while cells from tolerized rats were not. Injections made between 15 d and 17 d of gestation produced optimal tolerization. Transplanted human hepatocytes in rat livers were visualized by immunohistochemical staining of human albumin. By dot blotting of genomic DNA in livers of tolerized rats 16 weeks after hepatocyte transplantation, it was found that approximately 2.5 X 10(5) human hepatocytes survived per rat liver. Human albumin mRNA was detected in rat livers by RT-PCR for 15 wk, and human albumin protein was also detectable in rat serum., Conclusion: Tolerization of an immuno-competent rat can permit transplantation, and survival of functional human hepatocytes.