Kittichai Promrat

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis

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. (HEPATOLOGY 2004;39:188–196.)

Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.

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/m2) 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 (≥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. (HEPATOLOGY 2009.)

The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis

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 μg/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. (HEPATOLOGY 2007.)

Outcome of screening for hepatitis C virus infection based on risk factors.

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.

Weight loss amelioration of non‐alcoholic steatohepatitis linked to shifts in hepatic ceramide expression and serum ceramide levels

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.

Multi-center colonoscopy quality measurement utilizing natural language processing

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.

Effect of CBT on Depressive Symptoms in Methadone Maintenance Patients Undergoing Treatment for Hepatitis C

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).

Frequency and predictors of nonalcoholic fatty liver disease in myotonic dystrophy

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 μIU/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. Muscle Nerve, 2010

Acanthosis nigricans in patients with nonalcoholic steatohepatitis: an uncommon finding.

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.

Viral epitope-specific T cell responses induced in chronic, hepatitis C virus-infected patients

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, TH1-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.