Hari S. Conjeevaram

Prognosis of hepatocellular carcinoma: Comparison of 7 staging systems in an American cohort

Currently there is no consensus as to which staging system is best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aims of this study were to identify independent predictors of survival and to compare 7 available prognostic staging systems in patients with HCC. A total of 239 consecutive patients with cirrhosis and HCC seen between January 1, 2000, and December 31, 2003, were included. Demographic, laboratory, and tumor characteristics and performance status were determined at diagnosis and before therapy. Predictors of survival were identified using the Kaplan–Meir test and the Cox model. Sixty‐two percent of patients had hepatitis C, 56% had more than 1 tumor nodule, 24% had portal vein thrombosis, and 29% did not receive any cancer treatment. At the time of censorship, 153 (63%) patients had died. The 1‐ and 3‐year survival of the entire cohort was 58% and 29%, respectively. The independent predictors of survival were performance status (P < .0001), MELD score greater than 10 (P = .001), portal vein thrombosis (P = .0001), and tumor diameter greater than 4 cm (P = .001). Treatment of HCC was related to overall survival. The Barcelona Clinic Liver Cancer (BCLC) staging system had the best independent predictive power for survival when compared with the other 6 prognostic systems. In conclusion, performance status, tumor extent, liver function, and treatment were independent predictors of survival mostly in patients with cirrhosis and HCC. The BCLC staging system includes aspects of all of these elements and provided the best prognostic stratification for our cohort of patients with HCC. (HEPATOLOGY 2005.)

One-year intense nutritional counseling results in histological improvement in patients with nonalcoholic steatohepatitis : A pilot study

BACKGROUND AND AIM:In individuals with biopsy-proven non-alcoholic steatohepatitis (NASH), short-term weight loss has been shown to improve biochemical abnormalities; however, its effect on liver histology is largely unknown. The aim of the article is to determine if dietary intervention is effective in improving histological features of steatohepatitis in patients with biopsy-proven NASH.METHODS:Twenty-three patients (11M/12F) with BMI >25 kg/m2 and biopsy-proven NASH received standardized nutritional counseling aimed at reducing insulin resistance (IR) and weight. Blood tests were checked at baseline and every 1–4 months, and liver biopsy was repeated at month 12. IR was assessed by the homeostasis model assessment (HOMA). Liver biopsies were scored according to modified Brunt criteria for NASH. “Histologic response” was defined as a reduction in total NASH score of ≥2 points with at least one point being in the non-steatosis component.RESULTS:Sixteen patients (8M/8F) completed 12 months of dietary intervention, and 15 underwent repeat liver biopsies. At month 12, mean weight decreased from 98.3 to 95.4 kg. Mean waist circumference, visceral fat, fasting glucose, IR, triglycerides, AST, ALT, and histologic score were all reduced but the difference was not significant. Nine patients had a histologic response, six had stable scores, and none had a worsened score. Compared to patients with unchanged histologic scores, patients with improved scores had significantly greater reduction in weight, waist circumference, AST, ALT, steatosis grade, and total NASH score.CONCLUSION:Among patients who successfully completed 1 yr of intense dietary intervention, nine of 15 patients with NASH displayed histologic improvement. This pilot study suggests that dietary intervention can be effective in improving histology in patients with biopsy-proven NASH.

Race, insulin resistance and hepatic steatosis in chronic hepatitis C

Hepatic steatosis is common in chronic hepatitis C and has been linked to concurrent obesity, insulin resistance, diabetes, disease severity, and poor response to therapy. Racial differences in rates of obesity and diabetes may contribute to racial differences in hepatic steatosis and treatment response. The aim of the present study was to compare hepatic steatosis and its associations between African American (AA) and Caucasian American (CA) patients with chronic hepatitis C, genotype 1, participating in a prospective study of peginterferon and ribavirin therapy. Liver biopsy results were available from 194 AA patients and 205 CA patients. The 2 groups were compared for anthropometric, clinical, and biochemical features and insulin resistance estimated by the homeostasis model assessment index (HOMA‐IR). Sixty‐one percent of the AA patients and 65% of the CA patients had hepatic steatosis (P = 0.38). In univariable analysis, steatosis was associated with HOMA‐IR, body mass index, waist circumference, serum triglycerides, aminotransferase level, and histological scores for inflammation and fibrosis. After adjusting for these features, AA patients had a lower risk of steatosis than did CA patients (OR 0.54, 95% CI 0.32‐0.91, P = 0.02). Insulin resistance but not steatosis was associated with a lower rate of sustained virological response when adjusted for known factors that predict response (relative risk 0.87, 95% CI 0.77‐0.99, P = 0.028). Conclusion: After adjusting for the higher prevalence of features associated with hepatic steatosis, AA patients had a lower prevalence of hepatic steatosis than did CA patients with chronic hepatitis C, genotype 1. Insulin resistance but not steatosis was independently associated with lower sustained virological response. (HEPATOLOGY 2006;45:80–87.)

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study

BACKGROUND & AIMS The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. METHODS In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. RESULTS Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency ≤7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. CONCLUSIONS Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

Metabolic Syndrome Is Associated with Greater Histologic Severity, Higher Carbohydrate, and Lower Fat Diet in Patients with NAFLD

OBJECTIVES:Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome. Insulin resistance (IR) is a key component of metabolic syndrome. The aim was to determine the dietary composition, physical activity, and histologic severity between NAFLD patients with and without metabolic syndrome.METHODS:Ninety-one patients with NAFLD completed the Block Food Frequency Questionnaire and the Paffenbarger Physical Activity Questionnaire. IR was assessed by the homeostasis model assessment (HOMA) index. Metabolic syndrome was defined by the ATP III clinical definition. Nonalcoholic steatohepatitis (NASH) Clinical Network Scoring System was used to determine the histologic severity of NAFLD.RESULTS:Thirty-one patients (34%) had metabolic syndrome. Patients with metabolic syndrome had a higher HOMA index (7.66 vs 4.45, p = 0.04), and consumed more carbohydrates (51% vs 45%, p = 0.03) and less fat (34% vs 40%, p = 0.01) compared with those without metabolic syndrome; total daily calorie, protein consumption, and physical activity were similar between the two groups. Patients with metabolic syndrome had higher scores for steatosis (2.0 ± 0.8 vs 1.37 ± 1, p = 0.02), NASH activity (4.13 ± 1.4 vs 3.13 ± 1.7, p = 0.004), and global NASH score (5.9 ± 1.7 vs 4.4 ± 2.3, p = 0.0006) compared with those without metabolic syndrome. When controlled for other factors including dietary composition and physical activity, the presence of metabolic syndrome was a significant risk factor for global NASH severity in addition to HOMA index and female gender.CONCLUSION:Metabolic syndrome in patients with NAFLD is associated with a diet containing more carbohydrate and less fat and greater histologic severity. The role of a carbohydrate-restricted diet in decreasing the risk for metabolic syndrome and histologic severity should be assessed in patients with NAFLD.

Effectiveness of Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but the effectiveness of a surveillance program in clinical practice has yet to be established. Aims: To evaluate the effectiveness of a surveillance program with ultrasound and alpha-fetoprotein (AFP) to detect early HCCs. Methods: Four hundred and forty-six patients with Child A/B cirrhosis were prospectively enrolled between January 2004 and September 2006 and followed until July 2010. HCC surveillance using ultrasound and AFP was conducted per the treating hepatologist, although the standard was every 6 to 12 months. HCC was diagnosed using American Association for the Study of Liver Disease (AASLD) guidelines and early HCC defined by Barcelona Clinic Liver Cancer (BCLC) staging. Performance characteristics were determined for surveillance using AFP, ultrasound, or the combination. Results: After a median follow-up of 3.5 years, 41 patients developed HCCs, of whom 30 (73.2%) had early HCCs. The annual incidence of HCC was 2.8%, with cumulative 3- and 5-year incidence rates of 5.7% and 9.1%, respectively. Surveillance ultrasound and AFP had sensitivities of 44% and 66% and specificities of 92% and 91%, respectively, for the detection of HCCs. Sensitivity significantly improved to 90%, with minimal loss in specificity (83%) when these tests were used in combination. Conclusions: When used as a surveillance program in a real-world clinical setting, combination of ultrasound and AFP is the most effective strategy to detect HCC at an early stage. Impact: Our results differ from the guidelines of the AASLD. Cancer Epidemiol Biomarkers Prev; 21(5); 793–9. ©2012 AACR.

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of GS-9450 in Subjects With Nonalcoholic Steatohepatitis

In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS‐9450 has a potential for altering the course of the liver disease. In this phase 2, double‐blind study, 124 subjects with biopsy‐proven NASH were randomized to once‐daily placebo or 1, 5, 10, or 40 mg GS‐9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase‐3–cleaved cytokeratin (CK)‐18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40‐mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40‐mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK‐18 fragment levels had decreased to 393 (723) U/L in the GS‐9450 10‐mg group and 125 (212) U/L in the 40‐mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment‐emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS‐9450 treatment groups versus 35% in the placebo group. Conclusion: GS‐9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK‐18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH. (Hepatology 2012)

Sustained virologic response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence

Sustained virologic response (SVR) after antiviral therapy for recurrent hepatitis C virus (HCV) infection in liver transplant (LT) recipients is consistently lower than that achieved in non‐LT patients. We evaluated efficacy and safety of pegylated interferon (IFN) and ribavirin (RBV) therapy in LT recipients with recurrent HCV and factors associated with SVR. All subjects with histologic evidence of recurrent HCV were intended to be treated for 48 weeks with full‐dose pegylated IFN; target dose of RBV was 800 mg/day. Thirty‐five LT recipients with recurrent HCV, median age 48.5 years, 77% genotype 1, and median pretreatment HCV RNA 6.4 log10 IU/mL were treated between January 2000 and February 2006. Antiviral therapy was discontinued prematurely in 15 subjects as a result of adverse events. Median overall treatment duration was 46 weeks. Early virologic response at week 12 was seen in 17 (49%) and an end‐of‐treatment virological response in 19 (54%) patients. SVR was achieved in 13 patients (37%), and all 9 patients followed for >1 year after treatment had durable response. Patients with SVR had significantly lower pretreatment HCV RNA (5.7 vs. 6.5 log10 IU/mL, P = 0.003), more likely to have a week 12 virological response (85% vs. 27%, P = 0.0009) and received higher cumulative doses of pegylated IFN (75% vs. 33%, P = 0.029) and RBV (90% vs. 26%, P = 0.016) compared with patients whose disease did not respond to therapy. In conclusion, SVR was achieved in 37% of patients with recurrent hepatitis C after LT. Similar to non‐LT patients, those with lower pretreatment HCV RNA, a week 12 virological response, and pegylated IFN and RBV dose adherence were more likely to achieve SVR. Liver Transpl, 2007.

Clinical and Histopathologic Features of Fluoroquinolone-Induced Liver Injury

BACKGROUND & AIMS Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatotoxicity from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features. METHODS We identified subjects with fluoroquinolone hepatotoxicity enrolled in the DILIN from September 2004 to January 2010. Demographic, clinical, and laboratory data were analyzed by descriptive statistical methods. RESULTS Of the 679 registrants in the DILIN prospective study, 12 had fluoroquinolone hepatotoxicity (6 ciprofloxacin, 4 moxifloxacin, 1 levofloxacin, and 1 gatifloxacin). Seven were women; median age was 57 years (range, 23-80 years), and median time from fluoroquinolone start to symptoms was only 4 days (range, 1-39 days). Nine patients developed symptoms on medication; 3 did so 2, 8, and 32 days after stopping the medication. Cases were equally distributed among hepatocellular injury (predominantly increased levels of alanine aminotransferase), cholestatic injury (predominantly increased levels of alkaline phosphatase), and both. Seven patients had immunoallergic features. Patients with mixed hepatocellular and cholestatic injury had mild disease without jaundice; all recovered. In contrast, 2 of 4 patients with hepatocellular injury and jaundice died, 1 of acute liver failure. One patient with cholestatic injury developed vanishing bile duct syndrome and required liver transplantation; another had a persistently increased serum level of alkaline phosphatase. CONCLUSIONS Fluoroquinolone liver injury is rapid in onset and often has immunoallergic features, indicating a hypersensitivity reaction. The pattern of injury can be hepatocellular, cholestatic, or mixed; mixed cases are the least severe. Acute and chronic liver failure can occur.

Associations between serum lipids and hepatitis C antiviral treatment efficacy

Approximately one half of patients who undergo antiviral therapy for chronic hepatitis C virus (HCV) genotype 1 infection do not respond to treatment. African Americans (AAs) are less responsive to treatment than Caucasian Americans (CAs), but the reasons for this disparity are largely unknown. Recent studies suggest that serum lipids may be associated with treatment response. The aims of this study were to evaluate baseline and changes in serum lipids during therapy, determine whether serum lipids are associated with virological response, and assess whether these measures explain the racial difference in efficacy. The study participants were from Virahep‐C, a prospective study of treatment‐naïve patients with genotype 1 HCV infection who received peginterferon (PEG‐IN) alfa‐2a plus ribavirin therapy for up to 48 weeks. Fasting serum lipids were analyzed at baseline and during and after therapy in 160 AAs and 170 CAs. A relative risk (RR) model was employed to evaluate characteristics associated with sustained virological response (SVR). Antiviral therapy was associated with changes in serum lipids during and after antiviral therapy, with the changes differing by race and the amount of PEG‐IFN taken. Baseline lipid measures independently associated with higher rates of SVR were lower triglyceride and higher low‐density lipoprotein cholesterol, with an interaction between high‐density lipoprotein cholesterol (HDLc) and gender. Lipid measures did not contribute significantly to an explanation of the racial difference in SVR. Conclusion: Serum lipids are associated with SVR, although these paramaters did not explain the racial difference in treatment response. The results of this study are compatible with proposed biological mechanisms of HCV entry, replication, and secretion, and may underscore new potential therapeutic targets for HCV eradication. (Hepatology 2010)