SACRED: Effect of simvastatin on hepatic decompensation and death in subjects with high-risk compensated cirrhosis: Statins and Cirrhosis: Reducing Events of Decompensation.

BACKGROUND/AIMS: The development of decompensation in cirrhosis demarcates a marked change in the natural history of chronic liver disease. HMG-CoA reductase inhibitors (statins) exert pleiotropic effects that reduce inflammation and fibrosis as well as improve vascular reactivity. Retrospective studies uniformly have associated statin utilization with improved outcomes for patients with cirrhosis. Prospective human studies have shown that statins reduce portal hypertension and reduce death in patients with decompensated cirrhosis after variceal hemorrhage when added to standard therapy with an acceptable safety profile. This proposal aims to extend these findings to demonstrate that simvastatin reduces incident hepatic decompensation events among cirrhotic patients at high risk for hepatic decompensation. METHODS: We will perform the SACRED Trial (NCT03654053), a phase III, prospective, multi-center, double-blind, randomized clinical trial at 11 VA Medical Centers. Patients with compensated cirrhosis with clinically significant portal hypertension will be stratified based upon the concomitant use of nonselective beta-blockers and randomized to simvastatin 40 mg/day versus placebo for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), hepatocellular carcinoma, liver-related death, death from any cause, and/or complications of statin therapy. Ancillary studies will evaluate patient-reported outcomes and pharmacogenetic corollaries of safety and/or efficacy. CONCLUSION: Statins have a long track-record of safety and tolerability. This class of medications is generic and inexpensive, and thus, if the hypothesis is proven, there will be few barriers to widespread acceptance of the role of statins to prevent decompensation in patients with compensated cirrhosis. ClinicalTrials.gov Identifier: NCT03654053.

Patients with post-transplant biliary strictures have significantly higher rates of liver transplant failure and rejection: A nationwide inpatient analysis.

BACKGROUND AND AIM: Biliary strictures are a common complication of liver transplantation. We assess the impact of post-transplant biliary strictures and describe the outcomes of endoscopic retrograde cholangiopancreatography (ERCP), interventional radiology (IR), and surgical therapies. METHODS: Using the Nationwide Readmissions Database (NRD), hospitalized liver transplant recipients were identified using the International Classification of Diseases 10th Revision codes. Patients with post-transplant biliary strictures were identified, and outcomes (inpatient mortality, 30-day readmission, transplant rejection/infection/failure, and disposition) were compared with transplant recipients without strictures. Among transplant patients with biliary strictures who underwent therapeutic intervention, corresponding outcomes were compared between IR, surgical interventions, and ERCP. RESULTS: Of the 8300 liver transplant recipients meeting selection criteria, 554 patients (age 48.9 ± 18.2 years, mean ± SD; 39.5% women) had biliary strictures. Compared with patients without strictures, the adjusted odds ratio (OR) for various outcomes in patients with biliary strictures were as follows: 1.46 (1.20, 1.77; P < 0.001) for 30-day non-elective readmission, 2.71 (2.04, 3.59; P < 0.001) allograft rejection, 2.32 (1.61, 3.37; P < 0.001) liver transplant failure, 3.05 (1.39, 6.73; P < 0.01) infection, and 1.41 (1.08, 1.82; P = 0.01) disposition to skilled nursing or intermediate care facility. Therapeutic interventions during index hospitalization were performed in 350 patients: ERCP 46.6% (n = 163), surgery 41% (n = 144), and IR 12.3% (n = 43) patients. Compared with ERCP, the adjusted odds for various outcomes were disposition to skilled nursing or intermediate care facility 2.72 (1.08, 6.87; P = 0.03) and 2.09 (1.05, 4.15; P = 0.036), prolongation of hospitalization 14.4 (3.7, 25.1; P = 0.008) and 15.0 (7.4, 22.7; P < 0.001), and failure of liver allograft 8.47 (1.47, 48.6; P = 0.017) and 12.23 (2.74, 54.4; P = 0.001) for IR and surgical interventions, respectively. CONCLUSION: Post-liver transplant biliary strictures are associated with increased rates of allograft rejection, allograft failure/infections, and readmissions. Compared with ERCP, management of these patients with IR or surgical interventions is associated with significantly higher rates of allograft failure and hospital stay.

PNPLA3 gene predicts clinical recovery after sustained virological response in decompensated hepatitis C cirrhosis.

BACKGROUND: Patients with decompensated hepatitis C virus (HCV) cirrhosis experience various outcomes after sustained virological response (SVR), ranging from clinical recovery to further deterioration. We hypothesised that the genetic risk for steatosis, namely the polymorphisms rs738409 of Patatin-like Phospholipase Domain-Containing 3 (PNPLA3), rs58542926 of Transmembrane-6-Superfamily-2 (TM6SF2), and rs641738 of Membrane-bound O-acyltransferase Domain-Containing 7 (MBOAT7), is predictive of recovery. METHODS: We prospectively enrolled 56 patients with Child-Pugh (CPT) B/C cirrhosis who underwent antiviral therapy. The primary outcome was change in CPT score at 12, 24, and 48 weeks after SVR. We used a linear mixed-effects model for analysis. RESULTS: Forty-five patients (PNPLA3: 21 CC, 19 CG, 5 GG) survived to the first endpoint without liver transplantation. The mean change in CPT score at 12, 24, and 48 weeks was -1.57 (SE=0.30), -1.76 (SE=0.32), and -2.0 (SE=0.36), respectively, among the patients with the PNPLA3 CC genotype and -0.50 (SE=0.20), -0.41 (SE=0.25), and -0.24 (SE=0.27), respectively, among the other 24 patients. After adjustment for baseline characteristics, the PNPLA3 CG/GG genotypes were associated with a 1.29 (SE=0.30, p<0.0001) point higher CPT score. Most of the difference came from differences in hepatic encephalopathy and bilirubin. The results for rs58542926 and rs641738 were not significant. CONCLUSION: The PNPLA3 CG/GG genotypes could identify a subgroup of patients with decompensated HCV cirrhosis that had suboptimal clinical recovery despite SVR. An understanding of the genetic factors that influence clinical outcomes will help target patients for liver transplant based on individual genetic risk factors and provide insight leading to new therapeutic approaches.

Impact of sustained virological response to chronic hepatitic C antiviral therapy on new onset diabetes mellitus type 2 after controlling for metabolic syndrome.

The high cost associated with antiviral treatment for chronic hepatitis C virus (HCV) infection mandates further investigation in the context of preventing complications such as type 2 diabetes mellitus (DM2). We determined the cumulative incidence of DM2 in subjects with chronic HCV infection who received concomitant pegylated interferon (Peg-IFN) and ribavirin. We conducted a retrospective analysis of data obtained from Veterans Administrations Informatics and Computing Infrastructure (VINCI) to identify an adult cohort of patients without diabetes with chronic HCV infection who received Peg-IFN-based therapy between October 2001 and December 2011. Patients with history of HIV, hepatitis B infection, hepatocellular cancer (HCC), non-HCC cancers, and history of transplantation were excluded. Sustained virological response (SVR) was defined as negative HCV RNA 3 months after completion of therapy. Using Cox proportional hazards regression for multivariable analysis, we determined that patients who achieved SVR were at a significantly less risk of developing DM2. Adjusted survival rates showed that the responders' group was significantly less likely to develop DM2 over time (HR 0.60, CI 0.48 to 0.74, p<0.001). Peg-IFN-based therapy in chronic HCV patients that resulted in SVR significantly decreased the risk of developing DM2 and independently predicts the development of new onset disease after controlling for correlates of metabolic syndrome.

Impact of sustained viral response postcurative therapy of hepatitis C-related hepatocellular carcinoma: a systematic review and meta-analysis.

Antiviral therapy with interferon based therapies (IBT) has shown potential in improving survival in patients who have undergone resection or locoregional therapy for hepatitis C-associated hepatocellular carcinoma (HCV-HCC). However, this benefit has not been definitively ascribed to sustained viral response (SVR). Since IBT has been replaced with new directly acting agents (DAA), which are more efficacious in the treatment of HCV, we sought to better determine the prognostic impact of SVR in HCV-HCC. A systematic search of MEDLINE and EMBASE from inception through October 2015 was performed to identify studies that described the impact of presence of SVR in patients who underwent curative treatment of HCV-HCC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated for recurrence-free survival (RFS) and overall survival (OS) utilizing a random-effects model. After reviewing 858 abstracts, ten studies which included a total of 1,794 patients were selected and data was extracted. Of these ten studies, the impact of SVR on RFS and OS was reported in eight and seven studies respectively. In a meta-analysis which included 1,519 patients, SVR was associated with improved OS (HR 0.18; 95% CI 0.11-0.29, I2  = 2%). We also found that SVR was associated with better RFS in a meta-analysis (1,241 patients; HR 0.50; 95% CI 0.40-0.63, I2  = 0). In conclusion, SVR is associated with improved OS and RFS in patients with HCV who have undergone resection or locoregional therapy for HCC. Newer DAA therapies which offer increased tolerability and viral eradication should be considered as adjunctive therapy.

Hepatorenal syndrome in hospitalized patients with chronic liver disease: results from the Nationwide Inpatient Sample 2002-2012.

Hepatorenal syndrome (HRS) is one of the leading causes of hospitalizations in patients with chronic liver disease (CLD). We conducted a retrospective national database study to determine the epidemiology of HRS in hospitalized patients with CLD. Data from a Nationwide Inpatient Sample were extracted from 2002 to 2012 using ICD-9-CM codes related to CLD and HRS. The following outcomes were examined: in-hospital mortality, total charges, length of stay (LOS), patient demographics, procedures, complications, and comorbidities. Statistical analysis including regression was performed to examine factors associated with HRS. During 2002-2012, hospital discharges related to CLD increased from 407,246 to 836,475 with an increase of 37.9% for HRS as a complication in this population. Patients with CLD and HRS had worse outcomes compared with patients with CLD without HRS. This was manifested as a higher mortality rate (32.0% vs 10.3%), increased LOS (median 7 vs 5 days), and increased hospital costs (median $16,000 vs $11,000). Logistic regression demonstrated that HIV/AIDS (adjusted OR 2.9, 95% CI 2.2 to 3.9), pneumonia (aOR 2.8, 95% CI 2.3 to 3.2), and esophageal variceal bleeding (aOR 1.9, 95% CI 1.7 to 2.0) were associated with higher mortality in patients with HRS. Conversely, liver transplantation (aOR 0.1, 95% CI 0.1 to 0.1), transjugular intrahepatic portosystemic shunt (aOR 0.5, 95% CI 0.4 to 0.6), and hospitalization in the Midwest region of the USA (aOR 0.7, 95% CI 0.6 to 0.7) were associated with reduced mortality. The incidence of HRS in hospitalized patients with CLD increased during 2002-2012. HRS is associated with significant mortality and morbidity in these patients.

Predictors of Early Discontinuation of Pegylated Interferon for Reasons Other Than Lack of Efficacy in United States Veterans With Chronic Hepatitis C.

During the dual-therapy era, many patients with chronic hepatitis C discontinued therapy for reasons other than lack of efficacy (non-LOE). We determined whether selected patient characteristics predicted non-LOE discontinuation using national databases of U.S. veterans with Genotypes 1-4. We identified U.S. veterans in the Veterans Health Administration system in 2004-2009 who had hepatitis C-confirming RNA laboratory results and initiated therapy with pegylated interferon and ribavirin. We used a rule to classify patients who discontinued pegylated interferon early, based on pharmacy refill and viral response data. Multivariate Cox regression was used to identify predictors of non-LOE discontinuation. Of 321,238 patients with a hepatitis C International Classification of Diseases, Ninth Revision, code, 15,297 (4.8%) met all inclusion criteria. Non-LOE discontinuers comprised 30.3% of patients. For Genotypes 1-4, the predictors (adjusted hazard ratio) of greatest magnitude were comorbidities of myocardial infarction/congestive heart failure (1.36), renal disease (1.34), and platelets 100/mm or more (1.38). For Genotypes 2 and 3, predictors of greatest magnitude were Black race (1.30), myocardial infarction/congestive heart failure (1.84), albumin 3.5 mg/dl or more (1.65), sleep aid use (1.32), and poor persistence with antidepressants (1.31) and antihypertensive agents (1.37). Our study suggests that many host factors may have contributed to non-LOE dual-therapy discontinuation in veterans and may possibly predict non-LOE discontinuation in triple therapy.

Sustained virologic response and other potential genotype-specific roles of statins among patients with hepatitis C-related chronic liver diseases.

BACKGROUND: While statins have shown antiviral effects in different studies, few data are available about their effect among different HCV genotypes. AIM: To evaluate the effect of concomitant statin use on sustained virologic response (SVR) and other treatment outcomes among patients with HCV genotypes 1-3. METHOD: Using US Department of Veterans Affairs database, multivariate (MV), propensity score matched (PSM) and repeated measures mixed model analyses were performed on patients who received combination therapy with Peg-IFN and Ribavirin for treatment of HCV genotypes 1-3 between October 2001-December 2011. Concomitant statin users were matched with non-users in each genotype and SVR rates were compared. Changes in serum ALT during treatment was assessed. RESULTS: Of 37,611 treated patients, 236 genotype 1 (GT1), 78 genotype 2 (GT2) and 23 genotype 3 (GT3) statin users and non-users were used for PSM. SVR among GT1 patients was 22.8% (overall), significantly higher among statin users (26.3% vs. 19.5% P<0.01 from PSM; OR=1.49 CI 1.06-2.08 P=0.02 from MV). No significant impact of statin use was observed among GT2 (overall SVR - 55.8%, statin users vs. non-users - 53.9% vs. 57.7%, P=0.32), and GT3 (overall SVR - 58.7%, statin users vs. non-users - 60.9% vs. 56.2%, P=0.39) patients. Higher baseline LDL was positively associated with SVR while statin use reduced ALT during treatment in GT1 patients. CONCLUSION: In view of additional benefits of statins, and the prohibitive cost of newer HCV therapies, statins could be a potential assist for hard-to-treat GT1 patients especially in resource-poor settings.

Emergency department visits related to cirrhosis: a retrospective study of the nationwide emergency department sample 2006 to 2011.

There is scant literature about cirrhosis and its associated complications in a non-hospitalized population.To study the epidemiology of cirrhosis-associated Emergency Department visits in the US.Estimates were calculated in patients' ≥18 years using the Nationwide Emergency Department Sample.The number of visits associated with an International Classification of Diseases-9 diagnosis code of cirrhosis increased non-significantly from 23.81/10,000 population (2006) to 23.9/10,000 population (2011; P = 0.05). A majority of these patients (75.30%) underwent hospital admission, the greatest risk factor for this was the presence of ≥3 comorbidities (adjusted odds ratio 30.8; 95% Confidence Interval 30.4-31.2). Infection was the most frequent concurrent complicating diagnosis associated with cirrhosis (20.1%). There was a decreased incidence in most of the complicating conditions except for hepatorenal syndrome and spontaneous bacterial peritonitis.Our results indicate a stable trend for cirrhosis-associated Emergency Department visits from 2006 to 2011. Further studies are required to investigate the increased incidence of spontaneous bacterial peritonitis and hepatorenal renal syndrome in the cirrhotic population.

Emergency department visits related to Clostridium difficile infection: results from the nationwide emergency department sample, 2006 through 2010.

OBJECTIVES: The objective was to estimate emergency department (ED) visits for Clostridium difficile infection in the United States for the years 2006 through 2010. METHODS: Estimates of ED visits for C. difficile infection were calculated in patients 18 years and older using the Nationwide Emergency Department Sample. RESULTS: During the calendar years 2006 through 2010, there were an estimated total of 491,406,018 ED visits. Of these, 462,160 ED visits were associated with a primary International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis of C. difficile. The C. difficile infection ED visit rate (visits/100,000 census population) increased from 34.1 in 2006 to 42.3 in 2010, an increase of 24% (p < 0.01). There was also a significant overall increased trend in the number of ED visits for C. difficile from 2006 through 2010 (p < 0.01). The highest ED visit rate for C. difficile was observed for patients 65 years and older (163.18 per 100,000), while the lowest visit rate was for patients aged 18 to 24 years (5.10 per 100,000). The greatest increase in C. difficile infection visits occurred in the age group 18 to 24 years. CONCLUSIONS: These results indicate an increased trend of ED visits for C. difficile in the period 2006 through 2010 with an overall population-adjusted increase of 24%. This represents important complementary data to previous studies reporting an increase in the rate of C. difficile infections in the U.S. hospitalized population.

Predicting Discontinuation of Pegylated Interferon as a Result of Lack of Efficacy in United States Veterans With Chronic Hepatitis C on Dual Therapy.

BACKGROUND: Many patients with chronic hepatitis C virus (HCV) being treated with pegylated interferon (peg-IFN) plus ribavirin (RBV) do not respond to therapy and do not clear the virus. Standard of care during the era of dual therapy was to discontinue the patient's therapy based on insufficient decreases in viral load after 12 and/or 24 weeks on therapy. OBJECTIVES: We identified patient characteristics that were significant predictors of discontinuation as a result of lack of efficacy (LOE) in a national database of US veterans with genotypes 1 and 4. METHODS: We identified US veterans who received care at Veterans Affairs medical centers in 2004-2009 and who had lab-confirmed HCV diagnoses and initiated therapy with peg-IFN plus RBV. Patients who discontinued therapy early were classified as either LOE or non-LOE discontinuers based on pharmacy refill patterns and laboratory response data. Predictors of LOE discontinuation were identified using univariate and multivariable Cox proportional hazards modeling. RESULTS: Of 321 238 HCV patients with an ICD-9 diagnosis code, 31 215 (9.7%) initiated dual therapy with peg-IFN plus RBV, and 10 333 (3.2%) met all inclusion criteria and were included in the analysis. Overall, 13.6% of the cohort was classified as LOE. Significant predictors of LOE discontinuation included treatment for drug abuse (hazard ratio [HR] = 2.18), age >65 years (HR = 1.75), antiretroviral therapy for HIV (HR = 1.48), black race (HR = 1.47), platelet count >100/mm3 (HR = 1.46), and drug therapy for insomnia (HR = 1.40). CONCLUSIONS: We identified risk factors for discontinuation caused by LOE. Future work should focus on determining whether these characteristics are also predictive of triple-therapy LOE discontinuations.

High rates of early treatment discontinuation in hepatitis C-infected US veterans.

BACKGROUND: Patients with chronic hepatitis C (HCV) frequently discontinued dual therapy with pegylated interferon alfa (Peg-IFN) plus ribavirin (RBV) before reaching the recommended duration of 48 or 24 weeks for genotypes (G) 1/4 or 2/3, respectively. We quantified rates of discontinuation despite efficacy (non-LOE) versus lack of efficacy (LOE) versus discontinuation for unknown reasons in a national database of United States veterans. METHODS: We identified a population-based cohort of U.S. veterans with encounters from 2004 through 2009 who had lab-confirmed HCV infection and initiated therapy with Peg-IFN plus RBV in Veterans Health Administration medical centers. Pharmacy data were used to determine therapy duration, defined as the sum of Peg-IFN days supplied. Patients "discontinued" if they failed to receive at least 44 (G1/4) or 20 weeks (G2/3) of therapy. We classified discontinuations as due to non-LOE, LOE, or unknown reasons using a classification rule based on treatment duration and laboratory confirmed response. RESULTS: Of 321,238 diagnosed HCV patients during the evaluation period, 9.7% initiated therapy and 6.4% met all other inclusion criteria. 54.9% of patients discontinued early; of these, 41.2% discontinued due to non-LOE reasons, 12.5% discontinued for LOE reasons, and 46.3% discontinued for unknown reasons. Among non-LOE discontinuers, most (60.1%) discontinued in the first 4 weeks of therapy, which constitutes 13.6% of all treated patients. CONCLUSIONS: We observed a high proportion of early discontinuations with dual-therapy regimens in a national cohort of HCV-infected veterans. If this trend persists in the triple-therapy era, then efforts must be undertaken to improve adherence.

Chronic hepatitis C genotype 1 patients with insulin resistance treated with pioglitazone and peginterferon alpha-2a plus ribavirin.

UNLABELLED: Patients with chronic hepatitis C and insulin resistance are less likely to respond to anti-hepatitis C virus (HCV) therapy and are at risk for more rapid fibrosis progression. Coadministration of pioglitazone with peginterferon/ribavirin improves insulin sensitivity and increases virologic response rates in insulin-resistant HCV genotype 4 patients, but it is unclear whether this finding applies to genotype 1 patients. For this reason we randomized treatment-naive HCV genotype 1 patients with insulin resistance to receive either standard care (peginterferon alpha-2a plus ribavirin for 48 weeks, n = 73) or pioglitazone 30-45 mg/day plus standard care (n = 77) in an open-label multicenter trial. Patients randomized to pioglitazone received the drug during a 16-week run-in phase, the 48-week standard-care phase, and the 24-week untreated follow-up phase. Pioglitazone treatment improved hemoglobin A1c (HbA1c), plasma glucose, insulin levels, and homeostasis model assessment of insulin resistance score and increased serum adiponectin levels during the 16-week run-in phase and maintained these improvements during the standard-care phase. However, we observed no statistically significant difference between the two groups in the primary efficacy endpoint, the decrease from baseline to Week 12 of peginterferon alpha-2a/ribavirin treatment in mean log(10) HCV RNA titer (-3.5 ± 1.71 and -3.7 ± 1.62 IU/mL in the pioglitazone and standard-care groups, respectively, Δ = 0.21 IU/mL, P = 0.4394). CONCLUSION: Treatment with pioglitazone before and during treatment with peginterferon alpha-2a plus ribavirin improved several indices of glycemic control in patients with chronic hepatitis C and insulin resistance, but did not improve virologic response rates compared with peginterferon alpha-2a plus ribavirin alone.

Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C.

BACKGROUND & AIMS: Patients with chronic hepatitis C infection are 2- to 3-fold more likely to develop type 2 diabetes, which reduces their chances of achieving a sustained virologic response (SVR). To identify differences in predictors of SVR in patients with and without diabetes who received combination antiviral therapy, we conducted a retrospective analysis of a national Veterans Affairs administrative database. METHODS: We analyzed data from the Veterans Affairs Medical SAS Datasets and Decision Support System for entire cohort and separately for diabetic patients (n = 1704) and nondiabetic patients (n = 6589). Significant predictors of SVR were identified by logistic regression analysis. RESULTS: Diabetic patients had a lower SVR compared with nondiabetic patients (21% vs 27%, respectively, P < .001). Diabetic patients had higher clustering of previously established negative predictors of SVR. On multivariate analysis of diabetic patients for SVR, the positive predictors were higher low-density lipoprotein (odds ratio [OR], 1.45; P = .0129), use of statin (OR, 1.52; P = .0124), and lower baseline viral load (OR, 2.31; P < .001), whereas insulin therapy (OR, 0.7; P = .0278) was a negative predictor. Diabetic patients on statins had higher pretreatment viral loads (log 6.2 vs 6.4, respectively, P = .006) but better early virologic response. There was a graded inverse relationship between Hemoglobin A1c and SVR rate (P = .0482). This relationship was significant among insulin users (P = .0154) and non-significant among metformin users (P = .5853). CONCLUSIONS: Statin use was associated with an improved SVR among both diabetic patients and nondiabetic patients receiving combination antiviral therapy. Diabetic patients who received insulin achieved lower SVR compared with those not receiving insulin. Poor diabetes control was associated with lower SVR rates.

Predictors of hematological abnormalities in patients with chronic hepatitis C treated with interferon and ribavirin.

Hematological abnormalities including neutropenia, anemia, and thrombocytopenia are commonly seen in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The aim of this study was to identify factors which would help to predict the development of hematological abnormalities in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. During a 4-year period, all patients with chronic hepatitis C started on treatment with pegylated interferon and ribavirin were identified. Patients were defined as having hematological abnormalities if they had the presence of either anemia, neutropenia, thrombocytopenia, or a combination of the above during treatment with pegylated interferon and ribavirin. A total of 136 patients with chronic hepatitis C were included in this study. Fifty-two (38.2%) of the patients developed significant hematological abnormalities during treatment with pegylated interferon and ribavirin with 28 (20.6%), 30 (22.1%), and 11 (8.1%) developed neutropenia, anemia, and thrombocytopenia, respectively. Genotype 1, history of hypertension, low baseline platelet count, low baseline hemoglobin, as well as a raised creatinine were significant factors associated with the development of hematological abnormalities. Significant hematological abnormalities are commonly present in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. This study identifies pretreatment parameters that may help identify high-risk patients who are more likely to develop hematological abnormalities during treatment for chronic hepatitis C.

Severe thrombocytopenia due to hypersplenism successfully treated with partial splenic embolization in preoperative management.

Hypersplenism is a known complication of portal hypertension secondary to cirrhosis of the liver. Although thrombocytopenia secondary to hypersplenism does not cause clinically significant hemostatic defect, it may need to be addressed in selective circumstances, such as preoperative preparation for a surgery. This report describes a 30-year-old male with a history of cirrhosis of the liver and hypersplenism who had a recurrence of craniopharyngioma. A platelet count of 40 x 10(9)/L limited his treatment options. A stereotactic injection of radioactive P32 into the tumor was planned but was thought not to be feasible because of the thrombocytopenia. The thrombocytopenia responded favorably to partial splenic embolization, and the patient underwent successful stereotactic injection of radioactive P32 into the tumor.

Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis?

OBJECTIVES: Obesity is a risk factor for nonalcoholic steatohepatitis (NASH). Leptin plays an important role in the regulation of food intake, body composition, energy expenditure, and body weight. It has been suggested that leptin plays a role in the pathogenesis of NASH; however, adequate studies are lacking. We therefore conducted a study to explore the role of serum leptin in the pathogenesis of human NASH. METHODS: We measured the levels of serum leptin and its anthropometric, biochemical, metabolic, and histological correlates in a cohort of patients with NASH (n = 26) and well-matched controls (n = 20). Furthermore, we measured the levels of leptin in the serum and hepatic leptin and leptin receptor messenger RNA (mRNA) expression in liver biopsy specimens of patients with NASH (n = 5) and simple steatosis (n = 5). RESULTS: Serum leptin was not statistically different between patients with NASH and their controls (21 +/- 13 vs 18 +/- 11 ng/ml, respectively, p = 0.5). There was no correlation between serum leptin and hepatic histology, serum transaminases, fasting insulin levels, or a measure of insulin resistance. After adjusting for covariates in a multiple regression analysis, only percent body fat (p = 0.04) and subcutaneous abdominal fat area (p = 0.04) had significant correlation with serum leptin. There was no expression of leptin mRNA in the cell lysate of liver biopsy specimens of subjects with NASH or steatosis. Additionally, the serum leptin levels and the hepatic leptin receptor mRNA expression were not statistically different between patients with NASH and those with simple steatosis. CONCLUSION: These data do not support a direct role for leptin in the pathogenesis of human NASH.