https://www.liver.theclinics.com/article/S1089-3261(07)00054-2/pdf

Lipid-Lowering Agents That Cause Drug-Induced Hepatotoxicity

Aim The evaluation of the efficacy of ursodeoxycholic acid (UDCA), pentoxifylline, losartan, and atorvastatin in non-alcoholic steatohepatitis (NASH) treatment. Method 48 patients (25 males/23 females, aged 55 +/- 7.54 years) with histologically confirmed NASH were enrolled between 2001 and 2005. The batch was divided into four groups: A (10 dyslipidemic patients, receiving atorvastatin 10 mg/day), P (13 nonhypertensive/ nondyslipidemic patients receiving pentoxifylline 400 mg bid), L (12 hypertensive patients, treated with losartan, 50 mg/day) and U (13 nonhypertensive patients receiving UDCA 15 mg/kg/day). Mean duration of treatment was 37.8 +/- 5.4 weeks. Body mass index, liver biopsy and serum level of alanine-aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), total cholesterol (TC) and triglycerides (TG) were determined at inclusion and at the end of treatment. Liver biopsy samples were evaluated for necroinflammation, steatosis and fibrosis (Brunt's score). Results In group A, a significant reduction of ALT, GGT, TC and AP was noticed. Histology showed diminished steatosis, but no improvement of fibrosis and necroinflammation. In groups P and L we found a reduction of mean ALT and GGT levels and necroinflammatory score. Group U presented a significant reduction in ALT and GGT levels, without improvement in steatosis, necroinflammation or fibrosis. Conclusion Atorvastatin and losartan proved to be efficient in the treatment of dyslipidemia- and hypertension-associated NASH, by improving both biochemical parameters and steatosis/ necroinflammation. Pentoxifylline showed similar efficacy in non-hypertensive/non-dyslipidemic patients, while UDCA did not improve the histological score although it improved the biochemical parameters.

/pdf/therapeutic-options-in-non-alcoholic-steatohepatitis-nash-3cg6s8vy21.pdf

Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study.

Background/Aims Non-alcoholic fatty liver disease (NAFLD) is associated with the development of cardiovascular disease. While existing studies have examined cardiac remodeling in NAFLD, there has been less emphasis on the development of carotid atherosclerosis and stroke. We sought to conduct a meta-analysis to quantify the prevalence, risk factors, and degree of risk increment of carotid atherosclerosis and stroke in NAFLD. Methods Embase and Medline were searched for articles relating to NAFLD, carotid atherosclerosis, and stroke. Proportional data was analysed using a generalized linear mixed model. Pairwise meta-analysis was conducted to obtain odds ratio or weighted mean difference for comparison between patients with and without NAFLD. Results From pooled analysis of 30 studies involving 7,951 patients with NAFLD, 35.02% (95% confidence interval [CI], 27.36–43.53%) had carotid atherosclerosis with an odds ratio of 3.20 (95% CI, 2.37–4.32; P<0.0001). Pooled analysis of 25,839 patients with NAFLD found the prevalence of stroke to be 5.04% (95% CI, 2.74–9.09%) with an odds ratio of 1.88 (95% CI, 1.23–2.88; P=0.02) compared to non-NAFLD. The degree of steatosis assessed by ultrasonography in NAFLD was closely associated with risk of carotid atherosclerosis and stroke. Older age significantly increased the risk of developing carotid atherosclerosis, but not stroke in NAFLD. Conclusions This meta-analysis shows that a stepwise increment of steatosis of NAFLD can significantly increase the risk of carotid atherosclerosis and stroke development in NAFLD. Patients more than a third sufferred from carotid atherosclerosis and routine assessment of carotid atherosclerosis is quintessential in NAFLD.

/pdf/non-alcoholic-fatty-liver-disease-increases-risk-of-carotid-2lqt9uvb.pdf

Non-alcoholic fatty liver disease increases risk of carotid atherosclerosis and ischemic stroke: An updated meta-analysis with 135,602 individuals

Statins reduce cardiovascular risk Patients with cirrhosis have decreased hepatic clearance of statins and potentially increased risk for complications No studies assess mortality in patients with biopsy-confirmed cirrhosis Compare mortality in patients with cirrhosis on statins to those not on statins A retrospective cohort study evaluated patients from 1988 to 2011 at Partners Healthcare Hospitals The Partners Research Patient Data Registry identified patients with biopsy-proven cirrhosis on statins at biopsy and at least 3 months following Controls were matched 1:2 by age, gender and Child–Pugh class Decompensation was defined as ascites, jaundice/bilirubin >25 mg/dL, and/or hepatic encephalopathy or variceal hemorrhage Primary outcome was mortality Secondary outcome was decompensation in baseline-compensated patients Chi-square and two-way ANOVA testing compared groups Cox proportional hazards models for mortality controlled for age, Child–Pugh class, diabetes, coronary artery disease, non-alcoholic steatohepatitis and hepatocellular carcinoma Kaplan–Meier curves graphed mortality Eighty-one statin users and 162 controls were included Median follow-up: 36 months in statin users and 30 months in controls 704 % of patients were Child–Pugh A Model for End-Stage Liver Disease (MELD), albumin, varices and beta-blocker use were not significantly different between groups Statin users had lower mortality on multivariate analysis (HR 053, p = 001), and Child–Pugh A patients had longer survival on Kaplan–Meier analysis Cox multivariate analysis for decompensation showed lower risk of decompensation with statins while increased decompensation with low albumin, high MELD score and beta-blocker use In patients with cirrhosis, statin therapy is not associated with increased mortality and may delay decompensation

Statin Use in Patients with Cirrhosis: A Retrospective Cohort Study

Beneficial Effects of Statins on the Rates of Hepatic Fibrosis, Hepatic Decompensation, and Mortality in Chronic Liver Disease: A Systematic Review and Meta-Analysis

Background: Little is known about the potential adverse hepatic effects of HMG-CoA reductase inhibitors (‘statins’) in patients with existing liver disease; therefore, we examined the risk of liver toxicity with lovastatin exposure in these patients. Methods: A retrospective cohort study was performed using data from a large integrated health plan in Northern California, USA. Patients with laboratory or clinical evidence of liver disease were identified and their exposure to lovastatin was determined. The primary outcome was a pattern of liver-test abnormalities associated with a poor prognosis among patients with drug-induced liver disease, based on Hy’s Rule. Secondary outcomes included liver injury (defined as moderate or severe, depending on the degree of ALT level elevations) or the development of either clinical cirrhosis or liver failure. Incidence rate ratios (IRRs) were calculated and multivariate analyses conducted using extended Cox models. Results: A total of 93 106 patients met the entry criteria. Lovastatin exposure was associated with a lower incidence of all endpoints, including the primary outcome (IRR = 0.28, 95% CI 0.12, 0.55), moderate liver injury (IRR = 0.56, 95% CI 0.47, 0.65), severe liver injury (IRR = 0.50, 95% CI 0.29, 0.81) and the occurrence of either cirrhosis or liver failure (IRR = 0.29, 95% CI 0.21, 0.38); adjustment for age and sex resulted in some attenuation of this reduction in incidence. The observed effects were generally consistent across a range of baseline liver-disease diagnoses and greater cumulative lovastatin exposure was associated with fewer outcome events for some endpoints. Conclusions: In this retrospective analysis, exposure to lovastatin was not associated with an increased risk of adverse hepatic outcomes. These results do not support concern regarding lovastatin-related hepatotoxicity in patients with existing liver disease.

Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study.

OBJECTIVE: We have previously shown that the rate of subjects developing adverse liver outcomes was substantially lower during lovastatin-exposed periods compared to non-exposed periods in patients with pre-existing liver disease. The objective of this analysis was to estimate the dose-response relationship between differing levels of lovastatin exposure and adverse hepatic outcomes.
 METHODS: This was a retrospective cohort study. Eligible subjects were adult members of Northern California Kaiser Permanente with at least 2-fold ALT or AST elevations 6–18 months apart, evidence of chronic hepatitis B or C infection, or a diagnosis of a chronic liver disease. Outcomes included the composite of events as well as individual components:
 
 
 
 liver injury, defined as moderate (3X ULN<ALT<10X ULN) or severe (ALT<10X ULN);
 
 
 development of clinical cirrhosis;
 
 
 liver failure.
 
 
 
 The dose-response relationships were analyzed by estimating the risk of each outcome in subgroups defined by quartiles of total cumulative lovastatin exposure. Each of these risks was compared to that in the lovastatin-unexposed reference group and a test for trend applied, using orthogonal polynomial contrasts on the coefficients of categorical levels of the exposure variable.
 
 RESULTS: 93,106 eligible patients were identified, of whom 15% had been exposed to lovastatin. A strong and monotonic dose-response relationship was found for the composite outcome and moderate liver-injury endpoints. For the composite endpoint, hazard ratios declined from 0.81 in the quartile with least lovastatin exposure to 0.44 in the highest exposed group (
 p<
 .00001). Similarly, for the moderate liver-injury endpoint, hazard ratios declined from 0.97 to 0.27 with increasing lovastatin exposure (
 p<
 .00001).
 
 CONCLUSIONS: Among patients with liver disease, lovastatin exposure was associated with a dose-dependent reduction in the risk of several liver-disease outcomes. These results do not support labeling recommendations for avoiding the use of lovastatin at higher doses in patients with liver disease nor the need to closely monitor LFTs during lovastatin treatment.

Abstract 4163: Higher Dose Exposure of Lovastatin is Not Associated with Adverse Hepatic Outcomes in Patients with Existing Liver Disease

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Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study.

Abstract 4163: Higher Dose Exposure of Lovastatin is Not Associated with Adverse Hepatic Outcomes in Patients with Existing Liver Disease