Monocyte-Derived Hepatocyte-Like Cell Test: A Novel Tool for in vitro Identification of Drug-Induced Liver Injury in Patients with Herbal or Dietary Supplements.

BACKGROUND: Drug-induced liver injury caused by herbal and dietary supplements (HDS) has been an increasingly important phenomenon in recent years. Diagnosis is the major challenge. Definite causality assessment, especially in patients with concomitant prescription medicine or other potential causes of liver injury, can be impossible. OBJECTIVES: We investigated the usefulness of an in vitro test on the basis of peripheral monocytes of the individual patients in patients with acute liver injury consuming HDS. METHOD: Patients with acute liver injury who had been prospectively recruited by the University Hospital Munich (LMU, Munich) and the Chinese University of Hong Kong (CUHK) and who took at least 1 HDS were selected for this analysis. Diagnosis of drug-induced liver injury (DILI) was based on local expert adjudication, Roussel Uclaf Causality Assessment Method (RUCAM) score, and course of the disease and was supported by the monocyte-derived hepatocyte-like (MH) cell test. RESULTS: We identified 47 patients with liver injury and intake of at least 1 HDS: 32 (68%) were diagnosed with DILI. HDS was determined as the causative agent in 28 out of those 32 patients. The MH cell test could correctly identify 29 out of those 32 DILI cases and showed false positive results in only 2 out of the 15 non-DILI patients. The MH cell test therefore reached a sensitivity and specificity of 90.6 and 86.7%, respectively, in patients with acute liver injury and HDS intake. CONCLUSIONS: Our data provide evidence that the MH cell test can be a useful tool to identify the role of HDS in causing DILI and therefore support causality assessment in patients consuming HDS.

The changing epidemiology of liver diseases in the Asia-Pacific region.

This Review presents current epidemiological trends of the most common liver diseases in Asia-Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia-Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care.

Non-alcoholic fatty liver disease: spectral patterns observed from an in vivo phosphorus magnetic resonance spectroscopy study.

BACKGROUND & AIMS: Liver biopsy is the gold standard for diagnosing non-alcoholic fatty liver disease (NAFLD) but with practical constraints. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease. Our aims were to describe spectroscopic signatures in biopsy-proven NAFLD and to determine diagnostic performance of (31)P-MRS for non-alcoholic steatohepatitis (NASH). METHODS: (31)P-MRS was performed in 151 subjects, comprised of healthy controls (n=19) and NAFLD patients with non-NASH (n=37) and NASH (n=95). Signal intensity ratios for phosphomonoesters (PME) including phosphoethanolamine (PE), phosphodiesters (PDE) including glycerophosphocholine (GPC), total nucleotide triphosphate (NTP) including α-NTP, and inorganic phosphate (Pi), expressed relative to total phosphate (TP) or [PME+PDE] and converted to percentage, were obtained. RESULTS: Compared to controls, both NAFLD groups had increased PDE/TP (p<0.001) and decreased Pi/TP (p=0.011). Non-NASH patients showed decreased PE/[PME+PDE] (p=0.048), increased GPC/[PME+PDE] (p<0.001), and normal NTP/TP and α-NTP/TP. Whereas, NASH patients had normal PE/[PME+PDE] and GPC/[PME+PDE], but decreased NTP/TP (p=0.004) and α-NTP/TP (p<0.001). The latter was significantly different between non-NASH and NASH (p=0.047) and selected as discriminating parameter, with area under the receiver-operating characteristics curve of 0.71 (95% confidence interval, 0.62-0.79). An α-NTP/TP cutoff of 16.36% gave 91% sensitivity and cutoff of 10.57% gave 91% specificity for NASH. CONCLUSIONS: (31)P-MRS shows distinct biochemical changes in different NAFLD states, and has fair diagnostic accuracy for NASH.

Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.

BACKGROUND: Recent epidemiological studies have reported a dose-dependent protective effect of coffee on hepatocellular carcinoma (HCC) with risk reduction ranging from 30% to 80% in daily coffee drinkers compared with non-drinkers. This study examined whether coffee has a similar protective effect when consumed in moderate quantities in chronic hepatitis B virus (HBV) carriers, a group at high risk of developing liver cancer. METHODS: A case-control design was employed. 234 HBV chronic carriers (109 cases and 125 controls) were recruited from the Prince of Wales Hospital in Hong Kong from December 2007 to May 2008. Data collection included review of medical records and face-to-face interview. Univariate and multivariate logistic regressions adjusting for age, gender, cigarette smoking, alcohol use, tea consumption and physical activity were conducted with dose-response analysis. RESULTS: Moderate coffee consumption significantly reduced the risk of HCC by almost half (OR 0.54, 95% CI 0.30 to 0.97) with a significant dose-response effect (χ²=5.41, df=1, p=0.02), reducing the risk for moderate drinkers by 59% (OR 0.41, 95% CI 0.19 to 0.89). CONCLUSION: The findings provided evidence to support the protective effect of coffee consumption in moderate quantities in HBV chronic carriers.

A review of telbivudine for the management of chronic hepatitis B virus infection.

BACKGROUND: Chronic hepatitis B is a worldwide health problem. Research interests have focused on the development of potent and safe antiviral agents with low resistance rates. Telbivudine is a nucleoside analogue that has been approved for treatment of chronic hepatitis B. OBJECTIVE: This review article concentrates on the pharmacokinetics and therapeutic efficacy of telbivudine. The resistance and safety profiles are also addressed. METHODS: Relevant publications were identified from searches of MEDLINE (1996-June 2007), the Cochrane Library and BIOSIS (1993-June 2007). Search items included, but were not limited to, telbivudine, pharmacokinetics, hepatitis B, resistance and adverse events. CONCLUSIONS: Clinical trials demonstrated telbivudine to be a safe and potent antiviral agent for treatment of chronic hepatitis B. Telbivudine has superior efficacy compared to lamivudine and adefovir.

Phyllanthus urinaria ameliorates the severity of nutritional steatohepatitis both in vitro and in vivo.

Hepatic oxidative stress plays a critical role in metabolic forms of steatohepatitis. Phyllanthus urinaria, an herbal medicine, has been reported to have potential antioxidant properties. We tested the effects of P. urinaria on nutritional steatohepatitis both in vitro and in vivo. Immortalized normal hepatocytes (AML-12) or primary hepatocytes were exposed to control, the methionine-and-choline-deficient (MCD) culture medium, in the presence or absence of P. urinaria for 24 hours. Hepatocyte triglyceride, release of alanine aminotransferase, lipoperoxides, and reactive oxygen species production were determined. Age-matched C57BL/6 and db/db mice were fed control or MCD diet for 10 days with or without P. urinaria. Hepatic steatosis, necroinflammation, triglycerides, and lipid peroxide levels were determined. Hepatic expression of inflammatory factors and lipid regulatory mediators were assayed. P. urinaria reduced steatosis and alanine aminotransferase (ALT) levels in culture of hepatocytes in a dose-dependent manner. Phyllanthus prevented MCD-induced hepatic fat accumulation and steatohepatitis in mice. This effect was associated with repressed levels of hepatic lipid peroxides, reduced expression of cytochrome P450-2E1, pro-inflammatory tumor necrosis factor alpha, interleukin-6, dampened activation of inflammatory c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-kappaB), increased expression of lipolytic cytochrome P450 (Cyp4a10), and suppressed transcriptional activity of lipogenic CCAAT/enhancer binding protein beta (C/EBPbeta). Hepatic acyl co-enzyme A oxidase that regulated hepatic beta-oxidation of fatty acid and other lipid regulators were not affected by P. urinaria. In conclusion, P. urinaria effectively alleviated the steatohepatitis induced by the MCD, probably through dampening oxidative stress, ameliorating inflammation, and decreasing lipid accumulation.