CSH guidelines for the diagnosis and treatment of drug-induced liver injury.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.

Pirfenidone inhibits carbon tetrachloride- and albumin complex-induced liver fibrosis in rodents by preventing activation of hepatic stellate cells.

1. Pirfenidone (PFD; 5-methyl-1-phenyl-2(1H)-pyridone) is an effective and novel agent with antifibrotic and anti-inflammatory properties. In the present study, we investigated the antifibrotic effects of PFD on experimental liver fibrosis models in rodents and the possible underlying molecular mechanisms. 2. Liver fibrosis was induced by carbon tetrachloride (CCl(4)) in BALB/c mice. Pirfenidone (250 mg/kg) and silymarin (50 mg/kg) were given to different groups of rats by gastric gavage for 4 weeks. Pirfenidone significantly attenuated fibrosis severity, as determined by histopathological scores and hydroxyproline levels in liver tissue, by 49.8 and 44.9%, respectively, compared with the CCl(4)-treated group. The antifibrotic effects of PFD were significantly greater than those of silymarin, as indicated by a decrease of 23.5 and 24.8% in histopathological scores and hydroxyproline levels, respectively. 3. Liver fibrosis was also induced by albumin antigen-antibody complex in Wistar rats, which were then treated with the same doses of PFD and silymarin for 8 weeks. Pirfenidone significantly reduced the degree of fibrosis compared with CCl(4)-treated rats (by 45.0 and 51.0% as determined by histopathological scores and hydroxyproline levels in liver tissue, respectively). The antifibrotic effects of PFD were comparable to those of silymarin. 4. The effects of PFD on the expression of extracellular matrix-associated genes in human hepatic stellate cells (the LX-2 cell line) were measured by real-time quantitative polymerase chain reaction. LX-2 cells were treated with or without 100 micromol/L or 1 mmol/L PFD for 24 h. Pirfenidone significantly inhibited the expression of a-smooth muscle actin and Type I collagen in 8 ng/mL transforming growth factor-beta1- or 5% fetal bovine serum-activated LX-2 cells in a dose-dependent manner. 5. In conclusion, the results of the present study demonstrate that PFD is effective in ameliorating fibrogenesis induced by CCl(4) in mice and by the albumin complex in rats. These effects were mediated mainly via inhibition of the activation of hepatic stellate cells, as well as antifibrotic actions (i.e. inhibition of collagen synthesis) of PFD.

[Inhibitory effects of silymarin on hepatic fibrosis induced by dimethylnitrosamine: experiment with rats].

OBJECTIVE: To investigate the antifibrotic effects of silymarin on hepatic fibrosis. METHODS: Sixty-one male Wistar rats were randomly divided into three groups: control group (15 rats); DMN model group (23 rats), injected intraperitoneally with dimethylnitrosamine (DMN) 10 mg/kg twice per week for 8 weeks to induce hepatic fibrosis; and silymarin group (23 rats), injected intraperitoneally with DMN and given silymarin 50 mg/kg by gastric gavage daily for 8 weeks. Eight weeks late all rats were sacrificed. Blood samples were collected to measure the alanine transaminase (ALT), aspirate aminotransferase (AST), albumin, and total bilirubin (TBIL). The hydroxyproline (Hyp) content in the liver tissue was measured. The histopathological changes as well as the fibrosis stages and score were examined by microscopy. RESULTS: The levels of ALT, AST, and TBIL of the silymarin groups were 59 U/L +/- 19 U/L, 159 U/L +/- 39 U/L, and mean rank 24 respectively, all significantly lower than those of the DMN model group (128 U/L +/- 25 U/L, 246 U/L +/- 61 U/L, and mean rank 37 respectively, P < 0.01, P = 0.001, and P = 0.003). Compared with DMN rats, the level of Hyp of the silymarin was lower by 42.6%, the hepatic score of the silymarin was 6.2 +/- 2.4, significantly than that of the DMN model group (12.8 +/- 4.4, P = 0.001), and more cases in the silymarin group were at the lower stages. CONCLUSION: Silymarin markedly inhibits and reverse the progression of hepatic fibrosis induced by dimethylnitrosamine.

[The effect of Cpd 861 on chronic hepatitis B related fibrosis and early cirrhosis: a randomized, double blind, placebo controlled clinical trial].

OBJECTIVES: To further assess the clinical antifibrotic efficacy of Cpd 861 on chronic hepatitis B related fibrosis and early cirrhosis using a randomized, double blind, and placebo controlled clinical trial. METHODS: Total 136 patients with HBV-related fibrosis and early cirrhosis were allocated randomly into Cpd 861 treatment group and placebo group for 24 weeks treatment. Serum fibrosis markers including hyaluronic acid (HA), IV collagen (IV-C), amino terminal propeptide of type III procollagen (PIIIP), and laminin (LN) and serum MMP1, 2, 9, TIMP1, 2 level were determined before and after 24 weeks treatment. Liver biopsies before and after 24 weeks of treatment were assessed according to modified Scheuer and Chevallier's scoring system. RESULTS: Total 52 patients in Cpd 861 treatment group and 50 patients in placebo-controlled group completed the 6 months. ALT level decreased from 68.2 U/L+/-68.6 U/L to 45.9 U/L+/-26.1 U/L, AST level decreased from 60.4 U/L+/-62.6 U/L to 46.7 U/L+/-39.0 U/L (P < 0.05) after 24 weeks treatment, whereas there was no significant change in placebo group (ALT: 65.3 U/L+/-48.3 U/L to 85.4 U/L+/-115.5 U/L; AST: 60.4 U/L+/-44.6 U/L to 77.6 U/L+/-89.6 U/L, P > 0.05). Serum fibrosis markers, including HA, IV-C, PIIIP, and LN were decreased after treatment, but there is no statistically significant compared with placebo group. Compared with placebo group, serum TIMP1 and MMP9 level decreased significantly (TIMP1 172.0 ng/ml+/-79.6 ng/ml vs 133.5 ng/ml+/-66.8 ng/ml; MMP9 116.1 ng/ml+/-88.2 ng/ml vs 80.4 ng/ml+/-79.0 ng/ml), and the ratio of TIMP1/MMP1 (48.3+/-96.3 vs 19.9+/-28.0) were also decreased after 861 treatment. In patients treated with Cpd 861, hepatic inflammatory score (from 14.0+/-6.0 to 10.2+/-6.1), fibrosis score (from 11.9+/-6.5 to 8.2+/-4.5), and relative content of collagen (from 18.9%+/-9.5% to 14.9%+/-8.4%) decreased significantly. In contrast, there was no significant change in placebo group. The reversal (fibrosis score decrease > or = 2) rate of fibrosis in Cpd 861 group was 38.9% in S2, 53.3% in S3 (precirrhotic) and 78.6% in S4 (cirrhosis), significantly higher than those in placebo group (14.3%, 25.0%, and 41.7%, respectively). The overall reversal rate was 52.0% in Cpd 861 group, and 20.0% in placebo group (P < 0.05). No serious adverse effects were observed during Cpd 861 treatment. CONCLUSION: Liver fibrosis and early cirrhosis due to HBV infection in man could be definitely reversed by herbal remedy Cpd 861.