Sunday Plenary Session

 

 

ID# 4 – Valopicitabine (NM283), Alone or with Peg-Interferon, Compared to Peg Interferon/Ribavirin (pegIFN/RBV) Retreatment in Hepatitis C Patients with Prior Non-Response to PegIFN/RBV: Week 24 Results

P. Pockros; C. O'Brien; E. Godofsky; M. Rodriguez-Torres; N. Afdhal; S. Pappas; E. Lawitz; N. Bzowej; V. Rustgi; M. Sulkowski; K. Sherman; I. Jacobson; G. Chao; S. Knox; K. Pietropaolo; N. Brown

 

Background:

HCV genotype 1 non-responders (NR) to pegIFN/RBV comprise over 50% of currently treated patients and have no proven treatment options. NM283 has shown anti-HCV activity alone and in combination with pegIFN in Phase I-IIa trials, without viral breakthrough for study periods up to 6 months.

 

Methods:

This ongoing Phase IIb trial is comparing 5 treatments in NR patients with HCV-genotype 1, whose HCV RNA never became PCR-negative with ≥12 weeks of pegIFN/RBV. All patients had HCV RNA ≥5 log10 IU/mL by TaqMan PCR, ALT<5xULN, and compensated disease. Patients were randomized 1:2:2:2:2 among 5 treatments: NM283 monotherapy (800 mg/d), 3 combination (comboRx) arms with different NM283 dosing (400 mg/d; 800 mg/d; or dose-ramping 400 to 800 mg/d) +pegIFN, or pegIFN/RBV retreatment as control. PegIFNα-2a is dosed at 180 μg SQ/week with weight-based RBV (1000-1200 mg daily). Virologic response criteria are stipulated for week 4 (≥0.5 log reduction), week 12 (≥1.0 log), and week 24 (≥2.0 log); patients who fail these criteria are designated treatment failures and discontinue.

 

Results:

ITT results for the 162 patients who have reached week 24, including dropouts and failures by LOCF conventions:  HCV RNA responses in the 2 higher-dose NM283+pegIFN comboRx arms are significantly greater vs pegIFN/RBV retreatment. By comparison to other Phase IIb data, early HCV RNA reductions are substantially greater in HCV-1 treatment-naïve patients with similar NM283/pegIFN regimens, confirming the difficulty in suppressing HCV in NR patients. No viral breakthrough has been seen to date.

 

Conclusions:

In non-responders to pegIFN/RBV, valopicitabine+pegIFN treatment at optimal dosing produces significantly greater HCV suppression compared to pegIFN/RBV retreatment, with antiviral efficacy proportional to valopicitabine dose. Continued treatment will determine if these encouraging viral responses at 24 weeks will result in viral clearance and SVR.

 

                                

Response at 24 Weeks

Treatment Group

N

Mean ↓ HCV RNA
(log 10 IU/mL)

Median ↓ HCV
(log 10 IU/mL)

1 - PegIFN + RBV control

31

2.31

1.21

2- NM283 400 + pegIFN

40

2.49

2.31

3- NM283 400-800 ramp + pegIFN

38

3.01*

3.05

4- NM283 800 + pegIFN

32

3.32*

3.29

5- NM283 monoRx

21

0.54

0.42

 

 

 

 

* p<0.03 pooled 800+peg-IFN vs peg-IFN


ID# 1 – Antiviral Activity of the Non-Nucleoside Polymerase Inhibitor, HCV-796, in Patients With Chronic Hepatitis C Virus: Preliminary Results From a Randomized, Double-Blind, Placebo-Controlled, Ascending Multiple Dose Study

S. Villano; P. Chandra; D. Raible; D. Harper; J. Speth; G. Bichier

 

Purpose:

HCV-796 is an inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase that has demonstrated potent antiviral activity in vitro. We performed an ascending multiple-dose study to determine the antiviral activity, pharmacokinetics (PK), and safety of HCV-796 in patients with chronic HCV infection.

 

Methods:

This phase 1b trial was a randomized, double-blind, placebo-controlled study of HCV-796 administered orally for 14 days to patients with chronic HCV infection (> 6 months) who were naïve to treatment. Patients aged 18 to 64 years with ≥104 IU/mL HCV RNA levels were enrolled in sequential, ascending dose cohorts of up to 16 patients (12 active, 4 placebo) per cohort. Patients received 50, 100, 250, 500, 1000, or 1500 mg oral doses of HCV-796 or placebo given as monotherapy twice daily (q12h).

 

Results:

The mean baseline HCV RNA level was 6.6 log10, and 72% of patients were infected with HCV genotype 1. HCV-796 was generally well tolerated with no dose-limiting toxicities or serious treatment-emergent adverse events. Mild to moderate headache was the most frequently reported adverse event. The mean (± SD) PK parameters for the 1000 mg cohort on day 14 were as follows: Cmax = 2186 ± 764 ng/mL; Tmax = 1.8 ± 0.9 hr; t1/2 = 53.7 ± 28.7 hr; AUCt = 20046 ± 7633 ng*hr/mL; CL/F = 58.0 ± 25.5 L/hr; V/F = 4163 ± 1960 L; and the accumulation ratio was 4.2 ± 1.7. HCV-796 treatment resulted in reduced plasma HCV RNA levels. Maximal antiviral effects were achieved at study day 4, with peak mean reductions in HCV RNA across all doses ranging from 0.3 to 1.4 log10 (50% to 97%). In the 1000 mg cohort, the mean reduction in HCV RNA was 1.4 log10 (96%) on day 4, 1.3 log10 (95%) on day 7, and 0.7 log10 (80%) on day 14. In this group, 83% of patients had reductions from baseline > 1.0 log10 on day 4; 33% of these patients had reductions > 1.5 log10 and 25% had reductions > 2.0 log10. On day 14, 17% of patients in the 1000 mg cohort had reductions from baseline > 2.0 log10. Antiviral activity appeared similar among patients infected with HCV genotype 1 compared with those infected with other genotypes of HCV.

 

Conclusions:

HCV-796 demonstrated antiviral activity and was generally safe and well tolerated when given for 14 days. PK exposure was less than dose-proportional with increasing dose, and appeared to reach a plateau at the 1000 mg q12h dose.


S1923 – The influence of cigarette smoking on response to treatment with pegylated interferon alfa-2b and ribavirin in patients with chronic hepatitis C.

m. p. pauly; A. J. Sheinbaum; J. Szpakowski; J. B. Ready; R. S. Brown; B. Freilich; N. Afdhal; P. Kwo; J. Santoro; S. Becker; I. Jacobson; L. Griffel; C. Brass

 

Background:

Cigarette smoking has been associated with increased inflammation and fibrosis in patients with HCV. There is little data on the effect of cigarette smoking on response to antiviral therapy patients with HCV.

 

Aim:

To study the characteristics and response to therapy of HCV infected patients who smoked cigarettes and were treated with pegylated-interferon (PEG IFN) alfa-2b and ribavirin (RBV), compared with those who did not smoke cigarettes.

 

Methods:

The WIN-R study randomized 4913 patients to either PEG IFN alfa-2b and RBV 800 mg (FD) or RBV 800-1400 mg (WBD) (Jacobson, AASLD 2005). Patients with genotype 1 and 4 were treated for 48 weeks. Patients with genotype 2 or 3 were further randomized to 24 vs 48 weeks of therapy. Sustained viral response (SVR) was the primary endpoint with primary efficacy analysis including only those patients who were over 65 kg. Results showed that weight based dosing resulted in significantly greater SVR, especially in those with genotype 1, and that 24 weeks of therapy for genotype 2 and 3 was as effective as 48 weeks.

 

During enrollment, it was noted whether patients were smokers or non-smokers. Smoking data was available on 2865 (67.8%) of 4223 patients included in the primary efficacy analysis. We evaluated the influence of smoking on SVR.  Of patients with available data, 894 (31.2%) were smokers and 1971 (68.8%) were nonsmokers. 

 

Results:

SVR for smokers and non smokers in each group is noted in table 1.

 

Conclusions:

·       Cigarette smokers with genotype 2 and 3 had lower SVR than non smokers. This difference was not seen in the patients with HCV genotype 1.

·       Additional studies are need to evaluate the dose-related effects of cigaretter smoking and the effect on SVR of smoking cessation prior to treatment

 

Table 1. SVR for Smokers and Non-Smokers by Group

 

smokers

 

non-smokers

 

 

 

SVR number/total smokers

SVR percent

SVR number / total nonsmoker

SVR percent

p value

G1 FD

78/275

28

181/626

29

 

G1 WBD

81/268

31

220/651

34

 

G23 FD

88/173

51

218/349

62

0.014

G23 WBD

106/187

57

227/343

66

0.031


S1002. Acetaminophen as a co-factor in acute liver failure due to viral hepatitis determined by measurement of acetaminophen-protein adducts.

J. Polson; L. P. James; T. J. Davern; L. Hynan; L. Rossaro; A. M. Larson; C. Pezzia; W. M. Lee

 

Background:

Acetaminophen (APAP) use during the prodromal phase of acute viral hepatitis (AVH) is often reported and may worsen liver injury. In determining whether APAP plays a role in complicating certain cases of severe AVH, serum APAP levels are likely less reliable than a recently described serum assay for APAP adducts which remains positive up to 7 days after onset of liver damage.

 

Methods:

Sera from 72 consecutive patients with fulminant hepatitis A or B (IgM anti-HAV or anti-HBc positive) enrolled in the US ALF Study (1998-2004) were tested in blind fashion for APAP-protein adducts using high-pressure liquid chromatography with electrochemical detection (HPLC-ED). As a positive control group, 10 well-documented cases of ALF due solely to APAP overdose were included. Outcome and other clinical data were analyzed with Chi-square, Fisher’s exact test, and Kruskall-Wallis rank test as appropriate.

 

Results:

9/72 (12.5%) AVH patients had detectable APAP adducts:

·       5/49 (10.2%) patients with AVH B and

·       4/23 (17.4%) with AVH A.

 

All 10 known APAP-induced ALF cases had positive adducts at higher levels than those in patients with a primary diagnosis of AVH-induced ALF (median level 5.58 nmol/mL vs 0.45 nmol/mL for AVH cases). The lower levels in AVH cases suggest these were not intentional APAP overdoses. The admission serum ALT and total bilirubin levels differed among the 3 groups (p<0.002), the adducts-containing group (APAP-AVH) having values intermediate between the pure AVH group and the pure APAP group (median values - ALT: AVH only: 1580; APAP-AVH: 2658; APAP: 5570 IU/L; total bilirubin: AVH: 19.8; APAP-AVH: 9.7; APAP: 5.0 mg/dL). Neither admission coma grade nor degree of coagulopathy differed significantly among the groups. 8 of 9 AVH patients with adducts reported some APAP use in the days preceding admission; none reported doses exceeding 4 grams per day. No history was obtainable from the 9th patient. 4 patients received N-acetylcysteine (NAC) because they reported APAP use; 3 were enrolled in the trial of NAC versus placebo. 67% of AVH patients with APAP adducts died within 3 weeks of study admission as compared to 27% of AVH patients without adducts (p=0.017).

 

Conclusions:

·       HPLC-ED detects APAP adducts in more than 10% of patients with AVH-induced ALF, implicating APAP toxicity as a cofactor during the apparent use of therapeutic doses.

·       APAP may impact severe acute viral hepatitis, even in therapeutic doses.

·       Outcomes were worse for those patients with viral hepatitis who had APAP adducts.

·       Patients with moderate to severe acute viral hepatitis should avoid APAP as it may increase liver injury in this setting.  - Supported by NIH R-01 DK58369 and NIH R-03 DK067999.

 


S1016. Hepatic Steatosis is Associated with Increased Frequency of Hepatocellular Carcinoma in Patients with Hepatitis C-Related Cirrhosis.

J. Pekow; A. K. Bhan; Z. Hui; R. T. Chung

 

Chronic hepatitis C can result in fatty changes in the liver. Previous studies have suggested that hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with HCV infection. We sought to determine whether hepatic steatosis is associated with hepatocellular carcinoma (HCC) in a cohort of patients with hepatitis C-related cirrhosis.

 

Methods

We retrospectively identified 94 consecutive patients at our institution with hepatitis C cirrhosis with or without HCC as the principal indication for liver transplantation from 1992 to 2005 and who had pathology available for review. Of these, 32 had evidence of hepatocellular carcinoma and 62 patients had no evidence of malignancy on explant histology. All explant specimens were regraded for steatosis by a single, blinded pathologist based on the percentage of fat on microscopic examination. The following grades were used: 0 = absent; 1 = 1-5% of hepatocytes affected; 2 = 6-33%; 3 = 34-66 %; and 4 = >67%. Steatosis, age, gender, BMI, HCV RNA, HCV genotype, MELD score, chronic alcohol use, and diabetes were examined in univariate and multivariate analysis for association with HCC. In statistical analysis, values between the two groups were compared using Fisher's exact test for binary variables, Wilcoxon test for continuous variables, and logistic regression for multivariate analyses.

 

Results

In total, 69% of patients in the HCC group and 50% of patients in the control group had evidence of steatosis (1+) on histology. Relative risk for the development HCC for each grade of steatosis compared to grade 0: grade 1 (1.41 [.69-2.85]), grade 2 (2.19 [1.07-2.48]), and grade 3 or 4 (2.73 [1.04-7.17]). There was a significant association between the trend of increasing steatosis grade and risk of HCC (p=.03). In univariate analysis, steatosis (p=.03), age (56 vs. 49; p<.02), AST (122.5 vs. 91.5; p=.005), ALT (95.8 vs. 57.2; p=.002), median HCV RNA (239,000 vs 496,500; p=.02), and biologic MELD score (21.8 vs. 20.3; p=.03) were associated with HCC. In multivariate analysis including age, steatosis, AST, ALT, and MELD score, age was significantly (p=.01) associated with HCC, and steatosis (p=.08) trended toward significance.

 

Conclusion

In patients with HCV-related cirrhosis, the presence of hepatic steatosis is associated with an increased risk for development of hepatocellular carcinoma. These findings suggest that steatosis poses an additional risk for HCC and that increased vigilance should be practiced in persons with both HCV and steatosis.

 


S1578. Eryrthopoeitin Functions as a Cytoprotective Cytokine in Primary Murine Hepatocytes.

J. J. Maher; R. Hoque

 

Erythropoietin (Epo) has recently been identified as an anti-apoptotic, tissue protective cytokine in a variety of tissues. Epo is expressed in hepatocytes and upregulated by hypoxic stress. The erythropoietin receptor (Epo-R) is known to be expressed by fetal hepatocytes and to be present in adult murine liver extracts. The function of Epo and Epo-R in adult hepatocytes is currently unknown.

 

Objective:

The Objective of this study is to delineate a potential function of Epo and Epo-R in hepatocyte cytoprotection.

 

Methods:

Hepatocytes were isolated from mice by collagenase perfusion method. For toxin studies, cells were treated with human recombinant Epo for 2 hrs, exposed to toxin, and assessed for cytotoxicity by MTT assay after 20 hrs. For hypoxia experiments, cells were maintained overnight, treated with Epo, sealed in a gas chamber, and flushed with 95% N2/ 5% CO2 for 5 minutes; reoxygenation was achieved by opening the chamber, exchanging the media, and performing MTT assays after 7 hrs. Western blots of hepatocyte lysates were performed for Epo, Epo-R, and phosphorylated Akt. To explore the significance of Epo in known human disease states, immunostaining for Epo-R in paraffin-fixed human liver transplant explants was performed.

 

Results:

Epo and Epo-R were expressed in adult murine hepatocytes and stably expressed in cell culture with protein levels unchanged by hypoxia/reoxygenation (H/R) . Treatment of freshly isolated murine hepatocytes with Epo (10ng/ml to 1000ng/ml) for 20 hrs does not result in cytotoxicity. Pretreatment of hepatocytes with Epo does not appear to protect cells from the cytotoxicity of staurosporine, TNF-a/galactosamine, or H2O2 but is cytoprotective from H/R injury in a concentration dependent manner. Treatment with 100ng/ml erythropoietin effects the greatest benefit with a 10% decline in MTT value compared to a 33% decline in the untreated group at the end of the reoxygenation period. Additionally, treatment with Epo concurrent with hypoxia results in earlier induction of Akt phosphorylation, a known necessary intermediate in anti-apoptotic signaling by Epo in multiple cell types. Epo-R appears to be expressed in normal human hepatocytes and cholangiocytes, to be upregulated in these cell types in advanced PSC, PBC, and HCV cirrhosis.

 

Summary:

Epo-R is expressed by adult murine hepatocytes and Epo appears to be directly hepatoprotective in H/R injury in primary hepatocyte culture. Additionally, Epo-R appears to be markedly upregulated in hepatocytes and cholangiocytes in many advanced liver diseases in man.

 

Conclusion:

Epo functions as a tissue protective cytokine in hypoxic liver injury.

 


S1580. Beneficial effects of the herbal medicine Inchin-ko-to on liver function and regeneration after massive hepatectomy in rats.

T. Ogasawara; T. Ikemoto; Y. Morine; S. Imura; M. Fujii; Y. Soejima; M. Shimada

 

Background and Aim

The herbal medicine Inchin-ko-to (ICKT), extract power from three herbs, brings improvement of liver function by promoting biliary excretion and inhibits liver fibrosis in a hepatitis rat model. Little has been reported about effects of preoperative administration of ICKT after hepatectomy.

 

Materials and Methods

Rats were divided into two groups: the ICKT group, 90% hepatectomy and administration of ICKT (2g/kg) for three days before hepatectomy; the control group, 90% hepatectomy. Following parameters were compared between the groups: survival rate, serum alanine aminotransferase (AST), total bilirubin, total bile acid (TBA), recovery of remnant liver weight and liver proliferating cell nuclear antigen (PCNA), alpha-smooth-muscle actin (α-SMA), heme oxygenase-1 (HO-1) levels.

 

Results

The remnant liver / body weight ratio (L/B ratio) 48 hours after op. in ICKT group was significantly higher than that in control group (1.7 ± 0.21% vs. 1.2 ± 0.12%, p<0.05; figure.1). In ICKT group, transamirases, TBA and total bilirubin were quickly improved (figure.2). In immunohistochemical analysis, PCNA labeling index at 24 hours after op. was significantly higher than that in control group. The α-SMA labeling index at 48 hours after op. was significantly lower than that in control group. HO-1 of ICKT group was strongly present in comparison with control group.

 

Conclusions

ICKT promoted liver regeneration after massive hepatectomy and improved liver function and survival.

 

 


S1583. Green Tea Polyphenols Attenuate Acetaminophen Hepatotoxicity.

H. S. Oz; J. Zhong; W. J. de Villiers; T. Chen

 

Introduction

Acetaminophen (APAP) overdose is a frequent cause of acute hepatic failure and death. APAP elucidates its hepatotoxicity utilizing multifactorial pathways. APAP toxicity has been associated with increased apoptosis, production of inflammatory cytokines, generation of cyclooxygenase (Cox-2), release of reactive metabolites, depletion of reduced glutathione (rGSH) and hepatic injury. Green tea polyphenols (GrTP) are antioxidants and we have shown to protect against activation of NF-κB and inducible kinases in intestinal epithelium and hepatic injury.

 

Methods

Here, we further investigated the mechanisms by which GrTP protect against hepatic injury. BALB/c mice were provided with diets supplemented with GrTP or vehicle. After 5 consecutive days one group of these mice received IP injection with toxic dose of APAP and euthanatized at 0, 4h and 24h.

Results

APAP administration induced marked decreases in hepatic rGSH levels and endogenous SAMe concentrations compared with sham injected controls. APAP caused marked increase in hepatic transaminase (ALT), inflammatory cytokines, severe centrilubular necrosis/apoptosis and leukocytes accumulation. APAP administration upregulated BCL-2, Fas and Cox-2 production in hepatic tissue. GrTP administration normalized APAP induced BCL-2 activation (p<0.01), and Cox-2 expression detected with immunohistochemistry and western analysis. GrTP also improved hepatic histology (p<0.01), ALT activity (p<0.05), and depletion of rGSH (p<0.05).

Conclusion

This is the first report that oral administration of GrTP attenuates hepatotoxicity by normalizing BCL-2 and Cox-2 activation suggesting a potential use for GrTP against APAP toxicity.

 


S1584. Protective effects of glycyrrhizin on acetaminophen-induced hepatotoxicity in mice.

G. Jinsheng; W. Jiyao; H. Jinhua; K. M. Wing Leung

 

Glycyrrhizin (GL) is the major bioactive triterpene glycoside of licorice (Glycyrrhizza glabra L.), which has been found to exert a variety of pharmacological effects, such as antiinflammatory, anticancer, antiallergic, antioxidant, and antiviral.

 

In the present study the protective effects of glycyrrhizin (GL) on acetaminophen (AAP)-induced acute liver injury in mice were investigated. A single dose of AAP (500 mg/kg) was injected intraperitoneally (i.p.) in male ICR mice followed by two doses of GL (100mg or 200mg/kg, i.p.) at 1 and 12 h later. Serum and liver samples were collected at 24 h. Hepatotoxicity was evaluated by liver histopathology and serum activities of aspartate and alanine aminotransferases (AST and ALT). Liver glutathione (GSH) content, the activity of inducible nitric oxide synthase (iNOS), and lipid peroxidation level in the hepatic tissue were assessed. Cytochrome c release from mitochondria to cytosol fraction, and apoptotic cell death in the liver tissue were also analyzed. It was found that GL dose-dependently normalized the rise of serum AST and ALT levels and improved the liver damage induced by AAP. It reduced the increase of iNOS activity and lipid peroxidation, abrogated the GSH depletion, the cytochrome c release and the apoptosis of liver cells in the livers of AAP intoxicated mice.

 

It was concluded that GL protects mice against AAP-induced hepatotoxicity by reducing oxidative damage and it could be a promising agent for the treatment of drug-induced liver toxicity.


S1585. 10 Cases of Severe Hepatotoxicity Associated with Dietary Supplements from Herbalife® Products.

A. Engel; A. Schoepfer; K. Fattinger; U. Marbet; D. Criblez; J. Reichen; C. M. Oneta

 

Background/Aims:

Herbal agents are popular with the public which perceives them as safe since they are ‘natural’. In many countries, they are categorized as dietary supplements and therefore, neither safety nor efficacy has to be established prior to marketing. Herbalife® products are quite popular being mostly used for weight reduction. We report a case series of toxic hepatitis implicating Herbalife® preparations.

 

Methods:

Based on a questionnaire sent to all hospitals and departments of pathology in Switzerland (return rate 75%) and a request to the Swiss pharmacovigilance database, we retrieved 13 cases of toxic hepatitis with intake of Herbalife® preparations between 1998 and 2004. In 10 of these sufficient data could be retrieved to subject them to the WHO criteria for causality assessment of hepatotoxicity (www.who-umc.org/defs.html).

 

Results:

Median age of the 10 patients (6 females, 4 men) was 51 years (range 30 - 69). Median onset latency was 5 months (range 2 - 24). Liver biopsy was performed in 7 patients. Hepatic necrosis, marked lymphocytic/eosinophilic infiltration and mild to moderate cholestasis were noticed in 5 patients. One female patient developed fulminant liver failure (FLF); this patient originating from Thailand had serologic evidence of past hepatitis B infection. Autoimmune etiology could not be excluded histologically, but autoantibodies remained negative. One male patient showed venoocclusive liver disease (VOD). The 3 patients without liver biopsy presented with cholestatic hepatitis. Other causes of liver disease were excluded in all patients with appropriate serological testing. There was neither concurrent disease nor intake of other drugs or chemicals. Causality assessment of adverse drug reaction was classified as certain in 2 (positive rechallenge), as probable in 5 and as possible in 3 cases. All patients recovered within some weeks after withdrawal of Herbalife® products with exception of the patient with FLF who underwent liver transplantation and the patient with VOD who developed cirrhosis.

 

Conclusion:

To our knowledge, this is the first case series of toxic hepatitis implicating Herbalife® products. Pathophysiologically, mostly immuno-allergic mechanisms appear to be responsible. Liver toxicity may be severe, causing fulminant hepatic failure and VOD. A high degree of suspicion and appropriate history taking is mandatory to reveal the potential for hepatotoxicity of ‘innocuous’ dietary supplements. Also, better declaration of components and a more active role of regulatory agencies in surveillance of such products would be desirable.


S1587. Drug-induced liver injury in the outpatient hepatology clinic: frequency, causes and clinical features.

E. Bjornsson; M. Benito Devalle; N. Alem; V. av Klinteberg; R. Olsson

 

Background:

Limited data exists on the proportion of drug-induced liver injury (DILI) among outpatients seen in a hepatology clinic in comparison with other diagnoses. We aimed to determine the proportion of DILI cases and identify the most important agents and the nature of the liver injury.

 

Methods:

·       A computerized diagnoses database in an outpatient hepatology clinic in a University hospital in Sweden was analysed.

·       All cases with a diagnosis of a liver disease seen for the first time between 1994 and 2005 were identified from a computerized diagnoses. 

·       All medical records were retrospectively reviewed in order to look for evidence of drug-induced liver injury.

·       Patients with acute liver failure with significant coagulopathy (INR ≥1.5) and/or those led to liver transplantation who were seen at the outpatient clinic were excluded.

·       Causality assessmen6 was based on International Consenus Criteria (RUCAM: J Clin Epidemiol 1993:46: 1323)

 

Results:

A total of 1164 cases were seen for the first time during this period.

Initially, 114 patients were classified as drug-induced liver injury leading to withdrawal of a number of drugs.  After careful review of their medical records, 34 cases were excluded.  In a total of 23 cases the diagnosis was changed after further investigations and another 10 cases were classified as unlikely or excluded based on the International Consensus Criteria and in two cases the medical records were incomplete.

 

Patients with drug-induced liver injury with at least possible causal relationship was present in 77 cases (6.6%), 38 (3.3%) of whom were referred for evaluation of abnormal liver tests whereas 39 (3.3%) had a follow-up after hospitalization

 

A total of 26 (34%) were scored highly probably, 35 (45%) probable and 16 (21%) possible according to RUCAM.

 

The medical age of the 77 patients was 58 (41-68 IQR) and 43 (56%) were females.

 

The majority of cases were classified as hepatocellular (48%), cholestic in 40% and 12% mixed type of liver injury.

 

·       Antibiotics were the most common agents associated with DIlI in 23 out of the 77 cases (30%).

·       NSAIDs were responsible for 17 cases with diclofenac in 14.

·       Other caused included azathioprine, atorvastatin, oestrogens, herbal drugs, and disulfiram.

 

Conclusions:

·       Patients with drug-induced liver injury constituted approximately 6% of all outpatients and 3% of all referrals.

·       Antibiotics and diclofenac were the most common drugs associated with drug induced liver injury. 

 


S1588. Liver Injury Related to Complementary and Alternative Medicine (CAM): Compared with Conventional Medicine-related Liver Injury. 

Y. Huang; F. Chang; S. Lee

 

Background and Aim:

Complementary and alternative medicine (CAM) is generally considered innocuous, which has been challenged by the increasing reports of adverse drug reaction of CAM recently. Most cases with CAM-related liver injury were reported sporadically. Systemic data in this category is little. The aim of this study was to explore the characteristics of CAM-related liver injury in Taiwan, compared with the conventional medicine-related liver injury.

 

Methods:

All patients with drug-induced liver injury (DILI) in our hospital from 1988 to 2003 were enrolled prospectively. The diagnosis of DILI was based on CIOMs criteria with the RUCAM score > 5. The patients with viral hepatitis, alcoholic liver disease, and other systemic diseases which may cause abnormal liver biochemical tests were excluded.

 

Results:

A total of 619 cases were diagnosed to have DILI. Of them, 148 (24%) were CAM-related, and 471 (76%) were conventional medicine-related. The CAM group had higher mean age (58.9 + 13.3 vs. 55.8 + 17.0 years old, p < 0.05), percentage of education level below high school (68.2% vs. 51.4%, p < 0.05), and serum bilirubin level (8.9 + 10.1 vs 5.5 + 7.1 mg/dL, p < 0.05) than those of conventional medicine group. However, there was no statistical difference of gender, mean serum ALT (854.5 vs. 824.1 U/L), AST (796.3 vs. 710.9 U/L), alkaline phosphatase (232.4 vs. 224.3 U/L) and gamma-glutamyl transpeptidase (221.2 vs. 266.8) between 2 groups. Mortality of CAM group was 4.7% (7 cases), which was comparable to that of conventional medicine group (5.1%, 24 cases). The incriminated agents of CAM-related mortality cases were dry snake gall bladder 3, clerodendruon calamitosum 1, compound herbs 3. The leading offending drugs of conventional medicine group were anti-tuberculosis drugs, antibiotics and non-steroid anti-inflammatory drugs.

 

Conclusions:

·       One fourth of drug-induced liver injury in Taiwan is due to CAM.

·       The patients with CAM-related DILI had older age, lower educational level and higher mean serum bilirubin level than those of conventional medicine related.

·       Besides botanical herbs, the animal products (such as snake gallbladder in this series) may cause serious DILI.

·       CAM is not harmless as assumed.

·       Strict pharmaco-vigilance in CA< is urgently needed.

 

 


S1590. Excessive and Chronic Ethanol Consumption Promotes Hepatic Carcinogenesis by Altering the Normal Hepatocyte Homeostasis in the Liver of Diethylnitrosamine-initiated Rats.

P. R. Chavez; H. K. Seitz; P. Bannasch; R. M. Russell; X. Wang

 

Introduction

Chronic and excessive alcohol consumption has been related to an increased risk of several cancers including hepatocellular carcinoma. Previous animal models to elucidate ethanol’s role as a possible tumor promoter involved several confounding factors (e.g., partial hepatectomy, lack of certain dietary components or co-administration of diethylnitrosamine (DEN) along with ethanol). In contrast, an inhibitory effect of ethanol on hepatocarcinogenesis in an animal model has been reported when co-administering DEN with ethanol, and due to a possible competition for cytochrome p450 enzymes.

Aim

The aim of the present study was to elucidate ethanol’s role as a tumor promoter using a low dose of DEN acting as an initiator in rat model without the other confounding factors.

Methods

Male Sprague-Dawley rats (six groups, n=7/each group) were given as an intraperitoneal injection of 20 mg DEN/kg body weight one week before the feeding experiments began to avoid possible interactions between ethanol and carcinogen activation. Then the rats were fed either an ethanol liquid diet (Lieber-DeCarli diet) or a non-ethanol liquid diet with isocaloric maltodextrin for 1, 6 and 10 months, respectively. Hepatocyte proliferation was assessed by immunohistochemistry for proliferating cellular unclear antigen (PCNA) and Ki67, as well as cell cycle components (cyclin D1, and p21). Hepatocarcinogenesis was assessed by examining placental glutathione-s-transferase immunostaining of altered hepatic foci (AHF) and pathological lesions.

Results

·       Liver weights in the ethanol fed rats were significantly higher (P<0.05), no difference, and significantly lower (P<0.01) after 1-, 6- and 10-months of treatment, respectively, as compared with that of the non-ethanol fed rats at the same time points.

·       In contrast to the 1-month treatment, both PCNA and Ki-67 labeling, cyclin D1 levels as well as p21 expression in the livers of ethanol fed rats were significant lower, as compared with that of the non ethanol fed rats after the 6- and 10-months of treatment.

·       Ethanol feeding showed significantly lower numbers of AHF after a 10-month period.

·       However, hepatic amphophilic focus of cellular alteration, nodular regenerative hyperplasia, and hepatocellular adenoma were detected in the ethanol-fed rats after 10-months of treatment, but not in the non-ethanol fed rats with the same dose of DEN treatment.

Conclusion

The present study demonstrates that chronic and excessive ethanol consumption alone promotes hepatic carcinogenesis by altering the cell homeostasis in the rat liver. This animal model may be a useful tool for studying alcohol-related hepatic cancer prevention, especially for dietary intervention.