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
|
Median ↓ HCV |
|
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
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.
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 |
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.
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.
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.
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.