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BACKGROUND Whether hepatitis B virus (HBV) infection can affect the outcomes of drug-induced liver injury (DILI) is controversial. This study aimed to evaluate the characteristics and outcomes of DILI in Taiwan, with an emphasis on the impact of HBV infection. METHODS We prospectively recruited patients with DILI from multiple centers in Taiwan from 2010 to 2018. RESULTS A total of 1,014 patients were enrolled. The leading culprit drug category was antimicrobials (481, 47.4%), followed by non-steroidal anti-inflammatory drugs, anticonvulsants, and statins. Among the antimicrobials, antituberculosis agents were most likely to induce liver injury (257, 25.3%), followed by antibacterial, antifungal and antiviral agents. The liver-related mortality rate was 8.2% (83/1,014). The patients who died had higher rates of hepatocellular-type liver injury, elevated liver biochemical tests, preexisting liver cirrhosis, jaundice, chronic HBV infection and antituberculosis drug-induced liver injury (ATDILI) than the survivors. A total of 131 patients (12.9%) with DILI were HBV carriers, of whom 23 (17.6%) died of hepatic failure. The rate of HBV-DNA > 2000 IU/mL was higher in the patients who died (47.8% vs. 26.9%, p = 0.047) than in the survivors. After adjusting for possible risk factors, active HBV infection with HBV-DNA > 2000 IU/mL was the most significant risk factor for liver-related mortality (adjusted HR: 4.40, 95% CI: 2.31-8.38, p < 0.001). The other independent risk factors for mortality were ATDILI and albumin-bilirubin (ALBI) score (adjusted HR: 1.25 and 4.09, respectively, p < 0.003). CONCLUSION Antituberculosis agents were the leading cause of DILI in Taiwanese, and they were associated with poorer outcomes than other drug categories. Active HBV infection, ATDILI and ALBI score were independent risk factors for fatal DILI. Close monitoring of liver tests and timely anti-viral therapy should be implemented in HBV carriers during the administration of high-risk drugs, such as antituberculosis agents.

BACKGROUND & AIMS Severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are high-mortality adverse drug reactions. The risk factors and prognosis of drug-induced liver injury (DILI) concomitant with SCAR warrant clarification. We aimed to evaluate the characteristics and outcomes of DILI with SCAR. METHODS We analysed the database of a 10-year multi-centre prospective study in Taiwan from 2011 to 2020. RESULTS A total of 1415 patients with DILI were enrolled, including 81 cases combined with SJS/TEN, 74 with DRESS, 3 with AGEP and 1257 with pure DILI. Approximated 11.2% of patients had SCAR, of which allopurinol was the leading incriminated drug, followed by sulphonamides and carbamazepine. The SJS/TEN group had the highest mortality (34.6%). Jaundice, acute kidney injury and SJS/TEN were independent risk factors of mortality (odds ratio: 29.54, 4.43 and 4.86, respectively, P

Background Hyperbilirubinemia is a predictor of severe drug-induced liver injury (DILI). Hepatobiliary ATP-binding cassette (ABC) transporters play an important role in the transportation of many drugs and bilirubin; however, little is known about these transporters and the risk of DILI. The aim of this study was to explore associations between genetic variations in important ABC transporters and susceptibility to DILI, with a particular focus on hyperbilirubinemia. Methods A total of 200 patients with DILI and 200 healthy controls were enrolled as the training dataset. Another 106 patients with DILI were recruited as the validation dataset. They were genotyped for ABCB11 (BSEP) rs2287622, ABCB1 (MDR1) rs1128503, rs1045642, ABCB4 (MDR3) rs2230028, ABCC2 (MRP2) rs1885301, rs717620, rs2273697, rs3740066 and rs8187710 using polymerase chain reaction-based TaqMan genotyping assays. Results There were no statistical differences in any of the nine ABC transporter single nucleotide polymorphisms between the DILI and control groups. However, in the DILI group, the patients with hyperbilirubinemia had a higher frequency of the ABCC2 rs717620 C/T and T/T genotypes than those without hyperbilirubinemia (44.2% vs 20.2%, p = 0.001). After adjusting for other confounding factors, the ABCC2 rs717620 T variant was still associated with an increased risk of hyperbilirubinemia (adjusted odds ratio [OR]: 3.83, 95% confidence interval [CI]: 1.73-8.48, p = 0.001). This association was confirmed by the validation dataset (adjusted OR: 3.92, 95% CI: 1.42-10.81, p = 0.015). We also found that the mortality group had higher frequencies of the ABCC2 (MRP2) rs717620 C/T and T/T genotypes than the survival group (50.0% vs 27.9%, p = 0.048). Conclusion Carriage of the ABCC2 (MRP2) rs717620 T variant may increase the risk of hyperbilirubinemia and mortality in patients with DILI. Screening for this variant may help to prevent and mitigate drug-induced hyperbilirubinemia.

Background Nonalcoholic steatohepatitis (NASH) is closely related to reactive oxygen species (ROS). Superoxide anion radicals, the main product of ROS, can be reduced by manganese superoxide dismutase (SOD2) to hydrogen peroxide, which is further reduced by catalase (CAT) and glutathione peroxidase (GPX) to water. We aimed to investigate the association between the most important genetic variants of SOD2, CAT, and GPX1 and susceptibility to NASH. Methods A total of 126 adults with liver tissue-verified NASH, 56 patients with liver tissue-verified nonalcoholic fatty liver (NAFL), and 153 healthy controls were enrolled. Their DNA profiles were retrieved for genotype assessment of SOD2 47T>C (rs4880), CAT -262C>T (rs1001179), and GPX1 593C>T (rs1050450) variation. Results There were statistical differences between the SOD2 and CAT genotypes across the NASH, NAFL, and control groups, but not GPX1. The NASH group had a significantly higher frequency of subjects with SOD2 C allele (38.8%) compared with the NASL group (25.0%) and the controls (22.9%, p = 0.010). Similarly, the NASH group had a significantly higher percentage of subjects with CAT T allele (23.0%) compared with the NAFL group (10.7%) and the controls (7.2%, p = 0.001). For subjects with both the SOD2 C allele and CAT T allele, 88.2% were in the NASH group. After adjusting for confounders, the CAT mutant T allele and SOD2 mutant C allele were still the highest independent risk factors for NASH (odds ratio [OR] 3.10 and 2.36, respectively). In addition, there was a synergistic effect for those two alleles and the occurrence of NASH with an adjusted OR of 8.57 (p = 0.030). Conclusion The genetic variations of CAT and SOD2 may increase the risk of NASH, which may aid in the screening of patients who are at high risk of NASH, and offer a potential anti-oxidant targeting route for the treatment of NASH.

Hepatitis delta virus (HDV) is a defective virus that relies on the supply of hepatitis B surface antigen (HBsAg) from hepatitis B virus (HBV) to assemble HDV virions and infect hepatocytes. However, controversy remains in whether the presence of HDV increases the risk of hepatocellular carcinoma (HCC). Our aim is to evaluate the influence of HDV on the risk of HCC through a systematic review and meta-analysis.A review of all English-language literature was conducted in the major medical databases using the subject search terms "hepatocellular carcinoma," "liver cancer," "hepatic tumor," and "hepatitis delta." A meta-analysis of the qualifying publications was then performed.The meta-analysis included 21 studies, which revealed a significantly higher risk of HCC among patients with HDV/HBV dual infection (odds ratio [OR] = 2.08, 95% confidence interval [CI], 1.37-3.14, p 0.01) compared with those with HBV monoinfection. Those with HDV/HBV dual infection remained at higher risk of HCC in the subgroup analysis, irrespective of the status of hepatitis C virus (HCV) or human immunodeficiency virus (HIV) coinfection and in different ethnicities. The HCC risk remained higher in patients with HDV/HBV dual infection with heterogeneous fibrosis stage (OR = 2.04, 95% CI, 1.31-3.17, p 0.01). The difference in the risk of HCC between HDV/HBV dual infection and HBV monoinfection was not statistically significant in patients with cirrhosis or advanced fibrosis (OR = 1.84, 95% CI, 0.48-7.02, p = 0.37). However, this subgroup comprised only two studies.HDV and HBV dual infection significantly increase the risk of HCC development compared with HBV monoinfection.

BACKGROUND The mainstay therapy for latent tuberculosis infection is a 9-month regimen of daily isoniazid (9H) and a 3-month regimen of 12 once-weekly doses of isoniazid and rifapentine (3HP). We performed this updated meta-analysis to compare hepatotoxicity, efficacy and completion rate between these two regimens. METHODS We searched all literature in the major medical databases using the subject search terms "isoniazid" and "rifapentine", and performed a systemic review and meta-analysis. RESULTS A total of 14 studies were eligible for the meta-analysis, which included 5600 (49%) patients who received the 3HP regimen and 5919 (51%) patients who received the 9H regimen. A total of 202 (2%) patients had a drug-induced liver injury (DILI) and 11 317 (98%) did not. The pooled odds ratio (OR) of DILI in the 3HP regimen was 0.18 (95% confidence interval [CI], 0.12-0.26; p < 0.0001), compared with the 9H regimen. This result remained consistent in subgroup analyses of ethnicity and study design. The 3HP regimen was superior to the 9H regimen in the prevention of active tuberculosis (OR, 0.38, 95% CI, 0.18-0.80, p = 0.01). Furthermore, the 3HP regimen was associated with a better completion rate than the 9H regimen (OR: 2.30, 95% CI, 2.10-2.53, p < 0.0001). CONCLUSION The 3HP regimen is superior to the 9H regimen, with less hepatotoxicity, and better efficacy and completion rate in treating latent tuberculosis infection.

OBJECTIVES Sulfamethoxazole-trimethoprim (SMX-TMP) is one of the most frequently used antibiotics. SMX is metabolized by N-acetyltransferase (NAT) and cytochrome P450 2C9 (CYP2C9) to nontoxic or toxic intermediates. Little is known about the association between genetic variations of these enzymes and SMX-TMP-induced liver injury (SILI). The aim of this study was to explore the genetic polymorphisms of NAT2 and CYP2C9 and the susceptibility to SILI in a Han Chinese population. METHODS A total of 158 patients with SILI and 145 controls were recruited in this study. PCR-based genotyping with matrix-assisted laser desorption ionization-time of flight was used to assay the major NAT2 and CYP2C9 genotypes including NAT2 rs1495741, rs1041983, rs1801280, CYP2C9 rs1799853, rs1057910 and rs4918758. RESULTS The SILI group had a higher frequency of the NAT2 rs1495741 variant AA genotype and rs1041983 variant TT genotype than the controls (42.4 vs. 25.5%; P = 0.008, and 40.5 vs. 25.5%; P = 0.022, respectively). The SILI group had more slow acetylators than the controls (43.7 vs. 25.5%; P = 0.001). There were no significant differences in the genetic variations of CYP2C9 between the SILI and control groups. After adjusting for confounding factors, the NAT2 slow acetylators still had an increased risk of SILI (adjusted OR: 2.49; 95% confidence interval: 1.46-4.24; P = 0.001), especially in those with hepatocellular and mixed type SILI. CONCLUSIONS NAT2 slow acetylators are associated with a higher risk of SILI in the Han Chinese population. However, CYP2C9 genetic polymorphisms are not associated with the susceptibility to SILI.

BACKGROUND Worldwide, proton pump inhibitors (PPIs) are commonly used for the treatment of peptic ulcer and gastro-esophageal reflux disease. Recently, concern has arisen over the potential association between PPIs and hepatocellular carcinoma (HCC). The aim of the current study was to evaluate the influence of PPI use on the risk of HCC, through a systematic review and meta-analysis. METHODS A review of all English-language literature was conducted, using the subject search terms: "hepatocellular carcinoma", "liver cancer", "hepatic tumor", and "proton pump inhibitor" in the major medical databases. A meta-analysis of the qualifying publications was then performed. RESULTS A total of five studies, which had shown that PPIs were associated with HCC (crude risk ratio [RR] = 2.27, 95% confidence interval [CI]: 1.44-3.57; p < 0.01) when an unadjusted RR were adopted, were eligible for meta-analysis. It was observed that the cumulative dose of PPIs may increase the risk of HCC in a linear model (p < 0.01). However, when using data that were adjusted by comorbidities and concurrent medications, the association between PPIs and HCC became insignificant (adjusted RR = 1.62, 95% CI: 0.89-2.93; p = 0.11) and this result was consistent in the sensitivity analysis. CONCLUSION The current meta-analysis has shown that PPI use does not significantly increase the risk of HCC after adjusting for confounding factors. However, further studies are warranted to verify the association between PPIs and HCC in special populations, such as viral or alcoholic liver diseases.

BACKGROUND Antituberculosis (TB) drug-induced liver injury (ATLI) is a common adverse effect of anti-TB drugs. Whether regular monitoring of liver function can ameliorate ATLI has been widely debated. The current study aimed to investigate the liver test monitoring status of patients receiving anti-TB treatment in Taiwan, as well as the impact of scheduled liver function monitoring on the risk of ATLI. METHODS Patients who received anti-TB treatment at our hospital between 2009 and 2017 were enrolled for retrospective analysis. RESULTS A total of 1062 patients were included, and of them 469 (44.2%) received regular liver function monitoring (good monitoring group). ATLI was recognized in 100 (9.4%) patients. The good monitoring group detected more ATLI cases early compared with the poor monitoring group (14.7% vs 5.2%, and 21.4 vs 61.6 days, p < 0.01), with a lower peak serum alanine aminotransferase (276.1 vs 507.1 IU/L, p = 0.05). CONCLUSION In the current study, less than half of all patients who received anti-TB drugs had their liver function monitored regularly. Scheduled monitoring of liver function could facilitate the early identification of more ATLI cases, thus leading to less liver injury. The implementation of periodic liver function monitoring tests in patients receiving anti-TB treatment should be re-emphasized and encouraged.

Whether herbal and dietary supplements (HDS) are safer than Western conventional drugs is controversial. The aim of this study was to explore the characteristics and risk factors for HDS-induced liver injury (HILI) in Taiwan. This is a 9-year multi-center prospective study conducted in Taiwan from 2011 to 2019. Patients with HILI were compared to those with conventional drug-induced liver injury (CILI). A total of 1,297 patients were enrolled, of whom 285 (22.0%) had HILI and 1,012 (78.0%) had CILI. Compared to the CILI group, the HILI group had higher initial serum alanine aminotransferase, alkaline phosphatase (ALP), peak ALP and bilirubin levels, and higher rates of jaundice, ascites, encephalopathy, coagulopathy, sepsis and acute liver failure. In addition, the HILI group had a higher mortality rate than the CILI group (12.6 vs. 8.0%, p = 0.016). Hepatitis B carrier status, elevated baseline liver biochemical tests and the use of crude herbs (without processing) were associated with an increased risk of HILI-related mortality (adjusted hazard ratios [95% confidence intervals]: 2.90 [1.43–5.99], 2.40 [1.01–5.68] and 2.94 [1.45–5.97], respectively). HDS are popular and incriminated in more than one-fifth of drug-induced liver injuries in Taiwan. The patients with HILI were more severe than those with CILI in terms of liver biochemical tests, complications and mortality. Hepatitis B carriers, those with elevated baseline liver tests and crude herb users may have a higher risk of HILI-related mortality. The prudent use of HDS is suggested in these high-risk subjects.

Simultaneous random access attempts from massive machine-type communications (mMTC) devices may severely congest a shared physical random access channel (PRACH) in mobile networks. This paper presents a novel two-phase random access (TPRA) procedure to deal with the congestion caused by mMTC devices accessing the PRACH. During the first phase, the TPRA splits the mMTC devices into smaller groups according to a preamble selected randomly by the devices. Then, in the second phase, each group of devices is assigned with a dedicated channel to complete the random access procedure. The proposed concept allows a base station to adjust the number of dedicated channels in real-time according to the actual network load. We then present an analytical model to estimate the access success probability and the average access delay of the TPRA. Finally, we propose a simple formula to determine the optimal number of random access resources for the second phase of the proposed TPRA. Simulations are carried out to validate the analytical models and to demonstrate the benefits of the TPRA compared to competitive techniques.

Background N -Acetyltransferase (NAT) is an important enzyme with the capacity to metabolize carcinogenic aromatic amines. However, it remains controversial whether the encoded functional NAT2 genetic polymorphism is related to the risk of gastric adenocarcinoma (GA). The aim of this study was to evaluate the association between NAT2 genetic variation and gastric adenocarcinoma (GA), with special reference to the gastric noncardiac adenocarcinoma (GNA). Methods Peripheral white blood cell DNA from 368 GA patients and 368 age- and sex-matched controls were genotyped for NAT2 by a polymerase chain reaction method. The lifestyle habits of the participants were assessed using a semiquantitative food–frequency questionnaire. NAT2 genotype, interaction with lifestyle habits, and the risk of GA and GNA were analyzed by logistic regression. Results GA patients were more likely to have a smoking habit, ate more salted foods, and consumed more well-done meat than the controls. There was no association between the NAT2 genotypes and susceptibility to GA. However, if patients with gastric cardiac adenocarcinoma (GCA; n = 42) were excluded, the NAT2 slow acetylators (without rapid acetylator allele) had a higher risk of GA than intermediate and rapid acetylators (odds ratio = 1.53; 95% confidence interval, 1.05–2.23, p = 0.027). In addition, there was a synergic effect of NAT2 slow acetylator and well-done meat intake to the development of GNA (odds ratio = 3.83; 95% confidence interval, 1.68–8.76, p = 0.001). Conclusion NAT2 slow acetylators have a higher risk of GNA than intermediate and rapid acetylators have in a Taiwanese population. The intake of well-done meat, an additive to the acetylator status, may contribute to the incidence of gastric carcinogenesis.

Background Recent studies have shown that the peripheral inflammation may cause the up-regulation of central nervous system inflammation and therefore possibly plays a vital role in the pathophysiology of subsequent psychiatric disorders. Objective We explored the relationship between gastroesophageal reflux disease (GERD) and the subsequent development of psychiatric disorders including schizophrenia as well as bipolar, depressive, anxiety, and sleep disorders. Methods We investigated patients who were diagnosed with GERD according to the data in the Taiwan National Health Insurance Research Database. A comparison cohort comprised patients without GERD who were matched according to age and sex. The incidence rate and the hazard ratios (HRs) of subsequent new-onset psychiatric disorders were calculated for both cohorts, based on the diagnoses of psychiatrists. Results The GERD cohort consisted of 3813 patients, and the comparison cohort comprised 15,252 matched control patients without GERD. The risks of depressive disorder (HR = 3.37, 95% confidence interval [CI] = 2.49–4.57), anxiety disorder (HR = 2.99, 95% CI = 2.12–4.22), and sleep disorder (HR = 2.69, 95% CI = 1.83–3.94), were higher in the GERD cohort than in the comparison cohort. In addition, the incidence of newly diagnosed depressive, anxiety, and sleep disorders remained significantly increased in all of the stratified follow-up durations (0–1, ≥ 1 year). Conclusions GERD may increase the risks of subsequent depressive, anxiety, and sleep disorders. These psychiatric disorders have a negative effect on people's quality of life. Clinicians should pay a particular attention to psychiatric comorbidities in GERD patients.

Background Anti-tuberculosis drug-induced liver injury (ATDILI) is a major safety concern in the treatment of tuberculosis (TB). The impact of chronic hepatitis C (CHC) infection on the risk of ATDILI is still controversial. We aimed to assess the influence of CHC infection on ATDILI through a systematic review and meta-analysis. Methods We systemically reviewed all English-language literature in the major medical databases with the subject search terms “anti-tuberculosis drug-induced liver injury” and “anti-tuberculosis drug-induced hepatotoxicity”. We then performed a systematic review and meta-analysis of the papers relevant to hepatitis C in qualified publications. Results A total of 14 studies were eligible for analysis, which included 516 cases with ATDILI and 4301 controls without ATDILI. The pooled odds ratio (OR) of all studies for CHC infection to ATDILI was 3.21 (95% confidence interval (CI): 2.30–4.49). Subgroup analysis revealed that the CHC carriers had a higher risk of ATDILI than those without CHC both in Asians (OR = 2.96, 95% CI: 1.79–4.90) and Caucasians (OR = 4.07, 95% CI: 2.70–6.14), in those receiving standard four combination anti-TB therapy (OR = 2.94, 95% CI: 1.95–4.41) and isoniazid monotherapy (OR = 4.18, 95% CI: 2.36–7.40), in those with a strict definition of DILI (serum alanine aminotransferase [ALT] > 5 upper limit of normal value [ULN], OR = 2.59, 95% CI: 1.58–4.25) and a loose definition of DILI (ALT > 2 or 3 ULN, OR = 4.34, 95% CI: 2.96–6.37), and in prospective studies (OR = 4.16, 95% CI: 2.93–5.90) and case–control studies (OR = 2.43, 95% CI: 1.29–4.58). Conclusion This meta-analysis suggests that CHC infection may increase the risk of ATDILI. Regular liver tests are mandatory for CHC carriers under anti-TB therapy.

Background & Aims Non-alcoholic fatty liver disease is the most prevalent liver disease in the world. However, the exact mechanisms that lead to development of advanced non-alcoholic steatohepatitis (NASH) are unknown. Oxidative stress may be an important pathogenic factor in NASH. Manganese superoxide dismutase (SOD2) is an important antioxidant phase 2 enzyme that can reduce reactive oxidative substances and protect hepatocytes. In contrast, cytochrome P450 2E1 (CYP2E1) has pro-oxidant activity and may enhance oxidative stress and counteract the effect of SOD2. Little is known regarding the associations of genetic variants of these enzymes with the risk of NASH. We aimed to investigate the association of genetic variants of SOD2 and CYP2E1 with susceptibility to NASH. Methods Data from 100 patients with NASH, 31 patients with non-alcoholic steatosis (NAS) and 90 healthy controls were analysed. Their DNA was retrieved for genotyping SOD2 47T>C and CYP2E1 −1053C>T variation by polymerase chain reaction. Results There was no statistical difference in the frequency distributions of SOD2 and CYP2E1 genotypes among the NASH, NAS and control groups. However, the frequency of the SOD2 C variant was significantly higher in the NASH group than in the NAS and control groups (22% vs. 14.5% and 11.1%, respectively; P = 0.015). After adjustment for confounders, the SOD2 C/C and C/T genotypes remained associated with the risk of NASH (odds ratio, 2.81; 95% confidence interval, 1.37–5.76; P = 0.005). Conclusions The anti-oxidative SOD2 47T>C genetic variant might increase susceptibility to NASH in Chinese. Individuals with the SOD2 C variant may have a higher risk for NASH.

Antituberculosis drug-induced liver injury (ATDILI) is the most prevalent hepatotoxicity in many countries. All of the three first-line antituberculosis drugs, isoniazid, rifampicin, and pyrazinamide, may induce hepatic damage, especially isoniazid. The major drug-metabolizing enzyme of isoniazid is N-acetyltransferase (NAT). Other possible enzymes are CYP2E1, glutathione S-transferase (GST) and manganese superoxide dismutase (MnSOD, SOD2). There is evidence that variations of the genes that encode these enzymes may influence the activity of the corresponding drug-metabolizing enzymes. Recent studies have demonstrated that these genetic variations may be associated with the risk of ATDILI. Among them, NAT acetylation status has been most studied. The proposed risk-associated genotypes are NAT2 slow acetylator (without wild-type NAT2*4 allele), CYP2E1 *1A/*1A (homozygous wild type), homozygous null GSTM1 genotype and MnSOD mutant C allele. Although the available data in the field are complex and inconsistent, meta-analyses disclosed that NAT2 slow acetylator status possesses the highest association (odds ratio = 3.18). There are associations of CYP2E1 *1A/*1A and homozygous null GSTM1 genotype with ATDILI by meta-analyses, but the odds ratios were lower than that of NAT2. Of note, there was an ethnic difference in this association. The ATDILI in East Asians seems to have a higher correlation with genetic variations of NAT2, CYP2E1 and GSTM1. However, the meta-analyses could not validate these associations in Caucasians, although some showed positive correlations. To mitigate the crucial ATDILI, this review article underlines the importance of this pharmacogenetic endeavor to identify high-risk patients.

Aim Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations. Methods A population-based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort. Results Of the 90 847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10 000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration ≥ 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10 000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P < 0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI. Conclusions Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole.

Aims Statin-induced liver injury (SILI) is quite rare, but may be severe. Little is known about the impact of chronic hepatitis B infection (CHBI) on SILI. We aimed to investigate the risk factors and outcome of SILI, with special reference to its interaction with CHBI. Methods Patients with SILI were recruited from our hospital, and three-to-one drug-matched controls were randomly selected. The clinical data of the patients were then compared. Results A total of 108 patients with SILI and 324 controls were enrolled. The patients with SILI were both older and had a higher statin dose than the controls. There was no predilection of liver injury associated with the seven available statins. Among the SILI patients, there was no statistical difference between the baseline and peak liver enzyme tests, and latency and severity between hepatitis B carriers (n = 16) and non-carriers (n = 92). High dose of statin and age were the two independent risk factors of SILI (OR and 95% CI: 1.93, 1.08–3.35, P = 0.025, and 1.73, 1.07–2.80, P = 0.027, respectively). Permanent discontinuation of statin was noted in 50 (46.3%) patients with SILI due to severe SILI or recurrent hepatotoxicity after rechallenge of other statins. Conclusion High dose of statin and old age may increase patient susceptibility to SILI; however, CHBI and abnormal baseline liver tests are not risk factors of SILI. Nonetheless, SILI is still worthy of notice, because nearly half of the overt cases discontinued statin treatment due to severe hepatotoxicity in this study.

Background: Polymorphism of N-acetyltransferase 2 gene was reported to be associated with the susceptibility of various cancers and liver diseases. However, its relationship to alcoholic liver disease is controversial and open to debate. The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms and the susceptibility to alcoholic liver cirrhosis (ALC) in Chinese, with special emphasis on the interaction of smoking. Methods: Peripheral white blood cell DNA from 148 patients with ALC, 104 patients with long-term alcoholic drinking but without cirrhosis (ANC) and 209 healthy controls were genotyped for NAT2 using a polymerase chain reaction–restriction fragment length polymorphism method. The possible confounding factors were included for analysis. Results: There was no statistical difference in the frequency of NAT2 genotype or NAT2 acetylator status among the 3 groups. However, among the chronic alcoholic drinkers, the rapid acetylators with smoking habits had higher percentage of ALC than those without smoking habit (18.9% vs. 9.5%, p = 0.002). The adjusted odds ratio for rapid acetylator smoker to have ALC was 3.45 (95% CI = 1.53 to 7.76, p = 0.003). Conclusions: The genetic factor, NAT2 polymorphism, may interact with environmental factor, smoking, to confer different susceptibilities to ALC. NAT2 rapid acetylators with smoking habit may increase the risk of ALC in Chinese.

Heat stroke is a life-threatening illness, and the disease spectrum can include the involvement of multiple organs to varying degrees. Rhabdomyolysis with renal function impairment is frequently noted in this disease. However, acute hepatic failure has been rarely reported in non-exertional heat stroke. We report a case of acute hepatic failure combined with disseminated intravascular coagulopathy, acute renal failure, and neurological deficit caused by heat stroke after bathing in a hot spring. Molecular adsorbent recirculating system (MARS) treatment was performed daily on days 10–12 of admission. As a result of progressive azotemia, hemodialysis was performed. Unfortunately, after a long course of intensive care, the patient died from septic shock and multiple organ failure. According to available evidence, MARS and hemodialysis are beneficial in treating exertional heat stroke. However, a limited number of studies have treated non-exertional heat-stroke-related acute hepatic failure. Early cooling to reduce the overwhelming heat-stress-related cytokine storm, and advanced MARS to eliminate circulating toxin might have a role in treating this rare but fatal illness.

Background: Interleukin (IL)-12 is a proinflammatory cytokine produced by antigen-presenting cells upon stimulation by diverse stimuli. This study aimed to explore the relationship between IL-12 serum levels and different stages of alcoholic liver disease, alcoholic intake status and abstinence from alcohol. Methods: A total of 35 healthy controls without alcohol consumption and 94 patients with alcoholic liver disease (17 with alcoholic steatosis, 37 with alcoholic hepatitis, 40 with alcoholic cirrhosis) were included. Their serum IL-12 levels were measured and followed-up at the 3 rd ,6 th and 9 th months. Data were further analyzed according to abstinence from alcohol or not. Results: Mean serum IL-12 levels were higher in the alcoholic hepatitis group (163.1 ± 57.8 pg/mL) than in the alcoholic liver cirrhosis group (110.5 ± 41.6 pg/mL) and alcoholic steatosis group (74.4 ± 26.2 pg/mL). All of these 3 alcoholic groups had higher serum IL-12 levels than the control group (39.3 ± 8.3 pg/mL; p < 0.02). Among the patients who abstained from alcohol, there was no difference in serum IL-12 levels between control and steatosis patients at the 9 th month, but the serum IL-12 levels of the hepatitis and cirrhosis groups were still higher than in the control group (p < 0.001 and p = 0.001, respectively). In addition, the patients who continued to drink alcohol had higher serum IL-12 levels than those who abstained from alcohol in the steatosis, hepatitis and cirrhosis groups. At the cut-off value of 54 pg/mL, IL-12 had good sensitivity and specificity in the diagnosis of alcoholic liver disease. Conclusion: Serum IL-12 levels reflected the different stages of alcoholic liver disease and can represent the status of continuous alcohol consumption. It has the potential to be a biomarker of alcoholic liver disease. [J Chin Med Assoc 2010;73(2):67–71]

Idiosyncratic drug-induced liver injury (DILI) is the single most frequent adverse drug reaction (ADR) causing drug withdrawal from the market. It accounts for more than a half of acute liver failure in the USA. The advent of genomics has made great progress in pharmacogenetics and pharmacogenomics. Many studies concerning genetic tests in DILI have emerged, raising the question of: is it beneficial to tailor drug treatment for alleviating DILI based on these genetic studies? A compendium of positive genetic-association studies in DILI exist (Table 1). Most are related to the genetic polymorphisms of the drug metabolizing enzymes and some emphasize an association of HLA with DILI, but there are very little data regarding genetic polymorphisms of acquired immunity. Although a biomarker to predict idiosyncratic DILI is urgently needed, there is still no official recommendation for genotyping prior to initiating drug therapy in order to reduce the incidence of DILI. Why is the application of pharmaco genomics in DILI and other ADRs unable to keep abreast of the recent progress in genomic knowledge and techniques? Many obstacles seem to convert the initial optimism and expectation into skepticism. While the genetic approach for predicting therapeutic efficacy and safety is a crucial way of establishing optimal personalized medicine, many complex problems emerge when interpreting available genetic data. First, prospective clinical trails with genetic tests are an appropriate way to obtain beneficial information with little bias, but their value may be counteracted by their study designs. Through regular monitoring, they provide the opportunity to identify susceptible patients with a mild form of hepatotoxicity. Most trials warrant discontinuation of the drug when serum aminotransferase levels rise to three–five-times the upper limit of normal (ULN), or when serum bilirubin levels are elevated by two–threetimes the ULN. It is questionable whether these cohorts would have developed severe hepatotoxicity had therapy been continued. Therefore, cases with severe DILI or ‘Hy’s rule’ are rarely detected, even in large clinical trials, because of the low incidence of severe cases and the early discontinuation of the involved drug. Mild liver dysfunction cannot be neglected but is always less clinically significant and is easily confused with other background noise, such as fatty liver. For the US Drug-Induced Liver Injury Network (DILIN), the criterion for enrolling DILI patients is elevated serum transferase to more than five-times the ULN. The recruitment criteria and definition of DILI in genetic studies are diverse and include patients with mild DILI (Table 1). Second, many DILI patients may have the adaptation phenomenon, which means that they resume normal or near-normal liver function without discontinuing the incriminating drug. Such adaptation is observed in more than a half of patients with anti-tuberculosis DILI. However, prospective trials cannot always discriminate adaptors owing to early drug withdrawal. Furthermore, there is no consensus regarding the diagnosis of DILI in these genetic studies, such that the DILIN and the US FDA have recently endeavored to standardize the nomenclature and causality assessment through a series of workshops. The other skepticism of genetic tests involves environmental factors that may alter the gene expression of drug-metabolizing enzymes and drug responses. These include age, gender, nutritional status, drug co-administration, alcohol consumption, food, chronic viral hepatitis infection, fatty liver and comorbidities. The triangle interaction of drug, host genetic factors and environmental factors forms an intricate network pertinent to human drug responses. However, decisions regarding which environmental factors are important and which may influence incriminated drugs remain inconsistent.

Background/Aims Drug metabolizing enzymes may be related to drug-induced liver injury (DILI). Manganese superoxide dismutase (MnSOD), NAD(P)H:quinone oxidoreductase (NQO1), and glutathione S -transferase (GST) are important drug metabolizing enzymes. We aimed to elucidate the relationship between genetic polymorphisms of these enzymes and the susceptibility to DILI. Methods A total of 115 patients with DILI and 115 drug-, sex-, and age-matched controls were enrolled. Their genetic polymorphisms of MnSOD, NQO1, GSTM1 , and GSTT1 were assayed. Results Sixty-three (54.8%) of DILI patients were incriminated to anti-tuberculosis drugs. Subjects with a mutant C allele (T/C or C/C genotype) of MnSOD had a higher risk of DILI than those with MnSOD T/T genotype, both in overall drugs studied (adjusted OR: 2.44, 95% C.I.: 1.38–4.30, P =0.002), and in sub-category of anti-tuberculosis drugs (adjusted OR: 2.47, 95% C.I.: 1.13–5.39, P =0.02). In addition, subjects carrying GSTM1 null genotype had increased risk of anti-tuberculosis DILI (adjusted OR: 2.23, 95% C.I.: 1.07–4.67, P =0.03). Conclusions The MnSOD mutant C allele may increase the susceptibility to DILI, and GSTM1 null genotype may be related to anti-tuberculosis drug-induced hepatotoxicity. Determination of the MnSOD and GSTM1 genotypes may help identify patients at high risk for DILI.

Three first-line antituberculosis drugs, isoniazid, rifampicin and pyrazinamide, may induce liver injury, especially isoniazid. This antituberculosis drug-induced liver injury ranges from a mild to severe form, and the associated mortality cases are not rare. The major drug-metabolizing enzyme of isoniazid is N-acetyltransferase. Other possible enzymes are CYP2E1 and glutathione S-transferase. There is evidence that polymorphisms of the genes that encode these enzymes may influence the activity of the corresponding drug-metabolizing enzymes. Recent studies demonstrated that these genetic polymorphisms may be associated with the susceptibility to antituberculosis drug-induced liver injury. The proposed risk-associated genotypes are NAT2 slow acetylator (without wild-type NAT2*4 allele), CYP2E1 *1A/*1A (homozygous wild type) and homozygous null GSTM1 genotype. Although the available data in the field are still limited and warrants further confirmation in different ethnic populations with larger sample sizes, it still cast some light on the application of these pharmacogenetic or pharmacogenomic approaches to prevent grave antituberculosis drug-induced liver injury in the near future.

Aims Superoxide dismutase 2 (SOD2) is an important antioxidant phase 2 enzyme. The associations of SOD2 genetic variation and the risk of advanced alcoholic liver diseases are still debatable. We aimed to investigate the association of the main SOD2 genetic variant (47T>C) and the susceptibility to alcoholic cirrhosis. Methods A total of 80 patients with alcoholic cirrhosis (AC), 80 patients with alcoholic non-cirrhosis (ANC), 80 with viral hepatitis B-related cirrhosis (VC), and 165 healthy controls (HC) were enrolled into this study. A polymerase chain reaction was used to genotype their SOD2 47T>C (rs4880). Results There was no statistical difference in the frequency distribution of the three SOD2 47T>C genotypes among groups. However, if individuals with C variant were grouped together, the AC group had higher frequency of SOD2 C/C or C/T genotype than ANC, VC and HC groups had (38.7% vs. 21.3%, 26.3% and 21.8%, respectively, P = 0.010). After adjustment for confounders, the SOD2 C/C and C/T genotypes remained associated with the risk of AC (adjusted OR: 2.79 and 3.50, respectively, P < 0.03, compared with ANC and HC groups). In contrast, there was no significant difference of SOD2 genetic variation between VC and HC groups. Conclusions Anti-oxidative enzyme SOD2 47T>C genetic variant may increase the susceptibility to AC. This suggests that oxidative stress plays a role in the development of AC.

Background Irritable bowel syndrome (IBS) is the most common functional gastrointestinal (GI) disorder observed in patients who visit general practitioners for GI-related complaints. A high prevalence of psychiatric comorbidities, particularly anxiety and depressive disorders, has been reported in patients with IBS. However, a clear temporal relationship between IBS and psychiatric disorders has not been well established. Objective We explored the relationship between IBS and the subsequent development of psychiatric disorders including schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. Methods We selected patients who were diagnosed with IBS caused by gastroenteritis, according to the data in the Taiwan National Health Insurance Research Database. A comparison cohort was formed of patients without IBS who were matched according to age and sex. The incidence rate and the hazard ratios (HRs) of subsequent new-onset psychiatric disorders were calculated for both cohorts, based on psychiatrist diagnoses. Results The IBS cohort consisted of 4689 patients, and the comparison cohort comprised 18756 matched control patients without IBS. The risks of depressive disorder (HR = 2.71, 95% confidence interval [CI] = 2.30–3.19), anxiety disorder (HR = 2.89, 95% CI = 2.42–3.46), sleep disorder (HR = 2.47, 95% CI = 2.02–3.02), and bipolar disorder (HR = 2.44, 95% CI = 1.34–4.46) were higher in the IBS cohort than in the comparison cohort. In addition, the incidence of newly diagnosed depressive disorder, anxiety disorder, and sleep disorder remained significantly increased in all of the stratified follow-up durations (0–1, 1–5, ≥5 y). Conclusions IBS may increase the risk of subsequent depressive disorder, anxiety disorder, sleep disorder, and bipolar disorder. The risk ratios are highest for these disorders within 1 year of IBS diagnosis, but the risk remains statistically significant for more than 5 years. Clinicians should pay particular attention to psychiatric comorbidities in IBS patients.

Nonalcoholic fatty liver disease (NAFLD) is a fatty liver disease occurring in patients without alcohol consumption. It includes a broad spectrum of liver disease, from fatty infiltration, inflammation and fibrosis, to cirrhosis, usually having obesity, hyperlipidemia, and diabetes mellitus as its etiology. NAFLD-related cirrhosis has rarely been reported in Taiwan. We herein report a 41-year-old male patient with nonalcoholic fatty liver cirrhosis (NAFLC), with the first clinical manifestation being bleeding esophageal varices (EV). The patient was obese with diabetes mellitus, but without hyperlipidemia or any history of drinking alcohol. The laboratory tests, abdominal sonography, and computed tomography revealed a typical case of liver cirrhosis. The pan-endoscopy disclosed EV with red-color sign. EV ligation was performed successfully to stop the bleeding. When the patient was in a stabilized clinical condition, a liver biopsy showed a typical histologic finding of NAFLD. Most of the cases of NAFLC reported in the literature have silent signs and symptoms. Sudden onset of the EV as the first clinical manifestation, as in this case, is rare. This case reminds us that NAFLD may indeed induce severe liver impairment, such as liver cirrhosis. Liver biochemical tests and abdominal sonography should be considered in patients with overt obesity and diabetes.

Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug-induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hepatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2, 9.0%, P = .009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P = .017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis. (Hepatology 2003;37:924-930.)

Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis drug-induced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P =.013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P =.003) and age (OR, 1.09; 95% CI, 1.04-1.14; P

Objectives: to assess the prevalence and risk factors of gallstone disease (GSD) in Taiwan. Design: descriptive and cross-sectional. Methods: a prospective ultrasonographic study of GSD was conducted in 3647 Chinese subjects who received a paid hospital physical check-up. Their demographic characteristics and biochemical parameters were recorded and compared. Ultrasonographic diagnosis revealed 2946 (M/F: 1838/1108) with normal gallbladder, 286 (M/F: 196/90) with gallbladder stones, 100 (M/F: 56/44) with previous cholecystectomy for gallstones, 243 (M/F: 174/69) with gallbladder polyps, 17 (M/F: 1017) with mixed gallbladder stones/polyps and 35 as 'miscellaneous'. We enrolled subjects showing either gallbladder stones or cholecystectomy for gallstones in the GSD group. Results: excluding those subjects with mixed gallbladder stones/polyps, the overall prevalence of GSD in the studied group was 10.7%. The studied factors manifesting an increase in risk for the development of GSD were age (P< 0.05), high body mass index (P< 0.05), diabetes mellitus (adjusted odds ratio: l.998; PdH)S) and glucose intolerance (adjusted odds ratio: 2.056; P < 0.05) by multivariate analysis. Other demographic characteristics and biochemical parameters, such as body height, ABO blood type, cigarette smoking, alcohol consumption, blood pressure, lipid profiles, hepatitis B virus infection, liver function and multiparity did not show any correlation to GSD. Conclusions: age, high body mass index, diabetes mellitus and glucose intolerance are the risk factors for developing GSD in Taiwan.

epatocellular carcinoma (HCC) is one of the most common cancers H in Taiwan and in the world.',' The overall prognosis of HCC is very poor. Surgical resection is the only potentially curative treatment for HCC and is most effective for small turn or^.^-^ Unfortunately, many HCC patients have tumor recurrence after surgery and most patients are not eligible for surgery because of advanced stage at presentation. Other treatments, such as conventional radiotherapy"' or chemotherapy,*-'O are ineffective and the results unsatisfactory. Embolization for HCC may be palliative.'' Most of these treatments may have significant side effects. New, effective, and less toxic methods of treatment for patients with advanced HCC are urgently needed. HCC may be a hormone-dependent tumor and hormonal therapy has been recommended for further clinical investigations by several HCC may be an androgen-dependent tumor. Patients with aplastic anemia who developed HCC after long term therapy with androgenic steroids were first reported by Johnson et al." Thereafter, many androgeninduced HCCs were reported.16-" HCC was strongly associated with androgen in vitro and in vivo. Several rat hepatoma cell lines were reported to be androgen-dependent and contained cytoplastic androgen receptors IAR)." Androgen stimulates the growth of HCC cells implantated in rats when compared with controls.20 AR were positive in 74% of male and 33% of female HCC patients.''~22 Androgen may interact with AR of human HCC and enhance tumor growth and invasiveness. The recurrence rates

Polymerase chain reaction (PCR) is very sensitive. The aim of the study was to reevaluate viral replication in hepatitis D virus (HDV) superinfection by PCR.HDV and hepatitis B virus (HBV) were detected by PCR in 185 patients.The acute hepatitis group had the highest detection rate of HDV RNA compared with chronic hepatitis, cirrhosis, hepatocellular carcinoma, and remission groups (63 of 64 vs. 35 of 47, 17 of 23, 19 of 30, and 7 of 21) and the highest alanine aminotransferase (ALT) levels (mean, 1741 U/L vs. 266 to 27 U/L; P0.05). The detection rate of HBV DNA was the lowest in the acute group (41%) compared with 66%, 70%, 80%, and 57% in the remaining groups (P0.02). At the chronic stage, 13%-25% of cases had HDV RNA, and 30%-48% of cases had HBV DNA detected by PCR but not by traditional method. HDV RNA was associated with ALT levels in horizontal and longitudinal analyses.HDV superinfection may be divided into the following three phases: acute phase, active HDV replication and suppression of HBV with high ALT levels; chronic phase, decreasing HDV and reactivating HBV with moderate ALT levels; and late phase, development of cirrhosis and hepatocellular carcinoma caused by replication of either virus or remission resulting from marked reduction of both viruses.

Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations.A population-based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort.Of the 90,847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10,000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration ≥ 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10,000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI.Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole.

Polymorphism of N-acetyltransferase 2 gene was reported to be associated with the susceptibility of various cancers and liver diseases. However, its relationship to alcoholic liver disease is controversial and open to debate. The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms and the susceptibility to alcoholic liver cirrhosis (ALC) in Chinese, with special emphasis on the interaction of smoking.Peripheral white blood cell DNA from 148 patients with ALC, 104 patients with long-term alcoholic drinking but without cirrhosis (ANC) and 209 healthy controls were genotyped for NAT2 using a polymerase chain reaction-restriction fragment length polymorphism method. The possible confounding factors were included for analysis.There was no statistical difference in the frequency of NAT2 genotype or NAT2 acetylator status among the 3 groups. However, among the chronic alcoholic drinkers, the rapid acetylators with smoking habits had higher percentage of ALC than those without smoking habit (18.9% vs. 9.5%, p=0.002). The adjusted odds ratio for rapid acetylator smoker to have ALC was 3.45 (95% CI=1.53 to 7.76, p=0.003).The genetic factor, NAT2 polymorphism, may interact with environmental factor, smoking, to confer different susceptibilities to ALC. NAT2 rapid acetylators with smoking habit may increase the risk of ALC in Chinese.

Lidocaine is metabolized to form monoethylglycinexylidide (MEGX) via oxidative N-deethylation in the liver. To assess the clinical value of this lidocaine metabolite as a quantitative liver function test, we measured the serum MEGX concentration 15 min after intravenous administration of a single dose of lidocaine (1 mg/kg) in 24 adults with chronic hepatitis, 47 patients with cirrhosis and 26 normal controls. A fluorescence polarization immunoassay was used to obtain the MEGX value. The MEGX concentration in controls was 67 (54-95) ng/ml (median with 16th-84th percentile in parentheses), which was higher than 43 (23-61) ng/ml in patients with chronic hepatitis and 24 (7-52) ng/ml in those with cirrhosis (P0.05). In addition, the serum MEGX levels are proportional to the galactose elimination capacity, and inversely proportional to Pugh's score, the prothrombin time and indocyanine green retention ratio. If a MEGX concentration of below 54 ng/ml is taken as an indicator of hepatic dysfunction, its diagnostic sensitivity for hepatic disorder is 84.5%, specificity 88.5% and accuracy 85.6%. Furthermore, after a 10-month follow-up, patients with MEGX formation above 30 ng/ml had a higher survival rate than those with a MEGX concentration below this level (P = 0.004). In conclusion, the MEGX formation test reflects the severity of hepatic dysfunction quite well, making it valuable both in the quantitative evaluation of liver function and in the prognostic prediction of adults with liver diseases.

11/323 patients (3.4%) with symptomatic chronic hepatitis B were positive for antibody to hepatitis C virus (anti-HCV). The positive rate of anti-HCV in patients with serum alanine aminotransferase (ALT) levels greater than 200 U/l (n = 219) did not exceed that of the patients with ALT less than or equal to 200 U/l (n = 104) (2.7% vs. 4.8%). Of the 219 patients who were positive for hepatitis B e antigen (HBeAg) and/or hepatitis B virus-DNA (HBV-DNA), 5 (2.3%) had anti-HCV, while 6/104 patients (5.8%) who were positive for antibody to HBeAg (anti-HBe) had anti-HCV (p greater than 0.1). In contrast to the anti-HCV-negative patients, the patients with anti-HCV had a higher percentage of cirrhosis in their liver histological findings (36.4% vs 5.4%, p less than 0.005). In conclusion, the prevalence of HCV superinfection in symptomatic chronic hepatitis B patients is low and HCV superinfection is not an important factor in acute exacerbation of chronic hepatitis B. However, the superinfection with HCV may exacerbate the existing liver disease and accelerate its progression.

The genetic features in Eastern autoimmune hepatitis (AIH) patients are seldom surveyed. Previous studies on the linking of human leukocyte antigen (HLA) with AIH have highlighted the necessity of evaluating ethnically homogeneous populations, but no investigation for Taiwanese patients has been reported. This study aims to evaluate the HLA characteristics of Taiwanese AIH patients.Medical records of Taiwanese AIH patients (1990-2005) were reviewed and the correlation of HLA alleles with disease susceptibility and severity was surveyed. HLA typing was performed by polymerase chain reaction amplification with sequence-specific primers.Unlike the Western reports, HLA-A1, B8, and DR3 were not identified. The most frequently encountered was A11 (48.6%). DR4 (35.1%) was less often found than that in Japanese and Chinese series. As compared with Taiwanese normal controls, the frequency of B35 was significantly increased (18.9% vs. 5.4%, odds ratio = 4.072, Pc0.001). B35-postitive patients also had higher pretreatment serum aminotransferase concentrations. More of the patients were cholestatic and responded well to a lower dose of prednisolone as compared with those reported in the Western literature.HLA-B35 plays a distinct role in susceptibility and severity of AIH in Taiwan. Racial genetic backgrounds may account for the different results.

Among 30 consecutive patients diagnosed with primary biliary cirrhosis (PBC) in Taiwan, 27 were females and the median age of symptom onset was 54.5 years. Most had similar clinical manifestations to those reported in the Western countries, but ascites and oesophageal varices as commonly found at the late stages of cirrhosis of liver were noted in nine patients (30%) and 13 patients (43%) respectively. Only one patient was asymptomatic. Hyperbilirubinaemia was noted in 21 patients (70%) and hypoalbuminaemia in 8 patients (27%). All patients had elevated serum alkaline phosphatase and alanine aminotransferase and 28 (93%) had antimitochondrial antibodies. Ten out of 21 patients (48%) were positive in antinuclear antibodies, of which most were of speckled type. Sixteen out of 18 patients (89%) had elevated serum IgM levels. Interestingly, only one of 26 patients (3.8%) was positive for hepatitis B surface antigen, in contrast to its high prevalence (15%) in the Taiwan population. Special associated diseases, including systemic lupus erythematosus, scleroderma, malignant lymphoma and hepatocellular carcinoma, were each noted in one patient respectively. Eight patients had a history of gallstones before the diagnosis of PBC. The mean follow-up period was 23.6 +/- 19.8 months, and nine patients died during that period. In conclusion, the clinical manifestations of PBC in Taiwan are similar to those in Western countries, but most of our cases were at later stages.

Long-term nucleos(t)ide analogues (NUCs) treatment is usually required for patients with chronic hepatitis B (CHB). However, whether discontinuation of NUCs is possible in selected patients remains debated. The aim of this study was to assess the durability of NUCs and predictors of sustained response after cessation of NUCs. Ninety-three CHB patients (29 HBeAg-positive and 64 HBeAg-negative) from 2 medical centers in Taiwan with discontinuation of NUCs after a median of 3 years’ treatment were retrospectively reviewed. Fifteen (51.7%) HBeAg-positive and 57 (89.1%) HBeAg-negative patients achieved APASL treatment endpoints. Virological relapse (VR) and clinical relapse (CR) were defined according to APASL guidelines. Achieving APASL endpoint was associated with longer median time to CR in HBeAg-positive patients, but not in HBeAg-negative cases. The cumulative 1-year VR and CR rates were 55.3% and 14.4% in HBeAg-positive patients, and 77.7% and 41.9% in HBeAg-negative patients, respectively. In HBeAg-negative patients, baseline HBV DNA >105 IU/mL was the only predictor of VR (hazard ratio [HR] = 2.277, P = 0.019) and CR (HR = 3.378, P = 0.014). HBsAg >200 IU/mL at the end of treatment (EOT) was associated with CR (HR = 3.573, P = 0.023) in patients developing VR. HBeAg-negative patients with low baseline viral loads and low HBsAg levels at EOT had minimal risk of CR after achieving APASL treatment endpoint (P = 0.016). The VR rate is high, but the risk of CR is low within 1 year with consolidation treatment after HBeAg seroconversion. Longer consolidation treatment to reduce the risk of VR should be considered in HBeAg-positive patients. As high risk of VR and CR, cessation of NUCs therapy could be considered only in selected HBeAg-negative patients.