Yi-Shin Huang

Acute Hepatitis Induced by Chinese Hepatoprotective Herb, Xiao-Chai-Hu-Tang

Xiao-chai-hu-tang (syo-saiko-to in Japanese) is a herbal remedy that has been widely used in China for treatment of respiratory, hepatobiliary, and gastrointestinal diseases, particularly among patients with chronic liver disease. However, its safety has recently been challenged. We, herein, report a Chinese patient with acute hepatitis induced by this herb. A 52-year-old woman presented with weakness, fatigue, and tea-colored urine after continual consumption of the decoction of xiao-chai-hu-tang for 1.5 months. Laboratory studies disclosed acute hepatitis even though all of the viral hepatitis markers were negative. Liver biopsy also revealed a picture of acute hepatocellular hepatitis. The symptoms improved after discontinuing the drug, and liver biochemical tests normalized 2 months later. The case report reminds us of the probable adverse drug reaction of herbs, even in some that are claimed to have hepatoprotective effects.

Risk of Hepatic Failure After Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: Predictive Value of the Monoethylglycinexylidide Test

OBJECTIVES:Transcatheter arterial chemoembolization (TACE) is the major treatment modality for patients with unresectable hepatocellular carcinoma (HCC). Hepatic failure after TACE is relatively common in patients with preexisting liver dysfunction. The purpose of this study was to evaluate whether the monoethylglycinexylidide test and other parameters might predict hepatic failure after TACE in HCC patients.METHODS:One hundred forty-two HCC patients undergoing TACE were enrolled into this study. Before TACE, their venous blood was collected 15 min after a bolus injection of lidocaine (1 mg/kg body weight). A fluorescence polarization immunoassay was used to measure monoethylglycinexylidide concentrations in their sera. Univariate and multivariate analyses were performed on the monoethylglycinexylidide test and other parameters between patients with and without hepatic failure after TACE.RESULTS:Nineteen patients (13.4%) suffered hepatic failure after TACE. Univariate analysis revealed that the monoethylglycinexylidide concentration (17.7 ± 5.8 vs 43.9 ± 13.2 ng/ml), Child-Pugh score (6.9 ± 0.6 vs 6.0 ± 0.7), indocyanine green retention ratio at 15 min (32.4 ± 6.5% vs 15.7 ± 5.8%), prolonged PT, and serum total bilirubin and albumin showed significant differences between patients with and without hepatic failure after TACE. After a multiple logistic regression, only the monoethylglycinexylidide test was an independent predictor of hepatic failure (OR = 1.68, 95% CI = 1.07–2.65, p = 0.026). Among the 19 hepatic failure patients, three (15.8%) died of hepatic failure associated with TACE within 1 month after this procedure.CONCLUSIONS:As a predictor of hepatic failure after TACE, the monoethylglycinexylidide test is better than conventional liver function tests and clinical parameters. The monoethylglycinexylidide test may be used to select patients with relatively good liver reserves for safe TACE treatment.

Polymorphism of the N-acetyltransferase 2 gene, red meat intake, and the susceptibility of hepatocellular carcinoma

OBJECTIVE:Carcinogenic aromatic amines, derived from cooked meat, are activated or inactivated by hepatic N-acetyltransferase (NAT). The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms with hepatocellular carcinoma (HCC), with special reference to the interaction of dietary habits.METHODS:Peripheral white blood cell DNA from 185 HCC patients and 185 matched controls were genotyped for NAT2 by a polymerase chain reaction-restriction fragment length polymorphism method. All the subjects studied were chronic viral hepatitis B or C carriers with liver cirrhosis. Dietary habits of the subjects were assessed using a semiquantitative food frequency questionnaire.RESULTS:There was no association between the susceptibility of HCC and the overall NAT2 genotypes. However, in rapid acetylators (with two wild type NAT2*4 alleles), there was a trend of increased HCC risk from low to intermediate and high red meat intake (OR = 1, 2.66, 3.89; ptrend = 0.016), even when adjusted for family history of HCC and habitual alcohol drinking. The interaction between red meat intake and the NAT2*4 acetylator status for an increased risk of HCC was significant (p = 0.007).CONCLUSIONS:Polymorphisms of the NAT2 gene may confer different susceptibilities to the effect of red meat intake on HCC. In rapid acetylators with chronic viral hepatitis-related cirrhosis, red meat intake may play a role in hepatocarcinogenesis.

Risk of oral antifungal agent-induced liver injury in Taiwanese

AIMnOral 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.nnnMETHODSnA 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.nnnRESULTSnOf 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.nnnCONCLUSIONSnOral 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.

Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury

&NA; 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.

Comparison of clinical manifestations and epidemiology between acute hepatitis A and acute hepatitis E in Taiwan

Background and Aims : Acute hepatitis A (AHA) and acute hepatitis E (AHE) are endemic in developing countries. They share similar transmission routes and clinical manifestations. To compare the differences in epidemiology, clinical picture and prognosis between these two enterically transmitted forms of hepatitis, we enrolled 58 consecutive AHA or AHE patients (42 men and 16 women; age 16–74u2003years) from January 1990 to April 2001.

Serum interleukin-12 levels in alcoholic liver disease.

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 3rd, 6th and 9th 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 9th 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.

Durability of Nucleos(t)ide Analogues Treatment in Patients With Chronic Hepatitis B

AbstractLong-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 >105u200aIU/mL was the only predictor of VR (hazard ratio [HR]u200a=u200a2.277, Pu200a=u200a0.019) and CR (HRu200a=u200a3.378, Pu200a=u200a0.014). HBsAg >200u200aIU/mL at the end of treatment (EOT) was associated with CR (HRu200a=u200a3.573, Pu200a=u200a0.023) 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 (Pu200a=u200a0.016).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.

Multiple Organ Failure Caused by Non-exertional Heat Stroke After Bathing in a Hot Spring

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.

Genetic variations of superoxide dismutase 2 and cytochrome P450 2E1 in non-alcoholic steatohepatitis.

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.