Soon Woo Nam

MRP2 haplotypes confer differential susceptibility to toxic liver injury

Objectives Multidrug resistance protein 2 (MRP2, ABCC2) plays an important role in the biliary clearance of a wide variety of endogenous and exogenous toxic compounds. Therefore, polymorphisms and mutations in the MRP2 gene may affect individual susceptibility to hepatotoxic reactions. Methods Associations between genetic variations of MRP2 and toxic hepatitis were investigated using integrated population genetic analysis and functional molecular studies. Results Using a gene scanning method, 12 polymorphisms and mutations were found in the MRP2 gene in a Korean population. Individual variation at these sites was analyzed by conventional DNA screening in 110 control subjects and 94 patients with toxic hepatitis induced mostly by herbal remedies. When haplotypes were identified, over 85% of haploid genes belonged to the five most common haplotypes. Among these, a haplotype containing the g.−1774delG polymorphism showed a strong association with cholestatic or mixed-type hepatitis, and a haplotype containing the g.−1549G>A, g.−24C>T, c.334−49C>T, and c.3972C>T variations was associated with hepatocellular-type hepatitis. A comprehensive functional study of these sites revealed that genetic variations in the promoter of this gene are primarily responsible for the susceptibility to toxic liver injuries. The g.−1774delG variation and the combined variation of g.−1549G>A and g.−24C>T decreased MRP2 promoter activity by 36 and 39%, respectively. In addition, the promoter carrying the g.−1774delG allele showed a defect in the bile acid-induced induction of promoter activity. Conclusions These results suggest that genetic variations of MRP2 are an important predisposing factor for herbal-induced or drug-induced toxic liver injuries.

A prospective nationwide study of drug-induced liver injury in Korea.

OBJECTIVES:To address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea.METHODS:From May 2005 to May 2007, cases of DILI (alanine transferase >3 × upper normal limit or total bilirubin >2 × upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used.RESULTS:A total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included “herbal medications” (102, 27.5%), “prescription or non-prescription medications” (101, 27.3%), “health foods or dietary supplements” (51, 13.7%), “medicinal herbs or plants” (35, 9.4%), “folk remedies” (32, 8.6%), “combined” (30, 8.2%), “herbal preparations” (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hys law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM.CONCLUSIONS:DILI appears to be a highly relevant health problem in Korea. “Herbal medications” are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.

Hepatitis B Virus Genotype C Prevails Among Chronic Carriers of the Virus in Korea

Hepatitis B virus (HBV) is one of the major causative agents of chronic liver diseases in Korea. HBV has been classified into 8 genotypes by a divergence of >8% in the entire genomic sequence, and have distinct geographic distributions. There are limited data on the relevance between HBV genotypes and clinical outcomes in Korea. To investigate the clinical feature relating to HBV genotype in Korea, a total 120 serum samples with HBsAg (65 from Seoul and 55 from the other city in Korea) were obtained from each 30 chronic HBV carriers with asymptomatic carrier (ASC), chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). HBV genotype was determined by either enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies against genotype-specific epitopes in the preS2-region or the direct sequencing of small S gene. HBV genotypes were determined in 105 (87.5%) of 120 samples. HBV genotype C was identified in all HBV carriers with ASC, CH, LC, and HCC. Genotypes A, B, D, E, F and G were not detected in any of them. Genotype C HBV prevails predominantly among chronic carriers of the virus in Korea, irrespective of their clinical stages of liver disease and geographic origin.

Spontaneous regression of a large hepatocellular carcinoma with skull metastasis

Abstract  Spontaneous regression of hepatocellular carcinoma (HCC) is a rare phenomenon. This case of a 65‐year‐old Korean man with HCC and metastatic frontal bone mass that regressed after radiotherapy for frontal bone mass without any other therapeutic modalities is described. The clinical diagnosis of HCC was made because of the presence of a liver mass on abdominal computed tomography (CT) scan, high serum α‐fetoprotein value and tissue diagnosis on frontal bone biopsy. The patient refused any other recommended treatments, but accepted the radiation therapy due to a painful frontal bone mass, and ingested mushroom called Phellinus linteus for one and a half years. Ten months after radiation therapy, he experienced a reduction in size of the frontal bone mass and improvement of lesions in the liver, sternum and ribs. The patient is alive and in good condition without any symptoms or tumor aggravation in August 2002. It was concluded that a rare case of spontaneous regression of HCC had occurred.

The impact of hepatitis B viral load on recurrence after complete necrosis in patients with hepatocellular carcinoma who receive transarterial chemolipiodolization: implications for viral suppression to reduce the risk of cancer recurrence.

Hepatocellular carcinoma (HCC) has a high tendency for recurrence after radical treatment. Apart from tumor and liver function parameters, little is known about the role of hepatitis B virus (HBV) factors in the recurrence of HCC. The objective of this study was to identify the potential relation between viral load and HCC recurrence in patients undergoing transarterial chemolipiodolization.

A case of acute cholestatic hepatitis associated with the seeds of Psoralea corylifolia (Boh-Gol-Zhee).

The potential hepatotoxicity of herbal remedies is usually ignored in daily life. One such compound, Boh-Gol-Zhee (in Chinese, Bu Ku Zi), appeared to be associated with the occurrence of acute cholestatic hepatic injury in the following case. Some alternative medicine therapists claim that Psoralea corylifolia is effective for the treatment of osteoporosis. We observed a case of acute cholestatic hepatitis associated with the use of the seeds of Psoralea corylifolia in amounts over 10 times the usual dose in a postmenopausal woman. Liver biopsy showed zone three necroses, degenerating cells, cholestasis, and infiltrations with inflammatory cells. This case stresses the need to warn of the potential hepatotoxicity of the seed of Psoralea corylifolia, especially in a large dose.

Clinical Outcomes of Delayed Clearance of Serum HBsAg in Patients with Chronic HBV Infection

Background Spontaneous delayed clearance of hepatitis B surface antigen (HBsAg) in patients with chronic HBV infection is a rare event. The aim of this study was to investigate the incidence of delayed clearance of serum HBsAg in chronic HBV infection and to determine the characteristics and clinical outcomes of HBsAg delayed clearance in Korean patients. Methods From April 1981 to June 2003, 4,061 patients who were positive for HBsAg were evaluated retrospectively. The following assessments were undertaken in 47 patients who had spontaneous delayed clearance: liver biochemistry, viral markers, α-fetoprotein levels, and radiographic examinations including ultrasonography every three to six months for 6-264 months (median 87.9 months). Results Twenty-four of 47 patients were asymptomatic carriers. The others included seven patients with chronic hepatitis, seven with liver cirrhosis and nine with hepatocellular carcinoma. The estimated annual incidence of HBsAg seroclearance was 0.4%. The time span from positive HBsAg to HBsAg seroclearance in the AHC, CH, LC, and HCC was 62.9, 141, 63, and 95.3 months during follow up. Twenty-four of 24 AHC remained normal, 5 of 7 CH remained as CH and 2 patients remained normal, 1 of 7 with LC developed HCC and 6 of the LC remained as LC, and 4 of 9 HCC patients died. Conclusion The clinical course following delayed clearance of HBsAg had diverse outcomes from AHC to HCC. Therefore, these patients require close follow up for the possible development of hepatocellular carcinoma following HBsAg clearance.

Efficacy of initial treatment with peginterferon alpha-2a versus peginterferon alpha-2b in combination with ribavirin in naive chronic hepatitis C patients living in Daejeon and Chungcheong Province in Korea: A comparative study

BACKGROUNDS/AIMS Peginterferon alpha-2a or -2b is the standard treatment regimen in chronic hepatitis C. However, there have been few comparative studies of the efficacies of these two types of peginterferon. We evaluated their efficacies in combination with ribavirin as a initial treatment for chronic hepatitis C. METHODS Ninety-seven patients were treated with peginterferon alpha-2a (180 microg/week, n=48) or peginterferon alpha-2b (1.5 microg/kg/week, n=49) plus ribavirin (800 mg/day for 24 weeks in genotype non-1 or 1,000-1,200 mg/day for 48 weeks in genotype 1). Virologic responses including the early virologic response (EVR), end-of-treatment response (ETR), sustained virologic response (SVR), and adverse effects were analyzed retrospectively. RESULTS The virologic response rates did not differ significantly between peginterferon alpha-2a and -2b: 89.6% and 89.7% for EVR, 79.2% and 79.5% for ETR, 72.9% and 73.5% for SVR, respectively. Analysis of the virologic responses according to genotype also revealed no significant differences in SVR between peginterferon alpha-2a and -2b (59.3% vs. 59.7% for genotype 1 and 90.5% vs. 83.3% for genotype non-1, respectively), or in adverse effects including flu-like symptom, rash, itching, neutropenia, and thrombocytopenia. CONCLUSIONS We found no significant differences in therapeutic efficacies and adverse effects between the alpha-2a and -2b types of peginterferon as the initial treatment regimen in naive chronic hepatitis C patients.

Outcome of transarterial chemoembolization-based multi-modal treatment in patients with unresectable hepatocellular carcinoma

AIM To investigate the efficacy and safety of transarterial chemoembolization (TACE)-based multimodal treatment in patients with large hepatocellular carcinoma (HCC). METHODS A total of 146 consecutive patients were included in the analysis, and their medical records and radiological data were reviewed retrospectively. RESULTS In total, 119 patients received TACE-based multi-modal treatments, and the remaining 27 received conservative management. Overall survival (P<0.001) and objective tumor response (P=0.003) were significantly better in the treatment group than in the conservative group. After subgroup analysis, survival benefits were observed not only in the multi-modal treatment group compared with the TACE-only group (P=0.002) but also in the surgical treatment group compared with the loco-regional treatment-only group (P<0.001). Multivariate analysis identified tumor stage (P<0.001) and tumor type (P=0.009) as two independent pre-treatment factors for survival. After adjusting for significant pre-treatment prognostic factors, objective response (P<0.001), surgical treatment (P=0.009), and multi-modal treatment (P=0.002) were identified as independent post-treatment prognostic factors. CONCLUSION TACE-based multi-modal treatments were safe and more beneficial than conservative management. Salvage surgery after successful downstaging resulted in long-term survival in patients with large, unresectable HCC.

Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma.

Background & Aims Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactivation in HBsAg-negative patients undergoing transarterial chemoembolization (TACE). Methods A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2–3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46). Results During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216–116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation. Conclusions TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation.