Clinical characteristics and outcomes of acute hepatitis a in Korea: a nationwide multicenter study.

The aim of this study was to investigate the clinical characteristics of acute hepatitis A during a recent outbreak in Korea. Data of patients diagnosed with acute hepatitis A from 2007 to 2009 were collected from 21 tertiary hospitals retrospectively. Their demographic, clinical, and serological characteristics and their clinical outcomes were analyzed. A total of 4,218 patients (mean age 33.3 yr) were included. The median duration of admission was 9 days. The mean of the highest ALT level was 2,963 IU/L, total bilirubin was 7.3 mg/dL, prothrombin time INR was 1.3. HBsAg was positive in 3.7%, and anti-HCV positive in 0.7%. Renal insufficiency occurred in 2.7%, hepatic failure in 0.9%, relapsing hepatitis in 0.7%, and cholestatic hepatitis in 1.9% of the patients. Nineteen patients (0.45%) died or were transplanted. Complications of renal failure or prolonged cholestasis were more frequent in patients older than 30 yr. In conclusion, most patients with acute hepatitis A recover uneventfully, however, complication rates are higher in patients older than 30 yr than younger patients. Preventive strategies including universal vaccination in infants and active immunization of hepatitis A to adult population should be considered for prevention of community-wide outbreaks of hepatitis A in Korea.

Metronidazole-induced encephalopathy in a patient with liver cirrhosis.

Encephalopathy is a disorder characterized by altered brain function, which can be attributed to various causes. Encephalopathy associated with metronidazole administration occurs rarely and depends on the cumulative metronidazole dose, and most patients with this condition recover rapidly after discontinuation of therapy. Because metronidazole is metabolized in the liver and can be transported by the cerebrospinal fluid and cross the blood-brain barrier, it may induce encephalopathy even at a low cumulative dose in patients with hepatic dysfunction. We experienced a patient who showed ataxic gait and dysarthric speech after receiving metronidazole for the treatment of hepatic encephalopathy that was not controlled by the administration of lactulose. The patient was diagnosed as metronidazole-induced encephalopathy, and stopping drug administration resulted in a complete recovery from encephalopathy. This case shows that caution should be exercised when administering metronidazole because even a low dose can induce encephalopathy in patients with liver cirrhosis.

Association of serum alanine aminotransferase and γ-glutamyltransferase levels within the reference range with metabolic syndrome and nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) has recently been found to be a novel component of metabolic syndrome (MS), which is one of the leading causes of chronic liver disease. The serum alanine aminotransferase (ALT) and ⟨-glutamyltransferase (GGT) levels are suggested to affect liver fat accumulation and insulin resistance. We assessed the associations of serum ALT and GGT concentrations within the reference ranges with MS and NAFLD. METHODS: In total, 1,069 subjects enrolled at the health promotion center of Wonkwang University Hospital were divided into 4 groups according to serum ALT and GGT concentrations levels within the reference ranges. We performed biochemical tests, including liver function tests and lipid profiles, and diagnosed fatty liver by ultrasonography. Associations of ALT and GGT concentrationgrading within the reference range with fatty liver and/or MS were investigated. RESULTS: The presence of MS, its components, and the number of metabolic abnormalities [except for high-density lipoprotein-cholesterol (HDL-C) and fasting blood glucose] increased with the ALT level, while the presence of MS, its components, and the number of metabolic abnormalities (except for HDL-C) increased with the GGT level. The odds ratios for fatty liver and MS increased with the ALT level (P⟨0.001 and P=0.049, respectively) and the GGT level (P=0.044 and P=0.039, respectively). CONCLUSIONS: Serum ALT and GGT concentrations within the reference ranges correlated with the incidence of NAFLD and MS in a dose-dependent manner. There associations need to be confirmed in large, prospective studies.

Nucleotide changes related to hepatocellular carcinoma in the enhancer 1/x-promoter of hepatitis B virus subgenotype C2 in cirrhotic patients.

Hepatocellular carcinoma (HCC) is widely known to develop more frequently in cirrhotic patients with a high expression of Hepatitis B virus X protein (HBx), which is controlled by the enhancer 1 (Enh1)/X-promoter. To examine the effect of the mutations in the Enh1/X-promoter region in hepatitis B virus (HBV) genomes on the development of HCC, we investigated the differences in HBV isolated from cirrhotic patients with or without HCC along with the promoter activities of certain specific mutations within the Enh1/X-promoter. We examined 160 hepatitis B surface antigen (HBsAg)-positive cirrhotic patients (80 HCC patients, 80 non-HCC patients) by evaluating the biochemical, virological, and molecular characteristics. We evaluated the functional differences in certain specific mutations within the Enh1/X-promoter. The isolated sequences included all of the subgenotypes C2. The sites that showed higher mutation rates in the HCC group were G1053A and G1229A, which were found to be independent risk factors through multiple logistic analysis (P < 0.05). Their promoter activities were elevated 2.38- and 4.68-fold, respectively, over that of the wild type in the HepG2 cells. Similarly, both the mRNA and protein levels of HBx in these two mutants were much higher than that in wild type-transfected HepG2 cells. Mutated nucleotides of the Enh1/X-promoter, especially G1053A and G1229A mutations in the HBV subgenotype C2 of patients with cirrhosis, can be risk factors for hepatocarcinogenesis, and this might be due to an increase in the HBx levels through the transactivation of the Enh1/X-promoter.

Efficacy and tolerability of pegylated interferon-alpha2a plus ribavirin versus pegylated interferon-alpha2b plus ribavirin in treatment-naive chronic hepatitis C patients.

OBJECTIVES: The authors compared the efficacies and tolerabilities of pegylated interferon-alpha2a (PEG-IFN-alpha2a) + ribavirin and pegylated interferon-alpha2b (PEG-IFN-alpha2b) + ribavirin for the initial treatment of chronic hepatitis C. METHODS: A total of 126 treatment-naive patients (29.4% genotype 1, 70.6% genotype non-1) were treated with PEG-IFN-alpha2a 180 microg/week (group A, n = 79) or PEG-IFN-alpha2b 1.5 microg/kg/week (group B, n = 47) with ribavirin (800 mg/day for genotype non-1 or 1,000-1,200 mg/day for genotype 1) for 24 (genotype non-1) or 48 weeks (genotype 1). RESULTS: End-of-treatment virologic response, sustained virologic response, and biochemical response were not significantly different in groups A and B (84.8 vs. 89.4%, 70.9 vs. 72.3%, and 70.9 vs. 74.5%, respectively; p > 0.05). In patients with the HCV genotype 1 or non-1, treatment responses were not significantly different. Multivariate analysis showed that HCV genotype only was an independent factor that affected sustained virologic response (p = 0.048). The proportions of treatment discontinuations in groups A and B were similar (10.1 vs. 10.6%; p = 1.000). CONCLUSIONS: PEG-IFN-alpha2a or PEG-IFN-alpha2b + ribavirin combination therapies showed similar efficacies and tolerabilities as initial treatments for chronic hepatitis C.

Treatment outcomes of clevudine versus lamivudine at week 48 in naïve patients with HBeAg positive chronic hepatitis B.

The authors assessed the efficacy and antiviral resistance of 48-week clevudine therapy versus lamivudine in treatment of naïve patients with HBeAg positive chronic hepatitis B. In this retrospective study, a total of 116 HBeAg positive patients, who received 30 mg of clevudine once daily (n=53) or 100 mg of lamivudine once daily (n=63) for 48 weeks, were included. At week 48, clevudine therapy produced a significantly greater mean reductions in serum HBV DNA levels from baseline than lamivudine therapy (-5.2 vs. -4.2 log(10)IU/mL; P=0.005). Furthermore, a significantly higher proportion of patients on clevudine achieved negative serum HBV DNA by PCR (<13 IU/mL) at week 48 (60.4% vs. 38.1%; P=0.025). The incidence of virologic breakthrough in the clevudine group was significantly lower than in the lamivudine group (9.4% vs. 25.4%; P=0.031). However, rates of alanine aminotransferase normalization and HBeAg loss or seroconversion were similar in the two groups (83.0% vs. 81.0%, 11.3% vs. 11.1%; P=0.813, 1.000, respectively). In conclusion, clevudine is more potent for viral suppression and lower for antiviral resistance at week 48 than lamivudine in treatment of naïve patients with HBeAg positive chronic hepatitis B.

X gene mutations in hepatitis B patients with cirrhosis, with and without hepatocellular carcinoma.

Specific mutations in the hepatitis B virus (HBV) genome have been reported to be associated with the development of hepatocellular carcinoma (HCC). The goal of this study was to determine whether mutations in the HBV X gene are associated with the development of HCC in hepatitis B patients with cirrhosis. Forty-two patients infected with HBV genotype C2 with cirrhosis and HCC were compared with 46 patients with cirrhosis but without HCC. X gene mutations were determined by direct sequencing in all patients. The HCC and non-HCC groups were similar with respect to clinical characteristics, and the presence of T1762/A1764, T1653, and V1753 mutations was not significantly different between the two groups (P = 0.068, P = 0.097, P = 0.442, respectively). Only the B1499 mutation was associated significantly with HCC (P = 0.015) (odds ratio: 3.42, 95% CI: 1.24-9.48). In hepatitis Be antigen (HBeAg)-positive patients, advanced age was associated significantly with HCC (P = 0.038), whereas in HBeAg-negative patients, the B1499 mutation was associated more significantly with HCC (P = 0.01). Patients in the B1499 mutation group exhibited significantly higher AST and ALT levels compared with patients infected the wild-type virus. In conclusion, B1499 is a novel mutation associated with HCC in Korean patients with cirrhosis infected with HBV genotype C2.

[A case of hepatocellular carcinoma invading the gallbladder misdiagnosed as a primary gallbladder carcinoma].

Extrahepatic metastasis of hepatocellular carcinoma (HCC) is occasionally seen in the lung, bone, adrenal gland, and lymph nodes. It is well known that HCC sometimes invades the biliary system. Since there is no peritoneum between the gallbladder and the liver fossa, a gallbladder cancer easily invades the liver; however, HCC seldom invades the gallbladder because it rarely destroys the muscle layer or the collagen fibers of the gallbladder wall. Routes of gallbladder metastasis of HCC include direct invasion, extension to the biliary system, and invasion of the adjacent hepatic vascular system. Some cases of gallbladder metastasis of HCC without direct invasion have been reported. We report here a case of HCC that directly invaded the gallbladder, and that resembled gallbladder carcinoma invading the liver.

[Distribution of hepatitis B virus genotypes in Korea].

BACKGROUND/AIMS: Considering the incidence of prevailing hepatitis B virus (HBV) genotypes in neighboring nations, the predominance of genotype C in Korea is exceptional and needs to be confirmed by nationwide investigation. METHODS: A total of 510 HBsAg (+) or HBeAg (+) serum samples was collected from subjects in several cities and harbors throughout the Korean peninsula for genotype (A-G)-specific multiplex PCR analysis. Another 40 serum samples from chronic HBV carriers from Iksan city were selected for sequencing of the entire HBV genome. Phylogenetic analysis was performed with 22 whole genomic sequences of Korean HBV strains enrolled in GenBank. RESULTS: An amplicon was found in 377 specimens and genotype C occupied 98.1% (370 cases); none of the other genotypes were found. A mixed pattern of genotypes B and C was seen in seven specimens (1.9%), of which five were tested using PCR targeting the X fragment; no genotype B bands were found. With the exception of 1 case, which was subgenotype A2, whole sequences of Korean HBV strains (n=62) belonged to subgenotype C2. CONCLUSIONS: The prevailing HBV genotype in Korea is C2; the other genotypes occur only rarely. Future studies should include confirmation of the detection of genotypes other than C.

Does the endoscopic finding of esophageal metastatic hepatocellular carcinoma progress from submucosal mass to polypoid shape?

BACKGROUND: Esophageal metastasis of hepatocellular carcinoma (HCC) is extremely rare; it was not serially followed-up by endoscopy. OBJECTIVE: Our purpose was to report the endoscopic findings according to the progression of esophageal metastatic HCC. DESIGN: Case report. RESULTS: In the review of the cases, submucosal tumor or polypoid mass were the most common endoscopic findings, and the locations of esophageal metastatic tumors are variable. The tumors had progressed from a submucosal mass to a polypoid mass in the current case. LIMITATION: Small number of cases. CONCLUSIONS: The endoscopic findings of esophageal metastasis of HCC may be changed from submucosal mass to polypoid mass.

Cerebral and pulmonary embolisms after transcatheter arterial chemoembolization for hepatocellular carcinoma.

A cerebral lipiodol embolism is an extremely rare complication of transcatheter arterial chemoembolization for hepatocellular carcinoma. We present a case of cerebral lipiodol embolism that occurred after the third arterial chemoembolization, report the clinical and radiological findings, and review the medical literature.

[A case of metastatic cutaneous nodules of recurrent hepatocellular carcinoma].

Common metastatic sites of hepatocellular carcinoma include lung, peritoneum, adrenal gland and bone, but rarely, skin can be metastatic sites. Although hepatocellular carcinoma is the third commonest malignancy in Korea, cutaneous metastasis from hepatocellular carcinoma was rarely reported. Cutaneous metastasis from malignant neoplasm of the internal organ occur at the variable stage and the growth pattern of cutaneous lesions is nonspecific and various, so the differential diagnosis of skin lesions must be considered to other malignant condition. We report a case of cutaneous metastasis from recurrent hepatocellular carcinoma that was confirmed by skin biopsy with immunohistochemical stain.

[Pancreatic Panniculitis in Patients with Chronic Pancreatitis: Case Report and Review of Literature].

Pancreatic panniculitis is a rare complication characterized by subcutaneous fat necrosis associated with pancreatic disease. It has been postulated that pancreatic panniculitis is caused by the systemic activity of pancreatic enzymes that lead to microcirculatory disturbances. We report a 41-year-old heavy alcoholic woman with pancreatic panniculitis that coexisted with acute and chronic pancreatitis. She was diagnosed with chronic pancreatitis and alcoholic liver cirrhosis 5 years ago. She presented with multiple, tender, erythematous, subcutaneous nodules with heat sensation on both lower legs. Laboratory evaluation revealed an increase in the serum blood amylase and lipase. Histopathologic findings showed fat necrosis with inflammation around the necrotic subcutaneous fat tissue. The lesions subsided gradually with an improvement of acute pancreatitis.

Multiple Pyogenic Liver Abscesses Caused by Microperforation of an Idiopathic Cecal Ulcer.

Idiopathic cecal ulcer is a rare disease entity of unknown cause diagnosed by ruling out other known causes of cecal ulceration. The most common complication of an idiopathic cecal ulcer is bleeding; perforation, peritonitis, abscess, and stricture formation have been noted. The authors treated a 53-year-old woman who presented with fever and intermittent right upper quadrant abdominal pain. Multiple pyogenic liver abscess and a solitary cecal ulcer were diagnosed by radiologic, endoscopic, and pathologic examination, followed by laparoscopic cecectomy. After extensive study, we concluded that this patient's liver abscesses were a complication of the idiopathic cecal ulcer. Herein, we report a case of multiple pyogenic liver abscess caused by microperforation of idiopathic cecal ulcer.

[A case of congenital hepatic fibrosis presented with symptom of acute cholangitis].

Congenital hepatic fibrosis (CHF) is an autosomal recessive disease, presenting principally in children or young adults with portal hypertension, and infrequently associated with cholangitis. It is associated with renal malformation and Caroli's disease. The diagnosis of CHF is usually confirmed by its typical histological features. Cholangitis is a severe and frequently fatal complication. We report a 22-year-old man with congenital hepatic fibrosis who showed the cholangitis without radiological features of cystic dilatation or stone of intrahepatic ducts.

[Relevancy between liver injury, serum HBV-DNA, and intrahepatic HBcAg in young male chronic HBV carriers].

BACKGROUND/AIMS: Although the viral load is correlated with HBcAg, liver injury was not correlated to viral load in HBeAg positive patient. We aimed to study the inter-relationship of clinical parameters such as the level of HBV-DNA, the level of aminotransferase, intrahepatic expression of HBcAg and severity of histological liver damage in the young male chronic HBV carriers according to HBeAg status. METHODS: The study group included 85 young male patients (mean age: 19.8) with biopsy-proven chronic hepatitis B (HBeAg-positive group: n=60, HBeAg-negative group: n=25). RESULTS: Serum levels of HBV-DNA and the expression of intrahepatic HBcAg in the HBeAg-positive group were significantly higher than in the HBeAg-negative (p<0.001), but fibrosis score was lower (p<0.01). Serum levels of HBV-DNA positively correlated with lobular activity, portal/periportal activity, biochemical activities in the HBeAg-negative group but negatively correlated in the HBeAg-positive group. There were no significant differences in histological activity according to the pattern of expression of intrahepatic HBcAg in both groups. The lobular activity correlated positively with biochemical activity in both groups, and portal/periportal activity correlated with biochemical activity only in the HBeAg-positive group. CONCLUSIONS: There are close correlations among liver injury, intrahepatic expression of HBcAg, and detectable HBV-DNA in the young male chronic HBV carriers with HBeAg-negativity, but in the HBeAg-positive group, the correlations are diversified.

[Genotypes of hepatitis B virus on Jeju island].

BACKGROUND/AIMS: Hepatitis B virus (HBV) was classified into 8 genotypes by a sequence divergence in the entire genome designated from A to H. HBV genotypes have distinct geographic distributions. Recently, HBV genotypes have been partially found as influencing the clinical manifestation of chronic liver disease in hosts. In Korea, the distribution of HBV genotypes remains unclear. The aim of this study was to evaluate the prevalence of the HBV genotype on Jeju Island. METHODS: Hepatitis B virus genotypes were evaluated among 107 hepatitis B carriers residing on Jeju Island. We used single PCR and multiplex-PCR assay with genotype-specific primer pairs for HBV genotypes A-F for the genotyping. RESULTS: 1. Fifty nine samples (55%) were positive for HBV DNA. The positivity was different according to the pattern of HBeAg/ anti-HBe expression, as -/-; 2/3 (66.7%), -/+; 30/73 (30%), +/-; 24/28 (85.7%) and +/+; 3/3 (100%). 2. In the single primer set of genotype-specific PCR, 59 samples (100%) were detected as genotype C and 2 (3%) were also detected as genotype A and B. 3. In multiplex-PCR, 58 samples (98%) were detected as genotype C and only one (2%) as a mixed pattern of genotype B and C. 4. When the PCR products were amplified with universal sense and genotype specific anti-sense from one genotype A, one B, and 2 C, all were included in genotype C. CONCLUSIONS: These results suggest that on Jeju Island, almost all HBV genotypes are C.

Impact of Nucleotide Mutations at the HNF3- and HNF4-Binding Sites in Enhancer 1 on Viral Replication in Patients with Chronic Hepatitis B Virus Infection.

BACKGROUND/AIMS: The hepatitis B virus (HBV) genome contains binding sites for hepatocyte nuclear factors (HNF) 3 and 4 in the core domain of enhancer 1 (Enh1), and mutations in this domain have a strong impact on virus replication. We aimed to identify frequent base-mutation sites in the core domain of Enh1 and to examine the impact of these mutations on viral replication. METHODS: We studied virological characteristics and genetic sequences in 387 patients with chronic hepatitis B. We evaluated functional differences associated with specific mutations within the core domain of Enh1. RESULTS: Mutations in the core domain were found with significant frequency in C1126 (122/387 [31.5%], the binding site for HNF3) and in C1134 (106/387 [27.4%], the binding site for HNF4). A single mutation at nt 1126 (C1126) was identified in 17/123 (13.8%), and 105/123 (85.4%) had double mutations (C1126/1134). The level of HBV DNA (log10 copies/mL) was lower in single mutants (C1126, 5.81±1.25) than in wild (6.80±1.65) and double mutants (C1126/1134, 6.81±1.54). Similarly, the relative luciferase activity of C1126 and C1126/C1134 was 0.18 and 1.12 times that of the wild-type virus, respectively. CONCLUSIONS: Mutations in the HNF3 binding site inhibit viral replication, whereas mutations at the HNF4 binding site restore viral replication.

Co-development of autoimmune hepatitis and Sjögren's syndrome triggered by the administration of herbal medicines.

Autoimmune hepatitis (AIH) has been reported in association with Sjögren's syndrome (SS). Drug-induced AIH has been rarely reported. A rare case of the co-development of AIH and SS in a 53-year-old woman after the consumption of herbal medicines is described. After admission, the patient complained of dryness in her mouth, and she was subsequently diagnosed with SS, which had not been detected previously. The patient's bilirubin and aminotransferase levels initially decreased following conservative management; however, they later began to progressively increase. A diagnosis of AIH was made based on the scoring system proposed by the International Autoimmune Hepatitis Group. The patient was administered a combination of prednisolone and azathioprine, and the results of follow-up liver-function tests were found to be within the normal range. This is an unusual case of AIH and SS triggered simultaneously by the administration of herbal medicines.

Association between Hepatitis B Virus X Gene Mutations and Clinical Status in Patients with Chronic Hepatitis B Infection.

BACKGROUND/AIMS: Few reports have described the association between mutations in the entire X gene of the hepatitis B virus (HBV) and the clinical status of HBV-infected patients. We studied the association between HBV X gene mutations and the disease status of patients infected with HBV genotype C. METHODS: Mutations in the HBV X genes of 194 patients were determined by direct sequencing. The subject population consisted of patients with chronic hepatitis (n=60), liver cirrhosis (n=65), and hepatocellular carcinoma (HCC) (n=69). The sequencing results of these 3 groups were compared. RESULTS: Each of the mutations G1386M, C1485T, C1653T, T1753V, A1762T, and G1764A was significantly associated with the patient's clinical status. The T1753V (p<0.001) and A1762T/G1764A (p<0.001) mutations were found more frequently in Hepatitis B e antigen (HBeAg)-negative than in HBeAg-positive patients. Specific X gene mutations (G1386M, C1653T, and A1762T/G1764A) were more prevalent in patients with liver cirrhosis and HCC than in chronic hepatitis patients (p<0.005 for all). In addition, the T1753V (p<0.001) and C1485T (p<0.001) mutations were significantly more prevalent in HCC patients than in chronic hepatitis patients. Only the prevalence of the T1753V mutation increased as the HBV infection progressed from liver cirrhosis to HCC (p=0.023). CONCLUSIONS: Our findings show a difference in the pattern of X gene mutations that were associated with the clinical status of patients with chronic HBV infection.