Hyoung Su Kim

Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: A randomised, non-inferiority, open trial

BACKGROUND & AIMS Both corticosteroid and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis. However, few studies have directly compared the efficacy of pentoxifylline and corticosteroid in patients with this condition. METHODS In this multicentre, open-labelled, randomised non-inferiority trial, we assigned 121 patients with severe alcoholic hepatitis (Maddreys discriminant function ⩾32) to receive either pentoxifylline (400 mg, 3 times daily, in 62 subjects) or prednisolone (40 mg daily, in 59 subjects). The primary end point was non-inferiority in survival at the 1 month time point for the pentoxifylline treatment compared with prednisolone. RESULTS The 1-month survival rate of patients receiving pentoxifylline was 75.8% (15 deaths) compared with 88.1% (7 deaths) in those, taking prednisolone, for a treatment difference of 12.3% (95% confidence interval, -4.2% to 28.7%; p = 0.08). The 95% confidence interval for the observed difference exceeded the predefined margin of non-inferiority (Δ15%) and included zero. The 6-month survival rate was not significantly different between the pentoxifylline and prednisolone groups (64.5% vs. 72.9%; p = 0.23). At 7 days, the response to therapy assessed by the Lille model was significantly lower in the prednisolone group (n = 58) than in the pentoxifylline group (n = 5 9): 0.35 vs. 0.50 (p = 0.012). Hepatitis complications, including hepatorenal syndrome and side effects, such as infection and gastrointestinal bleeding, were similar in the two groups. CONCLUSIONS The findings demonstrate that the efficacy of the pentoxifylline is not statistically equivalent to the efficacy of prednisolone, supporting the use of prednisolone as a preferred treatment option in patients with severe alcoholic hepatitis.

Prognostic Values of α-fetoprotein and Protein Induced by Vitamin K Absence or Antagonist-II in Hepatitis B Virus-related Hepatocellular Carcinoma : A Prospective Study

Background/Aim Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are most widely used tumor markers in detecting hepatocellular carcinoma (HCC). Recently, there have been some studies about them as prognostic markers in hepatitis C virus-associated HCC. However, prognostic values of AFP and PIVKA-II remain clarified in hepatitis B virus (HBV)-associated HCC. This study was aimed to evaluate the prognostic values of AFP and PIVKA-II in HBV-associated HCC. Methods Patients (n=126) were divided into 4 groups according to median levels of AFP and PIVKA-II (L; low/low, A; high/low, P; low/high, H; high/high) at diagnosis. Clinical characteristics and survival were compared among the groups, and Cox regression analysis was performed to find independent factors for survival. Results Baseline host and viral factors were not significantly different among the 4 groups. High PIVKA-II groups (P and H) had more aggressive tumor characteristics (larger size of tumors, higher number of tumors, frequent portal vein thrombosis, P<0.05) and much shorter median survival time than low PIVKA-II groups (L and A) (P<0.05). In multivariate analysis, high PIVKA-II level was an independent predictor for survival (risk ration: 2.377, 95% confidence interval: 1.359-4.157, P=0.002) together with Child-Pugh score, advanced TMN stages, and treatment modality. Even after excluding 33 patients who had Child-Pugh class C and advanced tumor stages (tumor-nodes-metastasis stage III-IV) at diagnosis, high PIVKA-II level was still an independent predictor for survival (risk ration: 4.258, 95% confidence interval: 2.418-8.445, P<0.001). Conclusions Serum PIVKA-II level, not serum AFP, was a valuable independent prognostic factor in HBV-related HCC.

Polymorphisms of interleukin-1 and interleukin-2 genes in patients with gastric cancer in Korea

Background and Aim:  Interleukin (IL)‐1 gene polymorphism has been reported to be associated with the increment of gastric cancer (GC) and the decrement of duodenal ulcers (DU). In addition, IL‐2 is known to induce Helicobacter pylori (H. pylori)‐associated gastric atrophy, but it is not known whether IL‐2 gene polymorphism increases the risk of GC (GC) or peptic ulcer diseases. Therefore, we compared the genotypes of IL‐1B, IL‐1RN, and IL‐2 gene polymorphisms with risk of gastric ulcers (GU), GC, and DU in Korean patients.

Association of concurrent hepatitis B surface antigen and antibody to hepatitis B surface antigen with hepatocellular carcinoma in chronic hepatitis B virus infection.

Antibody to hepatitis B surface antigen (HBsAg) (anti‐HBs) can exist in patients with chronic hepatitis B virus (HBV) infection. To date, little is known about the association of concurrent HBsAg and anti‐HBs (concurrent HBsAg/ anti‐HBs) with hepatocellular carcinoma (HCC). The aim of this study was to investigate the clinical relevance of concurrent HBsAg/anti‐HBs with preS deletion mutations and HCC in chronic HBV infection. A total of 755 patients with chronic HBV infection were included consecutively at a tertiary center. Logistic regression analysis was used to identify risk factors for HCC, and serum HBV DNA was amplified, followed by direct sequencing to detect preS deletions. The prevalence of concurrent HBsAg/anti‐HBs was 6.4% (48/755) and all HBVs tested were genotype C. HCC occurred more frequently in the concurrent HBsAg/anti‐HBs group than in the HBsAg only group [22.9% (11/48) vs. 7.9% (56/707), P = 0.002]. In multivariate analyses, age >40 years [odds ratio (OR), 14.712; 95% confidence interval (CI), 4.365–49.579; P < 0.001], male gender (OR 2.431; 95% CI, 1.226–4.820; P = 0.011), decompensated cirrhosis (OR, 3.642; 95% CI, 1.788–7.421; P < 0.001) and concurrent HBsAg/anti‐HBs (OR, 4.336; 95% CI, 1.956–9.613; P < 0.001) were associated independently with HCC. In molecular analysis, preS deletion mutations were more frequent in the concurrent HBsAg/anti‐HBs and HCC groups than in the HBsAg without HCC group (42.3% and 32.5% vs. 11.3%; P = 0.002 and 0.012, respectively). In conclusion, concurrent HBsAg/anti‐HBs is associated with preS deletion mutations and may be one of the risk factors for HCC in chronic HBV infection with genotype C. J. Med. Virol. 81:1531–1538, 2009.

Coexistence of hepatitis B surface antigen and antibody to hepatitis B surface may increase the risk of hepatocellular carcinoma in chronic hepatitis B virus infection: A retrospective cohort study

The simultaneous detection of hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface (anti‐HBs) is unusual in chronic hepatitis B virus (HBV) infection, but may be related with more advanced liver diseases. This retrospective long‐term cohort study was aimed to investigate whether coexistence of HBsAg and anti‐HBs may increase the risk of hepatocellular carcinoma (HCC) in chronic HBV infection. A total of 1,042 non‐HCC patients were recruited and followed up for a median 4.3 years (range 1.0–22 years). Univariate and multivariate analyses were performed to identify the risk factors for HCC development. The prevalence of coexistence of HBsAg and anti‐HBs was 7.0% (73/1,042). In univariate analysis, the 5‐, 10‐, and 15‐year cumulative incidences of HCC were significantly higher in coexistence group than in HBsAg only group (12.7%, 23.4%, 69.4% vs. 4.9%, 13%, 20.6%, respectively; P = 0.008). In multivariate analysis, coexistence of HBsAg and anti‐HBs [Hazard ratio (HR), 2.001; 95% confidence interval (CI), 1.023–3.912; P = 0.043] as well as male gender [HR, 1.898; 95% CI, 0.31–0.896; P = 0.018], age over 40 years [HR, 14.56; 95% CI, 4.499–47.08; P = 0.0001], and cirrhosis [HR, 7.995; 95% CI, 4.756–13.439; P = 0.0001] was identified as the independent factor for HCC development. Also, the cumulative incidence of HCC increased in proportion to the number of the risk factors. In conclusion, coexistence of HBsAg and anti‐HBs may increase independently the risk of HCC development in chronic HBV infection. Therefore, consideration of HCC development is required in patients with coexistence of HBsAg and anti‐HBs. J. Med. Virol. 86:124–130, 2014.

Initial thrombocytopenia as a simple, valuable predictor for clinical manifestation in acute hepatitis A

OBJECTIVE Although acute hepatitis A (AH-A) is usually self-limited, the clinical manifestations can vary from mild to severe liver dysfunction. However, little is known about the simple, valuable predictors for clinical manifestation in AH-A. The objective of this study was to identify the simple clinical predictors for severe liver dysfunction and its clinical course. MATERIAL AND METHODS A total of 162 IgM anti-hepatitis A virus (HAV) positive patients were enrolled in the study. Severe AH-A was defined as a prothrombin time <40% of control activity. Various liver-unrelated and liver-related parameters at presentation were compared separately between the severe AH-A group and the non-severe group. RESULTS Mean age (+/-SD) was 27.5 (+/-7.1) years and the proportion of males was 54% (88/162). Fourteen patients (8.7%) experienced severe AH-A. Of the liver-unrelated parameters, leukopenia (<4000/microl), thrombocytopenia (<150,000/microl), and high serum C-reactive protein levels (>8 mg/l) at presentation were significant predictors for severe AH-A in a univariate analysis (p<0.05). On multivariate analysis, only thrombocytopenia was an independent predictor for severe AH-A (odds ratio (OR) 5.562, 95% confidence interval (CI) 1.153-26.834, p=0.033). Of the liver-related parameters, there were no independent predictors, as shown by multivariate analysis. The thrombocytopenia group (33%, 54/162) not only had a longer recovery time (28 days (range, 14-140) versus 37 days (20-128), p<0.001), but also more frequent complications (OR 4.632, 95% CI 1.886-11.372, p=0.001) than the non-thrombocytopenia group. CONCLUSIONS Initial thrombocytopenia may be a simple, valuable predictor for severity and clinical course in AH-A.Objective. Although acute hepatitis A (AH-A) is usually self-limited, the clinical manifestations can vary from mild to severe liver dysfunction. However, little is known about the simple, valuable predictors for clinical manifestation in AH-A. The objective of this study was to identify the simple clinical predictors for severe liver dysfunction and its clinical course. Material and methods. A total of 162 IgM anti-hepatitis A virus (HAV) positive patients were enrolled in the study. Severe AH-A was defined as a prothrombin time <40% of control activity. Various liver-unrelated and liver-related parameters at presentation were compared separately between the severe AH-A group and the non-severe group. Results. Mean age (±SD) was 27.5 (±7.1) years and the proportion of males was 54% (88/162). Fourteen patients (8.7%) experienced severe AH-A. Of the liver-unrelated parameters, leukopenia (<4000/µl), thrombocytopenia (<150,000/µl), and high serum C-reactive protein levels (>8 mg/l) at presentation were significant predictors for severe AH-A in a univariate analysis (p <0.05). On multivariate analysis, only thrombocytopenia was an independent predictor for severe AH-A (odds ratio (OR) 5.562, 95% confidence interval (CI) 1.153–26.834, p=0.033). Of the liver-related parameters, there were no independent predictors, as shown by multivariate analysis. The thrombocytopenia group (33%, 54/162) not only had a longer recovery time (28 days (range, 14–140) versus 37 days (20–128), p<0.001), but also more frequent complications (OR 4.632, 95% CI 1.886–11.372, p=0.001) than the non-thrombocytopenia group. Conclusions. Initial thrombocytopenia may be a simple, valuable predictor for severity and clinical course in AH-A.

A case of pedunculated hepatic hemangioma mimicking submucosal tumor of the stomach

Hepatic hemangioma is the most common benign tumor of the liver. Most such hemangiomas are small, asymptomatic, and have an excellent prognosis. Giant hepatic hemangioma has been reported in the literature, but the exophytic and pedunculated forms of hepatic hemangioma are rare. A 56-year-old woman was referred to our hospital under the suspicion of having a gastric submucosal tumor. Abdominal computer tomography (CT) scans showed a pedunculated mass from the left lateral segment of the liver into the gastric fundus, exhibiting the atypical CT findings of hepatic hemangioma. We therefore decided to perform laparoscopic resection based on the symptoms, relatively large diameter, inability to exclude malignancy, and risk of rupture of the exophytic lesion. The pathology indicated it to be a cavernous hemangioma of the liver. Herein we report a case of pedunculated hepatic hemangioma mimicking a submucosal tumor of the stomach due to extrinsic compression of the gastric fundus.

Diagnostic value of PIVKA-II and alpha-fetoprotein in hepatitis B virus-associated hepatocellular carcinoma

AIM To determine the cutoff values and to compare the diagnostic role of alpha-fetoprotein (AFP) and prothrombin induced by vitamin K absence-II (PIVKA-II) in chronic hepatitis B (CHB). METHODS A total of 1255 patients with CHB, including 157 patients with hepatocellular carcinoma (HCC), 879 with non-cirrhotic CHB and 219 with cirrhosis without HCC, were retrospectively enrolled. The areas under the receiver operating characteristic (AUROC) curves of PIVKA-II, AFP and their combination were calculated and compared. RESULTS The optimal cutoff values for PIVKA-II and AFP were 40 mAU/mL and 10 ng/mL, respectively, for the differentiation of HCC from nonmalignant CHB. The sensitivity and specificity were 73.9% and 89.7%, respectively, for PIVKA-II and 67.5% and 90.3% for AFP, respectively. The AUROC curves of both PIVKA-II and AFP were not significantly different (0.854 vs 0.853, P = 0.965) for the differentiation of HCC from nonmalignant CHB, whereas the AUROC of PIVKA-II was significantly better than that of AFP in patients with cirrhosis (0.870 vs 0.812, P = 0.042). When PIVKA-II and AFP were combined, the diagnostic power improved significantly compared to either AFP or PIVKA-II alone for the differentiation of HCC from nonmalignant CHB (P < 0.05), especially when cirrhosis was present (P < 0.05). CONCLUSION Serum PIVKA-II might be a better tumor marker than AFP, and its combination with AFP may enhance the early detection of HCC in patients with CHB.

Clinical aspects of tumor necrosis factor-α signaling in hepatocellular carcinoma.

Tumor necrosis factor alpha (TNF-α) is a multi-functional cytokine that regulates a variety of signaling pathways implicated in inflammation, immunity, cell death (apoptosis), cell survival (anti-apoptosis), and even tumorigenesis. TNF-α is predominantly produced by macrophages (or Kupffer cells within the liver), but generated by lymphoid cells, astrocytes, endothelial cells, and smooth muscle cells to some degree. In the liver, TNF-α not only serves as a key mediator of hepatocyte apoptosis resulting in the liver damage, but also plays an important role in cellular proliferation leading to liver regeneration or even hepatocarcinogenesis. TNF-α may indirectly contribute to carcinogenesis via various inflammatory conditions such as alcoholic and non-alcoholic fatty liver diseases and chronic viral hepatitis. On the one hand, in inflammation, TNF-α induces apoptosis repeatedly and subsequently enhances the chance of formation of anomalous cells during the process of regeneration and dysplasia. On the other hand, TNF-α exerts as an anti-angiogenic factor depending on its concentration. It shows an anti-tumorous effect by increasing vascular permeability in the tumors. When it is perfused in combination with chemotherapeutic drugs using isolated hepatic infusion, TNF-α may increase the responsiveness of hepatocellular carcinoma (HCC) or metastatic cancers to anti-cancer agents as isolated limb perfusion methods in an unresectable soft tissue sarcoma or melanoma. This article reviews the TNF-α signaling pathway in hepatocarcinogenesis and the new challenge of TNF-α as a new therapeutic strategy in HCC.

The COX-2-1195AA Genotype Is Associated with Diffuse-Type Gastric Cancer in Korea

Background/Aims The potential role of the cyclooxygenase (COX)-2 polymorphism has been reported in relation to the risk of gastrointestinal tract malignancies. Therefore, we investigated whether COX-2 polymorphisms are associated with the risk of gastric cancer (GC) in Korea, one of the areas with a high prevalence of this condition. Methods We evaluated the genotypic frequencies of COX-2-765 and -1195 in 100 peptic ulcer patients, 100 GC patients, and 100 healthy controls. The polymorphisms of the COX-2-765 and -1195 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphisms. Results The frequencies of the COX-2-1195 GG, GA, and AA genotype were 20%, 60%, and 20% in intestinal-type GC and 8%, 48%, and 44% in diffuse-type GC, respectively (p=0.021). There were no significant differences in the frequency of COX-2-765 genotypes between intestinal-type GC and diffuse-type GC (p=0.603). Age- and sex-adjusted logistic regression analysis showed that the COX-2-1195 AA genotype was the independent risk factor of diffuse-type GC compared with the COX-2-1195 GG genotype (p=0.041; odds ratio, 6.22; 95% confidence interval, 1.077 to 35.870). Conclusions The COX-2-1195 AA genotype may render subjects more susceptible to diffuse-type GC.