+49A/G polymorphism of cytotoxic T‐lymphocyte antigen 4 gene in type 1 autoimmune hepatitis and primary biliary cirrhosis: A meta‐analysis

Aim: Recently, the associations of +49A/G polymorphisms of cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) gene with the susceptibility to type 1 autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have been reported; however these associations are yet to be fully elucidated. This study aimed to identify the associations of CTLA‐4 gene +49A/G polymorphisms with the susceptibility to type 1 AIH and PBC by using a meta‐analysis. Methods: PubMed was searched by using the following keywords: “autoimmune hepatitis AND (polymorphism OR polymorphisms)” or “primary biliary cirrhosis AND (polymorphism OR polymorphisms)”. Meta‐analyses of five studies including 526 patients with type 1 AIH and 631 controls and seven studies including 1500 patients with PBC and 2345 controls were performed. Results: For type 1 AIH, the odds ratio (OR) of G allele was 1.26 [95% confidence interval (CI) 1.06–1.51] although G/G homozygosity was not associated with the susceptibility to type 1 AIH. On the other hand, the OR of A/A homozygosity for type 1 AIH was 0.66 (95% CI 0.50–0.86). For PBC, the OR of G allele was 1.20 (95% CI 1.06–1.34). Furthermore, G/G homozygosity was significantly associated with the susceptibility to PBC (OR 1.29, 95% CI 1.01–1.66). The OR of A/A homozygosity for PBC was 0.81 (95% CI 0.70–0.94). Conclusions: This study suggests that CTLA‐4 gene +49A/G polymorphisms may be associated with the susceptibility to type 1 AIH and PBC. Especially, while G/G genotype may be associated with the susceptibility to PBC, A/A genotype may be protective against type 1 AIH and PBC.     

Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma

Background and Aim: Sorafenib, the first agent demonstrated to have efficacy to improve the survival of patients with advanced hepatocellular carcinoma (HCC), is an active multikinase inhibitor affecting angiogenesis and tumor proliferation. We analyzed cytokines related to angiogenesis or cell proliferation, and tried to determine their utility as biomarkers of sorafenib treatment effect for HCC. Methods: Nine serum cytokines (angiopoietin‐2 [Ang‐2], follistatin, granulocyte colony‐stimulating factor [G‐CSF], hepatocyte growth factor [HGF], interleukin‐8 [IL‐8], leptin, platelet‐derived growth factor‐BB, platelet endothelial cell adhesion molecule‐1, and vascular endothelial growth factor) were measured in 30 HCC patients treated with sorafenib, and the effects of treatment were compared using modified Response Evaluation Criteria in Solid Tumors. Results: All but IL‐8 were significantly higher at baseline in patients with progressive disease. Progression‐free survival was significantly shorter in patients with high levels of Ang‐2, G‐CSF, HGF, and leptin, and the hazard ratios were 2.51, 6.89, 2.55, and 4.14, respectively. As the number of cytokines at a high level increased, the treatment response deteriorated. Disease progression was seen in three of 12 (25.0%) patients with zero to two high biomarkers, two of six (33.3%) patients with 3–5 high biomarkers, and 10 of 12 (83.3%) patients with six to eight high biomarkers (P = 0.008). The prognosis of all patients with eight high biomarkers was progressive disease. Conclusion: High levels of serum cytokines at baseline were correlated with poor effects of sorafenib treatment in patients with HCC.     

Inflammatory fibroid polyp occurring in the transverse colon diagnosed by endoscopic biopsy

A case of an inflammatory fibroid polyp occurring in the transverse colon and diagnosed by endoscopic biopsy is reported. The patient was an 82-year-old man who visited our hospital for further evaluation of occult blood in stool. The Colonoscopy revealed a small, red, and peduncular polyp, about 6 mm in diameter, in the transverse colon. Histological examination of the biopsy specimen obtained from the polyp revealed proliferation of fibroblasts and infiltration of inflammatory cells such as plasma cells and eosinophils. This polyp was diagnosed as an inflammatory fibroid polyp, which can appear in many different locations throughout gastrointestinal tract, though still rare in the transverse colon.     

Human leukocyte antigen class II associations with hepatitis C virus clearance and virus-specific CD4 T cell response among Caucasians and African Americans

The outcome of hepatitis C virus (HCV) infection has been associated with antiviral CD4 T cell response, human leukocyte antigens (HLA) class II genotypes, and ethnicity. However, HLA class II molecules restrict the nature of CD4 T cell response, and HLA distributions differ between ethnic groups. In this study, we asked whether HLA class II genotypes associated with HCV clearance are shared between Caucasian and African Americans and whether they contribute to enhanced antiviral CD4 T cell response. In a cohort of 93 HCV-seropositive subjects from Northeast America with defined ethnicity, virological outcome, and HCV-specific CD4 T cell proliferation, we confirm the previously reported associations between HCV clearance and two HLA types (DQB1*03, DRB1*11) while identifying a new association with DRB3*02. Strikingly, these associations were identified only among Caucasian [DQB1*03: odds ratio (OR), 10.4; P = 0.031, DRB1*11: OR, 7.0, P = 0.019; DRB3*02: OR, 8.3, P = 0.005; DQB1*03-DRB3*02: OR, 13.5, P = 0.001) but not among African American patients. Furthermore, although HLA DQB1*03, DRB1*11, and DRB3*02 genotypes were associated with increased HCV-specific CD4 T cell response in univariate analyses, these associations were lost when controlling for virological outcomes. CONCLUSION: We conclude that the immunogenetic basis for HCV clearance differs between ethnic groups and that the association between HLA class II and HCV clearance is not directly explained by antiviral CD4 T cell response.     

Severe liver injury associated with simeprevir plus pegylated interferon/ribavirin therapy in a patient with treatment-naïve genotype 1b hepatitis C virus: a case report

A second-generation direct-acting antiviral agent, simeprevir, now provides a new treatment option for hepatitis C virus (HCV) infection with good safety profile in combination with pegylated interferon and ribavirin. We herein report a rare case of severe liver injury under simeprevir plus pegylated interferon/ribavirin therapy. We initiated this therapy in a 65-year-old male with treatment-naïve genotype 1b HCV. On day 28, the patient’s HCV-RNA was successfully eliminated, and his liver function was fully restored. However, on day 49, the serum alanine aminotransferase level was elevated at 700 IU/L. The HCV-RNA titer was still undetectable and the involvement of other possible viruses was negligible. A liver biopsy performed on day 60 showed an acute hepatitis pattern. The discontinuation of therapy alone successfully improved his liver damage on day 84. No other treatments such as steroids were required. According to the diagnostic criteria for drug-induced liver injury in Japan (DDW-J2004), the liver injury observed in this case can be associated with the administration of simeprevir plus pegylated interferon/ribavirin therapy. In conclusion, simeprevir plus pegylated interferon/ribavirin should be used with caution, as these agents may cause unreported serious adverse events including severe liver injury, despite their clinical safety profile.     

A case of Wilson’s disease with characteristic laparoscopic findings

A 44-year-old male was pointed out liver function abnormality by medical check-up. Blood examination and computed tomography showed liver cirrhosis. Then, he was referred to our hospital for further examination. After blood test, viral markers revealed previous infection of hepatitis B virus (HBV). We estimated the etiology of his liver disease as previous HBV infection. On laparoscopic examination, his liver surface was nodular with mixed yellowish nodules and ash gray to copper-colored nodules in the diameter of 3–10 mm. There were large regenerative nodules in segments 3 and 4. Large regenerative nodules and irregular steatosis were contradictory to HBV-related liver cirrhosis, so then we supposed Wilson’s disease. The amount of copper excretion in the urine was 326.6 μg (>100 μg/24 h). After D-penicillamine administration, urinary copper excretion increased to 2151.5 μg/24 h. Though hepatic copper concentration was 174.5 μg/g wet tissue (>200 μg/g wet tissue), his laboratory data fulfilled the Leipzig diagnostic criteria proposed by EASL. Laparoscopic examination with liver biopsy has advantages to survey many disease-specific findings on liver surface and to obtain adequate liver sample. Laparoscopic examination is one of the effective procedures for diagnosing relatively rare liver disease like Wilson’s disease.     

Sugar alcohols enhance calcium transport from rat small and large intestine epithelium in vitro

We compared the effect of a variety of sugar alcohols on calcium absorption from the rat small and large intestine in vitro. An Ussing chamber technique was used to determine the net transport of Ca across the epithelium isolated from the jejunum, ileum, cecum, and colon of rats. The concentration of Ca in the serosal and mucosal Tris buffer solution was 1.25 mM and 10 mM, respectively. The Ca concentration in the serosal medium was determined after incubation for 30 min and the net Ca absorption was evaluated. The addition of 0.1–200 mM erythritol, xylitol, sorbitol, maltitol, palatinit, or lactitol to the mucosal medium affected net Ca absorption in the intestinal preparations. Differences in Ca transport were observed between portions of the intestine, but not between sugar alcohols tested. We concluded that sugar alcohols directly affect the epithelial tissue and promote Ca absorption from the small and large intestine in vitro.     

Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure

Background and Aims: In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte‐colony stimulating factor (G‐CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF). Methods: Serum levels of nine angiogenic factors (angiopoietin‐2, follistatin, G‐CSF, hepatocyte growth factor [HGF], interleukin‐8, leptin, platelet‐derived growth factor [PDGF]‐BB, platelet endothelial cell adhesion molecule‐1 and VEGF) were measured using the Bio‐Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls. Results: Serum levels of PDGF‐BB and VEGF were lower in FHF patients than AH patients and controls (PDGF‐BB; 2050 ± 1572 pg/mL vs 4521 ± 2419 pg/mL vs 8506 ± 5500 pg/mL, VEGF; 39 ± 38 pg/mL vs 144 ± 122 pg/mL vs 205 ± 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF‐BB and VEGF were associated with poor outcomes. Serum PDGF‐BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF‐BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38). Conclusions: We consider that serum levels of PDGF‐BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.     

Prognostic importance of fucosylated alpha-fetoprotein in hepatocellular carcinoma patients with low alpha-fetoprotein

Background and Aim: Fucosylated alpha‐fetoprotein (AFP‐L3) is known to be a marker of poor prognosis in patients with hepatocellular carcinoma (HCC). However, it has been difficult to measure AFP‐L3 under low AFP (≤ 20 ng/mL). The aim of this study was to elucidate the role of AFP‐L3 in HCC patients with low AFP conditions. Methods: One hundred and ninety six consecutive newly developed HCC patients with low AFP (≤ 20 ng/mL) were examined for serum AFP‐L3 expression by a newly‐developed micro‐total analysis system that could stably measure AFP‐L3 in low AFP circumstances, and its clinical importance was analyzed. Results: Positivity of AFP‐L3 in HCC patients was 13.3% at a cut‐off level of 10%. Five‐year survivals of HCC patients with AFP‐L3 (< 10%) and AFP‐L3 (≥ 10%) were 69.4% and 41.1%, respectively (P = 0.001). Among 18 clinical parameters, low alanine aminotransferase, large tumor size, presence of portal vein tumor thrombus, high AFP and high des‐gamma carboxy prothrombin were observed in the high AFP‐L3 (≥ 10%) group. Multivariate analysis revealed that high aspartate aminotransferase (AST) (risk ratio [RR] = 3.24, 95% confidence interval [CI] = 1.27–8.26), the presence of ascites (RR = 3.44, 95% CI = 1.22–9.34), multiple tumor number (RR = 3.06, 95% CI = 1.33–7.17), and high AFP‐L3 (RR = 8.36, 95% CI = 2.79–25.5) were risk factors for survival. High AFP‐L3 was also a risk factor for survival in HCC patients who received radiofrequency ablation (P = 0.048). Conclusions: AFP‐L3 is a strong prognostic factor for survival even in HCC patients with low AFP (≤ 20 ng/mL).