Manabu Daikoku

Anti‐gp210 and anti‐centromere antibodies are different risk factors for the progression of primary biliary cirrhosis

The predictive role of antinuclear antibodies (ANAs) remains elusive in the long‐term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy‐proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end‐point, positive anti‐gp210 antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuers stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end‐point in the early stage (Scheuers stage 1, 2) PBC patients, positive anti‐gp210 antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive anti‐centromere antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti‐gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere antibodies was most significantly associated with more severe ductular reaction. Conclusion: These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive‐anti‐gp210 and positive‐anticentromere antibodies, respectively. (HEPATOLOGY 2007;45:118–127.)

Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis

Abstract: Background: Although the pathogenesis of non‐alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients.

Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus

OBJECTIVES:The role of host genetic factors in chronic hepatitis B virus (HBV) infection is not fully understood. We studied the influence of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) gene promoter polymorphisms on disease progression in HBV carriers.METHODS:The sample population included 213 Japanese HBV carriers and 52 healthy volunteers. Of 213 HBV carriers, 66 were considered to be asymptomatic carriers based on the sustained normalization of serum ALT together with seropositivity for the antibody to hepatitis B e antigen (anti-HBe), and 147 were found to have chronic progressive liver disease including cirrhosis. Five biallelic polymorphisms in the TNF-α gene promoter and three biallelic polymorphisms in the IL-10 gene promoter were analyzed by polymerase chain reaction in combination with direct sequencing or restriction fragment length polymorphism assay.RESULTS:Allelic distributions of both gene promoters were not significantly different between HBV carriers and healthy volunteers. In HBV carriers, the TNF-α gene promoter polymorphisms were not linked to disease progression. In contrast, allelic frequencies of T and A at positions −819 and −592, respectively, in the IL-10 gene promoter, as well as the frequencies of ATA haplotype at positions −1082/− 819/− 592 (which is characterized with low capacity for IL-10 production), were significantly higher in asymptomatic carriers than in patients with chronic progressive liver disease. Even after adjusting for individuals positive for anti-HBe, such a relationship could be found between the two groups.CONCLUSION:In chronic HBV infection, inheritance of the IL-10 gene promoter polymorphisms is involved in a host genetic factor that is relevant to disease progression.

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-α, -β, -γ, interleukin (IL)-1β, -4, -6, -10, -12p40, -18, tumor necrosis factor-α) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-α, -β and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-α, -β) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-α is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-β and TLR-3. Furthermore, the level of IFN-α mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC.

Relationship between sustained elevation of serum alanine aminotransferase and progression from cirrhosis to hepatocellular carcinoma: comparison in patients with hepatitis B virus- and hepatitis C virus-associated cirrhosis.

Abstract  Most patients with hepatocellular carcinoma (HCC) in Japan have hepatitis B virus (HBV)‐or hepatitis C virus (HCV)‐associated cirrhosis. In the present study, the risk of HCC in patients with cirrhosis was analysed by the levels of serum alanine aminotransferase (ALT). One hundred and one (78%) of 129 patients with cirrhosis registered from April 1979 were followed at monthly intervals with the measurement of serum ALT. Of 101 patients, 38 tested positive for hepatitis B surface antigen (HBsAg) but negative for antibody to HCV (anti‐HCV; HBV group), 47 tested negative for HBsAg but positive for anti‐HCV (HCV group) and nine tested positive and seven tested negative for both. Mean serum ALT during follow‐up was calculated on the basis of monthly values during the observation period that started at enrolment and ended with the detection of HCC or at the end of March 1994. By the end of March 1994, 37 (37%) patients developed HCC; 12 were in the HBV group, 21 in the HCV group and four were in the group positive for both. Mean serum ALT during the observation period was similar in patients who developed HCC and those who did not develop HCC in the HBV group. In contrast, the value was significantly higher in patients who developed HCC than in patients who did not develop HCC in the HCV group (P < 0.05).

Lipopolysaccharide signaling induces serum amyloid A (SAA) synthesis in human hepatocytes in vitro

To investigate the role of lipopolysaccharide (LPS) in hepatocyte activation, we examined the expression of Toll‐like receptor 4 (TLR4), the putative receptor for LPS in human hepatocytes. TLR4 mRNA and protein expression was confirmed in human hepatocytes. Stimulation of human hepatocytes with LPS results in rapid degradation of IkappaB‐α and mitogen activated protein kinase activation. Human hepatocytes stimulated by LPS produced serum amyloid A protein. Our data suggest that human hepatocytes utilize components of TLR4 signal transduction pathways in response to LPS and these direct LPS‐mediated effects on hepatocytes may contribute to liver inflammation and injury.

Predictive role of anti-gp210 and anticentromere antibodies in long-term outcome of primary biliary cirrhosis.

Because some of the autoreactive T‐cell clones specific for human PDC‐E2 cross‐react to mimicry peptides having an EIExDK motif derived from nuclear antigens such as human gp210 and sp100, we studied the clinical significance of antinuclear antibodies (ANA) in primary biliary cirrhosis (PBC) patients registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). We found that there are two different types of progression in PBC; one is a hepatic failure‐type progression which is represented by positive anti‐gp210 antibodies and the other is a portalhypertension‐type progression which is represented by positive anticentromere antibodies. We discuss the predictive role of these ANA in the long‐term outcome of PBC and the mechanisms by which two different PBC progression types occur based on molecular mimicry and aberrant expression of nuclear antigens.

Detection of HBV core promoter and precore mutations helps distinguish flares of chronic hepatitis from acute hepatitis B.

Background and Aim:  Acute exacerbation of chronic hepatitis B has to be distinguished from acute hepatitis, because treatment strategies differ between them.

Prevalence of hepatitis B or C virus infection in patients with fulminant viral hepatitis. An analysis using polymerase chain reaction.

BACKGROUND/METHODS The cause of fulminant hepatitis is still not fully understood. We studied 23 patients with fulminant hepatitis, using polymerase chain reaction to detect hepatitis virus genomes. Tests for HBsAg and IgM anti-HAV and IgM anti-HBc were performed in all patients. Serum samples were stored at -70 degrees C for later analysis of anti-HCV and hepatitis virus genomes such as hepatitis B virus, hepatitis C virus and hepatitis D virus. RESULTS Of 23 patients, 17 (74%) had HBV-DNA and two (9%) had HCV-RNA. No patient was positive for both viruses or positive for HDV-RNA. Serological tests indicated that two patients, negative for HBV-DNA and HCV-RNA, were positive for IgM anti-HAV. In contrast, 8 of 17 (47%) HBV-DNA positive patients were negative for both IgM anti-HBc and HBsAg in conjunction with low levels of viremia. Four patients were positive for anti-HCV, but only one was positive for HCV-RNA. One patient, positive for HCV-RNA, was negative for anti-HCV. CONCLUSIONS Our results indicate that analysis of hepatitis virus genomes using polymerase chain reaction allows accurate identification of the virus causing fulminant hepatitis.

Expression of microsomal prostaglandin E synthase-1 in human hepatocelluar carcinoma

Background/Aims: The objective of this study was to evaluate the expression of microsomal prostaglandin E synthase‐1 (mPGES‐1) in hepatocellular carcinoma (HCC) tissues.