Kaname Yoshizawa

Epidemiology of hepatocellular carcinoma in Japan

Primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), is ranked third in men and fifth in women as a cause of death from malignant neoplasms in Japan. The number of deaths and death rate of HCC began to increase sharply in 1975. These numbers peaked at 34 510 and 27.4/100 000, respectively, in 2004, but decreased to 33 662 annual deaths and a 26.7/100 000 death rate in 2006. Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are both major causes of HCC, HCV-related HCC represents 70% of all cases. The incidence of HCC without hepatitis B surface antigen (HBsAg) or antibodies to HCV (anti-HCV) accounts for 8%–15% of HCC patients nationwide. Geographically, HCC is more frequent in western than eastern Japan, and death rates of HCC in each prefecture correlate with anti-HCV, but not HBsAg, prevalence. Interferon therapy for chronic hepatitis C reduces the risk of development of HCC, especially among patients with sustained virological response. Further research should focus on the mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and preventative approaches. Better understanding of HCC unrelated to HCV and HBV, possibly caused by steatohepatitis and diabetes, should also be a major concern in future studies.

Transmission of hepatitis C in an isolated area in Japan : community-acquired infection

Abstract Background/Aims: The spread of hepatitis C virus (HCV) infection not due to drug needle sharing or transfusion is largely unknown in communities. A search for risk factors for HCV infection in an endemic area might elucidate inapparent modes of transmission. Methods: We conducted screening for hepatitis virus markers and parenteral exposures to blood among 435 inhabitants in an isolated area known for its endemicity for non-A, non-B hepatitis and in a nonendemic area with 1542 inhabitants. Results: The prevalence of hepatitis B surface antigen was the same in both areas. The prevalence of antibody to HCV verified by the recombinant immunoblot assay was 32.4% in the highly endemic area and 2.3% in the nonendemic area ( P Conclusions: Folk remedies such as acupuncture and cutting of the skin using nonsterilized knives should be considered as possible routes of HCV transmission not associated with blood transfusion or sharing of drug paraphernalia.

Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors

The interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) and T‐helper type 1 and type 2 (Th1/Th2) ratio were analyzed along with other host and viral factors for their ability to predict the response of patients with chronic hepatitis C to pegylated interferon alpha‐2b (Peg‐IFN) and ribavirin (RBV) combination therapy. A total of 120 chronic hepatitis C patients with genotype 1 HCV and high baseline viral loads who were to undergo combination therapy scheduled for 48 weeks were enrolled. Sustained virologic response (SVR) was achieved in 54 (45%) of the 120 patients. The pretreatment factors significantly associated with SVR by logistic regression analysis were ISDR mutant [odds ratio (OR) = 86.0, P = 0.0008], Th1/Th2 ratio ≤ 15.5 (OR = 9.6, P = 0.0021), body weight 59 kg, and neutrophil count 2,300/μL. A logistic regression model to estimate SVR before combination therapy was constructed using these four factors. Patients fell into three groups when plotted according to estimated and actual SVR rates: actual SVR rate was 91% (32/35) in the high sensitivity group, 41% (15/37) in the intermediate sensitivity group, and 15% (7/48) in the low sensitivity group. Rapid or early virological responses were seen in 80% of patients with high sensitivity and who achieved SVR but were found in only 40% of patients with intermediate or low sensitivity. Null‐ and very late virological responses were quite rare in the high sensitivity group. In conclusion, a logistic regression model that includes the sequence of ISDR of the HCV, Th1/Th2 ratio, body weight, and neutrophil count can be useful for accurately predicting actual SVR rate before combination therapy. (HEPATOLOGY 2008;48:1753‐1760.)

Autoimmune pancreatitis and complement activation system.

Objectives: Autoimmune pancreatitis is characterized by increased serum level of IgG4, but its pathogenesis has not been fully elucidated. Because this disease is occasionally associated with decreased levels of complements, we sought to clarify which complement activation system was operating in its active state. Methods: We measured serum levels of complements, mannose-binding lectin, and circulating immune complex in patients with autoimmune pancreatitis, patients with chronic pancreatitis, and healthy controls. Results: We found high serum circulating immune complex values, which decreased significantly after corticosteroid therapy. In patients with autoimmune pancreatitis, elevated levels of circulating immune complex, as determined by C1q assay, were significantly associated with increased serum levels of IgG1 and decreased levels of C4, as well as with a tendency toward decreased levels of C3. There were no significant differences in the serum levels of mannose-binding lectin or in the frequency of a mutant allele of mannose-binding lectin between patients with autoimmune pancreatitis and those with chronic calcifying pancreatitis. Furthermore, corticosteroid therapy had no effect on the level of mannose-binding lectin. Conclusions: Autoimmune pancreatitis exhibits a high serum circulating immune complex values in its active state, which links to a complement activation system with a classic pathway rather than the mannose-binding lectin pathway or alternative pathways.

High prevalence of hypothyroidism in patients with autoimmune pancreatitis.

Autoimmune pancreatitis is a unique form of chronic pancreatitis and has been correlated with various extrapancreatic lesions. To search for a correlation between autoimmune pancreatitis and thyroid lesions, we measured thyroid functions in 41 patients with autoimmune pancreatitis and in 41 patients with chronic calcifying pancreatitis and investigated the correlation between HLA antigens and hypothyroidism. We found a significant difference in the prevalence of antithyroglobulin antibody and hypothyroidism between patients with autoimmune pancreatitis and those with chronic pancreatitis (34.1 vs. 7.3%, P = 0.005, and 26.8 vs. 0%, P = 0.0005, respectively). Patients with hypothyroidism had a significantly higher frequency of antithyroglobulin antibody (63.6%) than those without hypothyroidism but showed no differences in other findings, including serum IgG4 concentration. We could find no significant association between any HLA antigens and the hypothyroid state of autoimmune pancreatitis. One quarter of the patients with autoimmune pancreatitis have hypothyroidism that may be independent of the active state of the pancreatic lesion or systemic fibrosing disorder, and thus patients suspected of having autoimmune pancreatitis should be evaluated for possible hypothyroidism.

Two critical genes (HLA-DRB1 and ABCF1)in the HLA region are associated with the susceptibility to autoimmune pancreatitis

We have previously reported that autoimmune pancreatitis (AIP) is a bioclinical entity characterized by high serum immunoglobulin G4 concentrations and association with the HLA-DRB1*0405-DQB1*0401 haplotype. However, the precise identity of gene(s) within this haplotype directly responsible for AIP pathogenesis is yet to be established. To dissect the genetic contribution of the incriminated haplotype, we have now performed an association analysis within the human leukocyte antigen (HLA) region using various types of polymorphic markers. Genomic DNAs from 43 AIP patients and 213 unrelated Japanese controls were used in this analysis. In each DNA sample, we established the genotype of 25 microsatellite markers distributed throughout the HLA region, that of single nucleotide polymorphism within the 5′-flanking regions of the TNFA and IkBLI (also known as NFKBIL1) as well as HLA class I and II genes. The HLA-linked susceptibility regions for AIP were localized to two segments: HLA-DRB1 (*0405; OR = 3.20, P = 0.00063, Pc = 0.0016) -DQB1 (*0401; OR = 3.29, P = 0.00046, Pc = 0.0069) in the HLA class II and C3-2-11microsatellite (allele 219; OR = 2.96, P = 0.0076, Pc = 0.099) in the HLA class I regions. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium within the major histocompatibility complex, it was established that each segment contributed to disease pathogenesis. The two critical HLA regions for susceptibility to AIP are limited to the HLA-DRB1*0405-DQB1*0401 in the class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions.

A Novel Immunoglobulin-Immunoglobulin Interaction in Autoimmunity

Well over six decades since its first description, the Rheumatoid Factor (RF)—autoantibodies recognizing Fc (constant) portion of IgG through their own Fab (antigen binding variable segments)—is believed to have come of age. Autoimmune pancreatitis is a unique form of pancreatitis, biologically characterized by an elevated serum IgG4 concentration. Given the fact that IgG4 myeloma proteins can act as RF, we initially hypothesized that IgG4 in autoimmune pancreatitis might do likewise, hence potentially contributing to disease pathogenesis. Indeed Western blotting clearly showed that IgG4 binds to IgG1 κ, IgG2 κ, IgG3 κ myeloma proteins, as well as to IgG Fc, in line with a typical RF activity. Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc. These data therefore collectively describe a Novel RF (NRF) in autoimmune pancreatitis. In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4s role seems paramount, needs to be systematically assessed.

Peroxisome proliferator-activated receptor γ ligand troglitazone induces cell cycle arrest and apoptosis of hepatocellular carcinoma cell lines

Ligand activation of peroxisome proliferator‐activated receptor γ (PPARγ) results in the inhibition of proliferation of various cancer cells. The aim of this study is to investigate the mechanisms of cell growth inhibition of hepatocellular carcinoma (HCC) cell lines by the PPARγ ligand, troglitazone.

Down-regulation of SREBP-1c is associated with the development of burned-out NASH.

BACKGROUND & AIMS It is well-known that hepatic triglycerides (TG) diminish with the progression of non-alcoholic steatohepatitis (NASH), which has been designated as burned-out NASH, but its mechanism remains unclear. We aimed to explore the changes in hepatic fatty acid (FA) and TG metabolism with disease progression. METHODS Hepatic expression of key genes in healthy individuals (n=6) and patients with simple steatosis (SS, n=10), mild NASH (fibrosis stage 1-2, n=20), and advanced NASH (fibrosis stage 3-4, n=20) were assessed by quantitative polymerase chain reaction. RESULTS Hepatic expression of genes related to FA uptake and oxidation and very-low-density lipoprotein synthesis/export did not differ among the groups. However, the mRNA levels of sterol regulatory element-binding protein (SREBP)-1c and its downstream genes FA synthase, acetyl-coenzyme A carboxylase 1, and diacylglycerol acyltransferase 1 were inversely correlated with fibrosis stage. Immunoblot analysis revealed a remarkable reduction in mature SREBP-1c levels in advanced NASH. Furthermore, hepatic expression of tumor necrosis factor-alpha increased in accordance with fibrosis progression, which was possibly related to the decrease in hepatic SREBP-1c expression. CONCLUSIONS Down-regulation of SREBP-1c and lipogenic enzymes may be associated with the development of burned-out NASH.

Long‐term outcome of Japanese patients with type 1 autoimmune hepatitis

The long‐term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well‐defined. The aim of this study was to clarify the outcome of this disease over a long follow‐up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow‐up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4–positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long‐term treatment. Conclusion: Repeated relapses of AIH are significantly associated with a poorer long‐term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse. (HEPATOLOGY 2012)