Hironori Mawatari

High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH

BackgroundThe changes in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However, it has remained difficult to differentiate between NASH and nonprogressive NAFLD by clinical examination. We investigated the interrelationships between serum high-sensitivity C-reactive protein (hs-CRP) and the pathogenesis and progression of NASH.MethodsHs-CRP was measured in 100 patients with histologically verified NAFLD (29 with steatosis and 71 with NASH), and a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to measure the intrahepatic mRNA expressions of CRP and interleukin (IL)-6.ResultsThe results of a multiple regression analysis revealed that in comparison with cases of steatosis, hs-CRP was significantly elevated (P = 0.0048) in cases of NASH. Furthermore, among patients with NASH, hs-CRP was significantly elevated in those with advanced fibrosis compared with that in those with mild fibrosis (P = 0.0384), even after adjustment for age, sex, presence of diabetes, body mass index, visceral fat area, subcutaneous fat area, homeostasis model assessment for insulin resistance, high-density lipoprotein cholesterol, triglyceride, and low-density lipoprotein cholesterol. The results of the RT-PCR analysis showed that intrahepatic mRNA expression of CRP, but not IL-6, was increased in patients with NASH compared with those with steatosis (P = 0.0228).ConclusionsThis is the first report to demonstrate consistent and profound elevation of hs-CRP in cases of NASH compared with in cases of simple nonprogressive steatosis. Our results suggest that hs-CRP may be a clinical feature that not only distinguishes NASH from simple nonprogressive steatosis but also indicates the severity of hepatic fibrosis in cases of NASH.

Hyperresponsivity to Low-Dose Endotoxin during Progression to Nonalcoholic Steatohepatitis Is Regulated by Leptin-Mediated Signaling

Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.

Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis : An open-label, pilot study

Aim:  Non‐alcoholic steatohepatitis (NASH) is considered a hepatic manifestation of metabolic syndrome. However, effective drug therapy for NASH has not been established yet. In the present study, we evaluated the efficacy of 6 months of ezetimibe treatment for NASH patients with dyslipidemia for the comparison of improvement of the clinical parameters and histological alterations.

Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia and type 2 diabetes mellitus. However, other risk factors for the development of NAFLD are unclear. With the association between periodontal disease and the development of systemic diseases receiving increasing attention recently, we conducted this study to investigate the relationship between NAFLD and infection with Porphyromonas gingivalis (P. gingivalis), a major causative agent of periodontitis.MethodsThe detection frequencies of periodontal bacteria in oral samples collected from 150 biopsy-proven NAFLD patients (102 with non-alcoholic steatohepatitis (NASH) and 48 with non-alcoholic fatty liver (NAFL) patients) and 60 non-NAFLD control subjects were determined. Detection of P. gingivalis and other periodontopathic bacteria were detected by PCR assay. In addition, effect of P. gingivalis-infection on mouse NAFLD model was investigated. To clarify the exact contribution of P. gingivalis-induced periodontitis, non-surgical periodontal treatments were also undertaken for 3 months in 10 NAFLD patients with periodontitis.ResultsThe detection frequency of P. gingivalis in NAFLD patients was significantly higher than that in the non-NAFLD control subjects (46.7% vs. 21.7%, odds ratio: 3.16). In addition, the detection frequency of P. gingivalis in NASH patients was markedly higher than that in the non-NAFLD subjects (52.0%, odds ratio: 3.91). Most of the P. gingivalis fimbria detected in the NAFLD patients was of invasive genotypes, especially type II (50.0%). Infection of type II P. gingivalis on NAFLD model of mice accelerated the NAFLD progression. The non-surgical periodontal treatments on NAFLD patients carried out for 3 months ameliorated the liver function parameters, such as the serum levels of AST and ALT.ConclusionsInfection with high-virulence P. gingivalis might be an additional risk factor for the development/progression of NAFLD/NASH.

Hepatitis C virus directly associates with insulin resistance independent of the visceral fat area in nonobese and nondiabetic patients

Summary.  Insulin resistance (IR) is known to be associated with the visceral adipose tissue area. Elucidation of the relationship between hepatitis C virus (HCV) and IR is of great clinical relevance, because IR promotes liver fibrosis. In this study, we tested the hypothesis that HCV infection by itself may promote IR. We prospectively evaluated 47 patients with chronic HCV infection who underwent liver biopsy. Patients with obesity, type 2 diabetes mellitus (DM), or a history of alcohol consumption were excluded. IR was estimated by calculation of the modified homeostasis model of insulin resistance (HOMA‐IR) index. Abdominal fat distribution was determined by computed tomography. Fasting blood glucose levels were within normal range in all the patients. The results of univariate analysis revealed a significant correlation between the quantity of HCV‐RNA and the HOMA‐IR (r = 0.368, P = 0.0291). While a significant correlation between the visceral adipose tissue area and the HOMA‐IR was also observed in the 97 control, nondiabetic, non‐HCV‐infected patients (r = 0.398, P < 0.0001), no such significant correlation between the visceral adipose tissue area and the HOMA‐IR (r = 0.124, P = 0.496) was observed in the patients with HCV infection. Multiple regression analysis with adjustment for age, gender and visceral adipose tissue area revealed a significant correlation between the HCV‐RNA and the HOMA‐IR (P = 0.0446). HCV is directly associated with IR in a dose‐dependent manner, independent of the visceral adipose tissue area. This is the first report to demonstrate the direct involvement of HCV and IR in patients with chronic HCV infection.

Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver injury in many countries. Genetic factors are important for the development of NAFLD, as well as environmental factors. Recently an angiotensin II type 1 receptor (AGTR1) has been recognized as important in the aetiology of fibrosis in the liver.

Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage

BackgroundThe changes in nonalcoholic fatty liver disease range over a wide spectrum, extending from simple steatosis to nonalcoholic steatohepatitis (NASH). We investigated the clinical usefulness of the type IV collagen 7s domain and hyaluronic acid for predicting the severity of fibrosis before progression to the cirrhotic stage in NASH patients.MethodsThe type IV collagen 7s domain and hyaluronic acid were measured in 72 patients with histologically verified NASH.ResultsIn a univariate analysis, marked elevation of hyaluronic acid and the type IV collagen 7s domain was observed in the NASH patients with advanced fibrosis compared with those with mild fibrosis (P = 0.0028, P = 0.0006, respectively). For detection of NASH with advanced fibrosis, the area under the receiver-operating characteristic curves for type IV collagen 7s domain and hyaluronic acid were 0.767 and 0.754, respectively. However, multiple regression analysis revealed that the type IV collagen 7s domain, but not hyaluronic acid, was significantly elevated in patients with advanced fibrosis even after adjustment for age, sex, platelet count, prothrombin time, aspartate aminotransferase/alanine aminotransferase ratio, body mass index, and presence of underlying type 2 diabetes mellitus, all of which have previously been reported as useful predictors of advanced fibrosis in patients with NASH (P = 0.0127, P = 0.2804, respectively).ConclusionsThis is the first report to demonstrate a consistent and profound elevation of the type IV collagen 7s domain in NASH patients with advanced fibrosis (before progression to the stage of cirrhosis) compared with those with mild fibrosis.

Telmisartan, An Angiotensin II Type 1 Receptor Blocker, Controls Progress of Nonalcoholic Steatohepatitis in Rats

The term nonalcoholic steatohepatitis (NASH) has recently been proposed to identify a fatty liver disease accompanied by diffuse fatty infiltration and inflammation. However, no drug therapy has been established for NASH as yet. In the present study, we demonstrate the effect of the angiotensin II type 1 receptor antagonist telmisartan on the development of NASH in a rat model. Telmisartan, but not the angiotensin receptor antagonist valsartan, markedly attenuated hepatic steatosis, inflammation, and fibrosis in these rats. The quantitative parameters of steatosis, inflammation, and fibrosis were also ameliorated by treatment with telmisartan. Compared with telmisartan, the peroxisome proliferator-activated receptor-γ agonist pioglitazone attenuated hepatic steatosis and fibrosis of the liver to a similar degree. However, telmisartan, but not pioglitazone, dramatically decreased both subcutaneous and visceral fat. In conclusion, these results indicated that telmisartan should be the drug of first choice for the treatment of patients with NASH.

Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD)

BackgroundGenetic factors as well as environmental factors are important in the development of NAFLD and in this study we investigated associations between polymorphisms of peroxisome proliferators-activated receptor γ coactivator 1α polymorphism (PPARGC1A) and NAFLD.AimsWe recruited 115 patients with biopsy-proven NAFLD, 65 with NASH and 50 with simple steatosis, and 441 healthy control subjects and investigated 15 SNPs of PPARGC1A.ResultsSNP rs2290602 had the lowest p value in the dominant mode (p = 0.00095), and the odds ratio for NAFLD (95% CI) was 2.73 (1.48 – 5.06). rs2290602 was significantly associated with NAFLD even when the most conservative Bonferronis correction was applied (p = 0.0143). The frequency of the T allele of rs2290602 was significantly higher in the NASH patients than in the control subjects (p = 0.00093, allele frequency mode), and its frequency in the NASH patients tended to be higher than in the simple steatosis patients (p = 0.09). The results of the real-time RT-PCR study showed that intrahepatic mRNA expression of PPARGC1A was lower in the TT group than in the GG or GT group at SNP rs2290602 (p = 0.0454).ConclusionThis is the first study to demonstrate a significant association between genetic variations in PPARGC1A and NAFLD. This finding suggested that PPARGC1A polymorphism and lower expression of PPARGC1A mRNA in the liver are an important genetic contribution to etiology of NAFLD.

Plasma Pentraxin3 is a Novel Marker for Nonalcoholic Steatohepatitis (NASH)

BackgroundThe changes in the liver in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However it has remained difficult to differentiate between NASH and non-progressive NAFLD on the basis of the clinical findings alone.AimsIn this study we investigated the clinical usefulness of plasma Pentraxin3 (PTX3) levels to predict NASH. Plasma PTX3 was measured in 70 patients with histologically verified NAFLD (28 with non-NASH and 42 with NASH) and 10 healthy control subjects.ResultsThe plasma PTX3 level was significantly higher in the NASH cases than in the non-NASH cases (p = 0.0021) and control subjects (p = 0.045). And the plasma PTX3 level was significantly higher in the stages 3–4 NAFLD cases than in the stages 0–2 NAFLD cases (p < 0.0001). The PTX3 values were closely correlated with the stages of liver fibrosis (p < 0.0001, Kruskal-Wallis test). To detect NASH compared with non-NASH, the area under the curve for plasma PTX3 were 0.755, and to detect stages 3–4 NAFLD compared with stages 0–2 NAFLD, the area under the curve for plasma PTX3 were 0.850.ConclusionThis is the first study to demonstrate consistent and profound elevation of plasma PTX3 levels in NASH in comparison with non-NASH. The results suggest that plasma PTX3 levels may not only be laboratory values that differentiate NASH from non-NASH, but marker of the severity of hepatic fibrosis in NASH.