Hemobilia after laparoscopic cholecystectomy that was successfully treated conservatively: Case report.

INTRODUCTION: Hemobilia due to pseudoaneurysm rupture is a rare, life-threatening complication of laparoscopic cholecystectomy (LC) that can cause rapid hemodynamic instability. Therefore, symptoms of hemobilia must be assessed carefully. PRESENTATION OF CASE: An 88-year-old woman underwent LC in our hospital, and blood tests revealed elevation of hepatobiliary enzyme levels on postoperative day (POD) 12. Computed tomography (CT) showed a high absorption area in the common bile duct (CBD), and a diagnosis of hemobilia and a pseudoaneurysm without active bleeding into the abdominal cavity was made. There was no leakage of contrast medium outside the CBD during endoscopic retrograde cholangiography; thus, an endoscopic nasobiliary drainage (ENBD) tube was inserted on POD 12 and an endoscopic retrograde biliary drainage (ERBD) stent was placed in the CBD on POD 13. Thereafter, hepatobiliary enzyme levels gradually normalized and the ENBD tube and ERBD stent were removed on POD 27 and POD 54, respectively. The patient was discharged on POD 66. DISCUSSION: Hemostasis establishment using surgery or intervention radiology is often required for the treatment of hemobilia due to pseudoaneurysms; however, conservative treatment was effective in our case and we were able to pursue a minimally invasive approach. Erosion due to clip penetration or incomplete clipping of the cystic artery or its branches during surgery may have caused the cystic artery pseudoaneurysm. CONCLUSION: Hemobilia could be life threatening and cause acute hemodynamic instability; therefore, prompt diagnosis is required. Although the frequency of complication is low, the possibility of hemobilia after LC should be considered.

Real-world efficacy of sofosbuvir plus velpatasvir therapy for patients with hepatitis C virus-related decompensated cirrhosis.

AIM: Combination therapy with sofosbuvir (SOF) plus velpatasvir (VEL) is approved for patients with hepatitis C virus (HCV)-related decompensated cirrhosis. We analyzed the real-world efficacy of SOF/VEL therapy. METHODS: Thirty-three patients with HCV-related decompensated cirrhosis (25 and eight patients with Child B and C, respectively) were treated with SOF/VEL for 12 weeks. The HCV non-structural protein (NS)5A and NS5B drug resistance-associated substitutions (RASs) were determined by direct sequencing. RESULT: Thirty-two of 33 patients completed the treatment, but the remaining patient discontinued the therapy during third week of the treatment due to aggravation of hepatic encephalopathy. Serum HCV-RNA became negative during the treatment in all patients but relapsed after the end of therapy in five patients. In total, 28 out of 33 patients (85%) achieved sustained virological response 12 weeks following completion of treatment (SVR12). The SVR12 rate was 96% in patients with Child B, but significantly lower, at 50%, in patients with Child C (P < 0.05). In genotype 1b HCV-infected patients, all eight patients without baseline NS5A RASs, but only three of seven patients with RASs, achieved SVR12. Multivariate analysis identified Child B (odds ratio, 35.8 for Child C; P = 0.045) as an independent predictor of SVR12. Median serum albumin levels significantly increased only in patients who achieved SVR12. Child-Pugh scores improved in 16 of 28 patients (57%) following achievement of SVR12. CONCLUSION: The effect of SOF/VEL therapy is lower for patients with Child C. Improvement of hepatic function is expected after viral eradication with SOF/VEL therapy in patients with decompensated cirrhosis.

Eicosapentaenoic acid/arachidonic acid ratio as a possible link between non-alcoholic fatty liver disease and cardiovascular disease.

AIM: The main causes of mortality from non-alcoholic fatty liver disease (NAFLD) are cardiovascular disease (CVD) and malignancy. Eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio is known to be associated with CVD. However, a possible link between EPA/AA ratio and NAFLD is not well known. In this study, we investigated EPA/AA ratio in Japanese patients with NAFLD. METHODS: Two hundred and fifty-four patients with biopsy-proven NAFLD were retrospectively enrolled. Serum EPA/AA ratios were examined for each generation (<35, 35-44, 45-54, 55-64, ≥65 years), and the differences of EPA/AA ratios were evaluated based on steatotic grades and fibrotic stages. RESULTS: EPA/AA ratio in NAFLD patients was decreased compared to that reported in age-matched healthy controls. EPA/AA ratio, body mass index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and steatotic grades in younger NAFLD patients were significantly worse than those in older NAFLD patients. Fasting glucose, hemoglobin A1c and fibrotic stages in older NAFLD patients were significantly higher than those in younger NAFLD patients. No relation was found between EPA/AA ratio and histological findings. CONCLUSION: EPA/AA ratio was lower in NAFLD, especially in younger NAFLD patients. Considering the high mortality from CVD in NAFLD patients, low EPA/AA ratio in young age may influence the increased prevalence of CVD in their older age. EPA/AA ratio is suggested to be a possible link between NAFLD and CVD, and would become a useful marker for CVD in NAFLD.

Efficacy of probucol for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label pilot study.

AIM: Oxidative stress plays a pivotal role in the transition from simple steatosis to non-alcoholic steatohepatitis (NASH). Probucol is a lipid-lowering agent with strong antioxidant properties, and is reported to be effective for the treatment of NASH in several studies. The aim of the present study was to evaluate the efficacy of probucol for the treatment of NASH with dyslipidemia. METHODS: Twenty-six patients with biopsy-proven NASH accompanied by dyslipidemia were treated with 500 mg of probucol daily for 48 weeks. Body mass index, visceral fat area, liver function tests, serum lipids, fibrosis markers, ferritin, adiponectin, leptin, urinary 8-hydroxy-2'-deoxyguanosine (U-8OHdG) and elasticity were measured periodically during the study. Follow-up liver biopsy was performed in 18 patients. RESULTS: Serum levels of aminotransferases, total cholesterol and U-8OHdG significantly decreased (P < 0.01). Levels of hemoglobin A1c (HbA1c), the Homeostasis Model of Assessment - Insulin Resistance index and serum levels of ferritin, type IV collagen 7S and hyaluronic acid significantly decreased (P < 0.05). The serum levels of adiponectin tended to be increased. Liver stiffness significantly decreased from 8.8 ± 6.8 to 6.6 ± 4.0 kPa (P < 0.01). Non-alcoholic fatty liver disease activity scores were significantly improved from 4.2 ± 1.4 to 3.4 ± 1.6 (P < 0.05) and fibrotic stages tended to be improved from 1.6 ± 0.8 to 1.3 ± 1.1, respectively. No adverse effects of this treatment were noted. CONCLUSION: Probucol improved clinical and histological findings probably through its ability to reduce insulin resistance and oxidative stress. Probucol therapy was safe and effective for Japanese NASH patients with dyslipidemia.

Serum asymmetric dimethylarginine levels are independently associated with procollagen III N-terminal peptide in nonalcoholic fatty liver disease patients.

Although impaired synthesis and/or bioavailability of nitric oxide are considered to contribute to insulin resistance and the progression of liver disease in nonalcoholic fatty liver disease, role of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, has not been examined. We examined retrospectively which anthropometric and metabolic parameters were independently associated with serum levels of asymmetric dimethylarginine in nonalcoholic fatty liver disease. A total of 194 consecutive biopsy-proven nonalcoholic fatty liver disease patients with or without type 2 diabetes were enrolled. Serum asymmetric dimethylarginine levels in nonalcoholic fatty liver disease patients were significantly higher, irrespective of the presence or absence of diabetes, than those in healthy control. Multiple stepwise regression analysis showed that decreased total protein and procollagen N-terminal peptide levels, markers of advanced liver disease and hepatic fibrosis, respectively, were independently associated with asymmetric dimethylarginine levels in nonalcoholic fatty liver disease subjects without diabetes, whereas soluble form of receptor for advanced glycation end products and density ratio of liver to spleen in computed tomography were independent correlates of asymmetric dimethylarginine in diabetic patients. The present study suggests that asymmetric dimethylarginine may be associated with nonalcoholic fatty liver disease, especially subjects without diabetes.

Serum levels of pigment epithelium-derived factor (PEDF) are independently associated with procollagen III N-terminal peptide levels in patients with nonalcoholic fatty liver disease.

OBJECTIVES: Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors with complex anti-oxidative, anti-fibrotic, and anti-inflammatory properties, thus being involved in cardiometabolic disorders. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome as well. However, the pathophysiological role of PEDF in NAFLD remains largely unknown. We studied here the relationship between serum PEDF levels and various clinical markers of NAFLD in humans. DESIGN AND METHODS: The study involved 194 biopsy-proven NAFLD patients (102 male and 92 female) with a mean age of 51.3±13.8 years. We examined which anthropometric, metabolic and inflammatory variables, and liver steatosis and fibrosis markers are independently associated with serum levels of PEDF. RESULTS: Mean serum levels of PEDF were 16.4±5.7 µg/mL. Univariate analysis revealed that age (inversely), male, body mass index, waist circumference, numbers of white blood cells and platelets, aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, glycated hemoglobin, uric acid, procollagen type III N-terminal peptide (P-III-P), subcutaneous fat areas, visceral fat areas and liver to spleen density ratio in computed tomography, the presence of diabetes and medication for hyperlipidemia were significantly associated with serum levels of PEDF. In multiple stepwise regression analysis, age (p<0.01, inversely), male (p<0.05), waist circumference (p<0.01), white blood cell number (p<0.05), P-III-P (p<0.05), and the presence of diabetes (p<0.05) and medication for hyperlipidemia (p<0.01), were independently correlated to serum levels of PEDF (R(2)=0.285). CONCLUSIONS: The present study reveals that serum levels of PEDF are independently associated with P-III-P levels, suggesting that PEDF level is a novel biomarker of liver fibrosis in patients with NAFLD.

Increased insulinogenic index is an independent determinant of nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance.

BACKGROUND: Although insulin resistance is involved in nonalcoholic fatty liver disease, role of abnormalities in early phase of insulin secretion has not been examined. AIMS: We examined which anthropometric and metabolic parameters, including insulinogenic index during oral glucose tolerant test, were independently associated with the disease activity of nonalcoholic fatty liver disease. METHODS: A total of 114 consecutive biopsy-proven nonalcoholic fatty liver disease patients without type 2 diabetes were enrolled. RESULTS: Age, aspartate aminotransferase, free fatty acid, ferritin type IV collagen, hyaluronic acid, procollagen N-terminal peptide, fasting plasma glucose and 2-h insulin after glucose loading were significantly higher in patients with impaired glucose tolerance than those with normal glucose tolerance. Multiple stepwise regression analysis revealed that glycated haemoglobin, decreased density ratio of liver to spleen in computed tomography and increased insulinogenic index were independently associated with nonalcoholic fatty liver disease activity score in normal glucose tolerance patients, whereas aspartate aminotransferase and 2-h insulin in impaired glucose tolerance subjects. However, there were no significant independent correlations between insulinogenic index and steatosis grade/fibrosis stage in normal glucose tolerance patients. CONCLUSION: The present study suggests that increased early phase of insulin secretion may contribute to nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance.

Efficacy of rosuvastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label, pilot study.

AIM: Statins, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are reported to be useful for the treatment of non-alcoholic steatohepatitis (NASH). Currently, there is no proven therapy for NASH. In this study, we assessed the efficacy of rosuvastatin in NASH patients with dyslipidemia. METHODS: Nineteen patients with biopsy-proven NASH with dyslipidemia who agreed to participate in this prospective study were enrolled. The patients were treated for 24 months with 2.5 mg/day rosuvastatin. Clinical and histological alterations were comparatively evaluated before and after treatment. Standard weight-loss counseling was continued during the treatment period. Follow-up liver biopsy was performed in nine patients. RESULTS: Twenty-six percent of patients had hyperlipoproteinemia type IIa and 74% had hyperlipoproteinemia type IIb at baseline. Body mass indices were not significantly changed during the treatment. The levels of transaminases were relatively low at the beginning, and were not significantly changed during the treatment. Lipid profiles were significantly improved by the treatment with rosuvastatin for 24 months. While non-alcoholic fatty liver disease activity score and fibrotic stage did not change significantly in all patients, they were improved in 33.3% and 33.3% individual patients, and stayed stable in 33.3% and 55.6%, respectively. CONCLUSION: NASH-related metabolic parameters improved with therapy including histology in some patients. However, one of nine patients had progression of fibrosis during the treatment. Our pilot study demonstrated the efficacy of rosuvastatin for the treatment of NASH with dyslipidemia, even if transaminases are not so elevated and controlled trials are needed in the future.

Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-α-lowering property.

BACKGROUND: We have previously found that atorvastatin decreases liver injury markers in patients with nonalcoholic steatohepatitis. However, how atorvastatin treatment ameliorates the disease activity in nonalcoholic steatohepatitis patients remains unknown. AIMS: We examined here which anthropometric, metabolic and inflammatory variables were improved and related with amelioration of disease activity in atorvastatin-treated nonalcoholic steatohepatitis patients. METHODS: Forty-two biopsy-proven nonalcoholic steatohepatitis patients with dyslipidemia were enrolled. Patients were treated with atorvastatin (10mg/day) for 12 months. RESULTS: Atorvastatin significantly decreased liver transaminase, γ-glutamyl transpeptidase, low-density lipoprotein-cholesterol, triglycerides, type IV collagen, and tumour necrosis factor-α levels, whilst it increased adiponectin and high-density lipoprotein-cholesterol. Atorvastatin improved nonalcoholic fatty liver disease activity score and increased liver to spleen density ratio. Multiple stepwise regression analysis revealed that γ-glutamyl transpeptidase, tumour necrosis factor-α and liver to spleen density ratio (inversely) were independently associated with nonalcoholic fatty liver disease activity score. Aspartate aminotransferase, low-density lipoprotein-cholesterol and nonalcoholic fatty liver disease activity score were independent determinants of decreased liver to spleen density ratio. CONCLUSION: The present study suggests that atorvastatin improves the disease activity of nonalcoholic steatohepatitis partly via its tumour necrosis factor-α-lowering property.

Postprandial insulin secretion pattern is associated with histological severity in non-alcoholic fatty liver disease patients without prior known diabetes mellitus.

BACKGROUND AND AIM: Insulin resistance and diabetes mellitus (DM) are known to contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, the relationship between glucose metabolism and NAFLD is not well known. In this study, we investigated whether secretion patterns of glucose and insulin could influence the histological severity in NAFLD patients without prior known type 2 DM. METHODS: A 75-g glucose tolerance test was performed on 173 biopsy-proven NAFLD patients without prior known type 2 DM. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading. RESULTS: Of the 173 NAFLD patients, 168 had non-alcoholic steatohepatitis, whereas no patient had cirrhosis. Irrespective of the hemoglobin A1c levels, impaired glucose tolerance, including DM, was detected in 60% of the NAFLD patients. While the secretion pattern of glucose after glucose loading was similar among the NAFLD patients, postprandial insulin levels increased and delayed insulin secretion increased in severity in parallel with the aggravation of histological findings (fibrosis stages). Factors associated with advanced fibrosis were higher insulin levels at 120 min after oral glucose loading (P = 0.0001; odds ratio [OR], 3.56; 95% confidence interval [CI], 1.61-7.86), aspartate aminotransferase (P = 0.003; OR, 2.70; 95% CI: 1.19-6.12), and age (P = 0.02; OR, 2.49; 95% CI: 1.15-5.37) as determined by multivariate analysis. CONCLUSIONS: Postprandial hyperinsulinemia (but not glucose levels) was associated with advanced fibrosis. The oral glucose tolerance test should be considered in NAFLD patients without prior known type 2 DM in order to facilitate early therapeutic intervention.

Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH.

BACKGROUND: Advanced glycation endproducts (AGEs), final reaction products of protein with sugars, are known to contribute to various disorders, including diabetes, aspects of aging, and neurodegenerative diseases. Recently, we reported elevated levels of serum AGEs in patients with nonalcoholic steatohepatitis (NASH); further, we found that AGEs induced the generation of reactive oxygen species followed by the proliferation and activation of hepatic stellate cells, a major contributor to liver fibrosis. In this study, to explore the clinical usefulness of AGEs as a biomarker for the attenuation of NASH, we investigated whether the treatment of NASH with dyslipidemia could decrease serum levels of AGEs. METHODS: This study included 43 patients with biopsy-proven NASH with dyslipidemia. Serum glyceraldehyde-derived AGE measurements and clinical laboratory tests were performed periodically during an open-label study of atorvastatin (10 mg daily) for 12 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance tests and liver density assessment by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 22 patients. RESULTS: All 43 patients had dyslipidemia. The body mass indexes and serum glucose levels did not change during the treatment. After the treatment, NASH-related metabolic parameters were significantly improved. Serum glyceraldehyde-derived AGE levels were significantly decreased (10.4 +/- 3.8 and 2.5 +/- 1.1 IU/mL before and after treatment, respectively). The steatosis grade and nonalcoholic fatty liver disease (NAFLD) activity score were significantly improved. CONCLUSIONS: The present data demonstrated that atorvastatin decreased the serum levels of AGEs in NASH patients with dyslipidemia and suggest the usefulness of AGEs as a biomarker for the attenuation of NASH.

Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia.

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of the metabolic syndrome. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the efficacy of atorvastatin in the treatment of NASH associated with hyperlipidemia. This prospective study included 31 patients with biopsy-proven NASH with hyperlipidemia. Body mass index, serum lipids, liver function tests, fibrosis markers, and adipocytokines (adiponectin, leptin, tumor necrosis factor-alpha) were measured periodically during an open-label study of atorvastatin (10 mg daily) for 24 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance test and liver density assessed by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 17 patients. All 31 patients had high cholesterol levels at baseline, and 20 also presented high triglyceride levels. The body mass index and serum glucose levels did not change during the treatment. After treatment, 23 patients (74.2%) presented normal transaminase levels. Adiponectin levels were significantly increased, and the levels of tumor necrosis factor-alpha were significantly decreased. However, leptin levels were not changed significantly. The concentration of long-chain fatty acids was decreased; and significant decreases were observed in C18:2,n-6 (linoleic acid, -21%) and C20:4,n-6 (arachidonic acid, -22%). Liver steatosis and nonalcoholic fatty liver disease activity score were significantly improved, whereas 4 patients had increased fibrosis stage. The NASH-related metabolic parameters improved with therapy, including fibrosis in some patients. However, 4 of 17 patients had progression of fibrosis over the 2-year period, with 3 of them progressing to stage 3. It is unclear whether this divergent response represents sampling error, heterogeneity in the population, or untreated postprandial hyperglyceridemia. Controlled trials are needed to further investigate and resolve this.

Elevated levels of serum advanced glycation end products in patients with non-alcoholic steatohepatitis.

BACKGROUND AND AIM: Advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate in diabetes, play important roles in the pathogenesis of diabetic vascular complications. Recently, AGE have also been found to be involved in insulin resistance. Although non-alcoholic steatohepatitis (NASH) is generally considered a hepatic manifestation of insulin resistance, there are no reports showing the link of AGE to NASH. The aim of this study was to evaluate the clinical significance of AGE in patients with NASH. METHODS: Glyceraldehyde-derived AGE levels were assayed from serum obtained from 106 patients: 66 with NASH, 10 with simple steatosis, and 30 controls. RESULTS: Serum glyceraldehyde-derived AGE levels (U/mL) were significantly elevated in NASH patients (9.78 +/- 3.73) compared with simple steatosis (7.17 +/- 2.28, P = 0.018) or healthy controls (6.96 +/- 2.36, P = 0.003). Moreover, these were inversely correlated with adiponectin, an adipocytokine with insulin-sensitizing and anti-inflammatory properties. In addition, immunohistochemistry of glyceraldehyde-derived AGE showed intense staining in the livers of NASH patients. CONCLUSION: The present data suggest that the sustained increase of glyceraldehyde-derived AGE could at least in part contribute to the pathogenesis of NASH. The serum glyceraldehyde-derived AGE level may be a useful biomarker for discriminating NASH from simple steatosis.

A nuclear receptor-mediated choleretic action of fibrates is associated with enhanced canalicular membrane fluidity and transporter activity mediating bile acid-independent bile secretion.

Fibrates are commonly used lipid-lowering agents that act via PPARalpha, a member of the nuclear hormone receptor superfamily. The mechanism(s) of fibrate-induced changes in the hepatic canalicular membrane and bile lipids are still unknown. Therefore, the aim of this study was to investigate the influence of fibrates on hepatic lipid metabolism and to assess the hepatocellular cytoprotective effect on hepatocyte canalicular membrane. Male ICR mice were fed standard chow with or without bezafibrate (100 mg/kg) for 6 days. The expression of canalicular membrane transporters (Mdr2 and Mrp2) was evaluated by RT-PCR and Western blotting. Canalicular membrane fluidity was also investigated. Canalicular membrane fluidity was markedly increased by fibrates. The expression of mdr 2 and mrp2 mRNA and protein showed a significant increase in fibrate-treated mice. These results suggested that fibrates improve liver function by enhancing bile secretion. The mechanism of the choleretic action of fibrate therapy might involve the enhancement of bile acid-independent bile secretion, since increased expression of Mdr2 and Mrp2 was found in fibrate-treated animals. These changes were very likely mediated by PPARalpha, and the increase of canalicular membrane fluidity may have been partly associated with enhancement of this transporter activity.