Type IV Collagen 7S Is the Most Accurate Test For Identifying Advanced Fibrosis in NAFLD With Type 2 Diabetes.

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. Conclusion: COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.

Relationship between Streptococcus mutans expressing Cnm in the oral cavity and non-alcoholic steatohepatitis: a pilot study.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a severe state of non-alcoholic fatty liver disease (NAFLD), which is pathologically characterised by steatosis, hepatocyte ballooning, and lobular inflammation. Host-microbial interaction has gained attention as one of the risk factors for NASH. Recently, cnm-gene positive Streptococcus mutans expressing cell surface collagen-binding protein, Cnm (cnm-positive S. mutans), was shown to aggravate NASH in model mice. Here, we assessed the detection rate of cnm-positive S. mutans in oral samples from patients with NASH among NAFLD. METHODS: This single hospital cohort study included 41 patients with NAFLD. NASH was diagnosed histologically or by clinical score. The prevalence of cnm-positive S. mutans, oral hygiene and blood tests, including liver enzymes, adipocytokines and inflammatory and fibrosis markers, were assessed in biopsy-proven or clinically suspected NASH among NAFLD. RESULTS: Prevalence of cnm-positive S. mutans was significantly higher in patients with NASH than patients without NASH (OR 3.8; 95% CI 1.02 to 15.5). The cnm-positive S. mutans was related to decreased numbers of naturally remaining teeth and increased type IV collagen 7S level (median (IQR) 10.0 (5.0-17.5) vs 20.0 (5.0-25.0), p=0.06; 5.1 (4.0-7.9) vs 4.4 (3.7-5.3), p=0.13, respectively). CONCLUSIONS: Prevalence of cnm-positive S. mutans in the oral cavity could be related to fibrosis of NASH among NAFLD.

The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study.

BACKGROUND: The FIB4 index is clinically useful, but because its formula includes age, the appropriate cutoff point may differ by age group. Here, new FIB4 index cutoff points were validated using cohort data from 14 hepatology centers in Japan. METHODS: The FIB4 index was determined in biopsy-confirmed NAFLD patients (n = 1050) who were divided into four groups: ≤ 49, 50-59, 60-69, and ≥ 70 years. ROC analysis predicted advanced fibrosis in each age group; low and high cutoff points were defined by a sensitivity and specificity of 90%. The new and conventional cutoffs were compared for detecting advanced fibrosis. RESULTS: The modified low and high cutoff points were 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50-59 years, 1.88 and 3.24 in 60-69 years, and 1.95 and 4.56 in ≥ 70 years. In ≥ 60 years, the false-negative rate was increased using the modified high cutoff point, and the high cutoff point was better with the conventional cutoff point. The new proposed low and high cutoff points are 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50-59 years, 1.88 and 2.67 in 60-69 years, and 1.95 and 2.67 in ≥ 70 years; these cutoff points improved the accuracy of advanced fibrosis diagnosis. CONCLUSIONS: FIB4 index cutoff points for predicting advanced fibrosis in NAFLD increased with age. Cutoff points modified by age improved the diagnostic accuracy of estimations of advanced liver fibrosis using the FIB4 index.

A dural metastatic small cell carcinoma of the gallbladder as the first manifestation: a case report.

BACKGROUND: A dural metastasis is one of the essential differential diagnoses of meningioma. In general, carcinomas of the breast and lung in females and prostate in males have been the most commonly reported primary lesions of dural metastases. However, dural metastasis of gallbladder carcinoma is extremely rare. Here, we report a unique case of a dural matter metastasis of gallbladder carcinoma as the first manifestation, which was autopsy-defined as small cell carcinoma. CASE PRESENTATION: A 78-year-old man came to our hospital complaining of left hemianopia. Brain computed tomography (CT) revealed a sizeable parasagittal dural-based extra-axial tumor. However, the findings for meningioma were atypical by magnetic resonance imaging, suggesting a meningioma mimic. A contrast-enhanced CT scan of the abdomen revealed a large gallbladder carcinoma. The patient opted for the best supportive care and died 2 months later. The post-mortem examination revealed small cell carcinoma in gallbladder carcinoma. Moreover, an immunologically similar carcinoma was detected in the dural metastasis. CONCLUSIONS: To the best of our knowledge, this is the first case of a dural metastasis of gallbladder small cell carcinoma. A systemic examination is essential for clinicians when atypical findings of meningioma are observed, suggesting a meningioma mimic. We present this rare case with a review of the literature.

Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with non-alcoholic fatty liver disease.

AIM: Type 2 diabetes mellitus (T2DM) is a major complication of patients with non-alcoholic fatty liver disease (NAFLD). The aim of this retrospective study is to determine the risk factors for development of T2DM in patients with biopsy-proven NAFLD. METHODS: One hundred and sixty two consecutive patients with biopsy-proven NAFLD who received a 75-g oral glucose tolerance test were enrolled as the total cohort. Among them, we analyzed 89 patients without T2DM diagnosed by oral glucose tolerance test to estimate the cumulative rate for development of T2DM as the follow-up cohort. RESULTS: Of 162 patients, the glucose tolerance pattern were DM in 45 patients (27.8%), impaired glucose tolerance in 68 (42.0%), and normal glucose tolerance in 49 (30.2%). Patients with NAFL tended to be more likely to have normal glucose tolerance than those with non-alcoholic steatohepatitis (NASH). The serum levels of pre- and post-load insulin were significantly higher in the NASH group. Of 89 patients without T2DM, 13 patients newly developed T2DM during a follow-up period of 5.2 years. The cumulative rate of T2DM incidence was 8.8% at the end of the 5th year and 23.4% at the end of the 10th year. Multivariate analysis identified homeostasis model of assessment - insulin resistance (≥3.85, hazard ratio 40.1, P = 0.033) as an independent risk factor for development of T2DM. CONCLUSIONS: Patients with NASH have an underlying potential of glucose intolerance. In NAFLD patients, insulin resistance is the most important risk factor for the incidence of T2DM. Appropriate therapy against insulin resistance could be needed for patients with NAFLD to prevent development of T2DM.

Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression.

AIM: Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy-proven NAFLD. METHODS: In this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for >5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long-term changes in biomarkers. RESULTS: Of 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow-up period of 6.1 years, 10 patients (4.2%) with non-alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow-up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group. CONCLUSIONS: In Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled.

Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus.

AIMS: No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy and safety of dulaglutide, a novel glucagon-like peptidase-1 receptor agonist, in Japanese NAFLD patients with T2DM. METHODS: Fifteen biopsy-proven NAFLD patients with T2DM refractory to diet intervention who received once weekly dulaglutide 0.75 mg for 12 weeks were retrospectively enrolled after exclusion of two patients by 12 weeks. In five patients, transient elastography and body composition were also evaluated before and after the treatment. RESULTS: Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased after the 12-week therapy with dulaglutide. Total body fat mass and liver stiffness measurement also decreased after the treatment. CONCLUSION: Dulaglutide, a new glucagon-like peptidase-1 receptor agonist, could be a novel promising agent for the treatment for NAFLD patients with T2DM due to its efficacy in body weight reduction, the nature of weekly injection, and patient preference. Prospective randomized controlled trials are warranted to confirm this impact of dulaglutide on NAFLD with T2DM.

Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus.

AIM: No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD). Sodium glucose cotransporter 2 inhibitor (SGLT2I) was developed for the treatment of adults with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM. METHODS: Twenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24 weeks were retrospectively enrolled as the SGLT2I group. Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibitor (DPP4I) for 24 weeks were selected as the DPP4I group. Clinical data were evaluated at baseline and at 4, 12, and 24 weeks. Seventeen patients in the SGLT2I group were evaluated by body composition before and after therapy. RESULTS: Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased in the SGLT2I group. Reductions in transaminase activities were similar between SGLT2I and DPP4I groups. In the SGLT2I group, body mass index and fasting plasma glucose also decreased after the treatment. CONCLUSION: Sodium glucose cotransporter 2 inhibitor can be a novel promising agent for the treatment for NAFLD patients with T2DM. Prospective randomized controlled trials are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM.

Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey.

BACKGROUND: In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC. METHODS: Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013. RESULTS: The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and α-fetoprotein was a risk factor in ALD-HCC. CONCLUSIONS: Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.

High incidence of metachronous advanced adenoma and cancer after endoscopic resection of colon polyps ≥20 mm in size.

BACKGROUND AND AIM: There are limited studies on incidence rates of metachronous neoplastic lesions after resecting large colorectal polyps. In the present study, we analyzed metachronous lesions after endoscopic resection of colorectal polyps ≥20 mm in size. METHODS: We retrospectively analyzed consecutive patients who underwent endoscopic resection of polyps from 2006 to 2013 at two affiliated hospitals. All patients underwent at least two total colonoscopies before follow up to ensure minimal missed polyps. Only patients who had follow-up colonoscopy annually after resection were recruited. We separated patients according to size of polyp resected; there were 239 patients in the ≥20-mm group and 330 patients in the <20-mm group. Clinical characteristics and cumulative rates of metachronous advanced adenoma and cancer in both groups were analyzed. Advanced adenoma was defined as a neoplastic lesion ≥10 mm in size and adenoma with a villous component. RESULTS: Cumulative rate of development of metachronous advanced adenoma and cancer in the ≥20-mm group was significantly higher than in the <20-mm group (22.9% vs. 9.5%, P < 0.001) at 36 months. There was also more development of small polyps 5-9 mm in the ≥20-mm group than in the <20-mm group (45.2% vs. 28.8%, P < 0.001). With respect to metachronous lesions, there were more right-sided colonic lesions in the ≥20-mm group than in the <20-mm group (78.8% vs. 50.0%, P = 0.015). CONCLUSION: High incidence rates of development of metachronous neoplastic lesions were detected after resection of colorectal polyps ≥20 mm in size.

Helicobacter pylori infection might have a potential role in hepatocyte ballooning in nonalcoholic fatty liver disease.

BACKGROUND: Clinical data regarding Helicobacter pylori (H. pylori) infection in nonalcoholic fatty liver disease (NAFLD) are limited. The aim was to evaluate H. pylori infection in patients with NAFLD and its association with disease severity. METHODS: One hundred and thirty patients with biopsy-proven NAFLD [43 with nonalcoholic fatty liver (NAFL) and 87 with nonalcoholic steatohepatitis (NASH)] were recruited for blood samples for anti-H. pylori immunoglobulin G (IgG) and standard biochemical tests were obtained after overnight fasting. Glucose tolerance was evaluated by 75-g oral glucose tolerance test. Liver biopsies were scored for NAFLD activity score (NAS), fibrosis and iron deposits. RESULTS: H. pylori IgG seropositivity was found in 40 % of patients overall. The prevalence of NASH was significantly higher in the patients with H. pylori IgG seropositivity (81 %) than in those without (58 %, p = 0.008). Glucose intolerance was similar between the two groups. The total NAS and the grade of hepatocyte ballooning were higher in the patients with H. pylori IgG seropositivity than in those without, while the hepatic iron grade was lower in the patients with H. pylori IgG seropositivity than in those without. H. pylori infection (p = 0.030), female gender (p = 0.029), and NAFIC score ≥ 2 points (p < 0.001) could independently predict NASH in logistic regression analysis, independent of age, obesity and glucose tolerance. CONCLUSION: The association of H. pylori seropositivity with hepatocyte ballooning suggests that H. pylori infection may represent another contributing factor in the progression from NAFL to NASH. Eradicating H. pylori infection may have therapeutic prospects in NASH treatment.

Predictors of malignancies and overall mortality in Japanese patients with biopsy-proven non-alcoholic fatty liver disease.

AIM: Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC) and have higher mortality than others. The evidence causally linking NAFLD to extrahepatic malignancies is scarce. Our aim was to determine the incidence of and risk factors for HCC, extrahepatic cancer and mortality in Japanese patients with biopsy-proven NAFLD. METHODS: This retrospective cohort study analyzed outcomes including onset of malignant tumors and death in 312 patients with NAFLD diagnosed by liver biopsy. RESULTS: Of 312 patients, 176 (56.4%) were diagnosed with non-alcoholic steatohepatitis. During a median follow-up period of 4.8 years (range, 0.3-15.8), six patients (1.9%) developed HCC, and 20 (6.4%) developed extrahepatic cancer. Multivariate analysis identified fibrosis stage (≥3; hazard ratio [HR], 12.3; 95% confidence interval [CI], 1.11-136.0; P = 0.041) as a predictor for HCC and type IV collagen 7s (>5 ng/mL; HR, 1.74; 95% CI, 1.08-2.79; P = 0.022) as a predictor for extrahepatic cancer. Eight patients (2.6%) died during the follow-up period. The most common cause of death was extrahepatic malignancy. None died of cardiovascular disease. Multivariate analysis identified type IV collagen 7s (>5 ng/mL; HR, 3.38; 95% CI, 1.17-9.76; P = 0.024) as a predictor for mortality. CONCLUSION: The incidence of extrahepatic cancer was higher than that of HCC. Severe fibrosis was a predictor for HCC. Patients with NAFLD and elevated type IV collagen 7s levels are at increased risk for extrahepatic cancer and overall mortality.

Human placental extract treatment for non-alcoholic steatohepatitis non-responsive to lifestyle intervention: A pilot study.

AIM: No pharmacological therapies have been established for non-alcoholic steatohepatitis (NASH), which can lead to liver-related mortality. Human placental extract (HPE), which has anti-inflammatory effects, has been expected to be a promising treatment for chronic liver disease. This pilot study was conducted to evaluate the efficacy of HPE for biopsy-diagnosed NASH. METHODS: After a lifestyle intervention for 12 weeks, 10 subjects with abnormal alanine aminotransferase (≥30 IU/L) and biopsy-proven NASH (Non-Alcoholic Fatty Liver Disease Activity Score [NAS], ≥4) received i.m. injections of HPE (Laennec) at a dose of 4 mL/day twice per week for 24 weeks, and seven of them underwent a second liver biopsy after the treatment. Liver biopsies were scored for NAS and fibrosis. Histological response was defined as a decrease of 2 points or more in NAS and no increase in fibrosis. RESULTS: Serum transaminase activities were significantly lower at 8 weeks compared with pretreatment levels in nine patients who continued treatment for 24 weeks. One patient refused to continue the treatment soon after starting therapies. In seven patients undergoing post-treatment biopsies, NAS (mean [standard deviation]) mildly decreased from 5.29 (0.95) to 4.00 (1.83) without reaching statistical significance (P = 0.078). Histological response was observed in all three obese patients and in only one of four non-obese ones. No significant changes were observed in body mass index, lipid profiles and diabetic control/insulin resistance. CONCLUSION: In NASH patients who received HPE treatment, significant reductions in serum liver enzymes were obtained after 8 weeks. Histological efficacy may be better in obese patients than in non-obese ones.

Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients.

AIM: Some cases with non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic steatohepatitis (NASH), can ultimately progress to liver cirrhosis. However, studies to clarify factors predictive of histological change in patients with NASH remain scarce. Our aim is to determine predictors of histological progression in Japanese patients with biopsy-proven NASH. METHODS: This retrospective cohort study enrolled 52 patients with NASH who underwent serial liver biopsies. Histological evaluation included NAFLD activity score (NAS) and liver fibrosis. The median interval between initial and second liver biopsies was 968 days. An alanine aminotransferase (ALT) response was defined as a decrease of 30% or more from baseline. RESULTS: Of 52 patients, NAS was ameliorated in 30.8%, deteriorated in 30.8% and remained unchanged in 38.4%. Liver fibrosis was improved in 25.0% of patients, progressed in 25.0% and remained stable in 50.0%. Multivariate analysis identified ALT non-response as a predictor of deterioration of NAS (hazard ratio [HR], 5.85; P = 0.031) and progression of liver fibrosis (HR, 4.50; P = 0.029). The mean annual rate of fibrosis was 0.002 stages/year overall, increasing to 0.15 stages/year in ALT non-responders. CONCLUSION: A lack of reduction in serum ALT level by at least 30% from baseline was a predictor for histological progression in patients with NASH. Serum ALT level is a better predictor of histological change than insulin resistance or bodyweight and can be a valid index in treatment. Serum ALT should be strictly controlled to prevent liver histological progression in patients with NASH.

Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease.

AIM: Growth hormone (GH) deficiency may be associated with histological progression of non-alcoholic fatty liver disease (NAFLD) which includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Insulin-like growth factor 1 (IGF-1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF-1 in Japanese patients. METHODS: Serum samples were obtained in 199 Japanese patients with biopsy-proven NAFLD and in 2911 sex- and age-matched healthy people undergoing health checkups. The serum levels of IGF-1 were measured using a commercially available immunoradiometric assay. The standard deviation scores (SDS) of IGF-1 according to age and sex were also calculated in NAFLD patients. RESULTS: The serum IGF-1 levels in NAFLD patients were significantly lower (median, 112 ng/mL) compared with the control population (median, 121 ng/mL, P < 0.0001). IGF-1 SDS less than -2.0 SD from median were found in 11.6% of 199 patients. NASH patients exhibited significantly lower levels of IGF-1 SDS (n = 130; median, -0.7) compared with NAFL patients (n = 69; median, -0.3; P = 0.026). The IGF-1 SDS values decreased significantly with increasing lobular inflammation (P < 0.001) and fibrosis (P < 0.001). In multiple regressions, the association between the IGF-1 SDS values and the severity of NAFLD persisted after adjusting for age, sex and insulin resistance. CONCLUSION: Low levels of circulating IGF-1 may have a role in the development of advanced NAFLD, independent of insulin resistance. Supplementation with GH/IGF-1 may be a candidate for the treatment of NASH.

Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD. METHODS: In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated. RESULTS: The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7% (hypertriglyceridemia, 45.3%; increased low-density lipoprotein cholesterol, 37.5%; decreased high density lipoprotein cholesterol, 19.5%) of patients. Hypertension was present in 30.2%, and diabetes mellitus (DM) in 47.3%. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage. CONCLUSIONS: DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.

The association of insomnia with gastroesophageal reflux symptoms in biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND: It is suggested that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), can be associated with insomnia and gastro-esophageal reflux disease (GERD). The relationship between GERD and insomnia in subjects with biopsy-proven NAFLD was investigated. METHODS: This study enrolled 123 patients with biopsy-proven NAFLD. Insomnia was assessed by the Athens Insomnia Scale (AIS), a self-assessment psychometric instrument designed to quantify sleep difficulty based on ICD-10 criteria; AIS scores ≥ 6 were considered positive for insomnia. GERD symptoms were evaluated using a frequency scale for the symptoms of GERD (FSSG); FSSG scores ≥ 8 were considered positive. Logistic regression models were used to evaluate the association of insomnia with GERD, after adjusting for potential confounders. Thirteen patients with GERD were treated with the proton pump inhibitor rabeprazole (RPZ; 10 mg/day), for 12 weeks. RESULTS: Of the 123 patients, 76 (62%) were female and 87 (71%) were obese, with 34 (28%) having AIS scores ≥ 6 and 31 (25%) having FSSG scores ≥ 8. Liver biopsy revealed that 40 patients (33%) had NAFL and 83 (67%) had NASH. FSSG and AIS scores were similar in the two groups. HOMA-IR, FSSG scores and γGT (GGT) concentrations were significantly higher in insomniacs than in non-insomniacs. Logistic regression analysis demonstrated that FSSG score and GGT concentration were independently associated with insomnia. RPZ treatment resulted in significantly reductions in both AIS and FSSG scores. CONCLUSIONS: Nearly 30% of patients with biopsy-proven NAFLD had insomnia, which was related to GGT and GERD and could be relieved by RPZ treatment.

The 'donations for decreased ALT (D4D)' prosocial behavior incentive scheme for NAFLD patients.

BACKGROUND: Physicians often experience difficulties in motivating patients with non-alcoholic fatty liver disease (NAFLD) to undergo lifestyle changes. The aim of this study is to examine whether 'Donations for Decreased alanine aminotransferase (ALT)' (D4D) prosocial behavior incentive can serve as an effective intrinsic motivational factor in comparison with conventional dietary and exercise intervention alone for NAFLD patients. METHODS: Twenty-five NAFLD patients with elevated ALT were randomly assigned to a control group that received conventional dietary and exercise intervention alone, or a donation group whereby, as an incentive, we would make a monetary donation to the United Nations World Food Programme (WFP) based on the decrease in their ALT levels achieved over 12 weeks, in addition to receiving control intervention. In a donation group, we would donate US$1 to the WFP for every 1 IU/l of decrease in their ALT levels. RESULTS: There were no differences of pre-treatment clinical characteristics between the two groups. Significant reductions of ALT levels were achieved only in a donation group, although post-treatment ALT levels were not different between the two groups. These patients raised a total of $316 for the WFP. CONCLUSIONS: Promoting patients' intrinsic motivation by incorporating 'D4D' prosocial behavior incentive into conventional dietary and exercise intervention may provide a means to improve NAFLD.

Long-term (>=2 yr) efficacy of vitamin E for non-alcoholic steatohepatitis.

BACKGROUND/AIMS: Vitamin E is one of the most promising treatments for non-alcoholic steatohepatitis (NASH). However, the long-term efficacy of this treatment remains unknown. METHODOLOGY: We retrospectively examined 17 patients with biopsy-proven NASH who received vitamin E at a dose of 300 mg/day for >=2 yr, and underwent second liver biopsies after treatment. Variables were compared between patients with (group R) and without (group NR) fibrosis regression. RESULTS: The median interval between basal and second liver biopsies was 2.4 yr (range, 2.0-5.8 yr). Overall, transaminase activities, insulin resistance index, and hepatic fibrosis markers were significantly improved. Although histological steatosis, inflammation, and fibrosis did not change after treatment, liver fibrosis improved in seven patients (41.2%), progressed in five (29.4%), and remained unchanged in five (29.4%). At baseline, subjects in group R (n = 7) were more likely to have diabetes, insulin resistance, and severe fibrosis compared to those in group NR (n = 10). Lower NAFLD activity score and larger decrease of ALT and insulin resistance after treatment were observed in group R compared with group NR. CONCLUSIONS: Two years or longer treatment can be expected to ameliorate NASH fibrosis, especially in those whose serum transaminase activities and insulin resistance can be improved.