An association between dietary habits and traffic accidents in patients with chronic liver disease: A data-mining analysis.

The incidence of traffic accidents in patients with chronic liver disease (CLD) is high in the USA. However, the characteristics of patients, including dietary habits, differ between Japan and the USA. The present study investigated the incidence of traffic accidents in CLD patients and the clinical profiles associated with traffic accidents in Japan using a data-mining analysis. A cross-sectional study was performed and 256 subjects [148 CLD patients (CLD group) and 106 patients with other digestive diseases (disease control group)] were enrolled; 2 patients were excluded. The incidence of traffic accidents was compared between the two groups. Independent factors for traffic accidents were analyzed using logistic regression and decision-tree analyses. The incidence of traffic accidents did not differ between the CLD and disease control groups (8.8 vs. 11.3%). The results of the logistic regression analysis showed that yoghurt consumption was the only independent risk factor for traffic accidents (odds ratio, 0.37; 95% confidence interval, 0.16-0.85; P=0.0197). Similarly, the results of the decision-tree analysis showed that yoghurt consumption was the initial divergence variable. In patients who consumed yoghurt habitually, the incidence of traffic accidents was 6.6%, while that in patients who did not consume yoghurt was 16.0%. CLD was not identified as an independent factor in the logistic regression and decision-tree analyses. In conclusion, the difference in the incidence of traffic accidents in Japan between the CLD and disease control groups was insignificant. Furthermore, yoghurt consumption was an independent negative risk factor for traffic accidents in patients with digestive diseases, including CLD.

Effects of branched-chain amino acids and zinc-enriched nutrients on prognosticators in HCV-infected patients: a multicenter randomized controlled trial.

Branched­chain amino acids (BCAAs) and trace element deficiencies are associated with poor prognosis in hepatitis C virus (HCV)­infected patients. The aim of this study was to investigate the effects of BCAA and zinc­enriched supplementation on prognostic factors in HCV­infected patients. Fifty­three HCV­infected patients were enrolled in this multicenter randomized controlled trial. The patients were assigned to either the placebo (n=27) or supplement group (n=26; 6,400 mg/day BCAAs and 10 mg/day zinc) and were followed up for 60 days. Primary outcomes were prognostic factors for chronic liver disease, including the serum BCAA­to­tyrosine ratio (BTR), zinc levels and α­fetoprotein (AFP) levels. There were no significant differences in any of the prognostic factors between the placebo and supplement groups at baseline. In the supplement group, the BTR and zinc levels were significantly increased compared with the placebo group (BTR: 5.14 ± 1.59 vs. 4.23 ± 1.14, P=0.0290; zinc: 76 ± 11 vs. 68 ± 11 µg/dl, P=0.0497). No significant differences were observed in AFP levels between the groups in the whole analysis. However, a stratification analysis showed a significant reduction in ΔAFP levels in the supplement group, with elevated AFP levels compared with the other groups (­2.72 ± 3.45 ng/ml, P=0.0079). It was demonstrated that BCAA and zinc­enriched supplementation increased the BTR and zinc levels in the HCV­infected patients. Furthermore, the supplementation reduced the serum AFP levels in patients who had elevated serum AFP levels at baseline. Thus, BCAA and zinc­enriched supplementation may prolong the survival of HCV­infected patients by improving amino acid imbalance and zinc deficiency, and by partly downregulating AFP.

Exendin­4, a glucagon­like peptide­1 receptor agonist, modulates hepatic fatty acid composition and Δ­5­desaturase index in a murine model of non­alcoholic steatohepatitis.

Glucagon­like peptide­1 (GLP­1) is involved in the development of non­alcoholic steatohepatitis (NASH), which is characterized by fatty acid imbalance. The aim of this study was to investigate the effects of the GLP­1 receptor (GLP­1R) agonist, exendin­4 (Ex­4), on hepatic fatty acid metabolism and its key enzyme, Δ­5­desaturase, in a murine model of NASH. NASH was induced in db/db mice fed a methionine­choline deficient (MCD) diet. Ex­4 (n=4) or saline [control (CON); n=4] was administered intraperitoneally for 8 weeks. Steatohepatitis activity was evaluated by non­alcoholic fatty liver disease (NAFLD) activity score. Hepatic fatty acid composition and Δ­5­desaturase index were analyzed by gas chromatography. Ex­4 treatment significantly reduced body weight and the NAFLD activity score. Hepatic concentrations of long­chain saturated fatty acids (SFAs) were significantly higher in the Ex­4 group compared to the CON group (23240±955 vs. 31710±8436 µg/g•liver, P<0.05).Ex­4 significantly reduced hepatic n­3 polyunsaturated fatty acid (PUFA)/n­6 PUFA ratio compared to the CON group (13.83±3.15 vs. 8.73±1.95, P<0.05). In addition, the hepatic Δ­5­desaturase index was significantly reduced in the Ex­4 group compared to the CON group (31.1±12.4 vs. 10.5±3.1, P<0.05). In conclusion, the results showed that Ex­4 improved steatohepatitis in a murine model of NASH. Furthermore, Ex­4 altered hepatic long­chain saturated and PUFA composition and reduced the Δ­5­desaturase index. Thus, Ex­4 may improve NASH by regulating hepatic fatty acid metabolism.

Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis.

Branched-chain amino acids (BCAAs) constituting of valine, leucine, and isoleucine act as both substrates of proteins and as key regulators for various nutrient metabolisms. Patients with liver cirrhosis frequently lack sufficient BCAAs and therefore suffer from various metabolic disorders. Hepatic encephalopathy (HE) is a severe metabolic disorder with neurologic manifestations such as flapping tremors and coma in patients with liver cirrhosis. In addition, a mild form of HE known as minimal HE (MHE) is an important social issue because it occurs in up to 80% of patients with chronic liver disease and affects prognosis and activities of daily living, possibly resulting in falls and motor vehicle accidents. Although HE/MHE can be caused by various pathological conditions, including in an accumulation of mercaptans, short-chain fatty acids, and alterations in the gut flora, hyperammonemia has also been implicated in an important pathogenesis of HE/MHE. Besides urea cycle of liver, ammonia can be detoxified in the skeletal muscles by the amidation process for glutamine synthesis using BCAAs. Thus, BCAA supplementation may enhance detoxification of ammonia in skeletal muscle and may be a possible therapeutic strategy for HE/MHE. In this review, we summarize the clinical impacts of BCAA supplementation on HE/MHE and discuss possible mechanisms for a BCAA-induced improvement of HE/MHE. Furthermore, we present some modifications of oral BCAA therapy for improvement of efficacy in HE treatment. We also briefly describe pleiotropic benefits of BCAAs on life-threatening events and overall prognosis in patients with liver cirrhosis.

Dipeptidyl peptidase-4: a key player in chronic liver disease.

Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.

Lipid profile is associated with the incidence of cognitive dysfunction in viral cirrhotic patients: A data-mining analysis.

AIM: Cognitive dysfunction (CD) is frequently observed in cirrhotic patients. However, the biochemical profiles associated with CD remain unclear. We investigated the biochemical profiles associated with the incidence of CD in cirrhotic patients by using multivariate analyses, including a decision-tree algorithm. METHODS: In this study, 27 viral cirrhotic patients were enrolled. All subjects underwent neuropsychiatric tests; two or more abnormal results were defined as CD. A logistic regression model was used for multivariate stepwise analysis. A decision-tree algorithm was constructed, and the categorical differences based on the decision-tree model were analyzed by χ(2) -tests. RESULTS: Multivariate stepwise analysis showed the levels of total bilirubin, triglycerides and free fatty acids (FFA) as independent bioparameters associated with the incidence of CD in cirrhotic patients. The decision-tree algorithm showed that among patients with FFA of 514 mEq/L or more, 77.8% had CD. Meanwhile, among patients with FFA of less than 514 mEq/L and triglycerides of 106 mg/dL or more, 20.0% had CD. The sensitivity, specificity and accuracy for the incidence of CD using the lipid profile (FFA >514 mEq/L or triglycerides <106 mg/dL) were 85.7% (12/14), 61.5% (8/13) and 74.1% (20/27), respectively. CONCLUSION: The levels of total bilirubin, FFA and triglycerides are independently associated with the incidence of CD in cirrhotic patients. In addition, a decision-tree algorithm revealed that FFA of more than 514 mEq/L or triglycerides of less than 106 mg/dL is a profile associated with the incidence of CD. Thus, this lipid profile could be a possible screening bioparameter for CD in cirrhotic patients.

Decreased expression of insulin and increased expression of pancreatic transcription factor PDX-1 in islets in patients with liver cirrhosis: a comparative investigation using human autopsy specimens.

BACKGROUND: Glucose intolerance in patients with liver cirrhosis (LC), known as hepatogenous diabetes, is thought to be distinct from type 2 diabetes (T2DM) in some aspects. Hyperinsulinemia and/or insulin resistance in liver disease is associated with hepatocarcinogenesis, growth of hepatocellular carcinoma, and poor prognosis. However, the pathophysiological processes in islets that are responsible for hyperinsulinemia in LC are still not precisely known. Therefore, we investigated the histopathological differences in islets of Langerhans cells between LC and T2DM. METHODS: A total of 35 human autopsy pancreatic tissue samples were used in this study (control, n = 18; T2DM, n = 6; LC, n = 11). The expression of insulin, glucagon, somatostatin, pancreatic duodenal homeobox-1 (PDX-1), proliferating cell nuclear antigen (PCNA), and Ki-67 was examined using immunohistochemistry and quantitated by image analysis. RESULTS: Islet hypertrophy and a significant increase in PCNA-positive cells in islets were observed in the tissues from LC cases. The insulin-positive areas in islets were significantly decreased in LC cases compared with control and T2DM cases (P = 0.001, P = 0.035, respectively), whereas the PDX-1-positive area was significantly increased in LC cases (P = 0.001) compared with the control. Furthermore, disorganization of pancreatic endocrine cells and nucleocytoplasmic translocation of PDX-1 were both seen in the LC subjects. CONCLUSIONS: In LC, islets undergo hypertrophy and exhibit paradoxical expression of insulin and PDX-1. In the subjects autopsied, insulin expression was decreased, whereas expression of the pancreatic transcription factor PDX-1 was increased in LC. These results point to important distinctions between LC and T2DM.

Nutritional assessments for ordinary medical care in patients with chronic liver disease.

AIM: In patients with chronic liver disease who are at risk of malnutrition, simple and useful assessments for nutritional status should be established for ordinary medical care. The prognostic nutritional index (PNI) and controlling nutritional status (CONUT) are simple assessments constructed of only two or three laboratory data. We aimed to describe the potential of PNI and CONUT as a nutritional assessment tool in patients with chronic liver disease. METHODS: We enrolled 165 patients, aged 18-85 years, with chronic liver disease. These patients were nutritionally assessed by PNI or CONUT, demonstrating the association with the severity of chronic liver disease or anthropometric values. RESULTS: The value of PNI or CONUT was significantly associated with the severity of chronic liver disease (P < 0.001, respectively). In addition, the value of CONUT was significantly associated with all the anthropometric values such as body mass index (BMI, P < 0.05), mid-arm circumference (AC, P < 0.001), mid-arm muscle circumference (AMC, P < 0.001), and triceps skinfold thickness (TSF, P < 0.001), whereas the value of PNI was significantly associated with the values of AC (P < 0.01), AMC (P < 0.05) and TSF (P < 0.05). Approximately 80% of cirrhotic patients were assessed by PNI or CONUT to have obvious malnutrition. CONCLUSION: PNI and CONUT are potential tools for nutritional assessment in patients with chronic liver disease, especially for ordinary medical care, because of their simplicity.

Dipeptidyl Peptidase IV Inhibitor Improves Insulin Resistance and Steatosis in a Refractory Nonalcoholic Fatty Liver Disease Patient: A Case Report.

A 67-year-old Asian woman was referred to Kurume University Hospital due to abnormal liver function tests. She was diagnosed with nonalcoholic fatty liver disease (NAFLD). NAFLD was treated by diet therapy with medication of metformin and pioglitazone; however, NAFLD did not improve. Subsequently, the patient was administered sitagliptin. Although her energy intake and physical activity did not change, her hemoglobin A1c level was decreased from 7.8 to 6.4% 3 months after treatment. Moreover, her serum insulin level and homeostasis model assessment-insulin resistance value were also improved, as was the severity of hepatic steatosis. These findings indicate that sitagliptin may improve insulin resistance and steatosis in patients with refractory NAFLD.

Motor vehicle accidents: how should cirrhotic patients be managed?

Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs. Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit, which frequently occurs in cirrhotic patients independent of severity of liver disease. Although MHE is known as a risk factor for MVAs, the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown. Recently, Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT), and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs. Besides the ICT and lactulose, there are various diagnostic tools and therapeutic strategies for MHE. In this commentary, we discussed a current issue of diagnostic tools for MHE, including neuropsychological tests. We also discussed the advantages of the other therapeutic strategies for MHE, such as intake of a regular breakfast and coffee, and supplementation with zinc and branched chain amino acids, on the MVA-related societal costs.

Fish to meat intake ratio and cooking oils are associated with hepatitis C virus carriers with persistently normal alanine aminotransferase levels.

AIM: Dietary habits are involved in the development of chronic inflammation; however, the impact of dietary profiles of hepatitis C virus carriers with persistently normal alanine transaminase levels (HCV-PNALT) remains unclear. The decision-tree algorithm is a data-mining statistical technique, which uncovers meaningful profiles of factors from a data collection. We aimed to investigate dietary profiles associated with HCV-PNALT using a decision-tree algorithm. METHODS: Twenty-seven HCV-PNALT and 41 patients with chronic hepatitis C were enrolled in this study. Dietary habit was assessed using a validated semiquantitative food frequency questionnaire. A decision-tree algorithm was created by dietary variables, and was evaluated by area under the receiver operating characteristic curve analysis (AUROC). RESULTS: In multivariate analysis, fish to meat ratio, dairy product and cooking oils were identified as independent variables associated with HCV-PNALT. The decision-tree algorithm was created with two variables: a fish to meat ratio and cooking oils/ideal bodyweight. When subjects showed a fish to meat ratio of 1.24 or more, 68.8% of the subjects were HCV-PNALT. On the other hand, 11.5% of the subjects were HCV-PNALT when subjects showed a fish to meat ratio of less than 1.24 and cooking oil/ideal bodyweight of less than 0.23 g/kg. The difference in the proportion of HCV-PNALT between these groups are significant (odds ratio 16.87, 95% CI 3.40-83.67, P = 0.0005). Fivefold cross-validation of the decision-tree algorithm showed an AUROC of 0.6947 (95% CI 0.5656-0.8238, P = 0.0067). CONCLUSION: The decision-tree algorithm disclosed that fish to meat ratio and cooking oil/ideal bodyweight were associated with HCV-PNALT.

Aging modulates susceptibility to mouse liver Mallory-Denk body formation.

Mallory-Denk bodies (MDBs) are hepatocyte cytoplasmic inclusions found in several liver diseases and consist primarily of the cytoskeletal proteins, keratins 8 and 18 (K8/K18). Recent evidence indicates that the extent of stress-induced protein misfolding, a K8>K18 overexpression state, and transglutaminase-2 activation promote MDB formation. In addition, the genetic background and gender play an important role in mouse MDB formation, but the effect of aging on this process is unknown. Given that oxidative stress increases with aging, the authors hypothesized that aging predisposes to MDB formation. They used an established mouse MDB model-namely, feeding non-transgenic male FVB/N mice (1, 3, and 8 months old) with 3,5 diethoxycarbonyl-1,4-dihydrocollidine for 2 months. MDB formation was assessed using immunofluorescence staining and biochemically by demonstrating keratin and ubiquitin-containing crosslinks generated by transglutaminase-2. Immunofluorescence staining showed that old mice had a significant increase in MDB formation compared with young mice. MDB formation paralleled the generation of high molecular weight ubiquitinated keratin-containing complexes and induction of p62. Old mouse livers had increased oxidative stress. In addition, 20S proteasome activity and autophagy were decreased, and endoplasmic reticulum stress was increased in older livers. Therefore, aging predisposes to experimental MDB formation, possibly by decreased activity of protein degradation machinery.

Hepatitis C virus core protein upregulates the expression of vascular endothelial growth factor via the nuclear factor-κB/hypoxia-inducible factor-1α axis under hypoxic conditions.

AIM: Hepatitis C virus (HCV) core protein critically contributes to hepatocarcinogenesis, which is often observed in liver cirrhosis. Since the liver cirrhosis microenvironment is affected by hypoxia, we focused on the possible driving force of HCV core protein on signal relay from hypoxia-inducible factor (HIF)-1α to vascular endothelial growth factor (VEGF). METHODS: Human hepatocellular carcinoma cells stably overexpressing HCV core (Core cells) and NS5A (NS5A cells) were established; empty vector-transfected (EV) cells were used as controls. Hypoxia was induced by oxygen deprivation or by using cobalt chloride (CoCl(2) ). YC-1 was used to inhibit HIF-1α expression. Protein analyses for cultured cells and liver tissues obtained from CoCl(2) -treated HCV core-transgenic (Core-Tg) mice were performed by western blot and/or immunocytochemistry. Cellular mRNA levels were evaluated by quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Under hypoxia, the sustained expression of HIF-1α, but not HIF-2α, was profoundly observed in Core cells but, was faint in EV and NS5A cells. Immunocytochemistry revealed increased HIF-1α in the nucleus. HIF-1α mRNA levels were significantly higher in Core cells than in EV cells under both normoxia and hypoxia. The HIF-1α-targeted VEGF and Bcl-xL expressions were increased in Core cells under hypoxia and abolished by YC-1 treatment. Hypoxic liver samples of Core-Tg mice indicated significant increases in both HIF-1α and VEGF expression compared with the wild type. CONCLUSIONS: Hepatitis C virus core protein has the distinct potential to transcriptionally upregulate and sustain HIF-1α expression under hypoxia, thereby contributing to increased VEGF expression, a key regulator in the hypoxic milieu of liver cirrhosis.

Interaction of endothelial progenitor cells expressing cytosine deaminase in tumor tissues and 5-fluorocytosine administration suppresses growth of 5-fluorouracil-sensitive liver cancer in mice.

The drug delivery system to tumors is a critical factor in upregulating the effect of anticancer drugs and reducing adverse events. Recent studies indicated selective migration of bone marrow-derived endothelial progenitor cells (EPC) into tumor tissues. Cytosine deaminase (CD) transforms nontoxic 5-fluorocytosine (5-FC) into the highly toxic 5-fluorouracil (5-FU). We investigated the antitumor effect of a new CD/5-FC system with CD cDNA transfected EPC for hepatocellular carcinoma (HCC) in mice. We used human hepatoma cell lines (HuH-7, HLF, HAK1-B, KYN-2, KIM-1) and a rat EPC cell line (TR-BME-2). Escherichia coli CD cDNA was transfected into TR-BME-2 (CD-TR-BME). The inhibitory effect of 5-FU on the proliferation of hepatoma cell lines and the inhibitory effect of 5-FU secreted by CD-TR-BME and 5-FC on the proliferation of co-cultured hepatoma cells were evaluated by a tetrazolium-based assay. In mouse subcutaneous xenograft models of KYN-2 and HuH-7, CD-TR-BME was transplanted intravenously followed by 5-FC injection intraperitoneally. HuH-7 cells were the most sensitive to 5-FU and KYN-2 cells were the most resistant. CD-TR-BME secreted 5-FU and inhibited HuH-7 proliferation in a 5-FC dose-dependent manner. CD-TR-BME were recruited into the tumor tissues and some were incorporated into tumor vessels. Tumor growth of HuH-7 was significantly suppressed during 5-FC administration. No bodyweight loss, ALT abnormality or bone marrow suppression was observed. These findings suggest that our new CD/5-FC system with CD cDNA transfected EPC could be an effective and safe treatment for suppression of 5-FU-sensitive HCC growth.

Quick and simple method for increasing the reduced albumin fraction in human serum albumin preparations by using stronger neo-minophagen C.

AIM: Serum albumin exists in both oxidized and reduced forms. Reduced albumin shows higher antioxidative effects; however, the percentage of reduced albumin is low in human serum albumin (HSA) preparation. Stronger neo-minophagen C (SNMC) containing cysteine, a nucleophilic amino acid, has the potential to control the redox state of albumin. The aim of this study was to develop a method for increasing the fraction of reduced albumin in HAS preparation using SNMC. METHODS: Human serum albumin preparations were purchased from four different manufacturers. As a reducing agent, SNMC (50, 100, or 200 µL) was added to 62.5 mg of each HSA preparation, and the mixture was incubated at room temperature for 10-480 min. The percentages of reduced albumin were determined by high-performance liquid chromatography. RESULTS: The percentage of reduced albumin in the HSA preparation significantly increased 15 min after treatment with 200 µL of SNMC (manufacturer A; 27.7 ± 0.18% vs. 78.7 ± 0.36%, P < 0.01), and a dose-dependent relationship was observed between the increase in the percentage of reduced albumin and dose of SNMC. Similar results were obtained with the other three HSA preparations. The percentage of reduced albumin reached its peak at 15 min after mixing SNMC with an HSA preparation, and then gradually decreased with duration, irrespective of the dose of SNMC. CONCLUSIONS: We devised a method for increasing the reduced albumin fraction in an HSA preparation by using SNMC. We also determined the time-and dose-differences in the effect of SNMC on redox state of HSA.

Supplementation before endoscopic therapy for esophageal varices reduces mental stress in patients with liver cirrhosis.

BACKGROUND/AIMS: Esophageal varices are often seen in cirrhotic patients. Because endoscopic therapy for esophageal varices forces such patients to go on an extended fast until the endoscopic therapy occurs, physical and psychological stresses are induced. The aims of this study were to investigate the effects of a nutritional supplement before endoscopic therapy on such stresses, and on the safety of therapy. METHODOLOGY: Thirty-six cirrhotic patients with esophageal varices were enrolled in this study and classified into two groups. In the fasting group, no energy was supplied to patients prior to endoscopic therapy (n=18). In the supplement group, a supplement of 200kcal was given prior to endoscopic therapy (n=18). The effects of the supplement on the safety of therapy and on stresses were evaluated by the endoscopist and by the self-rating questionnaire. RESULTS: There were no significant differences in age, gender, BMI, or Child-Pugh score between the two groups. There was no interference with endoscopic therapy in the supplement group. Although physical symptoms were not significantly different between the two groups, stress scores for hypodynamia, was significantly lower in the supplement group than in the fasting group. CONCLUSION: We first demonstrated that the supplementation before endoscopic therapy does not interfere with endoscopic treatment for esophageal varices in cirrhotic patients. Supplementation improves fasting-related hypodynamia.

Insulin resistance and chronic liver disease.

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes. Distinctive factors including hepatic parenchymal cell damage, portal-systemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes. Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes, retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure, hepatocellular carcinoma and gastrointestinal hemorrhage. Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes. Moreover, exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis. Thus, pathogenesis, cause of death, assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes. In this article, we review features of insulin resistance in relationship to chronic liver disease. We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.

Copper incorporation into ceruloplasmin is regulated by Niemann-Pick C1 protein.

AIM: Wilson disease is a genetic disorder of copper metabolism characterized by impaired biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. Our previous study showed the late endosome localization of ATP7B and described the copper transport pathway from the late endosome to trans-Golgi network (TGN). However, the cellular localization of ATP7B and copper metabolism in hepatocytes remains controversial. The present study was performed to evaluate the role of Niemann-Pick type C (NPC) gene product NPC1 on intracellular copper transport in hepatocytes. METHODS: We induced the NPC phenotype using U18666A to modulate the vesicle traffic from the late endosome to TGN. Then, we examined the effect of NPC1 overexpression on the localization of ATP7B and secretion of holo-Cp, a copper-binding mature form of Cp. RESULTS: Overexpression of NPC1 increased holo-Cp secretion to culture medium of U18666A-treated cells, but did not affect the secretion of albumin. Manipulation of NPC1 function affected the localization of ATP7B and late endosome markers, but did not change the localization of a TGN marker. ATP7B co-localized with the late endosome markers, but not with the TGN marker. CONCLUSION: These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via an NPC1-dependent pathway and incorporated into Cp.

Serum level of free fatty acids is associated with nocturnal hypoglycemia in cirrhotic patients with HCV infection: a pilot study.

BACKGROUND/AIMS: Nocturnal hypoglycemia is an aggravating factor for liver cirrhosis. However, in patients with compensated liver cirrhosis, a clinical parameter associated with nocturnal hypoglycemia remains unclear. The aim of this study is to investigate a clinical parameter associated with nocturnal hypoglycemia in patients with hepatitis C virus (HCV)-related compensated liver cirrhosis. METHODOLOGY: Twenty patients with HCV-related compensated liver cirrhosis were enrolled in this study. Nocturnal glucose profile was examined by the Continuous Glucose Monitoring System. According to the glucose levels between 21:00 to 6:00, patients were classified into a normoglycemia group (glucose level >70 mg/dL, n=10) or a nocturnal hypoglycemia group (glucose level <70 mg/dL, n=10). Differences in body compositions and biochemical parameters were examined between the two groups. RESULTS: Fifty percent of compensated cirrhotic patients showed nocturnal hypoglycemia. The serum level of free fatty acids, but not any other parameters, was significantly higher in the nocturnal hypoglycemia group compared to that in the normoglycemia group (553 +/- 209 vs. 367 +/- 131 mEq/L; p < 0.05). CONCLUSIONS: Nocturnal hypoglycemia occurred even in compensated cirrhotic patients. Higher serum level of free fatty acids may suggest the presence of nocturnal hypoglycemia in HCV-related compensated cirrhotic patients.

Hybrid training of voluntary and electrical muscle contractions reduces steatosis, insulin resistance, and IL-6 levels in patients with NAFLD: a pilot study.

BACKGROUND: Physical inactivity is a risk factor for the development of non-alcoholic fatty liver disease (NAFLD). "Hybrid training", a training that involves both voluntary and electrical muscle contractions, causes beneficial alterations in muscles even after short durations of exercise. The aim of this study was to investigate the therapeutic efficacy of hybrid training in patients with NAFLD. METHODS: Thirty-five patients with NAFLD who were resistant to lifestyle counseling were assigned to a hybrid-training group (n = 12) or a control group (n = 23). In the hybrid-training group, quadriceps and hamstrings were contracted voluntarily or electrically for 19 min twice a week. In the control group, patients received lifestyle counseling. The therapeutic efficacy of the hybrid training was evaluated after 12 weeks of the intervention. RESULTS: Serum alanine aminotransferase (ALT) levels and hepatic steatosis grade were significantly decreased in the hybrid-training group compared to that of the control group (-14.1 ± 5.8 vs. 3.5 ± 5.4 IU/mL; P < 0.05, -0.67 ± 0.19 vs. 0.09 ± 0.06 grade; P < 0.01, respectively). No significant changes were seen between the two groups in skeletal muscle mass. The decreases in homeostasis model assessment of insulin resistance (HOMA-IR) value and in serum IL-6 levels were significantly greater in the hybrid-training group than in the control group (-6.2 ± 3.2 vs. 0.4 ± 0.6; P < 0.05, -3.1 ± 1.1 vs. 1.1 ± 0.5 pg/mL; P < 0.01, respectively). CONCLUSION: Hybrid training of voluntary and electrical muscle contractions improved hepatic steatosis and reduced insulin resistance and serum IL-6 levels in NAFLD patients who are resistant to lifestyle counseling.