To asses liver markers in older patients with hip fracture (HF) in relation to age, comorbidities, metabolic characteristics and short-term outcomes.

In 294 patients with HF (mean age 82.0±7.9 years, 72.1% women) serum alanine aminotransferase (ALT), gammaglutamyltransferase (GGT), alkaline phosphatase (ALP), albumin, bilirubin, 25(OH)vitaminD, PTH, calcium, phosphate, magnesium, adiponectin, leptin, resistin, thyroid function and cardiac troponin I were measured.

Elevated ALT, GGT, ALP or bilirubin levels on admission were observed in 1.7%-9.9% of patients. With age GGT, ALT and leptin decrease, while PTH and adiponectin concentrations increase. Higher GGT (>30 U/L, median level) was associated with coronary artery disease (CAD), diabetes mellitus (DM), and alcohol overuse; lower ALT (≤20 U/L, median level) with dementia; total bilirubin>20 μmol/L with CAD and alcohol overuse; and albumin>33 g/L with CAD. Multivariate adjusted regression analyses revealed ALT, ALP, adiponectin, alcohol overuse and DM as independent and significant determinants of GGT (as continuous or categorical variable); GGT for each other liver marker; and PTH for adiponectin. The risk of prolonged hospital stay (>20 days) was about two times higher in patients with GGT>30 U/L or adiponectin>17.14 ng/L (median level) and 4.7 times higher if both conditions coexisted. The risk of in-hospital death was 3 times higher if albumin was <33 g/L.

In older HF patients liver markers even within the normal range are associated with age-related disorders and outcomes. Adiponectin (but not 25(OH)vitaminD, PTH, leptin or resistin) is an independent contributor to higher GGT. Serum GGT and albumin predict prolonged hospital stay and in-hospital death, respectively. A unifying hypothesis of the findings presented.

High blood glucose level, elevated level of liver enzyme, necrosis and shrinkage of islets of Langerhans has been implicated in the pathogenesis of type 2 diabetes. High blood glucose cause oxidative stress, production of free radical as well as elevated SGPT and SGOT level. Both glibenclamide and simvastatin in fixed dose used as antihyperglycemic antidyslipidemic and antioxidative agents for type 2 diabetes treatment. This study therefore aimed to evaluate the antihyperglycemic, antidyslipidemic and antioxidative effect of fixed dose combination of glibenclamide (0.6 mg/70 kg body weight) and simvastatin (5 mg/70 kg body weight) on long term alloxan induced diabetic rats with cardiovascular disease using various diagnostic kits as a parameter of phamacotherapeutic and pharmacological effect. The study was carried out using 96 Swiss Albino male rats weighing about 200-220 g. Combination therapy induced a significant decrease in blood glucose level in alloxan induced diabetic rats, from 33.75 ± 1.65 to 5.80 ± 0.07 mmol/l 2 h after last dose administration, after 4 weeks treatment. In case of dyslipidemic effect, combination therapy reduced total cholesterol (45 %), triglyceride (36 %) and low density lipoprotein-cholesterol (32 %) levels significantly and increased high density lipoprotein-cholesterol level (57 %) in comparison with their respective diabetic control groups. Results of this study showed that combination therapy effectively decreased SGPT (ALAT) (55 %) and SGOT (ASAT) (51 %) in comparison with diabetic control group. It was also observed that catalase and superoxide dismutase enzyme activity was increased by 58 and 91 % respectively in comparison with diabetic control group after 4 weeks treatment with combination of both drugs. In conclusion, these findings of combination therapy (glibenclamide and simvastatin) on alloxan induced diabetes in rats are significantly better than monotherapy using single drug. The results of the present study suggest that, combination of the fixed dose of glibenclamide and simvastatin might be efficacious in patients with diabetic dyslipidemia and increased oxidative stress. Furthermore, this combination therapy offer dosage convenience to the patients and by virtue of its dual mode of action might be a useful addition to the therapeutic armamentarium for patients with diabetic dyslipidemia and oxidative stress.

Obesity is considered a risk factor for hepatocellular carcinoma (HCC). The relationship between adipocytokine and HCC in hepatitis B virus (HBV) carriers remains unclear. We prospectively investigated the association of adiponectin, leptin, and visfatin levels with HCC.

We conducted a nested case-control study in a community-based cohort with 187 incident HCC and 374 HCC-free HBV carriers. Unconditional logistic regression was conducted to estimate the ORs and 95% confidence intervals (CI).

Adiponectin, but not leptin and visfatin, levels were associated with an increased risk of HCC after adjustment for other metabolic factors and HBV-related factors. The risk was increased [OR = 0.51; 95% CI, 0.12-2.11; OR = 4.88 (1.46-16.3); OR = 3.79 (1.10-13.0); OR = 4.13 (1.13-15.1) with each additional quintiles, respectively] with a significant dose-response trend (P(trend) = 0.003). HCC risk associated with higher adiponectin level was higher in HBV carriers with ultrasonographic fatty liver, genotype C infection, higher viral load, and with elevated alanine aminotransferase. Longitudinally, participants with higher adiponectin were less likely to achieve surface antigen of hepatitis B virus (HBsAg) seroclearance and more likely to have persistently higher HBV DNA. Eventually, they were more likely to develop liver cirrhosis [OR = 1.65 (0.62-4.39); OR = 3.85 (1.47-10.1); OR = 2.56 (0.96-6.84); OR = 3.76 (1.33-10.7) for the second, third, fourth, and fifth quintiles, respectively; P(trend) = 0.017] before HCC.

Elevated adiponectin levels were independently associated with an increased risk of HCC.

Adiponectin may play different roles in the virus-induced and metabolic-related liver diseases, but the underlying mechanism remains unknown.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and can progress to cirrhosis, liver failure, and hepatocellular carcinoma. In the last two decades, the prevalence of NAFLD has been growing in most developed countries, mainly as a consequence of its close association with obesity and diabetes mellitus. The exact pathogenesis of NAFLD and especially the mechanisms leading to disease progression have not been completely understood. Adipocytes produce and secrete several bioactive substances known as adipocytokines which are implicated in the pathogenesis of the disease. Among them, adiponectin is an insulin-sensitizing adipocytokine possessing multiple beneficial effects on obesity-related medical complication. This review focuses on the role of adiponectin in NAFLD pathogenesis and its potential use as a diagnostic tool but also as therapeutic target for NAFLD management.

The metabolic syndrome may cause disease progression in patients with chronic hepatitis B (CHB). However, the interactions between hepatitis B virus (HBV) infection and metabolic factors remain unknown. We investigated the association of HBV infection with metabolic profiles in HBV-infected and noninfected subjects. In addition, the impacts of serum HBV DNA level on metabolic profiles were studied. Initially, a case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 322 patients with chronic HBV infection, and the control group consisted of 870 matched subjects without HBV infection. Fasting blood glucose, lipid profiles and adiponectin levels were compared. The results were then confirmed in a second retrospective cohort study in 122 CHB patients with serum HBV DNA levels and HOMA-IR index values. In the case-control analysis, the HBV group had significantly higher serum adiponectin, but lower triglyceride (TG) and high-density lipoprotein cholesterol (HDL) levels than the control group. These relationships already existed in subjects younger than 45 years of age and were modified by serum alanine aminotransferase (ALT) levels. In the retrospective cohort, serum HBV DNA levels were negatively proportional to TG levels, but not to other metabolic parameters. Moreover, this relationship was significant only in subjects with higher ALT levels. Compared with healthy adults, patients with chronic HBV infection have significantly higher serum adiponectin, but lower TG and HDL levels. These relationships are modified by ALT levels and already exist in middle-age patients with chronic HBV infection, implying HBV may interact with host metabolism.

Nonalcoholic fatty liver disease (NAFLD) has recently been found to be a novel component of metabolic syndrome (MS), which is one of the leading causes of chronic liver disease. The serum alanine aminotransferase (ALT) and ⟨-glutamyltransferase (GGT) levels are suggested to affect liver fat accumulation and insulin resistance. We assessed the associations of serum ALT and GGT concentrations within the reference ranges with MS and NAFLD.

In total, 1,069 subjects enrolled at the health promotion center of Wonkwang University Hospital were divided into 4 groups according to serum ALT and GGT concentrations levels within the reference ranges. We performed biochemical tests, including liver function tests and lipid profiles, and diagnosed fatty liver by ultrasonography. Associations of ALT and GGT concentrationgrading within the reference range with fatty liver and/or MS were investigated.

The presence of MS, its components, and the number of metabolic abnormalities [except for high-density lipoprotein-cholesterol (HDL-C) and fasting blood glucose] increased with the ALT level, while the presence of MS, its components, and the number of metabolic abnormalities (except for HDL-C) increased with the GGT level. The odds ratios for fatty liver and MS increased with the ALT level (P⟨0.001 and P=0.049, respectively) and the GGT level (P=0.044 and P=0.039, respectively).

Serum ALT and GGT concentrations within the reference ranges correlated with the incidence of NAFLD and MS in a dose-dependent manner. There associations need to be confirmed in large, prospective studies.

Hypoadiponectinaemia is an important risk factor for non-alcoholic fatty liver disease (NAFLD). However, little is known about its role in the Chinese population. This study sought to assess the prevalence of NAFLD and its association with hypoadiponectinaemia in middle-aged and elderly Chinese.

We conducted a population-based cross-sectional study in an urban Shanghai sample of 2201 participants age 50 years to 83 years (973 men, 1228 women). Hepatic ultrasonographic examination was performed for all participants. Serum adiponectin concentrations were measured by ELISA methods.

The prevalence of NAFLD was 19.8% (16.0% in men, 22.8% in women). Serum adiponectin levels were significantly higher in female than in male subjects (p < 0.001). Serum adiponectin levels were significantly lower in NAFLD subjects than those in control subjects (p < 0.001). The prevalence of NAFLD progressively increased with declining adiponectin levels (p(for trend) < 0.001). The participants in the lowest adiponectin quartile had a significantly increased risk for acquiring NAFLD (OR = 2.31, 95% CI 1.72-3.15) after adjustment for potential confounders.

Population-based screening suggests that NAFLD is highly prevalent in middle-aged and elderly people in Shanghai, particularly among women. Serum adiponectin level is negatively associated with NAFLD independently of potential cofounders, indicating that hypoadiponectinaemia may contribute to the development of NAFLD.

It has been observed that hepatic steatosis is related to an increased risk of cardiovascular disease (CVD). Alanine aminotransferase (ALT), an indicator of the severity of hepatic steatosis is also associated with CVD. This study focused on the relationship between hepatic steatosis and ALT with coronary calcification.

We performed a cross-sectional study to examine the association between hepatic steatosis and serum ALT with coronary calcification in 1218 subjects (772 men, 446 women; ages 30-75 years). We evaluated hepatic steatosis and ALT as categorical variables, and constructed four groups (reference group; only with hepatic steatosis; only with ALT >30 U/L; with both hepatic steatosis and ALT >30 U/L), which did not overlap. Multi-detected row computed tomography (MDCT) was used to measure coronary calcium score.

The adjusted ORs (95% CIs) for coronary calcification in the four groups were 1.00 (reference), 1.24 (0.68-2.26), 1.82 (0.78-4.23), and 2.12 (1.08-4.20) after adjusting for confounding variables. In addition, an increase in serum ALT activity of 10 U/L was associated with an increased risk of coronary atherosclerosis.

In summary, patients with both hepatic steatosis and increases in ALT are associated with coronary calcification as a marker of coronary atherosclerosis determined by MDCT. This finding suggested that subjects with both hepatic steatosis and increased ALT should be considered for further evaluation of coronary atherosclerosis.

Recently, attention has been focussed on adiponectin and its changes in different types of chronic liver disease. Its relation to hepatic fibrosis and insulin resistance in post-hepatitis liver disease is not clear. The aim of this study was to clarify the adiponectin changes in genotype 4 hepatitis C virus (HCV)-infected patient in relation to liver histology and insulin resistance, and its usefulness as a predictor of hepatic fibrosis and response to treatment. Total adiponectin and its high molecular weight (HMW) form as well as insulin levels were studied in 92 chronic HCV, genotype 4 and 66 healthy control volunteers. Neither total adiponectin (r = 0.101, P = 0.220) nor HMW adiponectin (r = 0.081, P = 0.328) correlated with viral load. Total and not HMW adiponectin was significantly correlated with hepatic fibrosis and inflammation (r = 0.267, P = 0.002, r = 0.278, P < 0.001, respectively).In addition, total adiponectin (r = 0.224, P = 0.002) and HMW adiponectin (r = 0.266, P < 0.0006) significantly correlated with insulin resistance. As fibrosis did not correlate with insulin resistance (r = 0.081, P = 0.204), the correlation between total adiponectin and fibrosis was not mediated by insulin resistance. Multivariable regression analysis, (including pretreatment cases and controls) revealed that total adiponectin was significantly associated with gender, being lower among male subjects (X(2) = 13.04, P = 0.0001). The multivariable regression model supported the lack of association between insulin resistance and total adiponectin levels (X(2) = 1.88, P = 0.171), while non cirrhotics had significantly lower total adiponectin levels than cirrhotics (X(2) = 10.90, P = 0.004) and lower level of inflammation significantly lower total adiponectin levels than more severe inflammation (X(2) = 8.95, P = 0.003). Total or HMW adiponectin did not yield receiver operating characteristic (ROC) curves with area under the curve (AUC) >75%, thus the cutoff points have poor sensitivity/specificity as predictors of fibrosis. However, as a predictor of end-of-treatment response, the ROC curve of adiponectin index gave yield an AUC = 81.4%. We can conclude that total adiponectin level, in HCV genotype 4 patients, increases with progression of hepatic fibrosis regardless of insulin resistance. Its high molecular form does not have such correlation. The adiponectin changes are not related to viral load, insulin resistance or other demographic data suggesting that this change is histologically related. In spite of this, no adiponectin cutoff level had reasonable sensitivity/specificity for predicting hepatic fibrosis stage, while this may be used as a predictor for antiviral response possibly reflecting improvement in hepatic inflammation post treatment.

Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases.

Adiponectin possesses anti-inflammatory and insulin-sensitizing properties. Little is known about the role of adiponectin in hepatitis B-related liver disease.

Serum adiponectin and hepatitis B viral factors were cross-sectionally assayed in 280 patients with chronic hepatitis B virus (HBV) infection including 120 patients with chronic HBV infection, 40 patients with cirrhosis, and 120 patients with hepatocellular carcinoma (HCC); 116 healthy adults were used as controls. The dynamics of serum adiponectin level was also studied longitudinally in 25 patients with hepatitis B e antigen (HBeAg) seroconversion (SC).

We found that serum adiponectin level in patients with chronic HBV infection was similar to that in healthy controls and was significantly lower than patients with cirrhosis and HCC. In univariate analysis, high serum adiponectin level significantly correlated with the presence of HBV-related cirrhosis or HCC, abnormal serum ALT level, and HBV genotype C. Multivariate analysis revealed that high serum adiponectin level significantly correlated with the development of HCC. Serum adiponectin levels remained stationary in patients experiencing HBeAg SC.

Our findings suggest that HBV infection itself does not affect adiponectin levels. Serum adiponectin level correlates with the progression of HBV-related liver diseases but not with the development of HBeAg SC.

To verify the clinical diagnostic criteria for metabolic syndrome (MetS-Criteria) for Japanese (Japanese-Criteria) from the viewpoint of reference intervals (RIs) of metabolic factors.

In healthy subjects selected from 1,379 males and 1,528 females aged 20-65 years, generation-and gender-specific RIs of metabolic factors were determined. Then, from the upper or lower limits of the RIs, new MetS-Criteria were tentatively set (New-Criteria).

RIs of some metabolic factors were associated with gender- and/or generation-specific differences. In both genders, the New-Criteria for subjects in their 40s and over (older adults) were comparable to the Japanese-Criteria, whereas the New-Criteria for these in their 30s and less (younger adults) were not. Levels of cut-off values in the New-Criteria for younger adults were mostly between those of the Japanese-Criteria and recently established MetS-Criteria for adolescents. The prevalence of metabolic syndrome estimated by the Japanese-Criteria and the New-Criteria well corresponded in older adults but significantly differed in younger adults.

MetS-Criteria prepared on gender- and generation-specific bases may be necessary. The Japanese-Criteria, which may still have room for minor changes, seem to be valid at least for older adults; however, new MetS-Criteria should be established for younger adults.

We evaluated total adiponectin, high-molecular weight (HMW), medium-molecular weight (MMW), low-molecular weight (LMW) adiponectin subfractions, clinical parameters, routine lab parameters, lipids, metabolic, inflammatory biomarkers, and intima-media thickness (IMT) of common carotid arteries in 70 obese juveniles and adolescents with preatherosclerosis and 55 normal weight controls of similar age and gender distribution. Compared with the controls, the obese probands had a significantly increased IMT (P < 0.001) and elevated ultra-sensitive C-reactive protein (P < 0.001) indicating early vascular burden. Total and HMW adiponectin were significantly decreased in the obese cohort. The ratio between HMW and total adiponectin was significantly decreased in obese probands whereas the LMW/total adiponectin ratio was increased. Overall, total-, HMW, and MMW adiponectin were significantly negatively correlated with carotid IMT. The HMW/total adiponectin ratio correlated significantly negatively, and the LMW/total adiponectin ratio significantly positively with the IMT. Furthermore, HMW adiponectin was significantly positively correlated with high-density lipoprotein (HDL)-cholesterol and serum apolipoprotein A1, and negatively with BMI, triglycerides, homeostatic model assessment (HOMA)-index, leptin, liver transaminases, and uric acid. This remained stable after controlling for gender. Multiple regression analysis of body measures and all other lab parameters showed the strongest correlation between HMW adiponectin and carotid IMT (beta = -0.35, P < 0.001). Taken together, our study provides the first evidence that preatherosclerosis in obese juveniles and adolescents is associated with altered subfractions of adiponectin, whereas after multiple testing the HMW subfraction showed a better correlation to IMT compared with total adiponectin.

It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (MCD) diet for up to 8 weeks and analyzed changes in liver pathology caused by either an AdipoR2 short hairpin RNA-expressing adenovirus or an AdipoR2-overexpressing adenovirus. Inhibition of hepatic AdipoR2 expression aggravated the pathological state of NASH at all stages: fatty changes, inflammation, and fibrosis. In contrast, enhancement of AdipoR2 expression in the liver improved NASH at every stage, from the early stage to the progression of fibrosis. Inhibition of AdipoR2 signaling in the liver diminished hepatic peroxisome proliferator activated receptor (PPAR)-alpha signaling, with decreased expression of acyl-CoA oxidase (ACO) and catalase, leading to an increase in lipid peroxidation. Hepatic AdipoR2 overexpression had the opposite effect. Reactive oxygen species (ROS) accumulation in liver increases hepatic production of transforming growth factor (TGF)-beta1 at all stages of NASH; adiponectin/AdipoR2 signaling ameliorated TGF-beta-induced ROS accumulation in primary cultured hepatocytes, by enhancing PPAR-alpha activity and catalase expression.

The adiponectin resistance and sensitivity mediated by AdipoR2 in hepatocytes regulated steatohepatitis progression by changing PPAR-alpha activity and ROS accumulation, a process in which TGF-beta signaling is implicated. Thus, the liver AdipoR2 signaling pathway could be a promising target in treating NASH.

Although insulin resistance affects liver fibrosis progression and treatment response in chronic hepatitis C (CHC), the relationship between chronic hepatitis C virus (HCV) infection and insulin resistance (IR) remains to be firmly established. We thus studied the impact of host, metabolic and viral factors on IR in CHC patients.

A total of 162 CHC patients with complete clinical data were enrolled. Among them, 94 received histological examinations. Quantitative HCV RNA was assayed by a real-time polymerase chain reaction (PCR) assay. Genotyping was performed by reverse transcription PCR with type-specific primers. The pretreatment IR index was determined using homeostasis model assessment (HOMA), and an index value of more than 2.4 was designated IR. Unadjusted and adjusted association of the HCV RNA level and IR was further analysed.

In multivariate linear regression analysis, a dose-response relationship was observed between the log(10) HCV RNA level and the presence of IR. IR was positively correlated with body mass index, triglyceride, HCV RNA and alanine aminotransferase levels, but negatively correlated with adiponectin level. Subgroup analysis stratified by HCV genotype showed that there was a trend towards a higher HOMR-IR index value and lower adiponectin levels in genotype 1 patients. Histological analysis showed that IR was positively associated with the severity of hepatic steatosis.

Our data indicate that higher HCV RNA levels are associated with the presence of IR in CHC patients. Further studies are needed to clarify the interplays between HCV infection, IR and adiponectin in an attempt to develop new adjuvant therapy for CHC.

Steatosis is an important cofactor in hepatitis C virus (HCV) because it is associated with fibrosis and reduces early and sustained virologic response. Recent studies suggest that HCV genotype 1 is not steatogenic if additional risk factors are not present. Because hypoadiponectinemia was found to be a feature of nonalcoholic steatohepatitis (NASH) independent of insulin resistance, its level in patients with hepatitis C genotype can reveal the optimal therapeutic strategy. This study was conducted to determine the role of the relationship between steatosis and serum adiponectin levels in the progression of liver damage in HCV genotype 1 without known risk factors for NASH. Patients (n=50) with biopsy-proven chronic hepatitis C (CHC), positive HCV RNA, and raised alanine aminotransferase were enrolled. They were carefully selected to rule out possible confounding factors for the presence of steatosis and additional systemic or liver disease. Associations between serum adiponectin levels and grade of steatosis, histologic activity index (HAI), fibrosis grade of liver biopsies, patient age, HCV viral load, and serum transaminase activities were studied. Also, adiponectin levels were compared with those of a control group of 30 healthy volunteers with normal ultrasound findings of the upper abdomen who had no known NASH risk factors. The investigators found that adiponectin levels in patients with CHC genotype 1 were similar to those in healthy subjects. No significant association was found between adiponectin levels and severity of steatosis, HCV RNA levels, HAI, transaminases, and fibrosis. Steatosis was present in 41 patients (82%) with CHC. Multivariate analysis of data on 50 patients revealed that severity of steatosis was independently related to age alone (P=.03). A correlation between HCV RNA load and HAI was observed (P=.02; r=0.712). HAI also was associated with stage of fibrosis (P=.00; r= 0.612). In cases of chronic HCV genotype 1 hepatitis, steatosis is a common histologic feature, although no risk factors are known. Results presented here cannot establish an association between adiponectin and severity of steatosis when risk factors for steatosis are unknown. Additional studies are needed to discover a metabolic treatment that would seek to improve the progression of hepatic steatosis in CHC infection.

Adiponectin possesses anti-inflammatory, insulin-sensitizing and anti-atherosclerotic properties. The aim of this study was to assess the levels of serum adiponectin in patients with chronic viral hepatitis C and B and correlate them with parameters exploring insulin resistance and indices of chronic liver disease. Seventy-two patients with chronic hepatitis C virus (HCV) infection and 73 patients with chronic hepatitis B virus (HBV) infection, matched for age and sex, were studied. All individuals were examined for serum concentrations of adiponectin, insulin, C-peptide and homeostasis model assessment for insulin resistance (HOMA-IR). Viral parameters and liver histology were also evaluated. Serum adiponectin levels were significantly higher in HCV compared with HBV-infected patients. Correlation analysis in the whole group demonstrated that serum adiponectin was positively correlated with aspartate aminotransferase, alkaline phosphatase, globulins, high-density lipoprotein cholesterol and staging score, while it was negatively correlated with body mass index, insulin, C-peptide and HOMA-IR. Logistic regression analysis identified type of infection (HCV vs HBV), alcohol consumption more than 25 g daily, serum total globulin and low C-peptide as significant predictive variables associated with high adiponectin levels. Higher levels of serum adiponectin in HCV compared with HBV patients could have a role in the slower disease progression of chronic HCV infection. In addition, alcohol intake more than 25 g daily seems to be a significant predictor for hyperadiponectinaemia in patients with chronic viral hepatitis C or B. Finally, in this study, a clear positive association between adiponectin and hepatic necroinflammation or staging score was not found.

We used available studies to answer two clinically relevant questions, i.e. whether those with type 2 diabetes should undergo hepatitis C virus screening and whether hepatitis C virus positive individuals should be screened for diabetes. Four reasons argue against the hypothesis of screening diabetics for hepatitis C virus. First, although it induces insulin resistance, hepatitis C virus is not directly diabetogenic. Second, the clinical phenotype of hepatitis C virus-associated type 2 diabetes might be a clue to target the specific diabetic population to be screened. Third, diabetic patients are expected to be poor responders to antivirals and evidence that this might result in recovery from type 2 diabetes is insufficient. Fourth, no econometric data are available in the specific subset of those with type 2 diabetes. Case finding of type 2 diabetes in those with hepatitis C virus infection, in contrast, might be considered in those patients with type 2 diabetes who have cirrhosis, in whom--due to increased prevalence and severity of hepatic encephalopathy--diabetes is associated with increased mortality. Preliminary evidence suggests that the prognosis of cirrhosis might benefit from improved glycemic control and thus from earlier diagnosis of type 2 diabetes. Finally, studies are needed to ascertain the most cost-effective strategy of case-finding type 2 diabetes among those who are hepatitis C virus-infected. In conclusion, available data enabled us to answer the two questions. Hepatitis C virus screening should best be restricted to those (lean) diabetic patients with (advanced) liver disease. Glucose tolerance testing should best be performed in those with hepatitis C virus-related cirrhosis. However, additional studies are needed to support the cost-effectiveness of our conclusions.

Adiponectin has been linked to the metabolic syndrome and coronary artery disease in recent years. The animal and human data also suggest that adiponectin may be beneficial for liver functions. The aim of this study was to investigate the correlation between plasma adiponectin level and liver function tests in adults with or without chronic hepatitis B virus (HBV) infection.

We analysed the blood levels of liver enzymes and adiponectin in 140 apparently healthy adults, including 21 HBV carriers.

We found that the plasma adiponectin levels were inversely correlated to aspartate aminotransferase (r = -0.314, P = 0.000) and alanine aminotransferase (ALT) (r = -0.430, P = 0.000). Among the HBV carriers, the ALT correlated with the plasma adiponectin levels (r = -0.521, P = 0.015). In linear regression models adjusting for age, sex and the other metabolic variables, the ALT was independently related to the plasma adiponectin levels (beta = -0.371 +/- 0.134, P = 0.007), even in HBV carriers (beta = -1.143 +/- 0.482, P = 0.034). The ALT was also independently correlated to the plasma adiponectin levels (beta = 0.552 +/- 0.132, P < 0.001) with adjustment for age, sex and insulin-resistance index by homeostasis model assessment, even in HBV carriers (beta = -1.202 +/- 0.562, P = 0.048). The subjects with normal ALT had a significantly higher least square mean of plasma adiponectin than those with abnormal ALT (4.01 +/- 0.19 vs 3.30 +/- 0.30, P = 0.014) with adjustment for age, sex, homeostasis model assessment insulin resistance and HBV status.

ALT was inversely related to adiponectin levels, independent of the metabolic factors and HBV status. Whether there is any potential prognostic and therapeutic value of adiponectin in human liver diseases remains to be investigated.

The relationship between adiponectin and gamma-glutamyltransferase (GGT) has yet to be clearly demonstrated especially in women. Among the parameters of the liver function test (LFT), it has become increasingly evident that GGT is associated with metabolic disease. The objective of this study was to characterize the relationship between adiponectin and GGT in nonalcoholic women without liver disease. The subjects in this study were recruited from participants in routine health examinations during February of 2004. Among the total of 115 subjects considered for recruitment, we ultimately included 86 patients without liver disease in the study after performing LFT and abdominal sonography. After a 12-hour overnight fast, levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, GGT, total cholesterol, high-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, fasting insulin, and adiponectin were measured in all subjects. We found a significant negative correlation between adiponectin and GGT (r=-0.35, P<.001) and a significant positive correlation between GGT and homeostasis model assessment (HOMA) (r=0.29, P<.01) after controlling for the confounding influences of age and fat mass. Although GGT is clearly related to adiponectin and HOMA, we determined aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly associated with adiponectin and HOMA. The present study suggests that only GGT among the LFTs is related to adiponectin in nonalcoholic women without liver disease.

In nonalcoholic fatty liver disease (NAFLD), increased alanine aminotransferase (ALT) concentrations are considered to be a consequence of hepatocyte damage. We performed a prospective study to examine the association between ALT within its reference interval and risk for subsequent development of NAFLD.

The study cohort comprised 5237 healthy men without diagnosed NAFLD and without increases of either ALT (> or =35 U/L) or gamma-glutamyltransferase (GGT; > or =40 U/L) above the reference intervals. We assessed alcohol intake via self-reporting (questionnaire) and performed biochemical tests for liver and metabolic function and abdominal ultrasonography. We used the Cox proportional hazards model to calculate the adjusted hazard ratios (aHRs) in the model for NAFLD.

During 13 276.6 person-years of follow-up over a 4-year period, 984 new incident cases of NAFLD developed. We adjusted for age, weight change, body mass index, glucose, blood pressure, triglycerides, HDL cholesterol, smoking, alcohol consumption, regular exercise, homeostasis model assessment of insulin resistance, C-reactive protein, and incident diabetes. Compared with an ALT concentration of <16 U/L, aHR values (95% confidence intervals) for ALT concentrations were 1.53 (1.18-1.98), 1.66 (1.29-2.13), 1.62 (1.26-2.08), and 2.21 (1.73-2.81) for ALT concentrations of 16-18, 19-21, 22-25, and 26-34 U/L, respectively. This relationship remained significant even among normal-weight participants who were still within the reference interval of ALT and GGT at all follow-up examinations.

In apparently healthy, nondiabetic Korean men, increased ALT concentration, even within the reference interval, was an independent predictor of incident NAFLD.

Various morbid conditions constituting the metabolic syndrome could be also caused by excessive ethanol consumption. Thus, it is conceivable that excessive ethanol consumption may affect the diagnosis of the metabolic syndrome using its current diagnostic criteria. Here, we investigated this.

A cross-sectional study involving 2,130 Japanese man subjects aged 20 to 65 was performed.

The rate of subjects judged to have metabolic syndrome using its diagnostic criteria for Japanese was 15.7%. However, the prevalence was significantly higher in excessive drinkers who consume more than 20 grams of ethanol per day (n=473, 22.0%) than average drinkers (n=1,657, 13.9%, chi2=18.0, p<0.0001). The rate of subjects who satisfied each component of the criteria of the metabolic syndrome, namely that of an excessive waist circumference, hypertension, dyslipidemia, or hyperglycemia was significantly higher in the former than in the latter, respectively. When subjects with a waist circumferences of 85 cm or more were selectively studied, the prevalence of the metabolic syndrome was still higher in excessive drinkers (39.2%) than in average drinkers (32.4%, chi2=4.0, p=0.049), whereas the waist circumference was not significantly different between the two groups.

Excessive ethanol consumption is associated with an increased prevalence of the metabolic syndrome following the current clinical diagnostic criteria. Excessive ethanol consumption could simply be a factor worsening the metabolic syndrome. However, we must be aware of another possibility that excessive ethanol consumption increases the number of subjects regarded as the metabolic syndrome via mechanisms differing from visceral fat accumulation.

For a long time, hepatic steatosis was believed to be a benign condition. Only recently, liver steatosis, also termed non-alcoholic fatty liver disease (NAFLD), has gained much interest. In most cases of NAFLD, a condition regarded as the hepatic component of the metabolic syndrome, the enzyme alanine aminotransferase (ALT) is elevated and consequently has been used as a marker for NAFLD. More recently, several cross-sectional and prospective studies have demonstrated associations of this liver enzyme with features of the metabolic syndrome and type 2 diabetes mellitus. This review discusses the biochemical and metabolic properties of ALT, its applicability as a marker of NAFLD and describes its possible role in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus and subsequent cardiovascular disease. In addition, treatment strategies to ameliorate NAFLD and the associated risks are discussed.

Metabolic syndrome, that is, obesity, hypertension, hyperlipidemia, and insulin resistance with hyperinsulinemia, is a new disease entity prevailing worldwide, and nonalcoholic steatohepatitis (NASH) is believed to be a hepatic expression of this syndrome. NASH is characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Indeed, 90% of NASH has been revealed to be complicated by visceral obesity, and two-thirds of NASH patients fulfill the criteria of metabolic syndrome. Therefore, a variety of lifestyle-related diseases such as obesity, hypertension, hyperlipidemia, and diabetes mellitus may share the same background. NASH is most prevalent and well characterized in Caucasians; however, little is known about its occurrence in Asia-Oceania, because obesity has not been frequent in countries in these areas. Obesity is expected to become a serious social problem in Asia-Oceania in the next two decades, so we need to prevent a corresponding increase of NASH. For that purpose, we need to know much about not only NASH but also ourselves. To elucidate the status of NASH in Japan, recent progress in the study of NASH in Japan is reviewed in this article.

A study was conducted to determine the relationship between ferritin and glycosylated isoforms of ferritin and insulin resistance in 69 HIV-infected men receiving HAART. Ferritin levels were significantly correlated with aspartate aminotransferase, alanine aminotransferase, bilirubin and with insulin resistance. The ferritin isoelectric focusing patterns of five insulin-resistant HIV-infected patients under HAART showed large amounts of hyperglycosylated isoforms, which was not found in 56 control subjects and 46 untreated HIV-1-infected patients.

To ascertain whether the etiology of hepatic steatosis modulates insulin resistance (IR) and to determine the predictors of IR.

We studied IR through HOMA IR in 146 subjects, 99 of whom had ultrasonographic and/or histologic steatosis. Twenty-two had familial heterozygous hypobetalipoproteinemia (FHBL), 48 had non-alcoholic fatty liver disease (NAFLD), 34 HCV infection (17 with HCV1b, 17 with HCV3a) and 42 were healthy controls without steatosis.

Steatosis was present in 77.3% of FHBL and, by enrolment criteria, in all NAFLD and HCV cases. Overall HOMA-IR correlated with BMI and GGT (P<0.01). FHBL and healthy groups had similar HOMA-IR and GGT values, whereas higher levels were observed in HCV and NAFLD. HCV3a and FHBL patients were hypolipidemic. HOMA-IR was similar in FHBL patients and controls and lower than in HCV and NAFLD. FHBL patients had a high extent of steatosis, similar to that observed in HCV3a, but lower grading and staging than NAFLD and HCV. At multivariate analysis, steatosis and GGT predicted HOMA-IR.

Data suggest that not all hepatic fat associates with IR. FHBL patients, for some aspects, resemble HCV3a infection, possibly suggesting a shared steatogenic mechanism. Among steatotic patients serum GGT levels is the independent predictor of IR.

Adiponectin, an adipose-derived plasma protein, has been well established to be an important biomarker for metabolic syndrome and its complications after exhausted studies in humans. Animal and cell culture experiments also support most claims from human observations of its roles in the metabolic syndrome. Reproducible results of human genetic studies of diverse ethnic origin and by different investigators may provide the evidence for its causative roles in the pathogenesis of the metabolic syndrome and further insight into the genetic constitutions of the metabolic syndrome. Some of the common polymorphisms in the promoter region, exon and intron 2, and the rare nonsynonymous mutations in exon 3 of the human adiponectin gene were repeatedly shown in many studies from many different ethnic populations to associate with the phenotypes related to body weight, glucose metabolism, insulin sensitivity, and risk of type 2 diabetes mellitus and coronary artery disease. The association of adiponectin genetic variations with dyslipidemia and blood pressure was less explored. The common polymorphisms and rare mutations of the human adiponectin gene itself were demonstrated to associate with differential expression of adiponectin at the plasma protein level and mRNA level in adipose tissue. The PPARgamma2 Pro12Ala variants were also shown to influence insulin sensitivity in interaction with adiponectin genotype or to influence plasma adiponectin levels. However, the results were not consistent. Three genome-wide scans for the loci that regulate plasma adiponectin concentration suggest further exploration on chromosomes 5, 9, 14, 15, and 18 is required. These human genetic studies on adiponectin and the metabolic syndrome strongly suggest that adiponectin is one of the causative factors in its pathogenesis and provide significant insights into the genetic makeup of the metabolic syndrome. Extension from these studies may accelerate the discovery of new molecular targets for future therapeutic interventions.

The adipocytokine adiponectin has been proposed to play important roles in the regulation of energy homeostasis, insulin sensitivity and shows anti-inflammatory properties.

In this study we investigated the role of circulating adiponectin in different chronic liver diseases, its regulation by systemic anti-tumour necrosis factor (TNF)-alpha treatment and its hepatic metabolism.

Plasma adiponectin levels were determined in 87 patients with liver cirrhosis of different aetiologies, seven patients with alcoholic steatohepatitis undergoing systemic anti-TNF-alpha treatment, in 11 patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt implantation and in 21 healthy controls.

Adiponectin levels were significantly higher in all subjects with liver cirrhosis of different aetiologies when compared with healthy controls and increased dependent on Child-Pugh classification. In subjects with alcoholic steatohepatitis, systemic anti-TNF-alpha treatment caused a significant decrease in circulating adiponectin. Adiponectin concentrations were similar in portal, hepatic and peripheral veins. No correlation between adiponectin levels and insulin resistance was found in any patient group.

Our data suggest that circulating adiponectin is increased in liver cirrhosis independent of the aetiology of liver disease. We suggest that high adiponectin levels in chronic liver disease might reflect one of the body's anti-inflammatory mechanisms in chronic liver diseases.

Adiponectin induces insulin sensitivity and modulates inflammatory responses. We thus studied the implications of adiponectin in patients with chronic hepatitis C virus (HCV) infection inherently linked to insulin resistance.

We analyzed the association of serum adiponectin levels with clinical, virologic, and histologic findings in 95 naive Taiwanese patients with chronic hepatitis C before and after antiviral therapy.

At baseline, 14 (15%) of the 95 patients were obese and 26 (27%) had type 2 diabetes mellitus. Fifty-seven patients were infected with HCV genotype 1 and 38 with genotype 2. Steatosis and periportal fibrosis was present in 44 (46%) and 69 (73%), respectively. In multivariate analysis, male gender, insulin resistance, high HCV load and genotype 2 were significantly associated with a lower serum adiponectin level. In contrast, intrahepatic gene expression of adiponectin receptors was higher in genotype 2 compared with genotype 1. Serum adiponectin level did not correlate with other clinical or histologic parameters. After treatment, change of steatosis also did not correlate with the change of adiponectin level (P=0.61).

Adiponectin correlated with hepatitis C viral factors at both serum and liver tissue levels. The interactions among adiponectin, insulin resistance and chronic HCV infection merit further studies.

Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116). When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R(2), 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R(2), 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R(2), 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011). The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.

Obesity and insulin resistance (IR) are closely related to hepatic steatosis (HS), and adiponectin is a hepatic insulin sensitizer that has important effects in liver function. This study aims at investigating the relationship between serum adiponectin concentration and the presence of HS.

We carried out a cross-sectional study in a check-up unit of a University Hospital in Mexico City. We enrolled 196 subjects, comprising 98 subjects with HS (27 women, 71 men) and 98 controls (37 women and 61 men). Anthropometric, metabolic and biochemical variables were measured in the two groups. Serum adiponectin and leptin concentrations were determined, their association with grade of HS tested, and concentrations, according to quartiles, compared between cases and controls. chi(2) analysis for linear trends was used to test for a dose-response relationship and logistic regression analysis was conducted to test for a protective effect of adiponectin.

The HS subjects were older and more obese than controls, with a central obesity pattern. In the fourth quartile of adiponectin concentrations, HS was less common and severe. In a multivariate model of the fourth quartile of the adiponectin concentrations, we observed a protective effect (OR = 0.17, 95%CI: 0.04-0.67, P = 0.01). In subjects with more severe HS, we observed higher leptin concentrations, and caloric intakes, total fat and iron consumption were higher than in controls.

The results of the present study suggest that a high serum concentration of adiponectin is associated with a protective effect against HS.

We aimed to investigate the relationship between nonalcoholic fatty liver disease (NAFLD), serum adiponectin concentration and brachial-ankle pulse wave velocity (baPWV) as a risk marker for atherosclerosis.

A total of 213 nonalcoholic subjects (67 males, 146 females) participated in this study. Division of subjects into the NAFLD group or the normal group was based on the existence of fatty liver detected by sonography.

Serum adiponectin levels in the NAFLD group were significantly lower than those in the normal group. After adjusting for age, body-mass index (BMI) and the homeostasis model of assessment (HOMA), there was a significant negative correlation between NAFLD and serum adiponectin level only in females (r = -0.22, P = 0.008). Multiple logistic regression analysis showed a tendency of inverse correlation between NAFLD and serum adiponectin level in females (P = 0.055). After adjustment for age, BMI and HOMA value, serum adiponectin levels were inversely correlated with serum alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT) levels (r = -0.199 (P = 0.004) and r = -0.282 (P < 0.001)). On the other hand, baPWV in the NAFLD group was also significantly higher than that in the normal group in females (P = 0.005). Individual levels of serum ALT, aspatate aminotransferase (AST), alkaline phosphatase (ALP) and GGT were positively correlated with baPWV after adjusting for age, sex, BMI, HOMA and systolic blood pressure (P < 0.05).

Serum adiponectin level and baPWV were significantly associated with NAFLD and various liver enzymes, especially in females.