Homeostatic Metabolic Assessment Research Articles

Hepatic fat, not visceral fat, is associated with gallbladder polyps: a study of 2643 healthy subjects.

Gallbladder polyps (GBPs) appear to be strongly associated with obesity and metabolic disease. To date, the relationship between GBPs and fatty liver has not been adequately evaluated. The aim of the present study was to investigate whether GBPs are associated with fatty liver, which is an ectopic regional fat deposit, independent of visceral adipose tissue (VAT). A cross-sectional study using 2643 health checkup subjects (961 patients with GBP and 1682 age- and sex-matched healthy controls) was conducted. The subjects underwent various laboratory tests, abdominal fat computed tomography (CT), and hepatic ultrasonography. The mean age of the subjects was 51.4 ± 8.3 years, and 74.1% were male. GBPs were significantly associated with fatty liver. Multivariate regression analysis revealed that GBPs were significantly associated with the presence of fatty liver (odds ratio [OR] 1.23, 95% confidence interval [CI]: 1.02-1.48), and adjusting for the homeostatic metabolic assessment index had little effect on this association (OR 1.23, 95% CI: 1.02-1.48). Additionally, GBPs remained significantly associated with the presence of fatty liver after adjustments for CT-measured VAT and subcutaneous adipose tissue (OR 1.24, 95% CI: 1.03-1.50). The degree of fatty liver showed an independent (OR 1.37 95% CI: 1.03-1.80) and dose-dependent relationship (moderate-severe fatty liver: OR 1.55 95% CI: 1.07-2.23, P for trend = 0.014) with large GBPs (≥ 5 mm). Fatty liver, an ectopic regional fat deposit, was found to be closely associated with GBPs independent of known metabolic risk factors, insulin resistance, and CT-measured VAT, confirming a relevant clinical relationship between the two diseases.

Preliminary data on the relationship between circulating levels of Sirtuin 4, anthropometric and metabolic parameters in obese subjects according to growth hormone/insulin-like growth factor-1 status

BackgroundThe main components of GH/insulin-like growth factor (IGF)-1 axis and Sirtuin 4 (Sirt4), highly expressed in liver and skeletal muscle mitochondria, serve as active regulators of mitochondrial oxidative capacity with opposite functions. In obesity both GH/IGF-1 status and serum Sirt4 levels, likely mirroring its reduced mitochondrial expression, might be altered. ObjectiveTo evaluate the association between circulating levels of Sirt4, body composition, metabolic parameters and cardio-metabolic risk profile in obese patients according to their different GH/IGF-1 status. DesignCross-sectional study with measurement of serum Sirt4, GH after GH releasing hormone (GHRH)+Arginine test, IGF-1 and assessment of body composition, glucose and lipid metabolism in 50 class II–III obese subjects (BMI 35.6 to 62.1kg/m2) and 15 normal weight subjects. Low GH secretion and IGF-1 were defined using pre-determined cutoff-points. The Homeostatic Metabolic Assessment of insulin resistance index and Visceral adiposity index were also calculated. The association of Sirt4 with peak stimulated GH and IGF-1, body composition, metabolic parameters and cardio-metabolic risk profile was assessed. ResultsSerum Sirt4 was inversely related to anthropometric and metabolic parameters and positively related to peak GH and IGF-1. After adjusting for peak GH and IGF-1, the relationships between Sirt4 and BMI became not significant. At multiple regression analysis IGF-1 (p<0.001) was the independent predictor for Sirt4. ConclusionThere was a close relationship between low IGF-1 and low serum Sirt4. This observation suggested that in obese patients, low GH/IGF-1 status was likely associated with a major compensatory decrease in circulating levels of Sirt4 to oppose to its negative regulator effect on mitochondrial oxidative capacity.

Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy

Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy. In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin. Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively). Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors.

Metabolic Management in Overweight Subjects with Naive Impaired Fasting Glycaemia by Means of a Highly Standardized Extract From Cynara scolymus: A Double‐blind, Placebo‐controlled, Randomized Clinical Trial

The aim of this study is to evaluate the efficacy of a dietary supplementation with an extract from Cynara scolymus (Cs) on the glucose pattern in a group of patients with naïve impaired fasting glycaemia (IFG). A randomized, double-blind, placebo-controlled trial has been performed in 55 overweight subjects with IFG (fasting blood glucose [FBG]: 6.11 ± 0.56 mmol/l). These subjects were randomly assigned to supplement their diet with either an extract from Cs (600 mg/d) (26 subjects) or placebo (29 matched subjects) for 8 weeks. The decrease of FBG was the primary endpoint. The assessment of Homeostatic Metabolic Assessment (HOMA), glycosylated haemoglobin, A1c-Derived Average Glucose (ADAG), lipidic pattern and anthropometric parameters were the secondary endpoints. The within groups and percent changes from baseline were analyzed by the signed rank test. The comparison between groups was performed by Wilcoxon's two sample test. The supplemented group had significant decreases of: FBG (-9.6%), HOMA (-11.7%), glycosylated haemoglobin (-2.3%), ADAG (-3.1%) and lipidic pattern. The placebo group did not show any significant difference. Compared with the placebo, the supplemented group showed a significant difference in FBG, HOMA and lipidic pattern. These data demonstrate the efficacy of Cs extract on the reduction of glycometabolic parameters in overweight subjects with IFG.

Adiposity factors are not related to the presence of colorectal adenomas

PurposeAdiposity has been thought to be related to colorectal carcinogenesis. The aim of this study was to explore any association between obesity factors and the presence of colorectal adenoma, a potential precancerous lesion.Patients and methodsTwo hundred and six consecutive patients undergoing colonoscopy without colorectal cancer were enrolled in the study. Anthropometric measures and other adiposity-related laboratory variables including insulin resistance and serum adiponectin levels were recorded and correlated with the presence of adenoma.ResultsColorectal adenoma was detected in 68/206 patients (33%), tubular adenoma(s) in 38 patients, and tubulovillous or villous in 30 patients. Twenty-one patients (10.2%) had at least one proximal polyp. The size of the largest adenoma was ≤10 mm in 40 patients and >10 mm in 28 patients. No statistically significant difference was observed in body mass index, waist circumference, fasting plasma glucose concentration, insulin, homeostatic metabolic assessment, cholesterol, low-density lipoproteins, high-density lipoprotein, or triglycerides between patients with and without adenoma. In addition, there was no difference in plasma adiponectin between patients with adenoma (11.1 ± 6 μg/mL) and controls (10.2 ± 7.8 μg/mL). Furthermore, no significant difference in any parameter was found between patients with advanced adenoma and no advanced adenoma, nor between patients with proximal or distal tumors.ConclusionThis study found that the presence of colorectal adenoma is not correlated with any adiposity factor. Moreover, obesity does not appear to be associated with the site or the presence of more advanced lesions.

Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy.

e19611 Background: Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome. We examined the trajectory of development over the first year of maintenance therapy. Methods: In a prospective cohort of pediatric ALL patients over the first year of maintenance therapy, we examined obesity, insulin resistance and associated biomarkers, testing the hypothesis that they would worsen over that time period. Endpoints included change in body mass index (BMI), fasting insulin and glucose, calculated Homeostatic metabolic assessment (HOMA), leptin and adiponectin. Paired t-tests and Wilcoxin-signed rank were used to compare continuous variables and Spearman (ρ) for correlations. Results: At the start of maintenance, 29% of patients were overweight and 16% were obese, rising to 48% and 29%, respectively, at the end of the first year of maintenance. The mean BMI z-score was 0.53 at maintenance start and increased over the next year to 0.93 (change (Δ) 0.4 95% confidence interval [CI] (0.1, 0.7) p=0.004). Mean fasting insulin levels increased over the first year of maintenance from 4.1µU/ml to 11.5 µU/ml (Δ 7.4 95% CI (1.3, 13.5) p=0.019), and mean HOMA increased from 0.9 to 2.6 (Δ 1.7 95% CI (0.3, 3.2) p=0.019). At the start of maintenance, 1/31 (3%) had insulin resistance by HOMA (>3.15) compared with 8/31 (26%) at one year (McNamer test p=0.016). BMI z-score at one year correlated with HOMA (p= 0.483 p=0.007). Mean leptin increased over year one of maintenance from 6.6 ng/ml to 12.8ng/ml (Δ 6.2 95% CI (1.5, 10.9) p=0.012). Leptin at one year correlated with BMI z-score (p= 0.635 p<0.001) and with HOMA (p= 0.741 p<0.001). Mean adiponectin levels decreased over one year of maintenance from 19.8µg/ml to 15.4 µg/ml (Δ -5.4 95% CI (-7.5,-1, 1) p=0.01) and were inversely correlated to BMI z-score (p= -0.483 p=0.011) but not to HOMA (p= 0.001 p=0.997). Conclusions: Obesity and insulin resistance worsen over the first year of maintenance therapy and are correlated with changes in leptin and adinopectin, suggesting that this time period may be an ideal time for a preventive intervention to limit increases in BMI/insulin resistance, which are known to extend to the long-term survivorship period.

Serum Bcl-2 concentrations in overweight-obese subjects with nonalcoholic fatty liver disease

To shed some light on the relationship between anti-apoptotic serum Bcl-2 concentrations and metabolic status, anthropometric parameters, inflammation indices, and non-alcoholic fatty liver disease severity were investigated in 43 young individuals with fatty liver (FL) and 41 with nonalcoholic steatohepatitis (NASH). Circulating levels of Bcl-2 were detected in 84 patients with ultrasonographic findings of "bright liver" and/or hyper-transaminasemia of unknown origin and/or increase in γ-glutamyl-transpeptidase (γ-GT) strictly in the absence of other acute or chronic liver disease, whose age was not advanced, who gave consent to liver biopsy and were then divided on the basis of the histological results into two groups (43 with FL and 41 with NASH). Twenty lean subjects, apparently healthy and young, were chosen as controls. Serum Bcl-2 concentrations were significantly higher in the FL group than in the NASH group. Insulin resistance and γ-GT activity were significantly higher in NASH subjects. Apoptotic hepatocytes were significantly more numerous in NASH patients. NASH patients presented with larger spleens and augmented C-reactive protein (CRP) concentrations than healthy subjects. Steatosis grade at histology was similar in both NASH and FL populations. The number of apoptotic cells was significantly related to anti-apoptotic Bcl-2 protein values in FL patients. Bcl-2 serum levels positively correlated to body mass index (BMI) values (P ≤ 0.0001) but not to age of the population. Triglycerides/HDL ratio correlated well to waist circumference in males (P = 0.0008). γ-GT activity was associated with homeostatic metabolic assessment (HOMA) (P = 0.0003) and with serum ferritin (P = 0.02). Bcl-2 concentrations were not related to either spleen size or CRP values. NASH patients presented a weak negative correlation between lobular inflammation and Bcl-2 levels. A prediction by low values of serum Bcl-2 towards a greater presence of metabolically unhealthy overweight/obese patients (MUOs) was evidenced. HOMA, BMI and uric acid, in that sequence, best predicted serum Bcl-2 concentrations. MUOs could be detected by Bcl-2 levels. By favoring the life span of hepatocytes, and enhancing triglyceride formation, the anti-apoptotic process inhibits free fatty acids toxicity in FL.

Human Immunodeficiency Virus Treatment–Induced Adipose Tissue Pathology and Lipoatrophy: Prevalence and Metabolic Consequences

Lipoatrophy and metabolic complications of treatment of human immunodeficiency virus (HIV) infection may share common associations with adipose tissue pathology and inflammation. To investigate these relationships, we undertook a large-scale study of adipose tissue, body composition, and metabolic outcomes among HIV-infected adult men at a tertiary hospital HIV cohort during the period 2001-2007. Assessments included adipose biopsies (n = 211) for investigation of adipocyte mitochondrial DNA content, adipocytokine expression, and adipose macrophage content; and whole-body dual-energy x-ray absorptiometry (DEXA) scans (n = 225) for objective body composition changes; 138 individuals contributed both biopsy and DEXA data. Compared with 78 treatment-naive control subjects, 98 zidovudine recipients (48%) and 49 stavudine recipients (67%) had leg fat measures <10% threshold value. Adipose samples associated with current stavudine or zidovudine (n = 99) revealed significant adipocyte mitochondrial DNA depletion, adipose tissue macrophage infiltration, and elevated proinflammatory cytokine levels, compared with samples from control subjects and nonthymidine nucleoside reverse-transcriptase inhibitor (NRTI) recipients (all P < .05). Improvements in adipose pathology after NRTI switching (n = 21 longitudinal samples) correlated with increased preswitch adipose inflammation and less severe fat loss (both P < .05). Elevated ratios of total to high-density lipoprotein cholesterol levels and Homeostatic Metabolic Assessment scores correlated independently with lipoatrophy severity (P < .05) and increased body mass index (P < .05) in thymidine NRTI-experienced individuals. No effect of demographic or HIV-related variables, or HIV protease inhibitor therapy exposure was detected. Adipose tissue pathology and lipoatrophic fat loss are highly prevalent among recipients of stavudine- or zidovudine-based HIV treatment and are associated with adverse metabolic outcomes. Restoring adipose tissue health appears to be an important issue in the long-term treatment of this patient population.

Visceral Obesity and Insulin Resistance as Risk Factors for Colorectal Adenoma: A Cross-Sectional, Case–Control Study

Colorectal adenoma is known to be associated with obesity, but the association between colorectal adenoma and visceral adipose tissue (VAT) area measured by abdominal computed tomography (CT) has not been documented clearly. In addition, the relationship between insulin resistance and colorectal adenomas, which underlies the mechanism that links obesity and colorectal adenoma, has not been studied extensively. The aim of this study was to examine VAT area and insulin resistance as risk factors of colorectal adenoma. A cross-sectional, case-control study was conducted in Koreans that presented for health check-ups. Subjects underwent various laboratory tests, abdominal CT, and colonoscopy. VAT, subcutaneous adipose tissue (SAT), and homeostatic metabolic assessment (HOMA) index were evaluated as potential risk factors of colorectal adenoma in 2,244 age- and sex-matched subjects. According to univariate analysis, the prevalences of smoking, hypertension, metabolic syndrome, and family history of colorectal cancer were higher in the adenoma group than in the normal control group. In addition, body mass index, waist circumference, triglyceride, high-density lipoprotein cholesterol, and VAT and SAT areas were significantly different in the two groups. According to the multivariate analysis adjusted for multiple confounders, VAT area was independently associated with the risk of colorectal adenoma (odds ratio (OR)=3.09, 95% confidence interval (CI): 2.19-4.36, highest quintile vs. lowest quintile). Mean HOMA index was higher in the adenoma group than in the control group (OR=1.99, 95% CI: 1.35-2.92, highest vs. lowest quintile). Visceral obesity was found to be an independent risk factor of colorectal adenoma, and insulin resistance was associated with the presence of colorectal adenoma.

Discipline-specific insulin sensitivity in athletes

Objective Weight status and abnormal liver function are the two factors that influence whole-body insulin sensitivity. The main goal of the study was to compare insulin sensitivity in athletes ( n = 757) and physically active controls ( n = 670) in relation to the two factors. Methods Homeostatic metabolic assessment for insulin resistance (HOMA-IR), weight status, and abnormal liver function (alanine aminotransferase and aspartate aminotransferase) were determined from 33 sports disciplines under morning fasted condition. This study was initiated in autumn 2006 and repeated in autumn 2007 ( n = 1508) to ensure consistency of all observations. Results In general, HOMA-IR and blood pressure levels in athletes were significantly greater than those in physically active controls but varied widely with sport disciplines. Rowing and short-distance track athletes had significantly lower HOMA-IR values and archery and field-throwing athletes had significantly higher values than the control group. Intriguingly, athletes from 22 sports disciplines displayed significantly greater body mass index values above control values. Multiple regression analysis showed that, for non-athlete controls, body mass index was the only factor that contributed to the variations in HOMA-IR. For athletes, body mass index and alanine aminotransferase independently contributed to the variation of HOMA-IR. Conclusion This is the first report documenting HOMA-IR values in athletes from a broad range of sport disciplines. Weight status and abnormal liver function levels appear to be the major contributors predicting insulin sensitivity for the physically active population.

Hepatic steatosis in overweight/obese females: Newscreening method for those at risk

To identify which parameters could help to distinguish the "metabolically benign obesity", which is not accompanied by insulin resistance (IR) and early atherosclerosis. Eighty two of 124 overweight/obese females formed the study population, which was divided into two groups (52 and 30 subjects, respectively) with and without IR according to a HO meostatic Metabolic Assessment (HOMA) cut-off of 2, and were studied in a cross-sectional manner. The main outcome measures were waist circumference, serum uric acid, high-density lipoprotein-cholesterol and triglycerides, alanine aminotransferase, blood pressure and the two imaging parameters, hepatic steatosis and longitudinal diameter of the spleen, which were measured in relation to the presence/absence of IR. A variable grade of visceral obesity was observed in all subjects with the exception of three. Obesity of a severe grade was represented more in the group of IR individuals (P = 0.01). Hepatic steatosis, revealed at ultrasound, was more pronounced in IR than in non-IR subjects (P = 0.005). The two groups also demonstrated a clear difference in longitudinal spleen diameter and blood pressure, with raised and significant values in the IR group. Metabolic syndrome was frequent in the IR group, and was not modified when adjusted for menopause (P = 0.001). At linear regression, the beta values of waist circumference and body mass index predicting HOMA were 0.295, P = 0.007 and 0.41, P = 0.0001, respectively. Measures of spleen longitudinal diameter were well predicted by body mass index (BMI) values, beta = 0.35, P = 0.01, and by HOMA, beta = 0.41, P = 0.0001. Blood pressure was predicted by HOMA values, beta = 0.39, P = 0.0001). HOMA and hepatic steatosis were highly associated (rho = 0.34, P = 0.002). Interestingly, IR patients were almost twice as likely to have hepatic steatosis as non-IR patients. Among the MS criteria, blood pressure was very accurate in identifying the presence of IR (AUROC for systolic blood pressure 0.66, cut-off 125 mm of Hg, sensibility 64%, specificity 75%; AUROC for diastolic blood pressure 0.70, cut-off 85 mm of Hg, sensibility 54.5%, specificity 75%). As health care costs are skyrocketing, reliable and mainly inexpensive tools are advisable to better define subjects who really need to lose weight.

Metabolic Characteristics of Elite Athletes: Role of Weight Status in HOMA values

PURPOSE: To determine whether elite athletes display distinct characteristics in insulin sensitivity compared to physically active non-athletes. METHODS: a cross-sectional study was performed to compare the values of homeostatic metabolic assessment (HOMA) and liver function test for the elite athletes from 36 sports disciplines (E group, N=758) and physically active controls (C group, N= 670). RESULTS: Fasting plasma glucose was not significantly different between groups. But four overweight athletes (BMI> 25) were found to reach pre-diabetes level (FPG> 100 mg). Mean BMI, HOMA, liver enzyme levels (GOT and GPT), and blood pressure (BP) of the E group were slightly greater than those of the C group. These metabolic measures were increased with BMI levels for both groups. The E group displays a substantially greater proportion of the subjects with BMI>30 than the C group. There were 22 sports disciplines displayed significantly greater mean BMI values above control. The relationships between metabolic measures (including insulin, HOMA, liver enzyme values, and BP) and BMI were not displayed in a simple linear manner. In particular, outlier numbers of HOMA, GPT, and BP above 95% confidence interval (CI) limit were significantly increased with BMI. For the low BMI quartiles (BMI 15-21.6), HOMA and BP in the E group were greater above control. CONCLUSIONS: This study found greater mean HOMA values of the elite athlete above physically active control. Greater prevalence of obesity in athletes appears to be a partial contributor for greater HOMA value, suggesting that weight control for elite athlete demands a close attention for their future health.

Metabolic Abnormalities, Insulin Resistance, and Metabolic Syndrome in Children With Primary Hypertension

We sought to describe the prevalence of metabolic abnormalities and of metabolic syndrome (MS) and its relationship to target-organ damage in children with primary hypertension (PH). Patients included 113 children with untreated PH at a mean age of 14.6 years (range, 5 to 18 years). The control group consisted of 134 healthy children at a mean age of 13.5 years (range, 5 to 20 years). We performed a cross-sectional assessment of anthropometric and biochemical cardiovascular risk factors, homeostatic metabolic assessment (HOMA-IR), the insulin sensitivity index (ISI[0,120]), and adiponectin. Metabolic syndrome, as defined by classic criteria, was present in 4 of 134 (3%) of controls versus 23 of 113 (20.4%) patients (P=.0001), but when PH was not taken as a criterion of MS, MS was diagnosed in 6.2% of patients (no significance). Left-ventricular hypertrophy (LVH) was found in 46 of 113 patients (40.7%), and severe LVH was found in 14 of 113 patients (12.5%). Patients with LVH had a greater body mass index, greater waist-to-hip-ratio, and greater number of parameters of metabolic syndrome (overall P<.05). Carotid (cIMT) and femoral superficial artery intima-media thicknesses correlated positively with HOMA-IR and negatively with ISI[0.120] and serum adiponectin (P<.05). The main predictor for cIMT was adiponectin (R2=0.178, beta=-0.466, P=.002). Left-ventricular hypertrophy was predicted (R2=0.332) by body mass index-standard deviation score (beta=0.551, P=.005) and HOMA-IR (beta=0.380, P=.04). Metabolic syndrome, as defined by classic criteria, was diagnosed in 20% of children with PH, but when PH was not a criterion, MS was present in 6.2% of patients. Irrespective of the definition of MS, the applied markers of MS and insulin resistance were the main predictors of target-organ damage.

701] PENTOXIFYLLINE FOR TREATMENT OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD): A RANDOMIZED, PLACEBO-CONTROLLED STUDY

Background: Insulin resistance plays an important role in pathogenesis of NAFLD. Adiponectin has antilipogenic and anti-inflammatory effects, while TNF-α reduces insulin sensitivity and has proinflammatory effects. The aims of this study are to determine the efficacy and safety of pentoxifylline, a TNF-α inhibitor, compare with placebo Methods: Thirty-two patients had biopsy-confirmed NASH and NAFLD with other causes of liver disease and secondary causes of NASH excluded. All patients had persistently elevated ALT (>1.5 times for more than 6 months, after dietary treatment for 2 months) were randomized into 2 groups. The first group was given pentoxifylline at a dosage of 400 mg t.i.d. plus dietary treatment and the second group was given placebo with dietary treatment for 6 months. The changes in ALT, AST, insulin resistance index (homeostatic metabolic assessment insulin resistance (HOMA IR) index, waist/hip ratio), TNF-α and adiponectin level from baseline to at the end of treatment were compared between 2 groups. Results: The 32 patients had a mean age of 48.9 ± 11.7 yr. Nineteen patients (59%) were male, Five patients (15.6%) were obese (BMI >30 kg/m 2 ) with mean BMI 26.5 ± 3.2 kg/m 2 , Five patients (15.6%) were type II DM, twelve patients (37.5%) were hypertension and twenty seven (84.4%) were dyslipidemia. There were no baseline demographic differences between both groups. The mean changes of serum alanine, aspartate aminotransferase and fasting plasma glucose levels difference significantly from baseline in the pentoxifylline group compared to the placebo group. (ALT + 68.2 ± 40.7 vs. + 18.2± 34.2, p = 0.001; AST + 27.3 ± 20.4 vs. + 7.9 ± 19.8, p = 0.008; FBS + 9.1 ± 10.7 vs. - 0.7 ± 5.7, p = 0.003, respectively) The pentoxifylline groups showed more improvement in BMI, waist/hip ratio and serum TNF-α, compared with the placebo groups, without any statistically significant. Adinopectin levels were not changed significantly between both groups. There was no serious adverse events occurred. Conclusions: Pentoxifylline therapy effectively achieved significant improvement in aminotransferase level among patients with NAFLD when compared to placebo.

Effects of vitamin E treatment on peroxisome proliferator‐activated receptor‐α expression and insulin resistance in patients with non‐alcoholic steatohepatitis: results of a pilot study

Insulin resistance (IR) is commonly associated with non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) may also play a role in the pathogenesis of NASH. A pivotal role in NASH pathogenesis depends on the hypothesis of increased oxidative stress. The aim of our study was to evaluate the effects of supplemental oral vitamin E, a potent antioxidant, on liver functions, PPAR-alpha expression and IR in patients with NASH. Nine patients with biopsy-proven NASH were given oral vitamin E 800 mg daily for 24 weeks. Liver functions, lipid parameters, IR index with homeostatic metabolic assessment and liver histology and PPAR-alpha staining index in biopsy specimens were detected before and after the treatment. Seven patients (78%) had IR initially. After 6 months of therapy in nine patients, fasting insulin improved (P = 0.01), but serum cholesterol, triglyceride, fasting blood glucose levels and body mass index remained unchanged. Aspartate aminotransferase and alanine aminotransferase levels decreased (P = 0.01 and P = 0.01, respectively). IR index with homeostatic metabolic assessment resistance improved (P = 0.01), but PPAR-alpha staining index did not change (P = 0.37). Although the histological grade of steatosis decreased (P = 0.01), necroinflammation and fibrosis remained unchanged. In seven patients with IR, however, necroinflammation and PPAR-alpha staining index were improved (P = 0.04 and P = 0.02). Vitamin E treatment, in addition to its previously shown beneficial effect by suppressing oxidative stress, may also achieve improvement by reducing IR and PPAR-alpha expression in NASH.

Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis.

Tumor necrosis factor-alpha (TNF-alpha) has been incriminated to play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Pentoxifylline, a TNF-alpha inhibitor could prove useful in treating patients with NASH. Eighteen patients (mean age, 34 +/- 7.8 yr) with histologically proven NASH and with persistently elevated ALT (>1.5 times) were given pentoxifylline at a dosage of 400 mg t.i.d. for 6 months. No lipid-lowering agent or antioxidants were concurrently advised. Impaired fasting glycemia, impaired glucose tolerance, diabetes mellitus, and hypertriglyceridemia were noted in 6, 35, 17, and 53% of the patients, respectively. After 6 months of therapy, fatigue improved (55.6 vs 20%, p= 0.016), but serum triglyceride (182 +/- 66 vs 160 +/- 55 mg/dl, p= 0.397), cholesterol (173 +/- 46 vs 162 +/- 40 mg/dl, p= 0.440), and body mass index (BMI) (27.3 +/- 3.1 vs 26 +/- 3.1 kg/m(2), p= 0.087) remained unchanged. Mean AST (66 +/- 29 vs 33 +/- 11 IU/l, p < 0.0001) and ALT (109 +/- 44 vs 47 +/- 20 IU/l, p < 0.0001) reduced significantly. ALT normalized in 23% at month 1 (p= 0.125), 35% at month 2 (p= 0.125), and 60% at month 6 (p= 0.008) of treatment. The insulin resistance index assessed by homeostatic metabolic assessment (HOMA(IR)) improved (5.1 +/- 3.4 vs 2.6 +/- 2, p = 0.046) and the serum TNF-alpha reduced significantly after therapy (22.15 +/- 2.49 vs 17 +/- 2.58 pg/ml, p = 0.011). The drug was well tolerated. In patients with NASH, pentoxifylline therapy effectively achieved significant clinical and biochemical improvement with reduction in HOMA(IR). These benefits are possibly mediated through suppression of TNF-alpha.

Defective Hepatic Mitochondrial Respiratory Chain in Patients With Nonalcoholic Steatohepatitis

Mitochondrial dysfunction might play a central role in the pathogenesis of nonalcoholic steatohepatits (NASH). The aims of this study were to evaluate whether free fatty acid (FFA) transport into the mitochondria or the activity of mitochondria respiratory chain (MRC) complexes are impaired in NASH. In patients with NASH and control subjects, we measured free carnitine, short–chain acylcarnitine (SCAC) and long–chain acylcarnitine (LCAC) esters, carnitine palmitoyltransferase (CPT) activity, and MRC enzyme activity in liver tissue as well as serum concentration of tumor necrosis factor α (TNF–α), homeostatic metabolic assessment of insulin resistance (HOMAIR), and body mass index (BMI). In patients with NASH, the LCAC/free carnitine ratio was significantly increased and the SCAC/free carnitine ratio was decreased. In patients with NASH, the activity of the MRC complexes was decreased to 63% ± 20% (complex I), 58.5% ± 16.7% (complex II), 70.6% ± 10.3% (complex III), 62.5% ± 13% (complex IV), and 42.4% ± 9.1% (adenosine triphosphate synthase) of the corresponding control values. Activity of these complexes correlated significantly with serum TNF–α and HOMAIR. Serum TNF–α (36.3 ± 23.1 pg/mL), HOMAIR (4.5 ± 2.38), and BMI (29.9 ± 3.5 kg/m2) values were significantly increased in patients with NASH. In conclusion, activities of MRC complexes were decreased in liver tissue of patients with NASH. This dysfunction correlated with serum TNF–α, insulin resistance, and BMI values. (Hepatology 2003;38:999-1007).

Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis

Mitochondrial dysfunction might play a central role in the pathogenesis of nonalcoholic steatohepatitis (NASH). The aims of this study were to evaluate whether free fatty acid (FFA) transport into the mitochondria or the activity of mitochondria respiratory chain (MRC) complexes are impaired in NASH. In patients with NASH and control subjects, we measured free carnitine, short-chain acylcarnitine (SCAC) and long-chain acylcarnitine (LCAC) esters, carnitine palmitoyltransferase (CPT) activity, and MRC enzyme activity in liver tissue as well as serum concentration of tumor necrosis factor α (TNF-α), homeostatic metabolic assessment of insulin resistance (HOMA IR), and body mass index (BMI). In patients with NASH, the LCAC/free carnitine ratio was significantly increased and the SCAC/free carnitine ratio was decreased. In patients with NASH, the activity of the MRC complexes was decreased to 63% ± 20% (complex I), 58.5% ± 16.7% (complex II), 70.6% ± 10.3% (complex III), 62.5% ± 13% (complex IV), and 42.4% ± 9.1% (adenosine triphosphate synthase) of the corresponding control values. Activity of these complexes correlated significantly with serum TNF-α and HOMA IR. Serum TNF-α (36.3 ± 23.1 pg/mL), HOMA IR (4.5 ± 2.38), and BMI (29.9 ± 3.5 kg/m 2) values were significantly increased in patients with NASH. In conclusion, activities of MRC complexes were decreased in liver tissue of patients with NASH. This dysfunction correlated with serum TNF-α, insulin resistance, and BMI values. (H epatology 2003;38:999-1007.)

Tumor necrosis factor a promoter polymorphisms and insulinp resistance in nonalcoholic fatty liver disease

Background & Aims:Nonalcoholic fatty liver disease, which can range from fatty liver alone to nonalcoholic steatohepatitis and cirrhosis, is related to insulin resistance. Tumor necrosis factor α (TNF-α) may induce insulin resistance, and polymorphisms of its promoter have been associated with an increased release of this cytokine. We analyzed (1) the prevalence of insulin resistance, (2) the prevalence of the 238 and 308 TNF-α polymorphisms, and (3) the relationship among TNF-α polymorphisms, insulin resistance, and the occurrence of steatohepatitis in 99 patients with nonalcoholic fatty liver diagnosed by ultrasonography and confirmed by histologic analysis in the 53 who underwent biopsy.Methods:Insulin resistance was evaluated by the homeostatic metabolic assessment insulin resistance indices and TNF-α polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis.Results:Insulin resistance was detected in almost all of the patients and was more severe in those With steatohepatitis. The prevalence of the 238, but not of the 308, TNF-α polymorphism was higher in subjects with nonalcoholic fatty liver than in controls (31% vs. 15%; P < 0.0001), and patients positive for TNF-α polymorphisms had higher insulin resistance indices, a higher prevalence of impaired glucose tolerance, and a lower number of associated risk factors for steatosis.Conclusions:TNF-α polymorphisms could represent a susceptibility genotype for insulin resistance, nonalcoholic fatty liver, and steatohepatitis.