(13C)-Methacetin breath test provides evidence of subclinical liver dysfunction linked to fat storage but not lifestyle.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterised by the presence of hepatic steatosis in the absence of other causes of secondary hepatic fat accumulation, and is usually associated with visceral, metabolically active obesity. However, the subclinical effects of body and liver fat accumulation on liver function are still unclear. METHODS: We used orally administered (13C)-methacetin and breath test to quantify the efficiency of hepatic extraction from portal blood flow and liver microsomal function in 81 participants, in relation to presence/absence of ultrasonographic NAFLD, extent of body fat accumulation, insulin resistance, dietary models, and lifestyle. RESULTS: NAFLD was present in 23% of participants with normal weight, and prevalence increased with body fat and insulin resistance. Fat accumulation, NAFLD, and insulin resistance were associated with decreased hepatic extraction efficiency, and liver microsomal function was impaired in moderate-to-severe NAFLD. Caloric intake, dietary models, and lifestyles had a minor role in promoting functional changes. CONCLUSIONS: The interplay between body fat accumulation, insulin resistance, and NAFLD is linked with altered hepatic extraction efficiency from blood flow and deranged microsomal function. Non-invasive diagnosis of subclinical alterations of liver function is relevant for primary and secondary prevention measures. Furthermore, the occurrence of NAFLD in lean individuals and the evidence that caloric intake, dietary models, and lifestyle played a minor role require further studies exploring the role of environmental factors in the natural history of these diseases. LAY SUMMARY: Obesity is progressively increasing worldwide and is paralleled by fat accumulation in the liver (non-alcoholic fatty liver disease [NAFLD]), the most common chronic liver disease worldwide. NAFLD can alter liver structure and function, with a variety of consequences ranging from asymptomatic and subclinical alterations to cirrhosis and cancer. (13C)-Methacetin breath test, a non-invasive diagnostic tool, can reveal early subclinical alterations of liver dynamic function in individuals with obesity and in patients with NAFLD.

Volatomic analysis identifies compounds that can stratify non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Analysis of volatile organic compounds (VOCs) in exhaled breath, 'volatomics', provides opportunities for non-invasive biomarker discovery and novel mechanistic insights into a variety of diseases. The purpose of this pilot study was to compare breath VOCs in an initial cohort of patients with non-alcoholic fatty liver disease (NAFLD) and healthy controls. METHODS: Breath samples were collected from 15 participants with Child-Pugh class A NAFLD cirrhosis, 14 with non-cirrhotic NAFLD, and 14 healthy volunteers. Exhaled breath samples were collected using an established methodology and VOC profiles were analysed by gas chromatography-mass spectrometry. The levels of 19 VOCs previously associated with cirrhosis were assessed. Peaks of the VOCs were confirmed and integrated using Xcalibur® software, normalised to an internal standard. Receiver-operating characteristic (ROC) curves were used to determine the diagnostic accuracy of the candidate VOCs. RESULTS: Terpinene, dimethyl sulfide, and D-limonene provided the highest predictive accuracy to discriminate between study groups. Combining dimethyl sulfide with D-limonene led to even better discrimination of patients with NAFLD cirrhosis from healthy volunteers (AUROC 0.98; 95% CI 0.93-1.00; p <0.001) and patients with NAFLD cirrhosis from those with non-cirrhotic NAFLD (AUROC 0.91; 95% CI 0.82-1.00; p <0.001). Breath terpinene concentrations discriminated between patients with non-cirrhotic NAFLD and healthy volunteers (AUROC 0.84; 95% CI 0.68-0.99; p = 0.002). CONCLUSION: Breath terpinene, dimethyl sulfide, and D-limonene are potentially useful volatomic markers for stratifying NAFLD; in addition, a 2-stage approach enables the differentiation of patients with cirrhosis from those without. However, these observations require validation in a larger NAFLD population. (ClinicalTrials.gov Identifier: NCT02950610). LAY SUMMARY: Breath malodour has been associated with a failing liver since the ancient Greeks. Analytical chemistry has provided us an insight into ubiquitous volatile organic compounds associated with liver (and other) diseases. This has vastly improved our understanding of the mechanistic processes of liver damage. Our study aims to identify volatile organic compounds which are specific to non-alcoholic fatty liver disease and that can be exploited for rapid diagnostics.

Higher phenolic acid intake independently associates with lower prevalence of insulin resistance and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The inverse association between non-alcoholic fatty liver disease (NAFLD) and diets rich in fruit and vegetables has been demonstrated, but the specific compounds that may be responsible for this association need to be elucidated. The aim of this study was to test the association between phenolic acid consumption, NAFLD, and insulin resistance (IR). METHODS: A cross-sectional cohort of individuals included in a metabolic screening program was studied. Liver steatosis was evaluated by ultrasonography and quantified by the hepatorenal index (HRI); fibrosis was assessed by FibroTest; IR by the sample upper quartile of the homeostatic model assessment score. Dietary intake was measured by a food frequency questionnaire. The phenolic acid content of food was calculated according to Phenol-Explorer. RESULTS: A total of 789 individuals were included (52.6% men, age 58.83 ± 6.58 years). Higher (above the upper median) phenolic acid intake was inversely associated with the presence of NAFLD (odds ratio [OR] 0.69; 95% CI 0.49-0.98; p = 0.036), higher HRI (OR 0.64; 95% CI 0.45-0.91; p = 0.013) and higher IR (OR 0.61; 95% CI 0.42-0.87; p = 0.007), when adjusted for age, gender, body mass index, and lifestyle factors. Considering specific classes of phenolic acids, higher hydroxybenzoic acid intake was independently associated with lower odds of NAFLD, higher HRI and fibrosis. Higher hydroxycinnamic acid intake was independently associated with lower odds of IR. CONCLUSION: A higher intake of phenolic acids is associated with a lower prevalence of liver steatosis and IR in a cross-sectional study, suggesting a possible protective effect that requires confirmation in prospective studies. LAY SUMMARY: High dietary intake of total phenolic acids is associated with a lower prevalence of non-alcoholic fatty liver disease and insulin resistance. A high intake of hydroxybenzoic acids, a class of phenolic acids, is associated with a lower prevalence of steatosis and clinically significant fibrosis, while a high intake of hydroxycinnamic acids, another class of phenolic acids, is associated with a lower prevalence of insulin resistance.

The role of bioactives in energy metabolism and metabolic syndrome.

Some food bioactives potentially exert anti-obesity effects. Anthocyanins (ACN), catechins, ß-glucan (BG) and n-3 long chain PUFA (LCPUFA) are among the most promising candidates and have been considered as a strategy for the development of functional foods counteracting body weight gain. At present, clinical trials, reviews and meta-analyses addressing anti-obesity effects of various bioactives or bioactive-rich foods show contradictory results. Abdominal obesity is an important criterion for metabolic syndrome (MetS) diagnosis along with glucose intolerance, dyslipidaemia and hypertension. Food bioactives are supposed to exert beneficial effects on these parameters, therefore representing alternative therapy approaches for the treatment of MetS. This review summarises outcomes on MetS biomarkers in recent clinical trials supplementing ACN, catechins, BG and n-3 LCPUFA, focusing mainly on anti-obesity effects. Overall, it is clear that the level of evidence for the effectiveness varies not only among the different bioactives but also among the different putative health benefits suggested for the same bioactive. Limited evidence may be due to the low number of controlled intervention trials or to inconsistencies in trial design, i.e. duration, dose and/or the method of bioactive supplementation (extracts, supplements, rich or enriched food). At present, the question 'Are bioactives effective in weight management and prevention of metabolic syndrome?' remains inconclusive. Thus, a common effort to harmonise the study design of intervention trials focusing on the most promising bioactive molecules is urgently needed to strengthen the evidence of their potential in the treatment of obesity, MetS and related diseases.

Sagittal Abdominal Diameter to Measure Visceral Adipose Tissue in Overweight or Obese Adolescent Children and Its Role as A Marker of Insulin Resistance.

BACKGROUND: Measurement of sagittal abdominal diameter using a revalidated caliper is simple, inexpensive, non-invasive method. It strongly correlates with insulin resistance and can be used as a surrogate marker to predict risk for Type II Diabetes Mellitus. AIM: To assess visceral abdominal fat by measuring sagittal abdominal diameter using sliding calipers and to predict insulin resistance in obese or overweight adolescent children. STUDY DESIGN: Explorative study for Paediatric age group among over weight and obese children aged 10-18 years in urban population in a Tertiary Care Centre. MATERIALS AND METHODS: Paediatric population satisfying ADA guidelines for diagnosis of prediabetes were included in the study. Anthropometric measurements with SAD were recorded. Blood was collected to investigate for prediabetes and insulin resistance using HOMA-IR. RESULTS: Out of 924 subjects who gave assent to participate in study 108 fulfilled ADA criteria. 33 subjects who didn't come for the follow up were excluded. Out of 75 subjects 12 were detected to have insulin resistance (16%) and 63 were normal (84%). Pearson's partial correlation of HOMA-IR and OGTT with SAD has demonstrated it to be better correlation with Insulin Resistance (IR) than other anthropometric measurements. Fasting Glucose correlated better with Waist Hip Circumference. CONCLUSION: Insulin Resistance was diagnosed in 16% of the population and these had high levels of insulin resistance. SAD in relation to glucose metabolism, had a better correlation with OGTT followed by HOMA-IR and fasting Insulin. SAD with anthropometric measurements had better correlation all the parameters other than Waist Circumference, which had negative correlation. SAD can be used in evaluation of obese or overweight children for evaluation.

Risk Factors Associated With Non-Alcoholic Fatty Liver Disease in Indians: A Case-Control Study.

BACKGROUND/AIMS: NAFLD has today emerged as the leading cause of liver disorder. There is scanty data on risk factors associated with NAFLD emanating from India. The present study was conducted to identify the risk factors associated with NAFLD. METHODS: 464 consecutive NAFLD patients and 181 control patients were subjected to detailed questionnaire regarding their lifestyle and dietary risk factors. Anthropometric measurements were obtained and biochemical assays were done. Comparison of different variables was made between NAFLD patients and controls using principal component analysis (PCA). RESULTS: NAFLD patients had higher BMI [26.25 ± 3.80 vs 21.46 ± 3.08 kg/m(2), P = 0.000], waist-hip ratio [0.96 ± 0.12 vs 0.90 ± 0.08, P = 0.000] and waist-height ratio [0.57 ± 0.09 vs 0.50 ± 0.06, P = 0.000] compared to controls. Fasting blood sugar [101.88 ± 31.57 vs 90.87 ± 10.74 mg/dl] and triglyceride levels [196.16 ± 102.66 vs 133.20 ± 58.37 mg/dl] were significantly higher in NAFLD group. HOMA-IR was also higher in NAFLD group [2.53 ± 2.57 vs 1.16 ± 0.58, P = 0.000]. Majority (90.2%) of NAFLD patients were sedentary. Family history of metabolic syndrome (MS) was positively correlated with NAFLD. Dietary risk factors associated with NAFLD were non-vegetarian diet [35% vs 23%, P = 0.002], fried food [35% vs 9%, P = 0.000], spicy foods [51% vs 15%, P = 0.001] and tea [55% vs 39%, P = 0.001]. Diabetes, hypertension, snoring and sleep apnoea syndrome were common factors in NAFLD. On multivariate PCA, waist/height ratio and BMI were significantly higher in the NAFLD patients. CONCLUSION: The risk factors associated with NAFLD are sedentary lifestyle, obesity family history of MS, consumption of meat/fish, spicy foods, fried foods and tea. Other risk factors associated with NAFLD included snoring and MS.

Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations.

A Randomized Controlled Trial Comparing Efficacy of Pentoxifylline and Pioglitazone on Metabolic Factors and Liver Histology in Patients with Non-alcoholic Steatohepatitis.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) involves increased hepatic macrosteatosis due to increased insulin resistance and non-hepatic processes including oxidative stress, apoptosis, and increased pro-inflammatory cytokines. Present study compared the efficacy of pentoxifylline and pioglitazone therapy in improving the metabolic factors and liver histology in patients with NASH. METHODS: Sixty consecutive biopsy proven NASH patients aged 18-70 years with ALT > 1.2 times the upper limit of normal were randomized to receive either pentoxifylline 1200 mg/day in three divided doses orally every day or pioglitazone (30 mg/day) daily for 6 months. All the patients were also instructed to reduce their calorie intake by 500 kcal/day as well as to perform modest exercise (brisk walking) regularly at least 5 days per week. Before and after treatment, liver function tests, serum insulin, C-peptide levels, TNF-α, adiponectin, leptin levels, HOMA-IR and hepatocyte injury and fibrosis scores on liver histology were assessed. RESULTS: Both pentoxifylline and pioglitazone were effective in improving transaminases, insulin resistance (HOMA-IR) and adiponectin levels significantly. TNF-α levels improved with either of the drugs but did not achieve significant levels. Both the drugs improved the markers of acute liver injury. However, only steatosis improved significantly with either of the drugs. Patients treated with pioglitazone had significant improvement in lobular inflammation, portal inflammation and Brunts grade. Brunts grade improved significantly with pioglitazone as compared to pentoxifylline at the end of the therapy. CONCLUSIONS: Pioglitazone shows better improvement in both metabolic factors and liver histology in patients with NASH compared to pentoxifylline.

Síndrome Metabólica, seus fenótipos e resistência à insulina pelo HOMA-RI / Metabolic syndrome, its phenotypes, and insulin resistance by HOMA-IR

O diagnóstico de síndrome metabólica (SM) segundo o National Cholesterol Education Program Adult Treatment Panel III não reflete necessariamente a presença de resistência à insulina (RI), um potencial alvo terapêutico para prevenção de diabetes tipo 2 e doenças cardiovasculares. Em estudo de corte transversal, assentado em dados anteriores de prevalência, avaliamos o comportamento do HOMA-RI, um parâmetro de RI bem difundido, frente à SM e anormalidades associadas. HOMA-RI foi maior nos indivíduos com SM (2,8 ± 1,6 vs. 1,8 ± 1,4) (p < 0,001) e mostrou excelente correlação com insulinemia de jejum (rS = 0,961). HOMA-RI > 2,5 aliou bons níveis de especificidade e sensibilidade para a associação de SM e RI. Diferente de aumento da glicemia, obesidade abdominal e elevação da trigliceridemia, componentes da SM mais bem relacionados com RI, a elevação da pressão arterial e a redução do HDL-c não mostraram associação com HOMA-RI > 2,5. A demonstração de que alguns fenótipos de SM ou anormalidades associadas foram mais preditivos de RI pode apontar para a possibilidade de uso do índice como um indicador de RI associada à SM.

The diagnosis of the metabolic syndrome (MS) according to the National Cholesterol Education Program Adult Treatment Panel III does not reflect necessarily the presence of insulin resistance (IR), a potential therapeutical target for type 2 diabetes and cardiovascular disease prevention. Based on previous prevalence data, a cross-sectional study was conducted to determine the HOMA-IR relationship to the MS and some associated abnormalities. HOMA-IR > was higher in individuals with the MS (2.8 ± 1.6 vs. 1.8 ± 1.4) (p < 0.001). HOMA-IR > or = 2.5 allied good specificity and sensitivity levels for the association of MS and IR. Hyperglycemia, hypertrigliceridemia, and abdominal obesity, the MS components best related to IR, were statistically associated with HOMA-IR > 2.5, but not hypertension neither low HDL-c. The demonstration that some of MS phenotypes or associated abnormalities were more predictive for IR could point out to the possibility of the use of the index as a marker of the presence of IR associated to MS.