Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials

AimThere are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease.MethodsWe systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH). Outcomes of interest included changes in serum liver enzyme levels, liver fat, liver fibrosis, or histologic resolution of NASH.ResultsWe included 29 RCTs involving a total of 2,617 individuals (∼45% had T2DM) that have used metformin (n = 6 studies), glitazones (n = 8 studies), glucagon-like peptide-1 receptor agonists (n = 6 studies), dipeptidyl peptidase-4 inhibitors (n = 4 studies) or sodium-glucose cotransporter-2 inhibitors (n = 7 studies) to treat NAFLD. Although most anti-hyperglycaemic drugs improved serum liver enzyme levels, only glitazones (especially pioglitazone) and liraglutide showed an improvement of histologic features of NAFLD, with a mild beneficial effect also on liver fibrosis for pioglitazone only.ConclusionRCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with pioglitazone may warrant caution. Further well-designed RCTs are needed to better characterize the efficacy and safety of monotherapy and combination therapy with anti-hyperglycaemic agents in patients with NAFLD.     

Non-alcoholic fatty liver disease in subjects with type 2 diabetes mellitus and non-diabetics with special reference to insulin resistance and hepatic histopathological changes

AimsNon alcoholic fatty liver disease (NAFLD) includes simple steatosis and non alcoholic steatohepatitis (NASH). The present study was intended to evaluate insulin resistance (IR) in patients with NAFLD and correlate Insulin resistance [IR] with histopathological grades of liver involvement.Material and MethodsIt constituted of forty two consecutive patients (ultrasonographically established) with fatty liver admitted to our hospital. Ninteen were patients with Type 2 diabetes mellitus, 23 were normoglycemic and 12 age-matched healthy persons served as controls. IR was assessed by using HOMA-IR. Histopathological grading and staging of NAFLD was done as per Brunt system.ResultsDiabetics had significantly higher IR than both the other groups while non diabetics with NAFLD also had higher IR (p  < 001) than controls. There was no difference in the HDLc values between the three groups, whereas all other lipid parameters were higher in the patients. The IR was significantly higher 6.83(±2.51) in patients with grade 3 NASH as compared to patients with grade I changes 3.04(±1.58) (p < 0.05) irrespective of glycemic status. Similarly, the level of total cholesterol was significantly higher in patients with grade-3 NASH as compared to grade-1. Serum billirubin and liver enzymes (AST, ALT, ALP) were significantly higher in subjects with Grade 3 NASH when compared with Grade-1.ConclusionInsulin resistance and dyslipidemia rather than the glycemic status.were the determinant factors that had positive correlation with higher histopathological grades of NAFLD.     

La PON1 est-elle un facteur du risque cardiovasculaire chez les diabétiques de type 2 ?

ObjectiveWe evaluate the association between the decrease of serum paraxonase 1 activity and the risk of cardiovascular disease in type 2 diabetes.MethodsOne hundred and fourteen patients with type 2 diabetes were included in the present study. Seventy-one of them have significant coronary disease. The control group consisted of 53 healthy adults.ResultsPON1 activity was significantly reduced in diabetic patients compared to controls (P = 0.021), especially in those with significant coronary disease (P = 0.013). No significant variation in PON1 activity according to age was observed both in controls and in patients. When HDLc ≥ 1.03 mmol/L, the PON1 activity was significantly higher in patients without significant coronary disease compared to those with significant coronary disease (0.030). In case of significant coronary disease, a decrease of 12.23% in PON1 activity was observed in smokers compared with non-smokers, but without statistical significance. The PON1 activity did not very significantly according to the presence or absence of hypertension in patients with significant coronary disease.ConclusionThe implication of diabetes in the decrease of PON1 activity seems highly probable but PON1 activity seems not to be in itself a marker of cardiovascular disease.     

Serum phospholipid omega-3 polyunsaturated fatty acids and insulin resistance in type 2 diabetes mellitus and non-alcoholic fatty liver disease

AimsTo investigate the relationship between serum phospholipid omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and insulin resistance (IR) in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD).Methods51 patients with T2DM and NAFLD (T2DM + NAFLD group), 50 with T2DM alone (T2DM group), 45 with NAFLD alone (NAFLD group), and 42 healthy control subjects (NC group) were studied. Serum ω-3 PUFA profiles were analyzed by gas chromatography, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and serum lipid concentrations were measured. Insulin resistance was assessed by the homeostasis model assessment method (HOMA-IR).ResultsHOMA-IR levels were higher in the T2DM + NAFLD group than in the T2DM, NAFLD and NC groups (p < 0.05), as were ALT, AST, GGT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) concentrations (p < 0.05). Conversely, serum ω-3 PUFA levels were significantly lower in the T2DM + NAFLD group than in the other groups (p < 0.05). The ω-3 PUFA level was negatively correlated with HOMA-IR, TC, LDL-C and TG.ConclusionsSerum phospholipid ω-3 PUFA levels were significantly decreased in patients with T2DM and NAFLD, and were negatively related with insulin resistance. Thus, reduced ω-3 PUFAs may play an important role in the development of T2DM and NAFLD.     

PNPLA3 polymorphism influences the association between high-normal TSH level and NASH in euthyroid adults with biopsy-proven NAFLD

AimWe aimed to evaluate the association between serum thyroid stimulating hormone (TSH) levels, within the reference range, and the histological severity of nonalcoholic fatty liver disease (NAFLD), and whether this association was modulated by the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism.Materials and methodsWe enrolled 327 euthyroid individuals with biopsy-proven NAFLD, who were subdivided into two groups, i.e., a ‘strict-normal’ TSH group (TSH level 0.4 to 2.5 mIU/L; n = 283) and a ‘high-normal’ TSH group (TSH level 2.5 to 5.3 mIU/L with normal thyroid hormones; n = 44). Logistic regression analyses were performed to assess the association between TSH status and presence of nonalcoholic steatohepatitis (NASH) after stratifying subjects by PNPLA3 genotypes.ResultsCompared to strict-normal TSH group, patients with high-normal TSH levels were younger and had a greater prevalence of NASH and higher histologic NAFLD activity score. After stratifying by PNPLA3 genotypes, the significant association between high-normal TSH levels and presence of NASH was restricted only to carriers of the PNPLA3 G risk allele and remained significant even after adjustment for potential confounding factors (adjusted-odds ratio: 3.279; 95% CI: 1.298–8.284; P = 0.012).ConclusionIn euthyroid individuals with biopsy-proven NAFLD, we found a significant association between high-normal TSH levels and NASH. After stratifying by PNPLA3 rs738409 genotypes, this association was observed only among carriers of the PNPLA3 G risk allele.     

N-glycan based biomarker distinguishing non-alcoholic steatohepatitis from steatosis independently of fibrosis

BackgroundNon-alcoholic fatty liver disease is a spectrum of disorders ranging from steatosis to non-alcoholic steatohepatitis (NASH). Steatosis of the liver is benign, whereas NASH can progress to cirrhosis or even hepatocellular carcinoma. Currently, a liver biopsy is the only validated method to distinct NASH from steatosis.AimThe objective of this study was to identify a biomarker specific for NASH based on the N-glycosylation of serum proteins.MethodsN-glycosylation patterns were assessed using DNA sequencer-assisted fluorophore-assisted capillary electrophoresis and compared with histology.ResultsInitially, a glycomarker (log[NGA2F]/[NA2]) was developed based on the results obtained in 51 obese non-alcoholic patients scheduled for bariatric surgery. Multivariate analysis showed that our glycomarker had the lowest P-value of all biomarkers in distinguishing NASH from steatosis (P = 0.069). The glycomarker was validated in a cohort of 224 non-alcoholic fatty liver disease patients. In both pilot and validation study, glycomarker score increased in ascending amount of lobular inflammation (single-factor ANOVA, P ≤ 0.001 and P = 0.012, respectively). The N-glycan profile of immunoglobulin G in the NASH population confirmed the significantly increased undergalactosylation present in these patients.ConclusionOur glycomarker specifically recognises liver inflammation in obese individuals which is the main trigger for the development of steatohepatitis and can differentiate between steatosis and NASH.     

Serum adipokine profile in Indian men with nonalcoholic steatohepatitis: Serum adiponectin is paradoxically decreased in lean vs. obese patients

BackgroundAsian Indians are known to be more insulin resistant for the same degree of weight gain. It is therefore likely that the adipokine profile in nonalcoholic fatty liver disease (NAFLD) in Asian Indian population could be different from the Western subjects.AimsTo study the serum adiponectin, resistin, leptin and TNF-α profile in NAFLD and cryptogenic cirrhosis patients.Subjects and methodsBody mass indices, insulin resistance and serum adipokine levels were studied in 56 patients; 10 with fatty liver, 30 with nonalcoholic steatohepatitis (NASH) and 16 with cryptogenic cirrhosis. Eighteen healthy controls were also included.ResultsPatients in general were obese compared to controls (mean BMI 26.9 ± 4.5 vs. 22.6 ± 2.5, respectively, p < 0.0001). In patients with NASH, adiponectin levels were lower than controls (5.4 ± 3 μg/ml vs.7.2 ± 2.9 μg/ml, p = 0.037). Insulin Resistance as assessed by homeostasis model assessment (HOMA) was higher in obese than lean, NAFLD patients (HOMA IR obese, median = 2.8, range = 0.8–16.3 and lean: median = 1.05, range = 0.51–2.75, p = 0.003). Lean NAFLD patients had adiponectin levels lower than obese patients (3 ± 1 μg/ml vs.6.7 ± 3.8 μg/ml respectively, p = 0.003). Serum resistin levels were higher in NAFLD patients (3.7 ± 3 ng/ml) than controls (2.1 ± 1.7 ng/ml, p = 0.007). This difference was significant even when cirrhotic patients were excluded (3.4 ± 2.7 ng/ml, p = 0.036). Serum leptin levels were raised in cryptogentic cirrhosis compared to NASH (p = 0.03). All adipokines tested were raised in cirrhotic patients compared to NAFLD and controls.ConclusionsA significant reduction in serum adiponectin and increase in serum resistin levels were observed in NAFLD patients, more so in lean than obese NAFLD. This paradoxical decrease of serum adiponectin as well as low frequency of insulin resistance in lean NAFLD suggests a possible different etiology for this subset of patients.     

Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease

Background and aimTo explore associations between serum 25-hydroxyvitamin D₃ [25(OH)D] concentrations and liver histology in patients with non-alcoholic fatty liver disease (NAFLD).Methods and resultsWe studied 60 consecutive patients with biopsy-proven NAFLD, and 60 healthy controls of comparable age, sex and body mass index (BMI).NAFLD patients had a marked decrease in winter serum 25(OH)D concentrations (51.0 ± 22 vs. 74.5 ± 15 nmol/L, P < 0.001) compared with controls. Metabolic syndrome (MetS; as defined by the Adult Treatment Panel III criteria) and its individual components occurred more frequently among NAFLD patients. The marked differences in 25(OH)D concentrations observed between the groups were little affected by adjustment for age, sex, BMI, creatinine, calcium, homeostasis model assessment (HOMA)-insulin resistance, and the presence of the MetS. Interestingly, among NAFLD patients, decreased 25(OH)D concentrations were closely associated with the histological severity of hepatic steatosis, necroinflammation and fibrosis (P < 0.001 for all) independent of age, sex, BMI, creatinine, calcium, HOMA-insulin resistance, and presence of the MetS.ConclusionsCompared with controls, NAFLD patients have a marked decrease in serum 25(OH)D concentrations, which is closely associated with histopathological features of NAFLD. Further investigation into whether vitamin D₃ may play a role in the development and progression of NAFLD appears to be warranted.     

Validation of PNPLA3 polymorphisms as risk factor for NAFLD and liver fibrosis in an admixed population

Introduction and aimStudies have shown that two polymorphisms were associated with steatosis and progression of non-alcoholic fatty liver disease (NAFLD) in different populations: the Patatin-like Phospholipase Domain Containing 3 (PNPLA3) and Transmembrane 6 Superfamily Member 2 (TM6SF2). However, the frequency and significance of these polymorphisms in an admixed population, i.e., Brazilian, is unknown. Therefore, we aimed to evaluate them in healthy subjects in comparison to patients with NAFLD.Material and methodsThis was a multicenter cross-sectional study in 248 patients with biopsy-proven NAFLD and in 134 healthy controls from two tertiary centers in Brazil. PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) polymorphisms were evaluated.ResultsIn controls, the frequencies of PNPLA3 CC and CG + GG were 49.25% and 50.74%, respectively; in NAFLD patients, this was 31.05% and 68.88% (p = 0.0044, 95% CI 1.037–2.977). PNPLA3 GG subjects had an increased risk (3.29-fold) of having NAFLD when compared to CC subjects (p = 0.0044, 95% CI 1.504–7.225). In patients with nonalcoholic steatohepatitis (NASH), PNPLA3 GG compared to CC was associated with higher AST levels [38.4 ± 25.3 versus 36.7 ± 40.1 IU/L, p = 0.0395)] and with the presence of liver fibrosis (≥F2 fibrosis, p = 0.0272). TM6SF2 polymorphisms were not in Hardy-Weinberg equilibrium in our NAFLD group precluding further analysis.ConclusionWe demonstrated for the first time that PNPLA3 CG + GG increase the risk of NAFLD among Brazilian subjects. Moreover, PNPLA3 GG was associated with liver enzyme elevation and fibrosis in NASH patients.     

Long-term effects of growth hormone replacement therapy on liver function in adult patients with growth hormone deficiency

ObjectiveNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are frequently observed in patients with adult growth hormone deficiency (AGHD) and short-term GH replacement therapy (GHRT) has reportedly been efficacious in NAFLD and NASH. The aim of this study was to investigate whether long-term GHRT is an effective treatment for the hepatic comorbidities in AGHD.DesignThis is a retrospective observational study. We recruited 54 consecutive hypopituitary patients with AGHD. Among them, 31 patients who had received GHRT for more than 24 months were compared with 19 age- and sex-matched patients without GHRT. We also analyzed the long term effect of GHRT on 14 patients diagnosed with NASH by liver biopsy. In addition, we subdivided the GHRT group into GH-responder and GH-non-responder groups and analyzed the factors associated with the efficacy of the treatment.ResultsFor a period of 24 months, the significant reduction of serum liver enzyme levels and a fibrotic marker was observed in patients receiving GHRT compared with the control group. Furthermore, GHRT also improved liver enzyme levels in AGHD patients with NASH. The GH-non-responder group showed a higher proportion of patients who gained weight during the study period.ConclusionsThese results indicate that GHRT is efficacious for improving serum liver enzyme levels for at least 24 months in patients with AGHD. To optimize this effect, it is important to avoid body weight gain during the treatment.     

Orlistat increases serum paraoxonase activity in obese patients

Background and aimPrevious studies have demonstrated that oxidative stress is increased in obese patients. The high-density lipoprotein (HDL) associated human paraoxonase 1 (PON1) can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. Our objective was to assess the effects of orlistat therapy combined with diet on body mass index (BMI), waist circumference, lipid parameters, blood pressure, serum glucose level and PON1 activity.Methods and resultsA longitudinal, multicenter, randomized study with and without orlistat treatment was performed. One hundred thirty nine otherwise healthy, obese subjects were divided in to two groups: 78 persons received orlistat (120 mg three times a day) combined with diet while 61 persons were kept on diet only. Anthropometrical parameters, serum lipid levels and PON1 activity were measured at baseline and after 6 months of treatment. BMI and waist circumference were reduced more pronouncedly in the orlistat group than in the control group. Patients receiving orlistat also had significantly greater improvements in fasting blood glucose levels and blood pressure. The orlistat-treated group showed a greater reduction in total cholesterol and triglyceride levels. In addition, the serum PON1 activity in these patients was significantly increased compared to the diet-only group.ConclusionsThe 6-month treatment with orlistat had a beneficial effect on the lipid profile and improved the antioxidant status by increasing serum PON1 activity. However, because of the limited therapeutic effectiveness, obese patients with hypercholesterolemia should receive additional lipid lowering medications.     

Polycystic ovary syndrome with feasible equivalence to overweight as a risk factor for non-alcoholic fatty liver disease development and severity in Mexican population

Introduction and objectivesPolycystic ovary syndrome (PCOS) is the most common endocrinology disorder in women of reproductive age; these patients have a higher risk of suffering from non-alcoholic fatty liver disease (NAFLD). We determine the frequency of NAFLD in Mexican patients with PCOS and matched-controls.Patients and methodsCross-sectional study, with 98 women of 18–44 years old. Rotterdam 2003 criteria integrated PCOS diagnosis. Those with significant alcohol consumption, chronic liver disease, use of steatogenic drugs, and pharmacological PCOS treatment or fertility protocol were excluded. Controls were matched in a 1:1 ratio by age and body mass index (BMI). The presence of NAFLD was determined by transient elastography performed by a single experienced operator.ResultsA total of 98 female volunteers at reproductive age were recruited. NAFLD denoted markedly higher in patients with than without PCOS at 69.3% vs. 34.6%, respectively. Compared to controls, PCOS patients had a significantly higher risk of NAFLD (OR = 4.26, 95% CI 1.83–9.93). Severe steatosis was the most frequent NAFLD stage between women with PCOS and NAFLD. Patients with hyperandrogenism have a significantly higher mean CAP 277.83 dB/m than controls without hyperandrogenism 191.57 dB/m. NAFLD prevalence was 84.3% in PCOS patients with phenotype A, while in another phenotype, it was 41.1%.ConclusionsPCOS is an independent risk factor for NAFLD development. NAFLD screening needs to be considered in all PCOS patients independently of BMI, except in PCOS patients without hyperandrogenism and BMI < 25.     

PONI and its association with oxidative stress in type I and type II diabetes mellitus

ObjectiveParaoxonase (PON) is an antioxidant enzyme linked with cardiovascular disease (CVD), diabetes as it prevents LDL oxidation. The relation of PON with the other established risk factor of diabetic complications has not been looked into.Research design and methods370 subjects were included in the study. Dividing into four group, i.e. group I included type II DM (n = 220), group II was age matched control (n = 100), group III were type I DM (n = 25) and group IV (n = 25) were age matched control group. The protocol of the study was approved by the ethical committee of the institute. SOD, GSH, PON (paraoxonase and arylesterase activity), GHb, and MDA were estimated.ResultsA highly significant decrease in paraoxonase and arylesterase activity was seen in the type II DM (p < 0.0001) while in type I DM both the activity was not significant (p > 0.05). Paraoxonase and arylesterase activity of PONI showed a negative significant correlated with MDA (r = ?0.51, p < 0.0001 and r = ?0.23, p < 0.001) in type II DM but was not correlated in type I DM. The GHb and MDA levels were significantly increased (p < 0.0001) while the levels of SOD and GSH have been decreased in type I and type II DM.ConclusionPONI is definitely associated with development of the complications of diabetes. This may be due to the role of it as an antioxidant. As it also show a negative correlation with MDA like the other antioxidants studied.     

Effect of Atorvastatin and Ezetimibe Treatment on Serum Lipid Profile and Oxidative State in Rats Fed With a High-Cholesterol Diet

IntroductionThe effects of ezetimibe and atorvastatin on serum lipid profile and oxidant-antioxidant system were investigated in rats.MethodsSeventy-two Sprague-Dawley rats were assigned to 6 groups. Group 1 was fed with standard rat chow. Group 2 and the other 4 groups were fed with a high-cholesterol diet: 10 mg/kg/d atorvastatin to group 3; 1 mg/kg/d atorvastatin to group 4; 10 mg/kg/d atorvastatin and 1 mg/kg/d ezetimibe to group 5; and 1 mg/kg/d ezetimibe to group 6. After 3 months, serum total, low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels, and the activities of malondialdehyde, glutathione peroxidase, and superoxide dismutase were measured in the plasma. In addition, the left anterior descending and femoral arteries were examined histopathologically.ResultsSerum total, low-density lipoprotein cholesterol, and triglyceride levels decreased slightly in group 3. However, administration of 1 mg/kg/d atorvastatin or 1 mg/kg/d ezetimibe did not significantly change lipid parameters. Plasma malondialdehyde levels slightly increased in group 2 compared with controls and decreased compared with both the atorvastatin regimens. However, malondialdehyde levels increased with the addition of ezetimibe to atorvastatin. Only the administration of ezetimibe significantly elevated the levels of malondialdehyde. Glutathione peroxidase and superoxide dismutase levels were also found to be significantly reduced in the groups receiving ezetimibe when compared with atorvastatin groups.ConclusionsAtorvastatin has a beneficial effect on oxidative stress in rats fed with high-cholesterol diet. A combination of ezetimibe with atorvastatin diminishes the beneficial effects of atorvastatin. Conversely, the sole administration of ezetimibe increases oxidative stress.     

Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease

BackgroundMetabolic risk factors are associated with non-alcoholic fatty liver disease (NAFLD), but they are less frequent in inflammatory bowel disease (IBD).AimThis study evaluates the frequency of NAFLD and its risk factors among IBD patients including anti-TNF-α therapy.MethodsIBD patients who underwent abdominal imaging from January, 2009 to December, 2010 were analyzed in this nested, case-controlled study. IBD patients with NAFLD by imaging were compared with those who had no evidence of NAFLD (control).ResultsAmong 928 IBD patients, 76 (8.2%) had evidence of NAFLD by imaging, and were compared to 141 patients without NAFLD evaluated (study: control ratio = ~ 1:2). NAFLD patients were older (46.0 ± 13.3 vs. 42.0 ± 14.1 years; p = 0.018) and had a later onset of IBD compared to the control group (37.2 ± 15.3 vs. 28.7 ± 23.8 years; p = 0.002). Metabolic syndrome was present in 29.0% of NAFLD patients, with a median Adult Treatment Panel risk factor of 2 [Interquartile range 1,3]. Patients not receiving anti-TNF-α therapy had a higher occurrence of NAFLD (p = 0.048). In multivariate analysis, hypertension (OR = 3.5), obesity (OR = 2.1), small bowel surgeries (OR = 3.7), and use of steroids at the time of imaging (OR = 3.7) were independent factors associated with NAFLD.ConclusionNAFLD occurred in 8.2% of the IBD population. NAFLD patients were older and had a later onset of IBD disease. IBD patients develop NAFLD with fewer metabolic risk factors than non-IBD NAFLD patients. It is also less common among patients who received anti-TNF-α therapy.     

A new marker for lipid peroxidation: serum paraoxonase activity in non-alcoholic steatohepatitis.

BACKGROUND/AIMS: Relationship between hepatic antioxidant paraoxonase 1 (PON1) activity, lipid peroxidation and liver injury was investigated in patients with non-alcoholic steatohepatitis. METHODS: A total of 23 patients with non-alcoholic steatohepatitis (15 males, 8 females; mean age: 40.30+/-7.67 yrs) and 23 healthy controls (14 males, 9 females; mean age: 39.70+/- 8.78 yrs) were enrolled in the study. Serum paraoxonase 1 activity and levels of a well-known lipid peroxidation marker, serum malondialdehyde, were determined. RESULTS: Serum paraoxonase 1 activity decreased significantly in non-alcoholic steatohepatitis compared to the control group (p<0.01). Serum malondialdehyde levels were significantly higher in patients with non-alcoholic steatohepatitis as compared with the control group (p<0.05). No statistically significant correlations were found between serum paraoxonase 1 activities and the grade-stage of non-alcoholic steatohepatitis, serum lipid levels or serum malondialdehyde levels (p>0.05). CONCLUSIONS: Increased lipid peroxidation may be either a cause or a result of liver injury in patients with non-alcoholic steatohepatitis. Although serum paraoxonase 1 activity does not reflect the degree of liver damage in non-alcoholic steatohepatitis, reduced paraoxonase 1 activity, especially in the presence of mild disease, could be interpreted as a biochemical marker of the lipid peroxidation.     

Effects of lifestyle interventions on clinical characteristics of patients with non-alcoholic fatty liver disease: A meta-analysis

Background/ObjectivesAlthough lifestyle modifications remain the cornerstone therapy for non-alcoholic fatty liver disease (NAFLD), the optimal lifestyle intervention is still controversial. The aim of this meta-analysis was to evaluate the effect of exercise and/or dietary interventions, type or intensity of exercise and type of diet, on liver function outcomes (liver enzymes, intrahepatic fat and liver histology), as well as on anthropometric and glucose metabolism parameters in NAFLD patients.Subjects/MethodsLiterature search was performed in Scopus and US National Library of Medicine databases to identify all randomized controlled clinical trials (RCTs) in adult patients with NAFLD, diagnosed through imaging techniques or liver biopsy, published in English between January 2005 and August 2016. Studies' quality was evaluated using the Cochrane Risk of Bias Tool. Heterogeneity was tested using the Cochran's Q test and measured inconsistency by I². Effect size was calculated as the standardized mean difference (SMD). The meta-analysis was performed in accordance with PRISMA guidelines.ResultsTwenty RCTs with 1073 NAFLD patients were included. Compared to standard care, exercise improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (all P < 0.05). Ιntrahepatic fat also improved, irrespectively of weight change (SMD = − 0.98, 95% CI: − 1.30 to − 0.66). Regarding the type of exercise, aerobic compared to resistance exercise did not yield any superior improvements on liver parameters, whereas moderate-to-high volume moderate-intensity continuous training was more beneficial compared to continuous low-to-moderate-volume moderate-intensity training or high intensity interval training. Interventions combining exercise and diet showed decreases in ALT (P < 0.01) and improvement in NAFLD activity score (SMD = − 0.61, 95% CI: − 1.09 to − 0.13). Moderate-carbohydrate diets yielded similar changes in liver enzymes compared to low/moderate-fat diets.ConclusionsExercise alone or combined with dietary intervention improves serum levels of liver enzymes and liver fat or histology. Exercise exerts beneficial effects on intrahepatic triglycerides even in the absence of weight loss.     

Postprandial modulation of serum paraoxonase activity and concentration in diabetic and non-diabetic subjects

ObjectivesTo analyse the HDL associated anti-oxidant enzyme paraoxonase-1, during postprandial hyperlipaemia.Methods and resultsType 2 diabetic patients (n = 72), glucose intolerant patients (n = 10) and controls (n = 38) consumed a high fat:high carbohydrate meal. Blood samples were collected up to 4 h and analysed for lipids and paraoxonase-1. In vitro studies examined HDL function with respect to the enzyme. There were significant postprandial increases in serum triglycerides. Paraoxonase-1 activity decreased significantly throughout the postprandial phase. Concentrations of the enzyme initially decreased significantly, but returned to fasting concentrations at 4 h. Specific activities were significantly lower at 4 h, compared to fasting. The decrease in specific activity was linked to the dynamic phase of postprandial lipoprotein metabolism. Apo AI limited loss of paraoxonase-1. HDL isolated after being subjected to postprandial conditions in vitro had reduced capacity to associate with and stabilise PON1.ConclusionsPostprandial hyperlipaemia was associated with changes to serum paraoxonase-1, consistent with a reduced anti-oxidant potential of HDL. No differences were observed between diabetic and non-diabetic patients, suggesting that the effect was linked to postprandial hyperlipaemia. Modifications to paraoxonase-1 could contribute to increased risk of vascular disease associated with postprandial lipaemia, particularly in diabetic patients, who are already deficient in serum paraoxonase-1.     

Vitamin D and histologic severity of nonalcoholic fatty liver disease: A systematic review and meta-analysis

BackgroundNAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several risk factors. Recent studies investigating the relationship between vitamin D levels and severity of NAFLD showed conflicting results. Thus we conducted a systematic review and meta-analysis to evaluate association between vitamin D and NAFLD histologic severity.MethodsA comprehensive search of the databases of the MEDLINE and EMBASE was performed from inception through November 2016. Observational studies compared serum vitamin D levels among NAFLD patients with high and low histologic severity, which was determined by NAFLD activity score (NAS) and fibrosis score. We calculated pooled mean difference (MD) of 25-hydroxyvitamin D levels with 95% confidence intervals (CI) using random-effects model.ResultsData were extracted from 6 studies involving 974 NAFLD patients. There was no difference in 25-hydroxyvitamin D levels among NAFLD patients with high NAS (score of ≥5) versus low NAS (pooled MD = −0.93, 95%CI −2.45 to 0.58, I² = 0%) and also high fibrosis score (score of ≥3) versus low fibrosis score (pooled MD = 0.88, 95%CI −2.65 to 4.42, I² = 64%).ConclusionsDespite evidence implicating vitamin D in NAFLD pathogenesis, serum 25-hydroxyvitamin D may not be associated with NAFLD histologic severity.     

Low 25-hydroxyvitamin D level is independently associated with non-alcoholic fatty liver disease

Background and aimsWe sought to explore associations between serum 25-hydroxyvitamin D [25(OH)D] levels and non-alcoholic fatty liver disease [NAFLD] in an integrated healthcare delivery system in the U.S.Methods and resultsSix hundred and seven NAFLD cases were randomly matched 1:1 with controls for age, sex, race and season of measurement. Conditional logistic regression was used to evaluate if serum 25(OH)D levels were associated with increased odds of NAFLD (diagnosed by ultrasound) after adjusting for body mass index and history of diabetes, renal, peripheral vascular and liver diseases (model 1) and also for hypertension (model 2). Mean (SD) serum 25(OH)D level was significantly lower in the group with NAFLD as compared with that in the matched control group (75 ± 17 vs. 85 ± 20 nmol/L [30 ± 7 vs. 34 ± 8 ng/mL], P < 0.001). Inadequate 25(OH)D status progressively increased the odds of NAFLD when classified categorically as sufficient (25(OH)D 75 nmol/L [>30 ng/mL], reference group), insufficient (37–75 nmol/L [15–30 ng/mL]; adjusted odds ratio [OR]: 2.40, 95% confidence interval [CI]: 0.90–6.34) or deficient (<37 nmol/L [<15 ng/mL]; adjusted OR: 2.56, 95% CI: 1.27–5.19). When modeled as a continuous variable, increased log₁₀ 25(OH)D was inversely associated with the risk of prevalent NAFLD (adjusted OR: 0.25, 95% CI: 0.064–0.96, P = 0.02).ConclusionCompared with matched controls, patients with NAFLD have significantly decreased serum 25(OH)D levels, suggesting that low 25(OH)D status might play a role in the development and progression of NAFLD.