Efficacy of N-Acetylcysteine on Liver Function and Metabolic Profiles in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Double-Blind, Randomized Controlled Trial

The present study is the first effort to evaluate the effects of vitamin B12 supplementation on the serum level of liver enzymes, homocysteine, grade of hepatic steatosis, and metabolic profiles in patients with non-alcoholic fatty liver disease (NAFLD). Forty patients with NAFLD were enrolled in a double-blind placebo-controlled trial to receive either one oral tablet of vitamin B12 (1000 µg cyanocobalamin) or a placebo per day for 12 weeks. We investigated serum levels of homocysteine, aminotransferases, fasting blood glucose (FBG), lipids, malondialdehyde (MDA), and homeostasis model assessment of insulin resistance (HOMA-IR). The grade of liver steatosis and fibrosis was measured by real-time 2-dimensional shear wave elastography. Vitamin B12 supplementation significantly decreased serum levels of homocysteine compared to placebo (medians: − 2.1 vs. − 0.003 µmol/l; P = 0.038). Although serum alanine transaminase (ALT) in the vitamin B12 group decreased significantly, this change did not reach a significant level compared to the placebo group (medians: − 7.0 vs. 0.0 IU/l; P > 0.05). Despite the significant within-group decrease in FBG, MDA, and liver steatosis in the vitamin B12 group, between-group comparisons did not reveal any significant difference. Vitamin B12 supplementation might decrease serum levels of homocysteine in patients with NAFLD. The fasting blood glucose and serum levels of MDA were significantly improved in the trial group who received vitamin B12. However, these changes did not reach a significant level compared to the placebo group. In this respect, further studies with larger sample sizes, different doses, and types of vitamin B12 will reveal additional evidence.Trial Registration: At http://irct.ir/ as IRCT20120718010333N5 on December 25, 2019.

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

BackgroundInsulin resistance (IR) related metabolic disorders are associated with a worse prognosis of chronic hepatitis B virus (CHB) infection or nonalcoholic fatty liver disease (NAFLD). However, the relationships among CHB, steatosis, IR and metabolic factors remain controversial. The study aims to evaluate the impact of insulin resistance severity on metabolic profiles in patients with CHB, NAFLD and the coincidence of the two.MethodsWe conducted a cross-sectional study between January 2011 and December 2018 that included 2768 consecutive Chinese subjects (healthy controls: 667, CHB: 970, NAFLD: 878, CHB with NAFLD: 253). IR was determined with the homeostasis model assessment for insulin resistance (HOMA-IR). Metabolic measures included fasting serum insulin, glucose, lipid profiles and uric acid.ResultsThe prevalence of IR was increased in CHB with NAFLD subjects compared with that in control subjects or subjects with CHB or NAFLD alone (41.5% vs 2.9%/11.9%/36.9%, respectively; P < 0.001). Within NAFLD and CHB with NAFLD group, the frequency of metabolic syndrome, hypertension and hyperuricemia increased as the HOMA-IR category increased (P for trend < 0.05). A higher risk for total cholesterol, low-density lipoprotein cholesterol and elevated alanine transaminase was observed with IR in the CHB with NAFLD group compared with that in the other groups, while no stepwise increase in hypertriglyceridemia was found in HOMA-IR in the CHB with NAFLD group.ConclusionInsulin resistance is highly prevalent in patients with CHB combined with NAFLD, and the increased metabolic risk, rather than hypertriglyceridemia, is driven by IR in CHB combined with NAFLD.

The effects of vitamin D supplementation on metabolic profiles and liver function in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials

Background: Obesity, insulin resistance, and diabetes are major risk factors for nonalcoholic fatty liver disease (NAFLD). This study aims to evaluate the association between different grades of NAFLD and abdominal subcutaneous fat thickness with the homeostasis model assessment of insulin resistance (HOMA-IR).Methods: In this pilot study, 59 obese nondiabetic participants with NAFLD were enrolled. Total cholesterol, HbA1c, and HOMA-IR were measured. Abdominal subcutaneous fat thickness in the midline just below the xiphoid process in front of the left lobe of the liver (LSFT) and in the umbilical region (USFT), and the degree of hepatic steatosis, were evaluated by ultrasound scans, and their correlation with the degree of steatosis and the NAFLD Activity Score in liver biopsy was assessed.Results: Of the 59 studied participants, 15 had mild, 17 had moderate, and 27 had severe hepatic steatosis by abdominal ultrasound. Themean ± SD HOMA-IR level in NAFLD patients was 5.41±2.70. The severity of hepatic steatosis positively correlated with body mass index (P<0.001), HOMA-IR (P<0.001), serum triglycerides (P=0.001), LSFT (P<0.001), and USFT (P<0.001). Receiver operating characteristics analysis showed that LSFT at a cut-off of 3.45 cm is the most accurate predictor of severe hepatic steatosis, with 74.1% sensitivity and 84.4% specificity. The best cut-off of USFT for identifying severe hepatic steatosis is 4.55 cm, with 63% sensitivity and 81.3% specificity.Conclusion: Abdominal subcutaneous fat thicknesses in front of the left lobe of the liver and in the umbilical region, together with HOMA-IR, are reliable indicators of the severity of NAFLD in obese nondiabetic individuals.

Changing Nomenclature from Nonalcoholic Fatty Liver Disease to Metabolic Dysfunction-Associated Fatty Liver Disease – Not Only Premature But Also Confusing

Background/ObjectivesRenaming non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) suggests a shift of emphasis to the accompanying metabolic disturbance. Controlled attenuation parameter (CAP) measured by FibroScan has been shown to be correlated with hepatic steatosis. We aim to validate its usefulness as a novel surrogate marker for evaluating metabolic derangement.Subjects/MethodsVolunteers were recruited from medical staff at our hospital to undergo CAP measurements. Anthropometrics, CAP, and laboratory assessments for metabolic profiles and insulin resistance were collected. CAP < 238 dB/m denoted no hepatic steatosis, 238 ≤ CAP ≤ 259 dB/m denoted mild, 260 ≤ CAP ≤ 291 dB/m denoted moderate, and CAP > 291 dB/m denoted severe hepatic steatosis according to previous reports.ResultsData of 824 participants were included for analysis. The age was 53.2 ± 15.4 years, body mass index (BMI) was 23.6 ± 3.1 kg/m2, 24.4% were male subjects, and 22.0% met the criteria for metabolic syndrome (MetS). Taking the group with CAP < 238 dB/m as control, subjects with mild, moderate, and severe hepatic steatosis had increased odds of MetS by 3.51-, 3.32-, and 5.12-fold, respectively, after adjusting for multiple confounders (p = 0.020). Metabolic profiles, insulin resistance, and presence of MetS were similar between normal-weight subjects with CAP ≥ 238 dB/m and overweight subjects with CAP < 238 dB/m. Even in subjects with no MetS components, those with CAP ≥ 238 dB/m had higher BMI, waist circumferences, uric acid, triglyceride, white blood cell count, and insulin resistance, whereas lower adiponectin and estimated glomerular filtration rate. Waist circumference [OR 1.11 (1.04, 1.18), p = 0.001] and homeostatic model assessment of insulin resistance (HOMA-IR) [OR 2.39 (1.18, 4.83), p = 0.016] were predictive of hepatic steatosis according to CAP ≥ 238 dB/m.ConclusionsCAP is a convenient, sensitive, and non-invasive indicator for metabolic derangement. Prospective studies are needed to further validate its usefulness as a surrogate marker for the transition of metabolic status over time.

Over recent years, the link between obesity, metabolic syndrome and Hidradenitis suppurativa (HS) has been explored. It has been demonstrated that HS patients have a high prevalence of the metabolic syndrome and an increased frequency of insulin resistance. The objective of our study is to estimate the effectiveness of an oral supplementation based on myo-inositol (MI), folic acid and liposomal magnesium (Levigon®, Sanitpharma; Milan, Italy) on the clinical and metabolic profile of patients affected by HS. Twenty subjects with HS and an impaired glucose metabolism were enrolled. Group A: 10 subjects received for 6 months MI 2000 mg, liposomal magnesium and folic acid associated to topical antibiotic therapy (clindamycin gel 1%), systemic antibiotic therapy (clindamycin 300 mg b.i.d. and rifampicin 600 mg daily for 6 weeks) and a normocaloric diet group B: 10 subjects received topical and systemic antibiotic therapy associated to a normocaloric diet for 6 months. After 6 months group A patients showed an average reduction of Sartorius Score from 38.3±7.75 to 27.3±13.53 (P value <0.04) while in the control group there was a reduction of the Sartorius from 38.4±7.88 to 31.1±8.02 (P value =0.55). Moreover in group A Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was significantly reduced from 2.43±0.35 to 2.1±0.31 (P<0.01) whereas in group B HOMA-IR did not significantly decrease (2.51±0.65 at T0 at 2.40±0.67 at T1). Our study underlines the importance of the evaluation of metabolic profile in patients with HS. Moreover, it suggests that the supplementation of MI, folic acid and liposomal magnesium in HS can improve the efficacy of concomitant therapies and the metabolic profile.

Background:Previous evidence revealed an association between folate deficiency and non-alcoholic fatty liver disease (NAFLD). This study is the first one investigating the effects of folic acid on hepatic steatosis grade, liver enzymes, insulin resistance, and lipid profile in NAFLD cases.Materials and Methods:Sixty-six participants with NAFLD were allocated randomly to take either a placebo or one oral tablet of folic acid (1 mg) on a daily basis within eight weeks. Serum folate, homocysteine, glucose, aminotransferases, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and lipids were assessed. Ultrasonography was used for assessing the liver steatosis grade.Results:The serum alanine transaminase, grade of hepatic steatosis, and aspartate transaminase significantly were decreased within both study groups; however, the between-group comparison was not statistically significant. Of note, the decrease in ALT was more pronounced in folic acid compared with the placebo group (-5.45 ± 7.45 vs. -2.19 ± 8.6 IU/L). The serum homocysteine was decreased after receiving folic acid compared to the placebo (-0.58 ± 3.41 vs. +0.4 ± 3.56 μmol/L; adjusted P = 0.054). Other outcomes did not significantly change.Conclusion:Supplementation with folic acid (1 mg/d) for eight weeks among cases with NAFLD did not change significantly the serum levels of liver enzymes, the hepatic steatosis grade, insulin resistance and lipid profile. However, it was able to prevent the increase in homocysteine in comparison with the placebo. Conducting further research is suggested with the longer duration and different doses of folic acid, adjusted to the genotypes of methylenetetrahydrofolate reductase polymorphism, among NAFLD patients.

BackgroundThe prevalence of non-alcoholic fatty liver disease (NAFLD) keeps increasing annually worldwide. Non-invasive assessment tools for evaluating the risk and severity of the disease are still limited. Insulin resistance (IR) and abdominal obesity (ABO) are closely related to NAFLD.MethodsA retrospective large-scale, population-based study was conducted based on the data from the 2017–2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Three ABO indices, namely lipid accumulation product (LAP), visceral obesity index (VAI), waist circumference-triglyceride index (WTI), and three IR indices, including triglyceride glucose index (TyG), homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR), were analyzed and compared for their relationships with NAFLD based on weighted multivariable logistic regression, spearman correlation heatmap, smooth curve fittings. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these indices for NAFLD. Differences among the AUCs were calculated and compared by Delong test.ResultsIn total, 3095 participants were included in our study among which 1368 adults were diagnosed with NAFLD. All six indices presented positive associations with NAFLD. There was a claw-shaped curve between HOMA-IR, VAI, LAP and NAFLD while a smooth semi-bell curve was observed in TyG, METS-IR and WTI. LAP and HOMA-IR had the best diagnostic capability for NAFLD (LAP: AUC = 0.8, Youden index = 0.48; HOMA-IR: AUC = 0.798, Youden index = 0.472) while VAI (AUC = 0.728, Youden index = 0.361) showed the lowest predictive value. The correlation heat map indicated positive correlations between all six indices and liver function, hepatic steatosis and fibrosis severity. In the NAFLD group, IR indicators presented a stronger association with alanine aminotransferase (ALT) compared with ABO indices.ConclusionsAll six indices can screen NAFLD withLAP and HOMA-IR being possibly optimal predictors. IR indices may be more sensitive to identify acute hepatic injury in NAFLD patients than ABO indices.

Introduction: Severe obesity is often present with non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA). Emerging researches suggest OSA plays an important role in NAFLD development and progression while the relationship between OSA and NAFLD is still conflicting. The interaction of OSA and NAFLD should be further evaluated as obesity surges. The purpose of this study was to assess the prevalence of OSA and NAFLD in patients with obesity undergoing bariatric surgery and evaluate the association between OSA and severity of NAFLD. Methods: 141 patients with severe obesity undergoing preoperative polysomnography and intraoperative liver biopsy during bariatric surgery were investigated. Clinical, anthropometric variables, liver enzymes, fasting blood glucose, fasting serum insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The severity of NAFLD was assessed by degree of steatosis, ballooning, intralobular inflammation, and NAFLD activity score. The diagnosis and severity assessment of OSA was based on an apnea/hypopnea index (AHI). Results: OSA was diagnosed in 127 (90.07%), NAFLD in 124 (87.94%), and non-alcoholic steatohepatitis in 72 (51.06%) patients. There was a statistical difference in BMI, waist circumstance, neck circumstance, high-density lipoprotein cholesterol, fasting insulin, and HOMA-IR among the three groups divided by the severity of AHI. In addition, the distribution of hepatic steatosis grades among the three groups was statistically different (p = 0.025). AHI was significantly associated with HOMA-IR and hepatic steatosis when assessing the association between OSA parameters and liver histology in NAFLD (p < 0.05). Patients with steatosis of grades 1–3 had significantly elevated aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, triglycerides, fasting insulin, fasting glucose, HOMA-IR, and AHI compared with the patients with steatosis of grade 0. In a multivariable logistic analysis, the positive association between AHI and hepatic steatosis attenuated after adjusting for HOMA-IR. Conclusion: Prevalence of OSA and NAFLD was high in patients with obesity eligible for bariatric procedures. HOMA-IR, but not AHI, was an independent risk factor for hepatic steatosis in this population.

OBJECTIVEPrediabetes and type 2 diabetes mellitus (T2DM) are believed to be common and associated with a worse metabolic profile in patients with nonalcoholic fatty liver disease (NAFLD). However, no previous study has systematically screened this population.RESEARCH DESIGN AND METHODSWe studied the prevalence and the metabolic impact of prediabetes and T2DM in 118 patients with NAFLD. The control group comprised 20 subjects without NAFLD matched for age, sex, and adiposity. We measured 1) plasma glucose, insulin, and free fatty acid (FFA) concentration during an oral glucose tolerance test; 2) liver fat by magnetic resonance spectroscopy (MRS); 3) liver and muscle insulin sensitivity (euglycemic insulin clamp with 3-[3H]glucose); and 4) indexes of insulin resistance (IR) at the level of the liver (HIRi= endogenous glucose production × fasting plasma insulin [FPI]) and adipose tissue (Adipo-IRi= fasting FFA × FPI).RESULTSPrediabetes and T2DM was present in 85% versus 30% in controls (P < 0.0001), all unaware of having abnormal glucose metabolism. NAFLD patients were IR at the level of the adipose tissue, liver, and muscle (all P < 0.01–0.001). Muscle and liver insulin sensitivity were impaired in patients with NAFLD to a similar degree, whether they had prediabetes or T2DM. Only adipose tissue IR worsened in T2DM and correlated with the severity of muscle (r = 0.34; P < 0.001) and hepatic (r = 0.57; P < 0.0001) IR and steatosis by MRS (r = 0.35; P < 0.0001).CONCLUSIONSPatients with NAFLD may benefit from early screening for T2DM, because the prevalence of abnormal glucose metabolism is much higher than previously appreciated. Regardless of glucose tolerance status, severe IR is common. In patients with T2DM, adipose tissue IR appears to play a major role in the severity of NAFLD.

Association between remnant lipoprotein cholesterol levels and non-alcoholic fatty liver disease in adolescents

IntroductionTo evaluate the efficacy of empagliflozin compared to pioglitazone in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM).MethodsIn this prospective randomized, double-blind, placebo-controlled trial, we assigned 106 patients with NAFLD and T2DM to receive empagliflozin 10 mg (n = 35), pioglitazone 30 mg (n = 34), or placebo (n = 37) for 24 weeks. Liver fat content and liver stiffness were measured using fibroscans. Body composition assessment was performed by dual-energy x-ray absorptiometry (DEXA) scans. The primary end point was change from baseline in liver steatosis, using the controlled attenuation parameter (CAP) score.ResultsA borderline significant decrease in CAP score was observed with empagliflozin compared to placebo, mean difference: − 29.6 dB/m (− 39.5 to − 19.6) versus − 16.4 dB/m (− 25.0 to − 7.8), respectively; p = 0.05. Using multivariate analysis, we observed a significant reduction in the placebo-corrected change in liver stiffness measurement (LSM) with empagliflozin compared to pioglitazone: − 0.77 kPa (− 1.45, − 0.09), p = 0.02, versus 0.01 kPa (95% CI − 0.70, 0.71, p = 0.98), p for comparison = 0.03. Changes in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), fasting insulin, homeostatic model assessment for insulin resistance (HOMA-IR), HOMA2-IR, fibrosis-4 index (FIB4 index), NAFLD fibrosis score, aspartate aminotransferase to platelet ratio index (APRI), android/gynecoid ratio (A/G ratio), and skeletal muscle index (SMI) were comparable between the two treatment groups, while significant reductions of the body weight and visceral fat area were observed only in the empagliflozin group (p < 0.001 and p = 0.01, respectively) and both were increased in the placebo and pioglitazone groups. There were no serious adverse events in either group.ConclusionTreatment for 24 weeks with empagliflozin, in contrast to pioglitazone, was associated with improvement of liver steatosis and fibrosis in patients with NAFLD and T2DM. In addition, body weight and abdominal fat area were decreased in the empagliflozin group.Trial RegistrationIranian Registry of Clinical Trials (IRCT), IRCT20190122042450N3.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01011-3.

Obesity and dyslipidaemia are the major risk factors for non-alcoholic fatty liver disease (NAFLD), and are known to increase cardiovascular disease (CVD), which is the leading cause of death in NAFLD patients. The present cross-sectional study aimed to investigate associations among severity of hepatic steatosis, NAFLD fibrosis score and atherogenic lipid profile. A total of 265 patients with NAFLD confirmed by ultrasonographic findings were included. The NAFLD fibrosis score and the fibrosis-4 (FIB-4) index were used to classify the probability of fibrosis as low, intermediate and high probability. Serum lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured, and then TC/HDL-C, LDL-C/HDL-C, TG/HDL-C and non HDL-C/HDL-C ratios were determined. Fasting blood sugar (FBS), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also assessed. The homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. The severity of hepatic steatosis was positively correlated with TC/HDL-C (r=0.29, P=.002), LDL-C/HDL-C (r=0.32, P<.001), TG/HDL-C (r=0.36, P<.001) and non-HDL-C/HDL-C (r=0.24, P=.001) ratios. Similarly, these parameters were positively correlated with NAFLD fibrosis score and FIB-4 index (P<.05). In addition, alanine aminotransferase and aspartate aminotransferase levels were positively correlated with TG/HDL-C ratio (r=0.31, P=.003; and r=0.27, P=.001 respectively). With increasing the severity of hepatic steatosis and NAFLD fibrosis score, the mean of all lipid ratios increased significantly (P<.01 and P<.05, respectively). Importantly, after controlling for potential confounders including age, gender, physical activity level, body mass index, waist circumference and HOMA-IR, the severity of steatosis, NAFLD fibrosis score and FIB-4 index remained independent predictors of atherogenic lipid profile. Severity of hepatic steatosis, NAFLD fibrosis score and FIB-4 index were significantly correlated with atherogenic lipid profile. As NAFLD is high among patients with metabolic risk factors for CVD, their dyslipidaemia should be aggressively managed.