Efficacy of Intragastric Balloons in the Markers of Metabolic Dysfunction-associated Fatty Liver Disease: Results from Meta-analyses

Background and AimsNonalcoholic fatty liver disease, now renamed metabolic dysfunction-associated fatty liver disease (MAFLD), is common in obese patients. Intragastric balloon (IGB), an obesity management tool with low complication risk, might be used in MAFLD treatment but there is still unexplained heterogeneity in results across studies.MethodsWe conducted a systematic search of 152 citations published up to September 2020. Meta-analyses, stratified analyses, and meta-regression were performed to evaluate the efficacy of IGB on homeostasis model assessment of insulin resistance (HOMA-IR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT), and to identify patients most appropriate for IGB therapy.ResultsThirteen observational studies and one randomized controlled trial met the inclusion criteria (624 participants in total). In the overall estimate, IGB therapy significantly improved the serum markers change from baseline to follow-up [HOMA-IR: 1.56, 95% confidence interval (CI)=1.16–1.95; ALT: 11.53 U/L, 95% CI=7.10–15.96; AST: 6.79 U/L, 95% CI=1.69–11.90; GGT: 10.54 U/L, 95% CI=6.32–14.75]. In the stratified analysis, there were trends among participants with advanced age having less change in HOMA-IR (1.07 vs. 1.82). The improvement of insulin resistance and liver biochemistries with swallowable IGB therapy was no worse than that with endoscopic IGB. Multivariate meta-regression analyses showed that greater HOMA-IR loss was predicted by younger age (p=0.0107). Furthermore, effectiveness on ALT and GGT was predicted by basal ALT (p=0.0004) and GGT (p=0.0026), respectively.ConclusionsIGB is effective among the serum markers of MAFLD. Younger patients had a greater decrease of HOMA-IR after IGB therapy.     

Predictors of fibrosis in Asian patients with non-alcoholic steatohepatitis

Background and Aim: Non‐alcoholic steatohepatitis (NASH) is increasingly recognized as an important cause of chronic liver disease. However, data on Asians with NASH is lacking in the literature. The aim of the present study was to describe the clinical, biochemical and histological characteristics of NASH in Asians and to determine the predictors for septal fibrosis. Method: Sixty consecutive patients aged over 18 years with elevated serum alanine transferase, sonographic evidence of steatosis, and consent for liver biopsy were included. Patients with chronic hepatitis B or C, alcoholic, autoimmune, genetic, or drug‐induced liver disease were excluded. Clinical, biochemical and histological variables were tested for association with septal liver fibrosis (F2/3). Results: Median age of the cohort was 45.5 years (range 21–75 years) and 63% were male. Ninety percent of patients were obese (body mass index [BMI]≥ 25), 70% had hypertriglyceridemia, 68% had hypercholesterolemia, 58% had metabolic syndrome, 53% had hypertension, 47% had diabetes mellitus (DM), and 18% had obstructive sleep apnea. Sixty‐eight percent had gamma‐glutamyl transferase (GGT) ≥ 2 × upper limit of normal (ULN), 55% had alanine aminotransferase (ALT) ≥ 2 × ULN, and 23% had aspartate aminotransferase (AST) ≥ 2 × ULN. Of the 40 non‐diabetic patients undergoing oral glucose tolerance testing, 45% had normal tests, 30% had impaired glucose tolerance, 23% DM, and 2% impaired fasting glucose. Eighteen patients (30%) had septal fibrosis (F2/3), but none had cirrhosis. Necroinflammatory grade ≥ 2 (odds ratio [OR] 13), AST ≥ 2 × ULN (OR 5.3) and DM (OR 5) were significantly and independently correlated with septal fibrosis. Conclusion: Septal fibrosis is common in Asians with NASH. Necroinflammatory grade ≥ 2, AST ≥ 2 × ULN and DM are independent predictors for septal fibrosis.     

Histological Characteristics of Non-alcoholic Steatohepatitis in NAFLD Patients With Low Degree of Hepatocyte Apoptosis

Background: Caspase-cleaved K18 (cK18) may accurately reflect hepatocyte apoptosis in patients with non-alcoholic steatohepatitis (NASH). However, NASH can also exist within the normal range of cK18. The aim of this study was to investigate the risk factors and characteristics of NASH within the normal serum levels of cK18.Methods: In the study, 227 histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) patients with normal cK18 levels (≤200 U/L), measured in serum using ELISA kits, were enrolled. The Rs738409 allele, coding patatin-like phospholipase domain-containing protein 3 (PNPLA3), was detected by MALDI-TOF mass spectrometry. Non-alcoholic steatohepatitis was defined as an NAFLD activity score (NAS) ≥5 with each part >0.Results: The prevalence of NASH was 31.7% among NAFLD patients with normal serum cK18 levels. Compared with non-NASH, NASH had a higher possibility of occurrence with central obesity, insulin resistance, and the G allele of PNPLA3. The mean serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were higher in NASH patients. Moreover, ALT, AST, TC, LDL-C, central obesity, and the PNPLA3 G allele were risk factors for NASH in NAFLD patients with normal serum cK18 levels, with odds ratios of 1.01 (95% CI: 1.00, 1.02), 1.03 (95% CI: 1.01, 1.05), 1.33 (95% CI: 1.04, 1.68), 1.41 (95% CI: 1.03, 1.92), 2.19 (95% CI: 1.15, 4.18), and 2.48 (95% CI: 1.15, 5.36), respectively; all P < .05.Conclusions: The major risk factors for NASH were central obesity, AST, and the PNPLA3 G allele, in NAFLD with low hepatocyte apoptosis.     

2型糖尿病合并代谢相关性脂肪性肝病患者血尿酸水平变化和其临床意义探讨*

目的 研究血尿酸(UA)对新诊断的2型糖尿病(T2DM)患者合并代谢相关性脂肪性肝病(MAFLD)的预测价值。方法 2012年1月～2019年12月我院内分泌代谢科病房收治的新诊断的T2DM患者514例,其中非MAFLD组167例,合并MAFLD组347例(67.5%)。收集一般临床资料,行Logistic回归分析引起MAFLD的危险因素,建立受试者工作特征曲线(ROC)评估UA对于T2DM患者合并MAFLD的诊断价值。结果 本组T2DM人群高尿酸血症(HUA)发生率为8.2%;MAFLD组HUA发生率为10.7%,显著高于非MAFLD组的4.2%(P＜0.05),血脂异常发生率为55.6%,显著高于非MAFLD组的41.3%(P＜0.05),肝功能异常发生率为45.2%,显著高于非MAFLD组的31.7%(P＜0.05);MAFLD组体质指数(BMI)为(25.9±3.8)kg/m²,显著高于非MAFLD组【(23.9±3.1)kg/m²,P＜0.05】,血清谷丙转氨酶、谷草转氨酶、谷氨酰转肽酶分别为29(19,43)U/L、18(13,25)U/L、39(25,64)U/L,显著高于非MAFLD组【分别为21(15,32)U/L、15(12,20)U/L、31(20,51)U/L,P＜0.05】,血清UA、空腹C肽、胰岛素抵抗指数分别为(294.3±91.3)μmol/L、(1.9±1.0)ng/ml、3.6(2.9,4.4),显著高于非MAFLD组【分别为(254.9±79.2)μmol/L、(1.6±0.8)ng/ml、3.2(2.7,4.0),P＜0.05】,总胆固醇、甘油三酯、高密度脂蛋白胆固醇分别为(5.0±1.2)mmol/L、2.3(1.7,3.5)mmol/L、(1.0±0.2)mmol/L,与非MAFLD组差异显著【分别为(4.7±1.2)mmol/L、1.8(1.4±2.9)mmol/L、(1.1±0.4)mmol/L,P＜0.05】;Logistic回归分析显示UA(OR=1.004,95%CI:1.001～1.006,P＝0.005)为罹患MAFLD的独立危险因素;ROC曲线分析显示UA预测T2DM患者发生MAFLD的曲线下面积为0.634。当以UA=267.35μmol/L为截断点,其诊断MAFLD的灵敏度为56.8%,特异度为66.5%。结论 在新诊断的T2DM合并MAFLD患者中,容易发生血脂异常、HUA、肝功能损害,UA是新诊断的T2DM患者罹患MAFLD的独立危险因素,提示为防治MAFLD,除了关注肥胖和血脂异常外,同样需要监测和控制血清UA水平。     

Liver function tests and metabolic-associated fatty liver disease: Changes in upper normal limits,does it really matter?

BACKGROUNDMetabolic-associated fatty liver disease (MAFLD) is the commonest cause of abnormal liver function tests (LFTs). Current upper normal of limit (UNL) of LFTs was derived from a “healthy” population, where undiagnosed MAFLD and viral hepatitis might be suspected. AIMTo evaluated potential implications of changes in UNL of alanine aminotransferase (ALT) in MAFLD.METHODSWe retrospectively assessed consecutive first referrals with a diagnosis of MAFLD from 2010 to 2017. The conventional UNL of ALT was 45 IU/L for men and 34 IU/L for women, while a low UNL of ALT was 30 IU/L for men and 19 IU/L for women. The UNL of aspartate aminotransferase (AST) was 40 IU/L.RESULTSTotal 436 patients were enrolled; of these, 288 underwent liver biopsy. Setting a lower UNL reduced the percentage of those with significant disease despite normal ALT; specifically, patients with advanced fibrosis (F ≥ F3) or definite “metabolic-associated steato-hepatitis (MASH)” (NAS ≥ 5) within normal ALT decreased from 10% to 1% and from 28% to 4% respectively. However, the proportion of those with elevated ALT and no evidence of advanced fibrosis or “definite MASH” increased from 39% to 47% and from 3% to 19%. Overall, LFTs performed poorly in distinguishing “definite MASH” from simple steatosis (receiver operating characteristic areas under the curves 0.59 for ALT and 0.55 for AST).CONCLUSIONLiver function tests might both under- and overestimate MASH-related liver disease. Reducing the UNL might not be beneficial and imply an increase in healthcare burden. Risk stratification in MAFLD should rely on a combination of risk factors, not on LFTs alone.     

Association Between Neutrophil-to-Lymphocyte Ratio with Inflammatory Activity and Fibrosis in Non-alcoholic Fatty Liver Disease

BackgroundInflammation plays an important role in the development and progression of non-alcoholic steatohepatitis (NASH), and NASH is a powerful driving force for the progression of fibrosis. The neutrophil-to-lymphocyte ratio (NLR) is a simple emerging indicator of inflammation. We aimed to assess the potential association between NLR and histological severity of non-alcoholic fatty liver disease (NAFLD).MethodsThis retrospective study consisted of 231 patients with biopsy-proven NAFLD in China from August 2017 to September 2019. The steatosis, activity, and fibrosis scoring system were used to evaluate liver biopsy tissue.ResultsOf the 231 patients with NAFLD, advanced inflammatory activity was present in 43.3% and significant fibrosis in 25.5% of patients. Multivariate logistic regression analysis showed NLR to be correlated with advanced inflammatory activity (Odds ratio (OR): 0.62, 95% CI: 0.42-0.94, P = .025) and significant fibrosis (OR: 0.57, 95% CI: 0.35-0.94, P = .028). The NLR was inversely associated with the degree of steatosis, lobular inflammation and fibrosis (r = −0.16, P = .014; r = −0.15, P = .019; r = −0.13, P = .046, respectively), but had no association with the severity of ballooning. The multivariate-adjusted models had good predictability for advanced inflammatory activity (area under curves (AUC) 0.790, 95% CI: 0.730-0.850) and for significant fibrosis (AUC 0.798, 95% CI: 0.728-0.868).ConclusionThis study showed negative correlations between elevated NLR levels with advanced inflammatory activity and significant fibrosis in patients with NAFLD. Our results also suggested that NLR could be considered as a simple and noninvasive mark to identify high-risk populations in NAFLD.     

Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis

BACKGROUND AND AIM: Inhibition of tumor necrosis factor (TNF)-alpha is a logical approach to manage patients with non-alcoholic steatohepatitis (NASH). Pentoxifylline reduces TNF-alpha and alanine aminotransferase (ALT) levels in patients with NASH. The aim of the present paper was to study if pentoxifylline can improve histological injury in patients with NASH. METHODS: Nine patients (mean age 31.6 +/- 7.2 years) with histologically proven NASH and with persistently elevated ALT (>1.5 times) were given pentoxyfylline at a dosage of 400 mg t.i.d. for 12 months. Besides biochemical assessment, a repeat liver biopsy was performed and the degree of inflammation and fibrosis was compared. RESULTS: After 12 months of therapy a significant reduction in ALT (111 +/- 53 IU/L vs 45 +/- 19 IU/L, P = 0.003) and aspartate aminotransferase (AST) (61 +/- 27 IU/L vs 33 +/- 12 IU/L, P = 0.005) levels was observed. Steatosis and lobular inflammation each reduced in 55% and six (67%) patients down-staged on Brunt's staging (P = 0.009). Four out of six patients with baseline fibrosis had reduction in their fibrosis stage. CONCLUSIONS: Long-term pentoxyfylline therapy effectively achieves sustained biochemical improvement. This correlates well with histological resolution of the disease.     

Efficacy and safety of pemafibrate in patients with hypertriglyceridemia in clinical settings: A retrospective study

Background and aimsRecently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings.Methods and resultsWe evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved.ConclusionIn this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis.     

Attitudes of Elderly Patients to Examinations and Treatments of Gastrointestinal Symptoms

Abstract

Objective. We sought to investigate whether serum proteomic pattern analysis obtained using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI TOF-MS) may help to diagnose non-alcoholic steatohepatitis (NASH) in the setting of non-alcoholic fatty liver disease (NAFLD). Material and methods. We enrolled 80 patients with biopsy-proven NAFLD and 19 healthy comparison subjects. Patients with NAFLD were classified according to their liver histology as having definite NASH (n = 48), borderline NASH (n = 22) or simple steatosis (n = 10). Liver ultrasound scanning was performed to assess the degree of steatosis. Mass spectra of serum samples were obtained using a Ultraflex II mass spectrometer. Results. The highest accuracy for NASH diagnostics was reached using 15 peaks. Corresponding sensitivity and specificity values were 73.95% ± 3.38% and 88.71% ± 1.39%, respectively. However, mass spectra did not allow us to distinguish NASH from simple steatosis. Conclusions. We conclude that proteomic analyses of serum samples from NAFLD patients by MALDI TOF-MS do not seem to have a major clinical value for diagnosing NASH. However, the identification of 15 peaks in our study may help to further elucidate the pathophysiology of NASH and merits further investigation.     

代谢相关性脂肪性肝病患者血脂分析*

目的 分析代谢相关性脂肪性肝病(MAFLD)患者血脂状况,观察应用血脂判断MAFLD程度的效能。方法 2021年1月～10月于辽宁中医药大学附属医院体检中心体检发现的MAFLD患者2210例,其中血脂正常组418例,血脂异常组1792例。建立受试者工作特征曲线(ROC),计算曲线下面积(AUC),评估血脂预测MAFLD脂肪变程度的效能。结果 血脂异常组体质指数为(32.8±10.8 )kg/m²,显著大于血脂正常组【(28.4±11.2) kg/m²,P＜0.05】,收缩压为(146.2±21.2 )mmHg,显著高于血脂正常组【(106.3±7.3 )mmHg,P＜0.05】,舒张压为(107.3±11.6 )mmHg,显著高于血脂正常组【(88.6±5.2)mmHg,P＜0.05】,血糖为(6.4±1.9)mmol/L,显著高于血脂正常组【(6.0±1.5)mmol/L,P＜0.05】,血清ALT和GGT水平分别为(42.2±23.8)U/L和(42.5±30.9 )U/L,均显著高于血脂正常组【分别为(38.3±13.7) U/L和(39.3±18.3 )U/L,P＜0.05】;血脂异常组轻度、中度和重度MAFLD患者血清TG、TC和LDL-C水平均显著高于血脂正常组,而血清HDL-C水平显著低于血脂正常组(P＜0.05);以HDL-C=0.84mmol/L为截断点,其AUC为0.72(P＜0.001),诊断轻度MAFLD的灵敏度为84.8%,特异度为52.8%;以TG=2.71mmol/L为截断点,其AUC为0.79(P＜0.001),诊断中度MAFLD的灵敏度为75.7%,特异度为74.4%;以TG=3.35mmol/L为截断点,其AUC为0.86(P＜0.001),诊断重度MAFLD的灵敏度为90.4%,特异度为73.9%。结论 MAFLD患者病程进展与血脂状况息息相关,并且对血糖和血压等也有较大的影响。综合肝脏超声和血生化检查,MAFLD合并血脂异常患者较血脂正常者病情更为严重。积极进行临床干预,阻断病情发展,将使患者获益。     

应用MRI多回波水脂分离技术评估代谢相关性脂肪性肝病患者肝脏脂肪含量的临床意义

目的 探讨运用MRI多回波水脂分离技术评估代谢相关性脂肪性肝病(MAFLD)患者肝脏脂肪含量的效能。方法 2018年6月～2019年10月我院收治的MAFLD患者97例和同期健康体检者46例,接受MR检查,应用MRI多回波水脂分离技术检测肝脂肪分数(FF),对MAFLD患者常规行肝穿刺活检,应用受试者工作特征曲线(ROC)分析FF诊断肝脏脂肪变性程度的效能。结果 MAFLD组BMI、ALT、AST、TG、TC和FF分别为(26.3±3.1)kg/m²、(85.6±5.4)U/L、(76.5±4.9)U/L、(3.2±1.0)mmol/L、(7.4±1.2)mmol/L和(23.7±5.3)%,显著高于健康人【分别为(23.2±2.2) kg/m²、(28.3±3.5) U/L、(26.5±4.1)U/L、(1.5±0.4)mmol/L、(3.9±0.8)mmol/L和(10.3±3.9)%,P<0.05】;28例中度组和18例重度组FF分别为(25.3±5.5)%和(44.7±6.7)%,与51例轻度组比,差异显著【(15.5±4.0)%,P<0.05】;以FF分别等于16.4%、26.4%和44.6%为截断点,其诊断轻度、中度和重度肝脏脂肪变性的ROC曲线下面积(AUC)分别为0.728(95%CI:0.628～0.829)、0.870(95%CI:0.784～0.957)和0.996(95%CI:0.985～1.000)。结论 MRI多回波水脂分离技术对诊断和区分MAFLD患者肝脏脂肪变性严重程度具有较高的效能。     

Clinical and Histologic Features of Patients with Biopsy-Proven Metabolic Dysfunction-Associated Fatty Liver Disease

Background/AimsFatty liver disease is defined as a cluster of diseases with heterogeneous etiologies, and its definition continues to evolve. The novel conceptional criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) were proposed in 2020 to avoid the exclusion of a certain subpopulation, but their evaluations have been limited. We aimed to examine and compare the clinical as well as histologic features of MAFLD versus nonalcoholic fatty liver disease (NAFLD) in patients with biopsy-proven hepatic steatosis.MethodsFrom January 2009 to December 2019, 175 patients with histology-proven hepatic steatosis and 10 with cryptogenic cirrhosis who were treated at National Taiwan University Hospital, Taipei, Taiwan, were enrolled. Patients were classified into different groups according to the diagnostic criteria of MAFLD and NAFLD. The clinical and histologic features were then analyzed and compared.ResultsIn total, 76 patients (41.1%) were diagnosed with both MAFLD and NAFLD, 81 patients (43.8%) were diagnosed with MAFLD alone, nine patients (4.9%) were diagnosed with NAFLD alone, and 19 patients (10.3%) were diagnosed with neither. Those with MAFLD alone exhibited a higher degree of disease severity regarding histology and laboratory data than those with NAFLD alone. Advanced fibrosis was associated with the presences of hepatitis B virus infection and metabolic diseases.ConclusionsThe novel diagnostic criteria for MAFLD include an additional 38.9% of patients with hepatic steatosis and can better help identify those with a high degree of disease severity for early intervention than can the previous NAFLD criteria. (Gut Liver 2021;15-458)     

Non-alcoholic steatohepatitis in liver transplant recipients diagnosed by serum cytokeratin 18 and transient elastography: A prospective study

BACKGROUNDNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) seem common after liver transplantation.AIMTo investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients, namely controlled attenuation parameter (CAP) and the serum biomarker cytokeratin 18 (CK-18). We also evaluated the diagnostic accuracy of CK-18 and CAP compared to liver histology.METHODSWe prospectively recruited consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018. Serial measurements of CK-18 and CAP were recorded. NAFLD and NASH were diagnosed by CAP ≥ 270 dB/m, and a combination of CAP ≥ 270 dB/m with CK-18 > 130.5 U/L, respectively. Incidences and predictors of NAFLD and NASH were investigated using survival analysis and Cox proportional hazards.RESULTSOverall, 40 liver transplant recipients (mean age 57 years; 70% males) were included. During a median follow-up of 16.8 mo (interquartile range 15.6-18.0), 63.0% and 48.5% of patients developed NAFLD and NASH, respectively. On multivariable analysis, after adjusting for sex and alanine aminotransferase, body mass index was an independent predictor of development of NAFLD [adjusted hazard ratio (aHR): 1.21, 95% confidence interval (CI): 1.04-1.41; P = 0.01] and NASH (aHR: 1.26, 95%CI: 1.06-1.49; P < 0.01). Compared to liver histology, CAP had a 76% accuracy to diagnose NAFLD, while the accuracy of CAP plus CK-18 to diagnose NASH was 82%.CONCLUSIONNAFLD and NASH diagnosed non-invasively are frequent in liver transplant recipients within the first 18 mo. Close follow-up and nutritional counselling should be planned in overweight patients.     

Low levels of Lysosomal Acid Lipase (LAL) activity increases necroinflammation in adult patients with biopsy-proven metabolic associated fatty liver disease

Introduction and objectiveMetabolic associated fatty liver disease (MAFLD), characterized by intra-hepatic fat accumulation, will soon be the leading cause of end-stage liver disease. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with biopsy-proven MAFLD.MethodsProspective cross-sectional study in patients with biopsy-proven MAFLD. Blood LAL-activity (pmol/punch/h) was measured with dried blood spot extracts using Lalistat 2. Demographic, clinical, and laboratory data were collected.Results101 adult patients were recruited. Among them, 11.9% had a diagnosis of MAFLD without steatohepatitis and 88.1% had MAFLD with steatohepatitis. The median of LAL-activity in patients with MAFLD was 76.8 pmol/punch/h. MAFLD patients with steatohepatitis showed an increase in gamma-glutamyl transferase (p = 0.042), insulin (p = 0.001), homeostatic model assessment for insulin resistance (HOMA-IR, p = 0.001) and advanced liver fibrosis (p < 0.001), compared to cases of MAFLD without steatohepatitis. There was no statistical difference in LAL-activity between the cases (p = 0.296). When considering LAL-activity above and below 77 pmol/punch/h as a cut-off value, patients with reduced LAL-activity had a significant increase in necroinflammatory activity according to the METAVIR score (p = 0.040), and NAFLD activity score (NAS, p = 0.031) compared to cases with higher LAL-activity.ConclusionOur findings suggest that reduced LAL-activity is associated with increased necroinflammatory activity and severity of the NAS. A better knowledge of the role of LAL may provide new insights into the pathogenesis and progression of MAFLD.     

Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

AIM To assess lactase gene(LCT)-13910CT polymorphisms in Brazilian non-alcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH) patients in comparison with healthy controls.METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, S?o Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence(LCT-13910CT) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients(steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed.RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients(66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls(59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism(LCT-13910CT) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase nonpersistence(low lactase activity or hypolactasia) phenotype was associated with higher insulin levels(23.47 ± 15.94 μU/m L vs 15.8 ± 8.33 μU/m L, P = 0.027) and a higher frequency of insulin resistance(91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes(P = 0.651), dyslipidaemia(P = 0.328), hypertension(P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0(95%CI: 1.35-20; P = 0.017)].CONCLUSION The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.     

The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease

OBJECTIVE: The ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is often greater than 2:1 in alcoholic hepatitis. The purpose of this study was to determine whether this ratio may be used to distinguish nonalcoholic steatohepatitis (NASH) from alcoholic liver disease. METHODS: Patients with NASH were matched with controls with alcoholic liver disease based on age, gender, and date of diagnosis. The diagnosis of alcoholic liver disease was based on exclusion of other causes and a significant history of alcohol consumption. The diagnosis of nonalcoholic steatohepatitis was based on exclusion of other causes of liver disease and a liver biopsy showing > 10% steatosis and inflammation. The two sided Student t test was used for statistical analysis. RESULTS: From 1990 to 1996, 70 patients with NASH were matched with 70 subjects with alcoholic liver disease. Patients with NASH had a mean AST to ALT ratio of 0.9 (range 0.3-2.8, median 0.7) and subjects with alcoholic liver disease a mean ratio of 2.6 (range 1.1-11.2, median 2.0). The mean AST levels were 66 U/L and 152 U/L, and the mean ALT levels 91 U/L and 70 U/L, in the nonalcoholic steatohepatitis and alcoholic liver disease groups, respectively. Although the absolute aminotransferase levels were significantly different in the two groups (p < 0.05), the greatest difference was observed in the AST to ALT ratio (p < 0.000001). Subset analysis of patients with NASH revealed mean AST to ALT ratios of 0.7, 0.9, and 1.4 for subjects with no fibrosis, mild fibrosis, or cirrhosis, respectively. The differences among these ratios were statistically significant (p < 0.05). CONCLUSIONS: The AST to ALT ratio appears to be a useful index for distinguishing nonalcoholic steatohepatitis from alcoholic liver disease. Although values < 1 suggest NASH, a ratio of > or = 2 is strongly suggestive of alcoholic liver disease.     

Dipeptidyl peptidase IV (DDP IV) in NASH patients

Objective(s): Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with unknown etiology. The insulin resistance, immune mechanisms and oxidative stress are the main factors in its pathogenesis. Dipeptidyl peptidase IV (DPPIV) or CD26 is a protein with endocrine and immune functions. This study aimed to elicudate the changes related to DPPIV in NASH patients. Methods: Serum and urinary DPPIV activities were measured in 31 NASH patients and 17 healthy controls. The liver biopsies of 29 patients were immunolabeled for CD26. Results: The mean age of patients were 46 ± 11 years and 14 (45%) of them were female. The serum DPPIV activity was higher in patients (57.3 ± 7.8 U/L) than controls (43.6 ± 10.6 U/L) (p < 0.0001), and correlated with the histopathological grade (p = 0.038, r = 0.373) and hepatosteatosis (p = 0.018, r = 0.423) but not with stage (p = 0.286), class (p = 0.286) or CD26 staining (p = 0.743). The urinary DPPIV activity was similar in patients (1.52 ± 0.94 U/mmol creatinine) and controls (1.37 ± 0.68 U/mmol creatinine) (p = 0.861). Three acinar zones of liver had equal CD26 expression (p = 0.076). The intensity of CD26 immunostaining was correlated with histopathological grade (p = 0.001) and hepatosteatosis (p = 0.003) but no correlation with stage or class could be detected (p = 0.610 and 0.956, respectively). In Conclusions: The serum DPPIV activity and the staining intensity of CD26 in liver are correlated with histopathologic grade of NASH and hepatosteatosis. DPPIV can be proposed as a novel candidate with several potential functions in NASH pathogenesis.     

Influence of age and gender in Japanese patients with non-alcoholic steatohepatitis

Aim: Nonalcoholic steatohepatitis (NASH) is considered to be a manifestation of metabolic syndrome. Because prevalence and severity of metabolic syndrome are different according to ages, gender and ethnic group, it is speculated that the clinicopathological features of NASH may also vary in relation to these factors. The present study was performed to clarify the influence of age and gender on the development of Japanese NASH. Subjects: One hundred 93 biopsy-proven NASH patients (86 women and 107 men) were included in this cross-sectional study. The patients were separately analyzed by generation; a younger group (<55 years old) and an older group (>/=55 years old). These groups were compared for their clinical and histological features. Independent risk factors for advanced fibrosis were also analyzed. Results: Comparison of our younger and older groups showed that older patients had much more advanced fibrosis than the younger ones (advanced fibrosis: 23.8%; youngergroup vs. 54.3%; older group, P < 0.001). Women were predominant in the older group (23.8%; younger group vs. 67.4%; older group, P < 0.001). According to the multivariate analysis for risk factors for advanced fibrosis, age (P = 0.007) and BMI (P = 0.028) were independent predictors of advanced fibrosis in the younger group. In contrast, the absence of hyperlipidemia (P = 0.042) was the only significant independent predictor of advanced fibrosis in the older group. Gender was not a risk factor for the severity of NASH. Conclusions: Clinicians need to be aware of age- and gender-specific differences when assessing the characteristics of NASH, and the findings may be useful for prevention and treatment of this disease.     

Leptin in nonalcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition associated with obesity and insulin resistance (IR). Leptin plays a key role in the control of energy balance, and insulin sensitivity. In this study, we aimed to examine whether serum leptin levels correlate with insulin resistance, oxidative stress parameters and the severity of histological changes in NAFLD. Methods: Fifty-two patients (M/F: 28/24) with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied. Serum leptin levels were measured by radioimmunoassay. HOMA (homeostasis model assessment) IR index was calculated. Comparisons between the patients with NAFLD and non-alcoholic steatohepatitis (NASH) were performed using the Student’s t test. Multivariate regression analysis and the area under the receiver operating characteristic (ROC) curve were used to identify the independent predictors for NASH. Results: We found no association between serum leptin, fasting insulin levels, and oxidative stress parameters. ROC curve and multiple regression analysis revealed no association between the severity of histological changes and serum leptin levels. During six months followed-up period only NASH group with elevated leptin levels had significant reductions of ALT and AST values (p = 0.03, and 0.005, respectively). Conclusion: Our findings show a preventive effect of leptin against progressive liver injury in NAFLD.     

Individualized treatment options for patients with non-cirrhotic and cirrhotic liver disease

The obesity pandemic has led to a significant increase in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). While dyslipidemia, type 2 diabetes mellitus and cardiovascular diseases guide treatment in patients without signs of liver fibrosis, liver related morbidity and mortality becomes relevant for MAFLD’s progressive form, non-alcoholic steatohepatitis (NASH), and upon development of liver fibrosis. Statins should be prescribed in patients without significant fibrosis despite concomitant liver diseases but are underutilized in the real-world setting. Bariatric surgery, especially Y-Roux bypass, has been proven to be superior to conservative and/or medical treatment for weight loss and resolution of obesity-associated diseases, but comes at a low but existent risk of surgical complications, reoperations and very rarely, paradoxical progression of NASH. Once end-stage liver disease develops, obese patients benefit from liver transplantation (LT), but may be at increased risk of perioperative infectious complications. After LT, metabolic comorbidities are commonly observed, irrespective of the underlying liver disease, but MAFLD/NASH patients are at even higher risk of disease recurrence. Few studies with low patient numbers evaluated if, and when, bariatric surgery may be an option to avoid disease recurrence but more high-quality studies are needed to establish clear recommendations. In this review, we summarize the most recent literature on treatment options for MAFLD and NASH and highlight important considerations to tailor therapy to individual patient’s needs in light of their risk profile.