Liver steatosis,but not fibrosis,is associated with insulin resistance in nonalcoholic fatty liver disease

Background To address the hypothesis that liver steatosis causes systemic insulin resistance, we sought to determine the liver histological feature that most strongly contributes to insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Methods Liver biopsy specimens were obtained from 131 patients with clinically suspected NAFLD. The stage, grade of nonalcoholic steatohepatitis (NASH), and level of steatosis were scored and analyzed in relation to the homeostasis model assessment of insulin resistance (HOMA-IR) and the metabolic clearance rate (MCR), measured using the glucose clamp method. Results In the univariate analysis, the degree of hepatic steatosis (r = 0.458, P < 0.001), stage (r = 0.360, P < 0.001), and grade (r = 0.349, P < 0.01) of NASH were significantly correlated with the HOMA-IR. Multiple regression analysis adjusting for age, sex, body mass index, and each histological score showed that steatosis was significantly and independently associated with HOMA-IR (coefficient = 1.42, P < 0.001), but not with the stage (coefficient = 0.33, P = 0.307) or grade (coefficient = 0.67, P = 0.134) of NASH. Similar independent relationships were observed between steatosis and MCR, but the relationship was weaker (coefficient = −0.98, P = 0.076). Conclusions Steatosis of the liver, but not the stage or the grade of NASH, is associated with insulin resistance in patients with NAFLD.     

Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD)

BACKGROUND: Liver fibrosis is the main predictor of the progression of nonalcoholic fatty liver disease. Transient elastography (FibroScan), which measures liver stiffness, is a novel, noninvasive method to assess liver fibrosis. AIM: We investigated the usefulness of liver stiffness measurement in the evaluation of liver fibrosis in nonalcoholic fatty liver disease patients. STUDY POPULATION: A total of 97 nonalcoholic fatty liver disease patients. METHODS: Transient elastography was performed for liver stiffness measurement in 97 nonalcoholic fatty liver disease patients. And the relationship between histological parameters and liver stiffness measurement was studied by multivariate analysis. Moreover, we investigated the relationship between liver stiffness measurement and the serum levels of hyaluronic acid and type IV collagen 7s domain. RESULTS: The liver stiffness was well correlated with the stage of liver fibrosis (Kruskal-Wallis test p < 0.0001). The areas under the receiver-operating characteristic curves were 0.927 for > or = F1, 0.865 for > or = F2, 0.904 for > or = F3, 0.991 for > or = F4. Only fibrosis stage was correlated significantly with liver stiffness measurement by multiple regression analysis. Liver stiffness was also strongly correlated with the serum levels of type IV collagen 7s domain (r = 0.525, p < 0.0001) and hyaluronic acid (r = 0.457, p < 0.0001). CONCLUSIONS: Our results show a significant correlation between liver stiffness measurement and fibrosis stage in nonalcoholic fatty liver disease patients, as confirmed by the results of liver biopsy, which remains the gold standard for evaluation of the severity of liver fibrosis in patients with nonalcoholic steatohepatitis.     

Biopsy rate and nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD)

Abstract

Background: Licensed therapies for nonalcoholic fatty liver disease (NAFLD) do not yet exist, but clinical trials are testing treatment options. Inclusion criteria often require liver biopsy showing fibrosis (F2/3) or cirrhosis (F4) and nonalcoholic steatohepatitis (NASH). However, histological criteria pose a serious obstacle for recruitment.

Aims: Characterize the relevance of liver biopsies in the selection of patients with NAFLD.

Methods: Patients between 2013 and 2018 with the ICD-10 code K76.0 were analyzed. Fibrosis was defined by the NASH clinical research network (CRN) fibrosis staging system, NASH by a NAFLD activity score (NAS) ≥4. Predictive factors were determined by logistic regression.

Results: Liver biopsy was performed in 87/638 (13.6%) patients (49% female, age 52.5?±?14.0, BMI 30.4?±?5.9?kg/m²). Fibrosis stage F0/F1/F2/F3/F4 was observed in N?=?7/47/7/17/9, an NAS ≥4 in N?=?27. Fibrosis stage F2/F3 and F4 along with NAS ≥4 was found in 1.7% and 0.5% of cases. Liver stiffness measurement, LSM (OR 2.3 per doubling of value; CI 1.3–4.4, p?=?.005) and FIB-4 (OR 2.3 per doubling of value; CI 1.2–4.4, p?=?.012) were significant predictors for fibrosis?≥?F2. Predictive factors for NASH were not identified.

Conclusion: The biopsy rate in NAFLD patients is low and fibrosis?≥?F2 along with NAS ≥4 only present in a few cases. Transient elastography and FIB-4 are useful to select patients at risk for fibrosis for liver biopsy.     

Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions

Background: Insulin resistance plays an important role in the pathogenesis of NAFLD. Pharmacological treatment of patients with NAFLD is still evolving. Insulin sensitizing drugs like metformin may be effective in these patients. Twenty five adult patients with NAFLD who did not achieve normalization of alanine transaminases (ALT) after 6 months of lifestyle interventions and UDCA were treated with metformin 500mg tid for 6 months. Insulin resistance was determined by HOMA-IR. Liver function tests were done monthly and patients were defined having no response, partial response or complete biochemical response depending on the change in ALT. Results were compared with 25 patients with NAFLD from the same cohort treated only with lifestyle interventions (disease controls). Results: Thirteen (52%) patients had class III (n = 5) or class IV (n = 8) disease amounting to histological NASH. Of these 13 patients none had severe inflammation and none had stage 4 fibrosis (cirrhosis). All 25 patients with NAFLD had insulin resistance in comparison to healthy controls. In comparison to disease controls (127.5 ± 41.8 vs. 118 ± 21.6 p = NS), all patients treated with metformin had partial biochemical response (mean ALT 122.2 ± 26.8 vs 74.3 ± 4.2 p < 0.01) and 14 (56%) of them achieved complete normalization of ALT. Conclusions: Metformin is effective to achieve biochemical response in patients with NAFLD who do not respond to lifestyle interventions and UDCA.     

Noninvasive monitoring of hepatic steatosis: controlled attenuation parameter and magnetic resonance imaging-proton density fat fraction in patients with nonalcoholic fatty liver disease

Introduction: With an increase in the worldwide prevalence of obesity, the incidence of non-alcoholic fatty liver disease (NAFLD) has been on the rise, such that it has been recently considered to be a major public health concern. Traditional interventions, such as lifestyle modifications, regular exercise, and healthy diet, have been significant in improving NAFLD with reduction of liver fat.

Areas covered: Although liver biopsy is still the gold standard for diagnosis of NAFLD, there is a need for non-invasive, quantitative assessments of hepatic steatosis, especially in clinical trials of anti-steatotic medications or in the follow-up of patients undergoing lifestyle modifications. Liver biopsy has various shortcomings, such as invasive nature, risk of complications and possibility of sampling error. Therefore, it is impractical to use liver biopsy routinely in patients with NAFLD, clearly indicating the need for non-invasive and accurate diagnostic methods. Recently, controlled attenuation parameter (CAP) and magnetic resonance imaging–proton density fat fraction (MRI–PDFF) have been employed in various studies to monitor the dynamic changes of hepatic steatosis in response to treatment in patients with NAFLD.

Expert commentary: Although further validations are required, CAP and MRI–PDFF could be used as potential diagnostic and monitoring tools in clinical setting.     

Oxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD)

BACKGROUND: One of the major pathogenic mechanisms for progression of nonalcoholic fatty liver disease (NAFLD) is oxidative stress. Recently, many studies have demonstrated the role of oxidative stress in NAFLD however, studies describing the antioxidant status in these patients are lacking. AIM: To study the levels of oxidative stress and antioxidant status among patients with NAFLD. PATIENTS AND METHODS: It was a prospective study in which 29 patients with NAFLD, 25 diseased controls with chronic viral hepatitis, and 23 healthy controls were enrolled. Apart from standard biochemical parameters, lipid peroxidation products were measured as thiobarbituric acid reactive substances. As measures of antioxidant capacity, superoxide dismutase, vitamin C levels and ferric reducing ability of plasma were measured. RESULTS: Level of thiobarbituric acid reactive substances was significantly higher among NAFLD patients as compared with diseased [4.7 nmol/mL (1.0 to 10.2) vs. 2.4 nmol/mL (0.8 to 10.7); P=0.02] or healthy controls [4.7 nmol/mL (1.0 to 10.2) vs. 1.8 nmol/mL (0.5 to 4.1); P=0.0001]. FRAP was found to be significantly higher in patients with NAFLD as compared with healthy controls [450.3 (197.6 to 733.3) vs. 340.8 (141.6 to 697.5) mumol Fe liberated; P=0.04], even though it was similar between NAFLD and diseased controls. Among NAFLD patients, there was no significant correlation between histological grading or staging and levels of pro and antioxidants. CONCLUSIONS: Products of lipid peroxidation are significantly increased among patients with NAFLD as compared with chronic viral hepatitis or healthy controls. Larger studies and newer markers of oxidative stress are required to clarify the association between oxidative stress and histological severity in NAFLD.     

影像学检查诊断非酒精性脂肪性肝病研究进展

随着健康管理的观念普及,精确地诊断和科学地管理非酒精性脂肪性肝病(NAFLD)患者变得越来越紧迫。影像学在NAFLD诊断中的作用越来越重要,深入研究影像学方法进行肝脏脂肪量化诊断对于NAFLD患者的预后和健康管理有着重大而深远的意义。     

Correlation of adipose tissue with liver histology in Asian Indian patients with nonalcoholic fatty liver disease (NAFLD)

Background. There is sparse literature on the association of adipose tissue with liver histology in patients with nonalcoholic fatty liver disease (NAFLD).Aim. To study the correlation of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and total adipose tissue (TAT) with liver histology in Indian patients with NAFLD.Material and methods. A single slice CT scan at the level of L4-L5 vertebrae was done to assess the abdominal VAT and SAT volumes in 21 patients with histological diagnosis of NAFLD. Adult treatment panel III criteria with modified abnormal waist were used to define metabolic syndrome (MS). Histological grading was done according to the NAFLD activity score (NAS).Results. Twenty-one patients with NAFLD [13 males, median age: 35 years, median BMI: 25.97 kg/m²] were included prospectively. Even though overweight/obese patients had severe liver disease, there was no difference in the volume of VAT adjusted for BMI between 6 (28.5%) lean and 15 (71.5%) overweight/obese patients. Patients with NASH and borderline NASH were older, obese with higher VAT and SAT volumes than no-NASH group. SAT volume (SATV) correlated significantly with hepatic steatosis but none of the adipose tissue volumes had any correlation with other histological variables. Both SATV and TAT volume (TATV) correlated significantly with severity of liver disease as determined by NAS score whereas presence of MS or insulin resistance had no correlation with histological severity.Conclusion. Both subcutaneous and total adipose tissue volume are related to the disease severity as determined by NAFLD activity score in Indian patients with NAFLD.     

Microbiota and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH)

Genetic predisposition, the intestinal microbiota (IM) and environmental factors, such as sedentary lifestyle and inadequate diet, should be considered as critical factors for the development of nonalcoholic fatty liver disease (NAFLD). Recently, some studies have demonstrated an association between dysbiosis and NAFLD; however, the exact mechanisms that lead to intestinal membrane damage, bacterial translocation and inflammation are not well elucidated. Due to the relevance of this theme, the IM and its metabolites have received special attention in recent years in an attempt to better understand the mechanisms related to the prevention, physiopathology, and treatment of NAFLD. In this paper, we provide a review of the human IM and its role in diet, obesity, and the development/progression of NAFLD/NASH, as well as the use of prebiotics and probiotics in the modulation of IM.     

Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can lead to hepatic fibrosis and cirrhosis. Portal fibrosis in the absence of NASH, called isolated portal fibrosis (IPF), has received less attention and has not been classified as a spectrum of NAFLD. The aims of this study were to determine the prevalence of IPF in subjects undergoing gastric bypass surgery, to identify biochemical variables associated with IPF, and to assess the metabolic syndrome as defined by the AdultTreatment Panel III criteria. We analyzed liver biopsies from 195 morbidly obese subjects after excluding all other causes of liver disease. The prevalence of fatty liver (FL) only, IPF, and NASH was 30.3%, 33.3%, and 36.4%, respectively. Several biochemical parameters significantly trended across the 3 groups, with IPF falling between FL and NASH. Hyperglycemia was the only metabolic parameter associated with NASH (OR, 5.4; 95% CI, 2.4-12; P < .0001) and IPF (OR, 2.8; 95% CI, 1.2-6.5; P = .01). Subjects with diabetes had the greatest risk for NASH (OR, 8; 95% CI, 3.3-19.7; P < .0001) and IPF (OR, 4.3; 95% CI, 1.6-11.6; P = .003). The metabolic syndrome was identified in 78.5% of subjects, and a significant trend for the number of metabolic criteria was observed across the spectrum of FL, IPF, and NASH. In conclusion, a significant subset of morbidly obese individuals has portal fibrosis in the absence of NASH that is associated with glycemic dysregulation. Therefore, IPF should be considered a spectrum of NAFLD that may prelude NASH in morbid obesity.     

Smoking is not associated with nonalcoholic fatty liver disease

AIM: To analyze the relationship between smoking and nonalcoholic fatty liver disease (NAFLD). METHODS: This is a cross-sectional study of a healthy population, carried out in a check-up unit of a university hospital in Mexico City. We enrolled 933 subjects, 368 current smokers (cases) and 565 persons who had never smoked (controls). Demographic, metabolic and biochemical variables were measured in the two groups. NAFLD was determined by ultrasound and metabolic syndrome according to ATPⅢ. RESULTS: A total of 548 men (205 cases and 343 controls) and 337 women (114 cases and 223 controls) were included in the analysis. Statistical differences between cases and controls were observed only in high blood pressure prevalence (6.6% vs 11.3%, P<0.05; cases and controls respectively), high-density lipoproteins (1.00±0.26 vs 1.06±0.28 mmol/L, P< 0.005), triglycerides (2.18±1.49 vs 1.84±1.1 mmol/L, P<0.001), and erythrocyte sedimentation rate (11.3±9.3 vs 13.5±11.9 mm/h, P<0.001). No differences were observed in the prevalence of NAFLD (22.27% vs 29.68%, P=NS) and metabolic syndrome (41.69% vs 36.74%, P = NS). Univariate analysis showed that smoking was not a risk factor for NAFLD (OR=0.89, 95% CI 0.65-1.21). CONCLUSION: No differences in NAFLD prevalence were observed between current smokers and nonsmokers, and furthermore, no differences were observed in heavy smokers (more than 20 packs/year), indicating that there is no relationship between smoking and NAFLD.     

Validation of the BARD scoring system in Polish patients with nonalcoholic fatty liver disease (NAFLD)

Background  

Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver diseases, ranging from pure steatosis to nonalcoholic steatohepatitis (NASH), and eventually to liver cirrhosis with its complications. Identifying advanced fibrosis in patients is crucial to evaluating prognosis and possible therapeutic intervention. A novel, simple, and highly accurate scoring system called BARD, which identifies patients with NAFLD and without significant fibrosis, has been recently introduced and validated in North America..The aim of this study is to validate the BARD scoring system in a Polish cohort with NAFLD.     

Epidemiology and risk factors of nonalcoholic fatty liver disease (NAFLD)

The nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis, determined by either imaging or histology, in the absence of secondary causes of hepatic fat accumulation. Nonalcoholic fatty liver is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes or fibrosis. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. Although initial epidemiological studies have focused on its prevalence in the Western countries, it is becoming increasingly clear that NAFLD is highly prevalent in the Asia Pacific region, and there may be important distinctions in its phenotype between Asia Pacific and Western countries. Of particular interest are “lean NAFLD” and the “urban-rural divide,” which will be discussed in this review article. Obesity, dyslipidemia, type 2 diabetes and metabolic syndrome are established risk factors for developing NAFLD. Many other risk factors (e.g., hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, hypopituitarism and hypogonadism) for NAFLD have been described in the Western countries, but these associations are yet to be investigated adequately in the Asia Pacific region.     

Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease. The progressive subtype of NAFLD or nonalcoholic steatohepatitits (NASH), may progress to cirrhosis and its complications. Unfortunately, accurate noninvasive modalities for diagnosing NASH and monitoring its progression are unavailable, necessitating a liver biopsy. Abdominal ultrasound (US) is widely used for screening asymptomatic patients with an incidental elevation of liver enzymes. However, US cannot detect small amounts of hepatic steatosis and cannot establish the diagnosis of NASH or stage of hepatic fibrosis. In this issue of AJG, a new radiologic scoring system has been reported to have excellent performance in diagnosing NAFLD and visceral obesity. However, the utility of this scoring system in establishing the diagnosis of NASH and hepatic fibrosis, has not been shown. Additionally, validity of this scoring system to other populations (i.e. obese) and in the setting of private practice must be proven. In summary, this study provides some valuable data regarding the utility of radiologic modalities in detecting hepatic steatosis and abdominal fat but still falls short in answering some important diagnostic and prognostic questions in NAFLD. The evolving field of diagnostic imaging for NAFLD holds promise. A combination of serum biomarkers and radiologic modalities may one day provide the best diagnostic approach for patients with NAFLD, and potentially replace the necessity for liver biopsy in most patients.     

线粒体功能不全与非酒精性脂肪性肝病

非酒精性脂肪性肝病（NAFLD）是遗传、环境、代谢、应激相关因素所致的一种慢性肝脏疾病,包括单纯性脂肪肝、脂肪性肝炎和脂肪性肝硬化三种类型。NAFLD的发病机制复杂,     

The efficacy of ezetimibe on nonalcoholic fatty liver disease (NAFLD)

The usefulness of ezetimibe was examined in 297 patients with dyslipidemia who did not achieve LDL-C target levels set in JAS 2007 Guidelines by lifestyle modification. The mean period of administration was 178.2±295.4 days. Ezetimibe significantly improved serum lipid levels in the patients with and without non-alcoholic fatty liver disease (NAFLD) (p<0.01). Significant improvement of AST, ALT and γ GTP levels were also observed in the patients with NAFLD (p<0.01, p<0.05, and p<0.01, respectively). Seventy of the patients with NAFLD who underwent abdominal ultrasound before and after administration of ezetimibe were followed. Of those, 38.6% of the patients showed disappearance of steatosis, indicating that administration of ezetimibe is useful in patients with NAFLD.     

Progression from isolated steatosis to steatohepatitis and fibrosis in nonalcoholic fatty liver disease

In patients with nonalcoholic fatty liver disease (NAFLD) isolated steatosis is considered a benign condition with no or minimal rate of progression, in contrast to nonalcoholic steatohepatitis (NASH) which can progress to cirrhosis. We report on a series of six patients with isolated steatosis on an initial liver biopsy, and NASH on a follow-up biopsy performed five years after. All but one of the initial biopsies were longer than 15 mm. At follow-up, inflammation and ballooning were present in all patients and mild fibrosis in three. All patients had one or more features of metabolic syndrome at baseline. Progression to steatohepatitis occurred independent of aminotransferase changes. Five patients experienced an increase in one or several metabolic risk factors during follow-up: body mass index, triglyceride levels, arterial hypertension and/or the HOMA index. One patient did not exhibit progression but was still exposed to metabolic risks factors at the end of follow-up. This report demonstrates that isolated steatosis is not necessarily a benign, non-progressive condition. Current recommendations for the absence of hepatic monitoring in patients with isolated steatosis are not adequate. If metabolic risk factors persist or deteriorate during follow-up and/or non-invasive markers suggest disease progression, a control liver biopsy should be considered.