Fatty Liver: a Link to Cardiovascular Disease – Its Natural History,Pathogenesis, and Treatment

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in western society and is increasing in parallel with the worldwide epidemic of obesity. It exists in a simple form, steatosis, or a more complex and more dangerous form, steatohepatitis, and it is often but not always associated with the metabolic syndrome. NAFLD can progress to cirrhosis and hepatocellular carcinoma. It is responsible for the majority of cryptogenic cirrhosis cases. Increasingly, NAFLD and its more sinister form, steatohepatitis, have been linked to the increased incidence of cardiovascular disease (CVD) worldwide, independent of the metabolic syndrome. Death from CVD surpasses death from liver complications, but that is beginning to change as people are living longer with CVD. In this article, we will review nonalcoholic fatty liver disease and its epidemiology, prevalence, pathology, and link to CVD.     

Liver disease and diabetes: Association,pathophysiology, and management

Diabetes is associated with a spectrum of liver diseases including nonalcoholic liver disease, steatohepatitis, and liver cirrhosis with their increased complications and mortality. Hepatitis C virus (HCV) and its associated liver cirrhosis has been associated with diabetes through insulin resistance. Cryptogenic diabetes occurs as a consequence of liver cirrhosis with the pathophysiology being complex, but mostly attributed to the increased insulin resistance in muscle, liver, and adipose tissue. As for the management of diabetes in patients with liver disease, lifestyle modification plays an important role. Oral diabetic medications are contraindicated in patients with advanced liver diseases with associated cirrhosis, ascites, or encephalopathy. As for stable liver disease, metformin and thiazolenediones have shown mixed results, with some showing them to be effective in improving liver transaminases in addition to histological improvement in steatosis and inflammation. α-glucosidase inhibitors may be helpful in decreasing hepatic encephalopathy. Upregulation of Dipeptidyl peptidase-4 (DPP-4) has been suggested as a possible pathogenetic mechanism for HCV-related insulin resistance, and treatment with DPP-4 inhibitors could improve insulin sensitivity in diabetic patients with liver disease. Patients with impaired liver function with associated insulin resistance may need increased insulin requirements. On the other hand patients with altered liver metabolism might need decreased insulin requirements.     

A prospective study on the prevalence of NAFLD,advanced fibrosis,cirrhosis and hepatocellular carcinoma in people with type 2 diabetes

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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.     

Long‐term prognosis of nonalcoholic fatty liver disease: Is pharmacological therapy actually necessary?

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) comprises a wide spectrum of liver injury, ranging from steatosis and steatohepatitis to cirrhosis. Reasons for the different natural course in individuals with NAFLD are still unclear. The aim of this study was to describe the natural course of disease in individuals with NAFLD who did not receive pharmacological therapy. Methods: A total of 27 individuals with NAFLD (male/female ratio: 10/17, mean age 49.7 years) were prospectively enrolled. Management after diagnosis consisted of establishment of an appropriate diet and exercise (walking and jogging) program, treatment of associated metabolic conditions such as diabetes and dyslipidemia, and discontinuation of potentially hepatotoxic drugs if the patient was taking these. Liver tests were performed at diagnosis and at 3‐month intervals during the follow‐up period. Mean follow‐up period was 43.3 months (range 36–49 months). Results: From baseline to the end of the follow‐up period, although there was no significant difference observed in terms of the mean body mass index, serum aminotransferase levels significantly improved (48.8 ± 29.9 U/L to 31.6 ± 16.0 U/L for aspartate aminotransferase [AST] and 66.3 ± 38.3 U/L to 39.6 ± 22.9 U/L for alanine aminotransferase [ALT]; P < 0.05). No significant differences in platelet counts, serum albumin level or prothrombin time were observed (P > 0.05). No patient developed signs of advanced liver disease during the follow‐up period. Conclusion: A treatment strategy comprising diet, exercise and management of associated metabolic conditions is associated with improvement in aminotransferases among patients with NAFLD. Further investigation is needed to examine the long‐term efficacy of this approach on liver histology and clinical outcomes.     

世界胃肠病学会全球指南:非酒精性脂肪性肝病及非酒精性脂肪性肝炎

<正>1介绍过去数十年中,非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)及非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)是西方国家肝病的首要原因。在过去20年其他慢性肝病发病率保持稳定甚至下降的情况下,NAFLD的发病率却呈现翻番。最近的数据证明,NAFLD及NASH在中东、远东、非洲、加勒     

Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Fatty infiltration and fibrosis are major issues in chronic liver disease. Recent reports suggest a role for the endocannabinoid system in these processes. AIM: To characterize localization and expression of CB2 in normal liver and nonalcoholic fatty liver. METHODS: We studied 64 liver biopsies: eight were considered normal; 56 had a diagnosis of nonalcoholic fatty liver disease (NAFLD); 32 with nonalcoholic steatosis and 24 nonalcoholic steatohepatitis (NASH). CB2 immunolocalization was studied in 38 samples in paraffin blocks using immunohistochemistry, and a computerized semiquantitative analysis was carried out. CB2 mRNA expression was assessed through RT-PCR in 26 frozen liver samples and the ratio CB2/beta-actin was used to evaluate differences between groups. Statistical analysis was performed with central tendency measures and the Mann-Whitney U-test. We considered as significant differences those with a P-value <0.05. RESULTS: Neither parenchymal nor nonparenchymal cells in normal liver tissue react towards anti-CB2 antibodies. All the samples from patients with steatosis and nonalcoholic steatohepatitis showed hepatocellular immunoreactivity. Cholangiocytes were positive only in the NAFLD group. Normal liver tissue showed a normalized CB2/beta-actin ratio of 0.001+/-0.01, steatosis 6.52+/-17.3 (P=0.05 vs normal) and NASH 6.49+/-12.2 (P=0.06 vs normal and P=0.6 vs steatosis). CONCLUSION: CB2 receptors are expressed by hepatocytes in nonalcoholic fatty liver disease but not in normal liver.     

Moderate to severe,but not mild,nonalcoholic fatty liver disease associated with increased risk of gallstone disease

Abstract

Objective. Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GSD) share some of the same risk factors. The association between NAFLD and GSD was inconsistent. Moreover, there are no studies on the association between GSD and the severity of NAFLD in the literature. The aim of this study was to determine the relationship between the severity of NAFLD and GSD in a Taiwanese population. Materials and methods. A total of 12,033 subjects were enrolled. The diagnoses of GSD and NAFLD were based on the finding of abdominal ultrasonography. The severity of NAFLD was divided into mild, moderate, and severe. Results. Compared with the non-GSD group, the GSD one was older and had a higher BMI, blood pressure, fasting plasma glucose, cholesterol, triglyceride, and higher prevalence of diabetes and hypertension, but they had a lower eGFR and HDL-C level and less prevalence of current smoking and alcohol drinking. There was a significant difference in the severity of NAFLD between subjects with and without GSD. Based on logistic regression, age ≥65 versus <40 years, 40–64.9 versus <40 years, female, current alcohol drinking, diabetes, hypertension, HDL-C level and moderate to severe NAFLD, but not mild NAFLD, were the independently associated risk factors of GSD. Conclusion. Moderate to severe, but not mild, NAFLD was associated with an increased risk of GSD, independent of the traditional cardio-metabolic risk factor. Age, female, diabetes, and hypertension were also related to a higher risk of GSD, but HDL-C level and moderate alcohol drinking showed a lower risk.     

Symptoms of Obstructive Sleep Apnea in Patients with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a term often used to describe two related conditions: a relatively benign, nonalcoholic fatty liver (NAFL) and potentially aggressive, nonalcoholic steatohepatitis (NASH). Both conditions (NAFL and NASH) occur in the setting of peripheral insulin resistance. Recently, obstructive sleep apnea (OSA) has been proposed as an independent risk factor for insulin resistance. To date, few studies have documented the prevalence of OSA or symptoms of OSA (SOSA) in NAFLD patients. The objectives of this study were (1) to document the prevalence of SOSA in patients with NAFLD and (2) to determine whether prevalence rates for SOSA differ in NAFL versus NASH patients. One hundred ninety biochemically defined NAFLD patients (116 NAFL and 74 NASH), of whom 50 (18 NAFL and 32 NASH) had undergone liver biopsy, completed a Modified Berlin Sleep Apnea Questionnaire for SOSA. Risk factors for NAFLD were also documented in NAFL and NASH patients. Eighty-seven of the 190 (46%) NAFLD patients met questionnaire criteria for SOSA. The prevalence of SOSA was similar in both biochemically (45% versus 49%, respectively; P= 0.66) and histologically (39% versus 63%, respectively; P= 0.11) defined NAFL and NASH patients. Other risk factors for NAFLD such as body mass index, plasma cholesterol and triglyceride levels, and prevalence of diabetes were also similar in the two groups. Approximately one-half of NAFLD patients, whether NAFL or NASH, have SOSA. Further studies are required to determine whether a causal link exists between NAFLD and OSA.     

Nonalcoholic fatty liver disease in lean subjects: Prognosis,outcomes and management

Nonalcoholic fatty liver disease (NAFLD) accounts for most cases of chronic liver disease worldwide, with an estimated global prevalence of approximately 25% and ranges from simple steatosis to nonalcoholic steatohepatitis and cirrhosis. NAFLD is strongly connected to metabolic syndrome, and for many years, fatty liver was considered to be an exclusive feature of obese patients. However, recent studies have highlighted the presence of NAFLD in non-obese subjects, with or without increased visceral fat or even in lean subjects without increased waist circumference. “Lean NAFLD” is a relatively new concept and there is significant scientific interest in understanding the differences in pathophysiology, prognosis and management compared with NAFLD in overweight/obese patients. In the present editorial, we discuss the clinical and metabolic profiles and outcomes of lean NAFLD compared with both obese NAFLD and lean healthy individuals from Asian and Western countries. Moreover, we shed light to the challenging topic of management of NAFLD in lean subjects since there are no specific guidelines for this population. Finally, we discuss open questions and issues to be addressed in the future in order to categorize NAFLD patients into lean and non-lean cohorts.     

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非酒精性脂肪性肝病(NAFLD)是常见病,2010年中国和意大利先后更新诊疗指南,对照解读有助于对本病的全面理解。两指南观点并无原则上差异,流行病学内容基本一致,两指南一致强调病理学是诊断NAFLD分期的金标准,意大利指南偏重临床诊断流程和对诊断方法的评价;而中国指南致力于制定临床、病理学、影像学等诊断标准。目前尚无NAFLD的特效治疗方法,两指南均主张使用改善胰岛素抵抗的措施和药物,中国指南推荐较多保肝抗炎药物。     

非酒精性脂肪性肝病与代谢综合征指标变化的相关性分析

目的探讨中老年人群中非酒精性脂肪性肝病(NAFLD)与代谢综合征相关指标变化的关系。方法收集2010—2011年暨南大学附属第一医院40岁以上体检人群腹部B超检查的数据,用多因素Logistic回归分析体重指数(BMI)、空腹血糖(FBG)、三酰甘油(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)及低密度脂蛋白胆固醇(LDL-C)、丙氨酸转氨酶(ALT)、血尿酸(UA)的变化值与NAFLD变化的关系。结果 2年内男性组和女性组NAFLD检出率都在增加,男性新增NAFLD总检出率为13.7%,明显高于女性新增NAFLD检出率7.5%(P<0.05);男性和女性的NAFLD消减率都是5.5%,且峰值都在60岁年龄组;BMI变化值与新增NAFLD密切正相关,BMI变化值的OR=1.474(95%CI 1.184～1.811),而TG和FBG的变化值与新增NAFLD无相关性;TG和BMI的变化值与NAFLD的消减呈负相关,TG变化值的OR=0.653(95%CI 0.508～0.838),BMI变化值的OR=0.628(95%CI 0.460～0.857),而FBG变化值未发现与NAFLD消减有相关性。结论 BMI变化值与NAFLD发生有密切相关性,TG和BMI的变化值与NAFLD的消减呈负相关,是影响NAFLD变化的重要因素之一。     

Multinodular fatty liver after herpes-zoster vaccine: Case report and review of the literature: Case Report

Multinodular fatty liver (MNFL) is a pattern of fatty infiltration of the liver characterized by multiple well-circumscribed nodules on hepatic imaging, often raising the concern of metastatic malignancy. Here we describe a case of MNFL and review the published literature. There is likely some association between traditional risk factors for hepatic steatosis (e.g. alcohol, rapid weight change, metabolic syndrome, medications, TPN) and MNFL. Further study and reporting of cases of MNFL are needed to better characterize its pathogenesis and natural history.     

Sampling variability of liver biopsy in nonalcoholic fatty liver disease

BACKGROUND & AIMS: In nonalcoholic fatty liver disease (NAFLD), the distinction between steatosis and steatohepatitis (NASH) and the assessment of the severity of the disease rely on liver histology alone. The aim of this study was to assess the sampling error of liver biopsy and its impact on the diagnosis and staging of NASH. METHODS: Fifty-one patients with NAFLD underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the kappa reliability test. RESULTS: No features displayed high agreement; substantial agreement was only seen for steatosis grade; moderate agreement for hepatocyte ballooning and perisinusoidal fibrosis; fair agreement for Mallory bodies; acidophilic bodies and lobular inflammation displayed only slight agreement. Overall, the discordance rate for the presence of hepatocyte ballooning was 18%, and ballooning would have been missed in 24% of patients had only 1 biopsy been performed. The negative predictive value of a single biopsy for the diagnosis of NASH was at best 0.74. Discordance of 1 stage or more was 41%. Six of 17 patients with bridging fibrosis (35%) on 1 sample had only mild or no fibrosis on the other and therefore could have been under staged with only 1 biopsy. Intraobserver variability was systematically lower than sampling variability and therefore could not account for most of the sampling error. CONCLUSIONS: Histologic lesions of NASH are unevenly distributed throughout the liver parenchyma; therefore, sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies.     

A nomogram for estimating the probability of nonalcoholic fatty liver disease in a Chinese population: A retrospective cohort study

Studies have showed that dyslipidemia is closely related to nonalcoholic fatty liver disease (NAFLD). However, less attention has been paid to the relationship between early dyslipidemia and long-term risk of NAFLD. Therefore, we aimed to develop a simple-to-use nomogram to predict early dyslipidemia and long-term risk of NAFLD onset.A retrospective cohort study including 3621 employees (including retirees) from 7 companies was conducted between 2012 and 2019. Anthropometric, potential laboratory parameters and abdominal ultrasound were performed at baseline and after a 5-year follow-up. Cox proportional hazards model was used to determine predictors for NAFLD onset. The effects of lipids, age, body mass index (BMI), and serum uric acid (UA) on NAFLD were evaluated with the use of Kaplan–Meier curves (log-rank test). A nomogram was developed based on the Cox proportional hazard model and a 2-piecewise linear regression model. The accuracy of model was evaluated according to the area under the receiver operating characteristic curves.A total of 1545 subjects were included in the final analysis. The mean follow-up time was 52 ± 6.6 months. Of the total subjects, 77.61% were male and 22.39% were female. The mean age at the time of initial visit was 45.21 ± 11.20 years. Five hundred fifty-five subjects (35.92% of all subjects) were finally diagnosed with NAFLD. Variables in the nomogram included age, BMI, triglycerides, high-density lipoprotein, low-density lipoprotein, and UA. The accuracy of the nomogram for predicting 5-year cumulative occurrence of NAFLD was 0.8135 (95% confidence interval: 0.7921–0.8349), and the sensitivity and specificity were 0.8108 and 0.6960, respectively.The combination of age, BMI, triglycerides, high-density lipoprotein, low-density lipoprotein, and UA translated into a nomogram can reliably estimate the incidence of NAFLD within 5 years. It may serve as a decision support tool to determine whether to intervene at an early stage.     

非酒精性脂肪性肝炎患者肠道菌群的变化及意义

目的探讨非酒精性脂肪性肝炎肠道菌群的变化及意义。方法选择肠道菌群中具有代表性的细菌共5种进行培养和计数。选择健康正常成人、单纯性非酒精性脂肪肝和非酒精性脂肪性肝炎(NASH)患者各30例,计数各组肠道菌群中5种细菌的数量,比较各组细菌数量的变化。结果 NASH组患者存在不同程度的肠道菌群失调,主要表现为厌氧菌减少(P<0.05),而需氧菌显著增多(P<0.05),而兼性厌氧菌酵母样真菌没有显著变化(P>0.05)。结论 NASH患者存在肠道菌群失调、革兰阴性杆菌过度生长的现象,提示肠道微生态失衡可能参与了NASH的发生发展。