肠道菌群和胆汁酸代谢对非酒精性脂肪性肝病发生发展的作用

随着肥胖及代谢综合征的流行,非酒精性脂肪性肝病的患病率逐年递增,在该病的发生和发展过程中,肠道菌群和胆汁酸代谢均发挥重要作用。讨论了肠道菌群和胆汁酸代谢之间的关系,重点强调了肠道菌群、胆汁酸和胆汁酸受体在非酒精性脂肪性肝病发生发展的过程中所起到的作用。     

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.     

Original research: Implementation of a care bundle improves the management of patients with non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is common and is associated with liver-related and cardiovascular-related morbidity. Our aims were: (1) to review the current management of patients with NAFLD attending hospital clinics in North East England (NEE) and assess the variability in care; (2) develop a NAFLD ‘care bundle’ to standardise care; (3) to assess the impact of implementation of the NAFLD care bundle.MethodsA retrospective review was conducted to determine baseline management of patients with NAFLD attending seven hospitals in NEE. A care bundle for the management of NAFLD was developed including important recommendations from international guidelines. Impact of implementation of the bundle was evaluated prospectively in a single centre.ResultsBaseline management was assessed in 147 patients attending gastroenterology, hepatology and a specialist NAFLD clinic. Overall, there was significant variability in the lifestyle advice given and management of metabolic risk factors, with patients attending an NAFLD clinic significantly more likely to achieve >10% body weight loss and have metabolic risk factors addressed. Following introduction of the NAFLD bundle 50 patients were evaluated. Use of the bundle was associated with significantly better documentation and implementation of most aspects of patient management including management of metabolic risk factors, documented lifestyle advice and provision of NAFLD-specific patient advice booklets.ConclusionThe introduction of an outpatient ‘care bundle’ led to significant improvements in the assessment and management of patients with NAFLD in the NEE and could help improve and standardise care if used more widely.     

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     

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非酒精性脂肪性肝病(NAFLD)是临床实践中肝功能异常最为常见的原因,肥胖症、2型糖尿病和代谢综合征是其常见原因。临床医生在处理NAFLD这一日益增多的"新的疾病"及其代谢并发症中的作用至关重要。文章主要谈谈中华肝病学会新版NAFLD的诊疗指南的重要性及相关问题。     

Steatosis and cirrhosis in an obese diabetic

Summary A 54-year-old woman with obesity, type II diabetes mellitus, hyperlipidemia, and massive hepatomegaly was found to have severe steatosis and cirrhosis on liver biopsy. Complete evaluation led to the diagnosis of fatty cirrhosis associated with obesity and diabetic mellitus. She underwent four months of fasting with a protein-carbohydrate and vitamin-mineral liquid supplement to control her weight and metabolic abnormalities and to evaluate the effect of this diet on her liver disease. She lost 40 pounds to ideal body weight, normalized her serum glucose and lipids, and decreased total liver height by one third. Liver biopsy at the completion of her diet showed inactive cirrhosis and complete resolution of steatosis. Supplemented fasting with only modest weight loss can safely resolve fatty liver in obese diabetics with nonalcoholic steatosis and cirrhosis. Aggressive dietary approaches to achieve long-term weight loss deserve study in this subgroup of diabetics with unexplained chronic liver disease.     

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.     

非酒精性脂肪性肝病患者肝纤维化指标与血清尿酸水平关系分析

[目的]分析非酒精性脂肪性肝病（nonalcoholicfattyliverdisease,NAFLD）患者肝纤维化指标与血清尿酸水平的相关性。[方法]人选符合B超诊断的60例NAFLD患者,其中脂肪肝程度轻度者21例、中度22例、重度17例,并选取40例健康体检者为正常对照组,对所有入选者进行血液生化指标[三酰甘油（TG）、总胆固醇（Tc）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、血清肌酐（SCr）、血清尿酸（SUA）、谷草转氨酶（AST）和丙氨酸转移酶（ALT）]和肝纤维化指标[透明质酸（HA）、层黏蛋白（LN）、Ⅲ型前胶原肽（PCm）、Ⅳ型胶原（CⅣ）]检测,并将血清SUA与肝纤维化指标进行偏相关性分析。[结果]与正常对照组相比,NAFLD组中脂肪肝中度患者TG、SUA、AST水平均显著升高;重度患者TC、LDL-C、SCr、AST、ALT、TG、SUA水平均显著升高,HDL-C水平极显著降低。NAFLD组患者的Pcm和HA均显著升高;脂肪肝中、重度患者CⅣ显著升高。NAFLD组患者SUA水平均与Pcm有显著正相关性,脂肪肝中度患者SUA水平与HA呈显著正相关。[结论]NAFLD患者多项血液生化指标及肝纤维化指标异常,其中,SUA与肝纤维化指标PCIII有正相关性。     

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 X receptors bridge hepatic lipid metabolism and inflammation

Liver X receptors (LXRs) are members of the superfamily of metabolic nuclear receptors, which play central roles in the regulation of cholesterol absorption, efflux, transportation and excretion and many other processes correlating with lipid metabolism. LXRs can also regulate inflammation in vitro and in vivo. Accumulating evidence demonstrates that LXR are involved in the metabolism and inflammation in human diseases. Nonalcoholic fatty liver disease (NAFLD) is classically associated with lipid metabolic disorders and inflammatory responses, especially in the nonalcoholic steatohepatitis (NASH) phase. The effects of LXRs on cholesterol metabolism and inflammation make them attractive as a potential target for the treatment of NAFLD. Since the ability to synthesize triglycerides may be protective in obesity and fatty liver, the hepatic lipogenesis by LXRs should not rule out the possibility of the use of LXRs in NAFLD.     

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.     

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.     

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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。     

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.     

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。