他莫昔芬诱发的非酒精性脂肪性肝病的研究进展

他莫昔芬是治疗激素受体阳性乳腺癌的一种抗雌激素类药物,被广泛地应用于临床.国内外的许多临床研究和动物实验已经证实他莫昔芬可以诱发非酒精性脂肪性肝病.全文主要对他莫昔芬的治疗现状及其诱发的非酒精性脂肪性肝病的流行病学、发病机制、诊断、预测因素、对乳腺癌预后的影响以及预防和管理进行系统全面的综述.     

非酒精性脂肪性肝病相关基因的单核苷酸多态性研究

背景与目的：探讨载脂蛋白B(Apolilpoprotein B, ApoB)、β3-肾上腺素能受体（β3-adrenergic receptor,β3-AR）、细胞色素P4502E1(cytochrome P4502E1,CYP2E1)基因单核苷酸多态性与非酒精性脂肪性肝病(Nonalcoholic fatty liver disease, NAFLD)发病的关系,并从分子水平探讨该病的发病机制。材料与方法: 应用聚合酶链反应和基因芯片技术,对194例NAFLD患者和189例健康对照的ApoB、β3-AR、 CYP2E1基因多态性进行了分析。结果: 轻度NAFLD组Apo BMspⅠ位点M+M-基因型频率(18.6%)和等位基因型频率(9.3%)均高于对照组( 分别为10.3%和5.2%),差别有统计学意义（p＜0.05） 。Apo BMspⅠ和CYP2E1基因多态性的联合作用使中重度脂肪肝发病的危险性增加近4倍。结论: Apo BMspⅠ位点多态性与轻度NAFLD有关,CYP2E1和Apo B MspⅠ基因多态性的联合作用分析从分子水平解释了NAFLD发生发展的机制,同时也为研究NAFLD遗传易感性从方法学上提供了新的思路。     

非酒精性脂肪肝与结直肠肿瘤关系的研究进展

非酒精性脂肪肝（non-alcoholic fatty liver disease,NAFLD）与代谢综合征（metabolic syndrome,MS）密切相关,其发病率随着肥胖和MS发病率的增加而增加,被认为是MS的肝脏表现。近年来,大量研究显示NAFLD与结直肠腺瘤及结直肠癌的发生有关,其中机制尚未完全明确,可能与胰岛素抵抗、炎症反应、肠道菌群等因素有关。本文就NAFLD与结直肠肿瘤的关系及发病机制的最新研究作一综述。     

非酒精性脂肪性肝病相关肝细胞癌发病机制研究进展北大核心

非酒精性脂肪性肝病(NAFLD)正逐渐成为肝细胞癌(HCC)的主要病因。到2030年,NAFLD相关肝癌的年发病率预计将增加45%~130%。尽管NAFLD已成为严重的全球健康威胁,但NAFLD相关HCC的分子机制仍不清楚,需要进一步探索,而NAFLD在HCC中的作用应该引起足够的关注。本文综述了NAFLD相关HCC流行病学最新进展,阐述了遗传易感性、肠道微生物群、代谢紊乱和免疫机制在促进NAFLD进展为HCC进程中的作用机制最新进展,为认识NAFLD相关HCC的现状和发病机制奠定基础。     

生酮饮食与代谢相关脂肪性肝病的研究进展

伴随生活方式的改变,代谢相关脂肪性肝病(MAFLD)在慢性肝病中占比逐渐增加,影响全球25%的成人,并被认为可与其他慢性肝病合并存在。MAFLD不仅与慢性肝炎、肝硬化、肝细胞癌发生发展密切相关,与肥胖、2型糖尿病互为因果,而且可促进甲状腺功能减退症、代谢综合征、心血管疾病、恶性肿瘤的发病。MAFLD目前尚无治疗的特效药物,改变不良生活方式和减轻体重是防治MAFLD及其合并症的关键措施。生酮饮食是一种低碳水化合物、高脂肪与适量蛋白质的配方饮食模式,可将机体由葡萄糖供能转换到脂肪动员,进而产生酮体的供能模式。基于此理论基础,生酮饮食被认为具有潜在的减轻体质量、改善胰岛素抵抗、调节糖脂代谢的作用,其对2型糖尿病、肥胖的辅助治疗效果已在许多动物模型及临床试验中得到验证,而生酮饮食在MAFLD的临床应用中多为短期研究,目前二者关系尚处于探索阶段。本文就生酮饮食在MAFLD患者减轻体质量、改善胰岛素抵抗方面的机制、研究报道进行综述。     

肠道微生态与消化道肿瘤的研究进展

人体微生态系统存在于胃肠道、口腔、泌尿生殖道、呼吸道和皮肤等多个部位,其中以肠道中的微生态系统最为主要和复杂。肠道微生态参与机体的生长发育、免疫调节、内分泌代谢等各种功能,并受到年龄、饮食、抗菌药物及心理压力、应激等因素的影响。肠道微生态的失调可能会引起许多疾病,包括皮肤病、肥胖、感染性疾病、心脑血管疾病和自身免疫病。随着肠道微生态与消化道疾病研究的不断深入,越来越多的学者发现,消化道肿瘤的发生、发展与肠道菌群失调有显著的相关性。肠道菌群失调通过微生物直接与肿瘤接触,调节机体免疫,产生细菌代谢物等机制直接或者间接作用影响肿瘤的发生、发展。此外,近年来研究还发现,肠道微生态与各类免疫检测点抑制剂如抗程序性死亡蛋白1抗体、抗程序性死亡蛋白配体1抗体及抗细胞毒性T淋巴细胞相关抗原4抗体的疗效密切相关,肠道微生态有可能是一个潜在的可预测肿瘤免疫治疗效果的生物标志物。本文归纳了肠道微生态的功能及其在消化道肿瘤发生、发展中的作用等,希望为今后的研究重点和发展方向提供参考。     

化合物治疗非酒精性脂肪肝病相关肝细胞癌的研究进展

目前非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)已成为全球健康的严重威胁,将成为肝细胞癌(hepatocellular carcinoma, HCC)的主要诱导因素,并最终导致NAFLD相关的HCC的发生。但目前为止,其具体分子机制仍不完全清楚。现越来越多的研究关注着化合物在NAFLD和NAFLD相关的HCC中的应用。因此本文在简要回顾了NAFLD相关HCC发病和进展可能机制的最新研究基础上,进行总结和整理化合物对NAFLD相关肝细胞癌治疗的最新进展,并将这部分药物分为以下五种作用机制：抗炎、抗氧化、调节脂质代谢、调节肠道菌群和抑制肝纤维化,以期为今后NAFLD相关HCC的治疗和预防提供有价值的信息。     

三苯氧胺与脂肪性肝病

三苯氧胺用于雌激素受体阳性乳腺癌患者的内分泌治疗效果肯定,但长期应用可诱发脂肪性肝病.其机制包括药物聚集于肝细胞线粒体、脂肪酸氧化异常、雌激素拮抗作用等.对服用三苯氧胺的乳腺癌患者需定期监测肝功能、血脂、超声及CT等.可选择托瑞米芬、芳香化酶抑制剂替代治疗及应用降脂药物等进行防治.     

三苯氧胺与脂肪性肝病

三苯氧胺用于雌激素受体阳性乳腺癌患者的内分泌治疗效果肯定，但长期应用可诱发脂肪性肝病。其机制包括药物聚集于肝细胞线粒体、脂肪酸氧化异常、雌激素拮抗作用等。对服用三苯氧胺的乳腺癌患者需定期监测肝功能、血脂、超声及CT等。可选择托瑞米芬、芳香化酶抑制剂替代治疗及应用降脂药物等进行防治。     

非酒精性脂肪性肝病与缺血性脑卒中发病风险的meta分析

目的 系统回顾并量化非酒精性脂肪性肝病（NAFLD）与缺血性脑卒中发病之间的关系。方法 截至 2020年 1月31日,系统检索了PubMed、Web of Science、中国学术期刊网络出版总库、万方数据期刊论文资源、Cochrane Library、中国生物医学文献数据库和Embase,使用STATA 15.0进行统计分析,合并纳入研究的OR及95%CI,同时根据地区、诊断方法、血清转氨酶水平进行亚组分析。结果 共纳入符合标准的9篇文章4206例患者。在8项研究中,NAFLD与缺血性脑卒中之间存在显著关联（OR=2.53,95%CI=1.83~3.49）。在所有比较中,各研究之间没有发现显著的异质性。在敏感性分析中排除任何一项研究后,这些结果基本保持不变。按地区进行亚组分析结果显示,在欧美地区,NAFLD患者发生缺血性脑卒中的综合风险为OR=2.17（95%CI=1.03~4.58）;在亚洲地区,风险为 OR=3.23(95%CI=1.83~5.7);在非洲,风险为 OR=2.28（95%CI=1.44~3.61）。按脂肪肝诊断的不同方法进行亚组分析表明,诊断方法可能是影响NAFLD与缺血性脑卒中风险关系的混杂因素（腹部超声诊断,OR= 2.60,95%CI=1.87~3.61;肝脏活检诊断,OR=1.08,95%CI=0.18~6.52）。按血清转氨酶水平进行亚组分析,结果表明谷丙转氨酶（ALT）水平与 NAFLD 患者发生缺血性脑卒中的风险增加有显著相关性（ALT 的平均差值为 1.14 U/L, 95%CI=0.68~1.61）。谷草转氨酶（AST）水平与 NAFLD 患者发生缺血性脑卒中风险的增加有显著的相关性（AST 平均水平差异为 0.57 U/L,95%CI= 0.25~0.80）;谷氨酰转移酶（GGT）水平与 NAFLD 患者发生缺血性脑卒中风险的增加有显著相关性（GGT 平均水平差异为1.08 U/L,95%CI=0.38~1.78）。结论 NAFLD可能会增加缺血性脑卒中的发生风险。     

Increased risk of colorectal polyps in patients with non-alcoholic fatty liver disease undergoing liver transplant evaluation

Background

Screening colonoscopy is a standard part of the liver transplant (LT) evaluation process. We aimed to evaluate the yield of screening colonoscopy and determine whether non-alcoholic fatty liver disease (NAFLD) was associated with an increased risk of colorectal neoplasia.

Methods

We retrospectively assessed all patients who completed LT evaluation at our center between 1/2008-12/2012. Patients <50 years old and those without records of screening colonoscopy, or with greater than average colon cancer risk were excluded.

Results

A total of 1,102 patients were evaluated, 591 met inclusion criteria and were analyzed. The mean age was 60 years, 67% were male, 12% had NAFLD and 88% had other forms of chronic liver disease. Overall, 42% of patients had a polyp found on colonoscopy: 23% with adenomas, 14% with hyperplastic polyps and with 1% inflammatory polyps. In the final multivariable model controlling for age, NAFLD [odds ratio (OR) 2.41, P=0.001] and a history of significant alcohol use (OR 1.69, P=0.004) were predictive of finding a polyp on colonoscopy. In addition, NAFLD (OR 1.95, P=0.02), significant alcohol use (OR 1.70, P=0.01) and CTP class C (OR 0.57, P=0.02) were associated with adenoma, controlling for age.

Conclusions

Screening colonoscopy in patients awaiting LT yields a high rate of polyp (43%) and adenoma (22%) detection, perhaps preventing the accelerated progression to carcinoma that can occur in immunosuppressed post-LT patients. Patients with NAFLD may be at a ~2 fold higher risk of adenomas and should be carefully evaluated prior to LT.     

Association between nonalcoholic fatty liver disease and colorectal adenoma: a systemic review and meta-analysis

Background

Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome (MetS) and the most common chronic liver disease worldwide. The association between NAFLD and colorectal adenoma has been investigated in multiples studies but the results have been conflicting. We performed a systematic review and meta-analysis to evaluate this in asymptomatic patients who underwent screening colonoscopy.

Methods

We searched the literatures of all languages from PubMed, EMBASE and the Cochrane library from January 1, 1980 through July 15, 2014. Combined and subgroup analyses stratified by study designs, study locations, characteristics of adenoma (location, size, number, and advanced adenoma) were performed.

Results

Four cross-sectional and one cohort studies with a total of 6,263 subjects were included in the meta-analysis. NAFLD was significantly associated with colorectal adenoma [pooled odds ratio (OR) 1.74, 95% confidence interval (CI): 1.53-1.97]. The association was more significant in Asian population (pooled OR =1.77, 95% CI: 1.52-2.05, n=3 studies), compared to European/North American population (pooled OR =1.42, 95% CI: 0.75-2.67, n=2 studies). NAFLD was significantly associated with the number of colorectal adenoma (pooled OR =1.78, 95% CI: 1.10-2.86, n=2 studies), but not the location, size, or presence of advanced adenoma.

Conclusions

Our results suggest NAFLD is significantly associated with the presence of colorectal adenoma in asymptomatic patients undergoing screening colonoscopy. This finding provides additional risk stratifications for applying colorectal cancer (CRC) screening strategies. However, more studies of western population are needed to further investigate the ethnic disparity.     

Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing?

Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.     

体质量指数及预后营养指数对晚期非小细胞肺癌合并非酒精性脂肪肝患者免疫治疗的预后价值

目的:探讨体质量指数（BMI）、预后营养指数(PNI)与晚期非小细胞肺癌（NSCLC）合并非酒精性脂肪肝（NAFLD）患者临床特征的关系及对免疫治疗预后的价值。方法:回顾性收集免疫检查点抑制剂（ICI）治疗晚期NSCLC合并NAFLD患者47例,收集治疗前临床参数,计算BMI及PNI值,分析PNI最佳界值及 BMI、PNI与临床特征的关系,比较肥胖组和不同PNI组免疫治疗反应及效果。结果:晚期NSCLC合并NAFLD患者PNI最佳界值为44.15。ICI治疗总ORR为31.9%,DCR为61.7%;BMI＜25 kg/m2和BMI≥25 kg/m2亚组ORR、DCR差异无统计学意义;低PNI和高PNI组ORR、DCR分别为13.3%、50.0%和64.7%、82.4%,差异有统计学意义;PD-L1表达、BMI值、PNI值是影响PFS的显著因素,肝转移、肿瘤分化、PD-L1表达、BMI是影响OS的显著因素。结论:免疫检查点抑制剂治疗晚期NSCLC合并NAFLD患者,基线BMI、PNI与生存改善相关。因此,基线BMI、PNI可能是未来免疫检查点抑制剂治疗的预后因素。     

大肠癌化疗后脂肪肝的临床研究

目的:研究大肠癌患者化疗后脂肪肝的发生率及其危险因素.方法:分析270例大肠癌患者化疗前后肝脏CT表现及实验室生化指标(AST、ALT、ALP、GGT、TG、CHOL、HDL、LDL)的变化.结果:化疗3个月、6个月及1年后,发生脂肪肝的例数分别为21例(7.8％)、64例(23.7％)、58例(21.5％),化疗后患者肝功能指标及血脂水平较化疗前均有不同程度的升高,差异具有统计学意义(P ＜0.05,除外高密度脂蛋白),脂肪肝组转氨酶及血脂水平均比非脂肪肝组高,差异具有统计学意义(P＜0.05,除外胆固醇).结论:大肠癌患者化疗后可以发生脂质代谢异常,导致肝脏的脂肪性病变,部分发展为脂肪肝.     

Screening strategies for colorectal cancer among patients with nonalcoholic fatty liver disease and family history

Patients with nonalcoholic fatty liver disease (NAFLD) and family history of colorectal cancer (CRC) are at higher risks but how they should be screened remains uncertain. Hence, we evaluated the cost‐effectiveness of CRC screening among patients with NAFLD and family history by different strategies. A hypothetical population of 100,000 subjects aged 40–75 years receive: (i) yearly fecal immunochemical test (FIT) at 50 years; (ii) flexible sigmoidoscopy (FS) every 5 years at 50 years; (iii) colonoscopy 10 yearly at 50 years; (iv) colonoscopy 10 yearly at 50 years among those with family history/NAFLD and yearly FIT at 50 years among those without; (v) colonoscopy 10 yearly at 40 years among those with family history/NAFLD and yearly FIT at 50 years among those without and (vi) colonoscopy 10 yearly at 40 years among those with family history/NAFLD and colonoscopy 10 yearly at 50 years among those without. The incremental cost‐effectiveness ratio (ICER) was studied by Markov modeling. It was found that colonoscopy, FS and FIT reduced incidence of CRC by 49.5, 26.3 and 23.6%, respectively. Using strategies 4, 5 and 6, the corresponding reduction in CRC incidence was 29.9, 30.9 and 69.3% for family history, and 33.2, 34.7 and 69.8% for NAFLD. Compared with no screening, strategies 4 (US$1,018/life‐year saved) and 5 (US$7,485) for family history offered the lowest ICER, whilst strategy 4 (US$5,877) for NAFLD was the most cost‐effective. These findings were robust when assessed with a wide range of deterministic sensitivity analyses around the base case. These indicated that screening patients with family history or NAFLD by colonoscopy at 50 years was economically favorable.     

Prognostic significance of tumor budding in gastrointestinal tumors

Tumor budding describes the presence of single tumor cells or small tumor cell clusters at the invasion front of carcinomas. It is currently thought to be the result of epithelial–mesenchymal transformation. Tumor budding can be appreciated histologically during routine evaluation of malignant polyps or surgical specimens of malignant tumors. Many studies have been published assessing cancers in all locations from the esophagus to the rectum, almost always reporting similar results. This seems especially remarkable as a generally accepted definition of how budding must be evaluated is still lacking. Regardless of the location, tumor budding generally is associated with nodal metastases and aggressive behavior, and it is mostly independent from other adverse factors. While the prognostic value of tumor budding is evident, especially in stage II colorectal cancers, it still has no therapeutic implications. This is owing to the heterogeneity of the performed studies and the lack of oncological studies, which are urgently needed.     

Gut microbiome in non-alcoholic fatty liver disease associated hepatocellular carcinoma: Current knowledge and potential for therapeutics

Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) are rising in incidence and are an increasingly common cause of cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is closely connected to the liver via the portal vein, and has recently been identified as a predictor of liver disease state. Studies in NAFLD, cirrhosis and HCC have identified certain microbial signatures associated with these diseases, with the disease-associated microbiome changes collectively referred to as dysbiosis. The pathophysiologic underpinnings of these observations are an area of ongoing investigation, with current evidence demonstrating that the gut microbiome can influence liver disease and carcinogenesis via effects on intestinal permeability (leaky gut) and activation of the innate immune system. In the innate immune system, pathogen recognition receptors (Toll like receptors) on resident liver cells and macrophages cause liver inflammation, fibrosis, hepatocyte proliferation and reduced antitumor immunity, leading to chronic liver disease and carcinogenesis. Dysbiosis-associated changes include increase in secondary bile acids and reduced expression of FXR (nuclear receptor), which have also been associated with deleterious effects on lipid and carbohydrate metabolism associated with progressive liver disease. Longitudinal experimental and clinical studies are needed in different populations to examine these questions further. The role of therapeutics that modulate the microbiome is an emerging field with experimental studies showing the potential of diet, probiotics, fecal microbiota transplantation and prebiotics in improving liver disease in experimental models. Clinical studies are ongoing with preliminary evidence showing improvement in liver enzymes and steatosis. The microbial profile is different in responders to cancer immunotherapy including liver cancer, but whether or not manipulation of the microbiome can be utilized to affect response is being investigated.