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发表于 2008-12-8 16:51
（引文英文录像略去）
来源：国际肝病作者：发布时间：2008-11-10阅读：140
导读：胰岛素抵抗导致HCC的机制还不是十分清楚，但是至少有两种猜测。其中之一是胰岛素抵抗是非酒精性脂肪肝人群中很普遍的一个现象。我们知道100%的非酒精性脂肪肝患者有胰岛素抵抗。而20%的非酒精性脂肪肝的患者会进展为非酒精性脂肪型肝炎（简称NASH）。
Heptology Digest：Hepatocellular carcinoma is increasing in frequency in China and the US. However, the causes for HCC might differ between China and the USA. In your article Epidemiology Of Hepatocellular Carcinoma In the US in Hepatology Research, you pointed out that Insulin Resistance Syndrome -- manifesting as obesity and diabetes -- is emerging as a risk factor for HCC. What is the current study status about insulin resistance as the risk factors for HCC?
国际肝病：中国和美国肝细胞癌（HCC）患病率呈逐渐升高趋势。而两国导致HCC的原因可能不一样。您在肝脏病学研究上发表了一项关于美国HCC流行病学的研究报道，您指出胰岛素抵抗综合征（特别是有明显的肥胖和糖尿病），是HCC新发现的危险因素。请您谈一下目前对HCC的危险因素胰岛素抵抗的研究进展？
Dr. El-Serag：Thank you for asking me this question. It is becoming more clearer that both diabetes and obesity are risk factors for hepatocellular carcinoma. Both independently, but perhaps more importantly by enhancing and promoting the risks already posed by other known risk factors such as hepatitis -C, hepatitis-B, and alcoholic liver disease. Also, there has been a meta-analysis compiling the information about the association between diabetes and hepatocellular carcinoma. That shows that in two distinct study designs, case controlled, as well as cohort studies, there seemed to be an approximately two-fold elevation in the risk of hepatocellular carcinoma among those who have diabetes versus those who do not have diabetes. There have also been several studies that show that obesity in patients with hepatitis-C, as well as in patients with cirrhosis, as well as in the general population, are all associated with a probably one-and-a-half to two-fold increase of hepatocellular carcinoma. Generally the study showed that the effect of obesity is greater in men than in women and this may relate to the presumed mechanism of action – which I will get into, shortly.
The new, and possibly exciting, area for research may have to do with the genetic variations in the susceptibility to develop diabetes, as well as to develop obesity, and whether these genetic variations are also linked to the increased risk of hepatocellular carcinoma. These studies are ongoing, but they offer a way for examining insulin resistance that is not affected by variables related to the cancer itself, and examining, rather, variables that do not change such as genetic variations.
Dr. El-Serag教授：谢谢你提的这个问题。糖尿病和肥胖都是HCC的危险因素已经越来越明确。它们都是独立的危险因素，但更重要的作用可能是通过增强和促进其他HCC已知的危险因素的作用，如丙型肝炎，乙型肝炎和酒精性肝病。已经有关于糖尿病和HCC之间关系的meta分析。研究发现在两项不同设计的病例对照队列研究中，糖尿病患者发生HCC的危险约是非糖尿病患者的2倍。也有一些研究显示丙型肝炎肥胖患者，肝硬化肥胖患者以及一般肥胖人群发生HCC的危险约增加1.5到2倍。总的来说，研究显示肥胖对男性的影响比对女性的影响要大，这可能和推测的作用机理有关，而这是我很快将要研究的方向。
新的令人振奋的研究领域是对糖尿病和肥胖易感性的遗传变异研究，以及这些遗传变异是否与HCC风险增加有关。这些研究尚在进行中，它们提供了检测胰岛素抵抗的一种方法，这些变异与癌症本身无关。
Heptology Digest：Do you believe obesity would be a factor for the Asian populations, especially China?
国际肝病：您认为肥胖也是亚洲人群的一个危险因素吗，特别是中国？
Dr. El-Serag：These studies were not conducted in Asian countries for the possibly good reason that obesity was not a major problem in those countries. However, to have the impression that obesity is just a US epidemic would be a mistake. I recently learned that approximately 7% of Chinese are considered obese by a BMI of 28 or greater. And because China is the most populous country in the world, multiplying the 7% by the total population and you actually have the highest number of obese people living in China.
So, while admitting that this is a developing field in terms of pinning-down the risk of obesity as related to hepatocellular carcinoma, if even a small proportion of this translates to the chinese population then I think it will be a problem in China, especially they have other big problem of endemic hepatitis-B infection.
Dr. El-Serag教授：这些研究没有在亚洲人群中进行，因为肥胖不是这些国家主要的问题。但是如果觉得肥胖只在美国流行那也是错误的。我最近了解到大约有7%的中国人（体重指数为28或更高）患有肥胖。因为中国是世界上人口最稠密的国家，虽然患有肥胖的比例仅为7%，但乘以总人口你会发现中国肥胖人口的绝对数是最多的。
虽然阻止肥胖这一危险因素目前还在发展中，由于与HCC发生有关，即使很小的比例发生，如果换做中国人，那么也将会是一个很大的问题，特别是中国目前还有较高HBV感染率的问题。
Heptology Digest：What is your opinion about the possible mechanism for insulin-resistance causing HCC?
国际肝病：您怎么看胰岛素抵抗导致HCC可能的机制？
Dr. El-Serag ：It is not exactly known, but there are at least two general hypotheses. One of them is insulin resistance is a universal phenomenon in persons who have nonalcoholic fatty liver disease. So, we know that 100% of nonalcoholic fatty liver disease patients have insulin resistance. We know that 20% of those nonalcoholic fatty liver disease patients will go on to progress to a condition called NASH, which is Nonalcoholic Steatohepatitis. And we know that approximately 20% of those with NASH will progress to the condition called cirrhosis. We know that once you develop cirrhosis – irrespective of the reason – you have a risk of 1% to 3%, per year, of developing hepatocellular carcinoma. So, that lays the ground for the first mechanism, which is: increasing the risk of developing fatty liver disease which eventually progresses to cirrhosis.
The other mechanism, which has nothing to do with nonalcoholic fatty liver disease, is that insulin resistance is characterized by increasing circulating markers such as insulin, IGF1, and other substances that have been shown to be carcinogenic on their own in animal models -- particularly the IGF1. So the thought is: irrespective of what happens in the liver in terms of nonalcoholic fatty liver disease, these markers will increase the susceptibility to HCC on their own. And why men have a greater propensity to develop cancer than do women: there are a number of studies and opinions trying to link the obesity issue to this very interesting sex difference in HCC. Men tend to carry more weight in their belly than do women – pound for pound. It is thought that visceral obesity – which is the major component of abdominal obesity – is the major source of pro-inflammatory cytokines which has the major role in damaging the liver and causing nonalcoholic fatty liver disease. So therefore it is thought that this dissolution of fat being more abdominal in men is one explanation for this interesting epidemiological observation.
Dr. El-Serag教授：胰岛素抵抗导致HCC的机制还不是十分清楚，但是至少有两种猜测。其中之一是胰岛素抵抗是非酒精性脂肪肝人群中很普遍的一个现象。我们知道100%的非酒精性脂肪肝患者有胰岛素抵抗。而 20%的非酒精性脂肪肝的患者会进展为非酒精性脂肪型肝炎（简称NASH）。另外20%的NASH患者会进展为肝硬化。我们知道如果发生了肝硬化，不管是什么原因，那么每年将有1%-3%发生HCC的风险。这是第一个可能机制的基础：增加发生脂肪肝的风险最终会进展为肝硬化。
另一个机制与非酒精性脂肪肝无关，是胰岛素抵抗特有的特征，即发生胰岛素抵抗时，循环中的生物标志增加，如胰岛素，IGF1和其它的一些物质（在动物模型中研究表明它们本身有致癌作用，特别是IGF1）。据此猜测：不管非酒精性脂肪肝的肝脏发生了什么变化，这些生物标志本身会增加HCC的易感性。对于男性为什么比女性更容易发生癌症的问题：已经有很多研究想设法找到肥胖和性别差异在HCC中的联系。有研究指出男性腹部比女性更容易积累脂肪。据报道内脏肥胖是腹部肥胖的主要组成部分。而这是产生前炎症细胞因子的主要来源，它们会导致肝脏损伤并引起非酒精性脂肪肝。因此，男性腹部可聚集更多的脂肪可能是男性HCC发生率更高的一个解释。
Heptology Digest：With the development of high-resolution imaging of the liver for diagnosis and improved efficacy of transarterial chemoembolization and sorafenib as palliative therapy, the outlook for HCC patients have improved greatly. In your article Diagnosis And Treatment Of Hepato-cellular Carcinoma, in Gastroenterology, you presented a recommended-management approach for HCC. Since there are some differences in the situation between China and the US, are there any special recommendations for theChinese HCC management?
国际肝病：随着肝脏诊断高分辨率影像技术的发展，经动脉化学栓塞疗效的提高以及索非尼拉姑息性疗法，HCC患者的预后大大改善。您在胃肠病学杂志上发表了1篇关于肝细胞癌诊断和治疗的文章，在这篇文章中你推荐了一种 HCC护理方法。然而由于中国和美国的情况有些不同，对于中国人HCC护理，你有特别的推荐吗？
Dr. El-Serag：Yes. The major difference between China and the US is in the major risk factor. In China it is hepatitis-B, and it is endemic, and it is acquired early in life, and therefore the risk of hepatocellular carcinoma without cirrhosis is higher than in the US. Which makes early detection of major importance because the possibility of curative resection is much greater in China given early detection than it is in the United States. So, that is one major difference between the two countries. It also given that liver transplant is the major route of treatment in the United States but is not widely available in China, the availability of the transarterial chemoembolization and sorafenib can give providers, as well as patients, more hope that with early detection – even if they do not qualify for curative resection – there are second-line and third-line therapy that have been shown to be efficacious.
Dr. El-Serag教授：是的，中国和美国主要的差别在于主要的危险因素不同。在中国乙型肝炎患病率高，并且患病较早，因而中国人发生HCC（不伴随肝硬化）的风险要高于美国人。由于早期诊断HCC的中国患者根治性切除术的可能性比美国高，因而早期诊断十分重要。这是两国主要的差别。此外，美国HCC患者的主要治疗措施是肝移植，而中国进行肝移植较少。经动脉化学栓塞和索拉非尼给医疗工作者和早期诊断患者带来了更多的希望。另外还有疗效较好的二线和三线治疗可供选择。
Heptology Digest：Intrahepatic Cholangiocarcinoma is a highly fatal disease with limited therapeutic options. In your paper Endoscopic And Surgical Therapy For Intrahepatic Cholangiocarcinoma in The United States: A Population-Based Study in the Journal Of Clinical Gastroenterology, you compared the different treatment options. According to your study, what is the best algorithm for treatment of intrahepatic cholangiocarcinoma?
国际肝病：肝内胆管细胞癌是高致死性疾病，治疗手段也有限。您在临床胃肠病学杂志上发表的文章《美国肝内胆管细胞癌内窥镜和外科治疗：基于人群的研究》中，你对不同的治疗方法进行了比较。根据您的研究，您觉得治疗肝内胆管细胞癌最好的方法是什么？
Dr. El-Serag：I want to emphasis that this paper described practice patterns in the community, and the point of that was to show what is being done rather than what should be done. But the current recommended algorithm for intrahepatic cholangiocarcinoma is detection and accurate staging to allow curative surgical resection. Short of that, there are few centers in the United States that offer the possibility of liver transplant. Unfortunately the majority of patients will not qualify for either option, therefore, photodynamic thereapy and palliate stenting are the second modalities to follow.
Dr. El-Serag教授：我要强调的是这篇文章描述的是社区诊疗模式，研究的是正在进行的诊疗模式，而不是应该进行的诊疗模式。目前肝内胆管细胞癌推荐的治疗方法是早期诊断和准确分期以利于根治性外科切除术的实施。除此之外，美国有少数医疗中心为患者提供了肝移植的可能性。但是大多数患者无法接受上述任何一种治疗方法，因此，光动力学疗法和支架缓解是可以选择的第二类治疗模式。
Heptology Digest：There is not complete agreement as to whether hepatitis-C increases risk of diabetes. In your article Hepatitis-C Infection And Risk Of Diabetes: A Systematic Review And Meta-Analysis in the Journal Of Hepatology you provided more evidence to the opinion that HCV increases the risk of diabetes with META analysis. However, the mechanism of HCV causing diabetes is still not clear. Is there any progress about this mechanism study?
国际肝病：关于丙型肝炎是否增加糖尿病风险还没有达成一致共识。您在肝脏病学杂志上发表的文章《丙型肝炎感染和糖尿病风险：系统综述和meta分析》，通过meta分析您提供了更多HCV增加糖尿病风险的证据。然而，HCV引起糖尿病的机制还不清楚。关于其机制的研究目前有什么进展吗？
Dr. El-Serag：The Major emphasis in the current research – and the accumulating evidence – is that it remains to be a function of liver damage. So hepatitis-C causing liver damage and that early liver damage affects the transport of lipids and the function of insulin on the liver and therefore produces insulin resistance.
What is the interesting new development is that the cure of hepatitis-C seems to lead to the improvement in insulin resistance, and possibly amelioration of the diabetes. The exact viral factors involved in the pathogenesis in addition to causing liver disease remain unknown.
Dr. El-Serag教授：根据目前已有的证据，主要的研究重点在于肝脏功能损伤。丙型肝炎导致肝损伤，早期肝损伤影响脂质运输以及胰岛素对肝脏的作用，进而导致胰岛素抵抗。新近的研究进展是随着丙型肝炎的治愈，胰岛素抵抗也得到改善。除导致肝脏疾病外，病毒学因素在胰岛素抵抗中的机制还不清楚。
Heptology Digest：Since chronic hepatitis-B is more prevalent in China, we have show many chronic hepatitis-B patients with diabetes. we have found that diabetes in chronic hepatitis-B patients is difficult to manage. What is your advice about this?
国际肝病：由于乙型肝炎在中国的患病率较高，我们也观察到很多有糖尿病的乙型肝炎患者。我们发现慢性乙型肝炎患者的糖尿病很难处理，您对此有什么建议吗？
Dr. El-Serag：I believe that China, given the obesity epidemic and the westernization of diet in several areas there, will experience an epidemic of insulin resistance irrespective of the presence of hepatitis-B. The addition to hepatitis-B may make the problem worse. I think the Chinese will have to do with issues that we do with all the time in the US, which is advising people to exercise, change their diet and lose weight. Those have been the corner-stones of managing diabetes with or without hepatitis-B. Clearly preventing hepatitis-B – for which the Chinese are mavericks -- should continue in the form of hepatitis-B vaccinations.
In drawing an analogy with the newer studies of hepatitis-C it is quite possible that successful treatment of hepatitis-B with antiviral may lead to improvement of diabetes at the same time.
So, these are the major things: prevent insulin resistance with treatment as you would treat it in a diabetic: treat it with medication – I don’t think we should be afraid of using insulin or oral hypoglycemics, prevent hepatitis-B, treat hepatitis-B, and possibly that treat may improve diabetes.
Dr. El-Serag教授：我认为随着中国一些地区饮食的西化，肥胖的流行率会上升，会出现更多胰岛素抵抗患者，而不论有没有乙型肝炎。乙型肝炎会导致该问题更严重。我认为中国也会遇到肥胖问题就像我们在美国遇到的一样。因此对于有或无乙型肝炎的肥胖糖尿病患者，要建议多锻炼，改变饮食习惯，减轻体重。而对于乙型肝炎患病率较高的中国，应该继续给予乙型肝炎疫苗来预防乙型肝炎。
和丙型肝炎新近研究结果相似，成功的乙型肝炎抗病毒治疗同时也能改善糖尿病。
因此，主要要做的事情是：进行治疗来预防胰岛素抵抗，就像治疗糖尿病那样，给予药物治疗。我认为我们不应该担心使用胰岛素或口服降糖药，此外我们还要预防乙型肝炎，同时治疗乙型肝炎患者，这些治疗可能会改善糖尿病。
翻译：北京大学第一医院感染疾病科吴学杰
审校：北京大学第一医院感染疾病科吴学杰 |
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