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[AASLD视点] 囊肿性纤维化及其相关肝病的治疗进展
——  作者:Mario Strazzabosco    时间:2015-11-17 07:16:53    阅读数: 381

——美国耶鲁大学医学院Mario Strazzabosco访谈
  编者按:囊肿性纤维化 (cystic fibrosis)是遗传疾病,目前仍未有治疗的方法。它可造成机体多个器官的受累,其中包括肝脏,长期影响可能堵塞胆汁导管,最终导致胆汁性肝硬化。在本届AASLD年会上,美国耶鲁大学医学院Mario Strazzabosco教授作为胆汁淤积性肝病Special Interest Group (SIG) 项目的客座教授,介绍了囊肿性纤维化性及其相关肝病的治疗进展。会后,本刊非常荣幸地对Janssen 教授进行了专访。
  《国际肝病》:囊肿性纤维化是种比较少见的疾病,请您给我们介绍一下它的发病率、致病因素和机制。
  Strazzabosco教授:该病是白种人中最常见的遗传性疾病之一。它由囊性纤维化跨膜转运调节因子(cystic fibrosis transmembrane conductance regulator,CFTR)基因突变而引起,CFTR是一种cAMP激活的ATP门控性氯离子通道。尽管早在25年之前就已经发现该基因,我们仍然不完全清楚它的所有功能,目前已了解的功能包括:产生和分泌氯离子,在分泌性上皮细胞的顶端膜分泌ATP,以及调节分泌运输等其他功能。因此,这是一个非常有意义的基因。当发生CFTR基因突变后,患者发生囊肿性纤维化的风险非常高。囊肿性纤维化是一种分泌性上皮细胞的疾病,常累及肺(最常累及)和消化道,胰腺也经常受累,在某种程度上,还包括肝脏。因此,根据被累及器官的不同,疾病的后果也不同。例如,如果累及肺,患者易发生复发性肺部感染,导致纤维化和呼吸受限,患者需要应用抗生素和肺部物理治疗。目前,这种疾病可以早期诊断,但是难以预防。由于可以早期诊断,患者的预后已有极大改善,患者的总体生存也有很大提高。
  it’s actually one of the most frequent genetic diseases in the Caucasian population. The disease is caused by a mutation in the gene, which is called the cystic fibrosis conductance regulator, or CFTR. The gene encodes for Chloride ion transport channel. It’s a peculiar kind of Chloride ion channel since it’s an ATP-binding domain. Although the gene was discovered more than twenty-five years ago, we are still searching for its complete functions so as to make it easier to understand. It does several things, among them: generates secretion of chloride, secretion of ATP in the apical membrane of secretory epithelia, but it also regulates secretion transport and several other functions. So it’s a very interesting gene. When it does not work, you get cystic fibrosis. Cystic fibrosis is a disease of secretory epithelia, which can affect the lung (which is the most frequently affected), the gut, the pancreas is also very frequently affected, and to a certain extent, also the liver. So the consequences of the disease are different according to the different organs, and the role the channel plays in the organ physiology. In the lung, you’ll have recurring infection, leading to fibrosis and forced respiratory ventilation and several infections. The patient is treated with psychosomatic antibiotics and with pulmonary physiotherapy. The disease is difficult to prevent. There’s early diagnosis, and that is important in order to recognize the disease. I have to say that the prognosis of patients has improved dramatically. Now, it’s not uncommon for patients to reach fifty years of age.
  《国际肝病》:请介绍一下该病现有的治疗状况。
  Strazzabosco教授:由于必须对大多数患者进行随访,所以囊肿性纤维化的治疗需要很大的投入。目前,最重要的进展是小分子药物治疗的研究,可以部分纠正氯离子通道的功能。问题是已知CFTR至少有2000种突变,并且这些突变属于不同的种类。因此,这些新药只对少数患者有效。但是,在该领域的研究仍然非常活跃。研究发现CFTR最常见的一种突变——δF508的突变是由于单个氨基酸缺失引起,可导致细胞内CFTR错误折叠,发生快速降解,从而无法在细胞膜发挥氯离子通道功能。然而,该致病基因产物的正常功能,需要纠正两种不同的结构缺陷。这一研究发现为未来开发出更有效的囊性纤维性变治疗策略指明了方向。
  就肝脏而言,有趣的是并非所有患者都发生严重的肝病,仅2%~5%的患者会继续进展至肝硬化,需要移植,而其他患者只发生不同程度的功能障碍。针对囊肿性纤维化性肝病患者,目前尚无真正的治疗。目前常应用的药物是熊去氧胆酸,在小型试验中表明可能有效,但缺乏大型临床研究。它可能是通过改变胆汁酸池而发挥作用,使胆汁酸的毒性降低,从而减轻对胆道的损害。
  此外,我们发现氯离子分泌的缺陷并不能解释所有问题,实际上CFTR是胆道上皮先天性调节机制的重要成分,如果缺乏CFTR,胆道上皮就会开始产生促炎细胞因子,吸引巨噬细胞和中性粒细胞,参与对胆道的损害。
  It’s a time and money-consuming treatment, because you really have to follow most of these patients. The most important novelty of it is the viability of small molecules that are able to correct, in part, the function of the channel. The problem is that there are at least two thousand mutations known in the CFTR, and these mutations belong to different classes. And these new drugs, correctors, or potentiators can only work in a minority of the patients. But the research is still very active in this area, and the biggest advantage would be to find drugs that are able to correct the defect in the DeltaF508 mutation—this is a mutation that causes the protein to be eliminated by the quality control mechanism because they are misfolded. But if they reach the membrane they can be active, so you need chaperones to shut them to the membrane. And once they are in the membrane you should try to find ways to increase their half-life in the membrane. So these are the major advances. Concerning the liver, the interesting question is that not all of the patients develop severe liver disease. Two to five percent of the patients go on to develop cirrhosis, needing transplantation; the other patients can have several different degrees of dysfunction. There’s no real treatment. The current treatment is to use Ursodeoxycholicacid. Ursodeoxycholicacid is probably working; there have not been major trials, but several small-sized trials showed possible activity, and my thought is that it works by changing the pool of the bile acid, making the bile acid less toxic and therefore less damaging for the biliary disorders. But we discovered that the defect in Chloride  iron secretion does not explain everything and actually, we found that CFTR is an important component of the innate regulatory mechanism in the biliaryepithelium. When you lack CFTR, the biliaryepithelium starts generating proinflammatory cytokines. Then, they are able to recruit macrophages and neutrophils—and they carry on the damage.
  《国际肝病》:请您介绍一下肝病管理中的“Value-based Care”的理念。
  Strazzabosco教授:“Value-based Care”是应用于美国医疗保险的一个概念,在欧洲和美国,由于有医疗保险,我们给患者提供的服务全面,但成本巨大。所以,关键是如何在控制成本的基础上,获得最佳的临床转归。由此,哈佛大学的两位经济学家Michael Porter和Elizabeth Teisberg便提出了“Value-based Care”的理念,主要的观点是医疗保险应该面向竞争,以产生最大的价值,即实现患者的最大获益。因此,患者报告的转归除以总体成本就是它的定义,与目前一味地降低成本的方法相比,这是更先进的理念了。价值公式表明不能以牺牲转归为代价,而降低成本——这是基本点。我去过中国,知道中国有致力于为这些疾病患者服务的机构。
  Value-basedmedicine is a concept that applies to European and American healthcare where there’s a lot that can be offered to the patient, but at a very high cost. So the question is how do you contain costs without having a negative impact on the outcome? The idea was generated by two economists from Harvard, Michael Porter and Elizabeth Teisberg, and the idea is that healthcare should be oriented on competition to generate the highest value. So what do we intend with value? Value is the value for the patient. And what does the patient want? The patient wants to be well, heal from the disease or improve his symptoms, but this has to be achieved at a reasonable cost. So patient-reported outcome divided by global cost defines the value, which is still a step forwardas compared to the current approach which is just to reduce the cost. This formula implies that you cannot reduce the cost at the expense of the outcome—the value will go down. This is the basic thing. I’ve been to China, you have this sort of thing. Hepatitis and cancer is a big thing and you do have institutions completely devoted to some of these diseases.
  专家简介:Mario Strazzabosco, MD, PhD, 美国耶鲁大学医学院胃肠及肝病主任,意大利肝病研究学会(IASL)前任主席,主要研究领域涉及囊性纤维化的病理生理学,多囊肝疾病和胆管的疾病的治疗,以及肝癌肝移植术和肝再生医学等研究,担任Hepatology, Gastroenterology, Journal of Hepatology, Hepatology等杂志的特约审稿人,Journal of Hepatology杂志编委成员。

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