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.
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.
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。