[MUSIC] Cirrhosis is a serious complication to NASH. It's characterized by loss of healthy liver cells and extensive scarring of the liver. Cirrhosis has severe consequences for the patient. In order to learn more, I've consulted Jonel Trebicka, who is an internationally recognized expert. So thank you very much Lise Lotte for inviting me, it's a pleasure to be here. Indeed cirrhosis is one of the the most important and serious complications of NAFLD and it develops due to inflammation and fibrosis. Nodules in the liver, they are generated by the proliferation of the hepatocytes, and then we have hepatic stellate cells, which are activated and produce extracellular matrix. This remodeling of the liver leads to increased portal pressure and also to complications. Cirrhosis is quite often even though we don't think about it. Chronic liver disease, there are about 80 million people worldwide suffering chronic liver disease, and deaths due to cirrhosis are about 2 million every year, so cirrhosis is one of the most deadly complications of NAFLD. If we look at the age-adjusted mortality, cirrhosis has a very high mortality in Europe, up to 20%, so this is really a serious complication of NAFLD. We often talk about cirrhosis as an end stage liver disease. How long can you live once you've had the diagnosis? Indeed, it is not easy to assess how long the patient can live after the diagnosis, because they may live from 30 years with the diagnosis of liver cirrhosis or end stage liver disease, up to several months if they develop complications and acute or chronic liver failure for example. Can you improve once you've had cirrhosis and you become very ill? Once, people in the textbooks had written that cirrhosis was an irreversible disease, but it's not. Now we know that if you remove the etiological factor, for example a viral or alcohol, if it's an alcohol-induced liver injury, then you can improve. Also not only fibrosis decreases, but also you can even reverse from cirrhosis with complications to a lower grade of fibrosis. Do you think theoretically that could happen to patients with NASH cirrhosis? I think this is a very good point, it depends on how intense the intervention is. For example, if the patients are on a diet and do physical activity, they improve very much. And there are data showing that they can even decrease more severe or end stage liver disease as shown by portal pressure, for example. You can decrease portal pressure by diet and exercise. What happens in the body once you've developed cirrhosis? Where does it go wrong for the liver? Indeed this is a very important event in the patient's life or career, because in the moment where the liver goes systemic, then the patient develops complications. That means that the problem is not only located in the liver, when you have cirrhosis, but then through the portal vein you have increased portal pressure. This leads to vasodilation in the splanchnic region, and the cardiac output consequently will increase. So you have an effect of the liver to the whole body, and this is the hyperdynamic circulation with portal hypertension, which decreases the perfusion of other organs and impairs function of other organs. And this is the moment where the patients really suffer from cirrhosis and complications. What about the liver function itself? As it is written already in the textbooks, the liver has a very strong regenerative capacity and can regenerate very fast. So you need very little liver tissue in order to fulfill the vital liver functions. So in the end, with a little function of the liver, the patients can survive but still, all the impairment of the functional extrahepatic organs, of the other organs except for the liver. This is what is limiting the life of the majority of the patients with liver cirrhosis. Do you use this in your assessment of prognosis? Of course, because prognosis is a combination. There are several prognostic scores which are dated back to the 60th of the last century. For example, the Child Pugh score or the MELD score, which was in the end of the last century. They include, for the Child Pugh score, it includes the liver function tests like bilirubin and albumin. But also it includes the development of ascites, which is a surrogate of renal dysfunction and portal hypertension. It includes hepatic encephalopathy, which means that the patients have a cerebral impairment and also a coagulation fraction, which also is due to the liver function. While in the MELD score, you have altered creatinine, besides bilirubin and INR, which are also markers of kidney function. So we see that the extra hepatic organs have a big impact in the outcome of the patients with liver cirrhosis. So the Child Pugh score that's class A, B and C, how would the prognosis be different for patient in Child A cirrhosis, compared to Child C? Child A cirrhosis are basically the patients we were talking about before. They will live 30 years with cirrhosis, and they will never suffer complications or a very low rate of complications. Child B patients have usually ascites, severe ascites, they have liver dysfunction, so you will see that the bilirubin has elevated, and they have lower albumin. So the synthesis capacity of the liver is decreased, and they have a degree of hepatic encephalopathy. Child C patients are severely ill patients, which usually are in-patients, and they need emergent treatments. What about other scores, we often have patients these days coming in with acute liver failure. Can you assess the prognosis based on this additional information? Indeed, acute-on-chronic liver failure, which is recently described by the CLIF Consortium and also by others, depends very much on the acute development of complications and hospitalization of the patients. And due to this, we know now that systemic inflammation is one of the key factors, leading to increased mortality in this patient development of organ failure, in these patients. Therefore, there are two different scores or there are three different scores, which we've been describing. The organ failures in patients with cirrhosis, one is the Clif-C organ failure score, which describes how the different organs are failing in these patients. The other one is Clif-C ACLF score, which describes the mortality rate of the the patients with ACLF. And the last one is the Clif-C AD score, which is for patients who do not have acute and chronic liver failures. So not ACLF, but they have an acute decompensation and come into the hospital, and this describes the prognosis of these patients in the next three months. Is this treatable? This is a good point. Actually, if you remove the precipitating event and if you treat these patients aggressively, you may treat some of them, and some of them also reverses from ACLF into acute decompensation state and they may be stabilized. But the acute-on-chronic liver failure itself has a very high mortality of almost 60% in three months. What if patients survive, will they become Child A cirrhosis with a prognosis of 30 years, or will it be different from before they had acute-on-chronic liver failure? This is a very good point. We were now analyzing the predict study, which was just accomplished. This is a study, as you know, because you participated with more than 1,300 patients in 48 hospitals in Europe, and we looked exactly on this topic. So what comes after acute-on-chronic liver failure, or better to say, what comes after acute decompensation. And we could describe three different trajectories of disease. The one trajectory is the patient who will develop ACLF in the next three months. The other one are the patients who will have an unstable trajectory in the three months, so they will have made several readmissions, but they will not develop ACLF. And the other patients are the patients who come to the hospital with acute decompensation, but they will stay stable. And these patients are 60% of patients. So there is a chance of 60%, if you come, if you enter the hospital with acute decompensation, that you will stay stable for the next year. Indeed in this patient group, only 9% of the patients died during the first year. And we have to imagine that these are of course Child B and C patients, so they are decompensated, so they had suffered the decompensation. But still, this is rather not so dramatic, the trajectory of disease in these patients. So in conclusion, would you say that there's a wide variety of clinical presentations for patients with cirrhosis? Yeah exactly, so actually we can divide, we can stratify the patients with cirrhosis into several groups. You have the compensated patients, which are advanced chronic liver disease patients or cirrhosis patients. As we said before, this is reversible, so you don't have a borderline there where you say - okay, there is no point of no return if you remove the injury. Then you have the decompensated patients with after decompensation, which is rather defined by development of ascites. In these patients we can stratify the patients who are stable, decompensated. When they usually come into the outpatient clinic, they don't need hospitalization, or the patients who are acutely decompensated. And in these patients, we have patients with very severe cause of acute decompensation, which is the acute-on-chronic-liver failure, ACLF group. And then you have the three other forms of trajectory, whether you have the patients who are stable decompensated patients or unstable decompensated patients. And pre acute-on-chronic liver failure, the patients who will develop acute-on-chronic liver failure after this first hospitalization. So we will have four, more or less states of decompensation, and you will have also the decompensated patients. So this would mean that you'd have to tailor your assessment of the patient and treatment exactly to the presentation, and that you can always at least try to to help. This is very desirable, but unfortunately we're not yet there. So we would like to be there, this would be perfect because then this would be personalized medicine. Nevertheless, this is still work in progress because the point is, how can we predict the development of one or the other trajectories? So this is very difficult. But these are their many investigations now running, and we hope that in the next years, we will be able to separate the patients or certify the patients according to their needs. [MUSIC]
