Thank you Jonel for taking the time to talk to us today about complications to cirrhosis. Do they all begin with portal hypertension? Indeed, complications of cirrhosis usually begin with portal hypertension. Especially, portal hypertension you cannot notice. It develops slowly due to fibrosis and due to changes in the vascular system. What are the most important complications? The early complications of portal hypertension are actually developed on the varices and subsequent bleeding, as well as development of ascites, which is an accumulation of fluid in the abdominal cavity. Could you tell us a little bit about ascites? How do you diagnose it? Ascites is not difficult to diagnose. You can even see it in the patients during the physical examination. The patients also report of having gained a lot of weight even though they do not eat much, or they have edema in their legs, in their lower limbs and so on. This is a sign of portal hypertension with hydropic decompensation with ascites. What about diagnostic imaging? Of course, the easiest thing to do is ultrasound and you can already see ascites very clearly in ultrasound if the patient has one. Indeed there are many patients with ascites which they don't know about and they do not complain about it, but in the routine ultrasound you may see ascites. Is it dangerous to have ascites? Spontaneous bacterial peritonitis can develop in patients with ascites often. This is when bacteria trans-pass the intestinal wall and get into ascites and they lead to a severe infection with abdominal pain, and this is a life-threatening complication. By that reason, of course ascites is very dangerous. How do you treat it? Early stages of ascites, you can treat it with diuretics and the patients will become fine for a long time. However, there is some point in the trajectory of the patients with ascites where they do not respond anymore to diuretics. So either they have ascites despite high doses of diuretics, or they develop renal dysfunction due to diuretics. When this point is reached, then we should consider to have them repeated paracentesis. So having always substituted with albumin, when you remove large-volume paracentesis. But in these patients you should always consider a TIPS and you should evaluate these patients for a TIPS. A TIPS is a transjugular portosystemic intrahepatic shunt. It's a stent which is placed between the portal vein and the hepatic vein to decompress the portal hypertension in the portal vein and thereby improve the profusion of the kidneys. and thereby treat ascites over time. Can that be dangerous? Yes. A TIPS is not a routine procedure for everybody. So we cannot do a preemptive TIPS in patients with ascites, but when they develop severe ascites or when they are in need of repetitive paracentesis, we should consider a TIPS in this patient. Because TIPS in the other hand is a shunt, which means that the blood does not flow through the parenchyma of the liver. It is shunted through the liver. Therefore, the patients may develop complications like hepatic encephalopathy through this bypass. You mentioned the kidneys. Can they be affected by ascites? Of course. The kidney dysfunction or ascites is a read-out, or is a surrogate of kidney dysfunction, which is not because kidneys are structurally impaired. So you don't have a structural damage in the kidneys, but they are functionally impaired. Portal hypertension leads indeed to kidney dysfunction through different activations of humoral systems like the urinary system and sympathetic nervous system. Thereby you have a vasoconstriction inside the kidney, and thereby you do not have water excretion, but instead you have sodium reabsorption in the kidney. So you lose very little sodium in these patients through urine and thereby, as you may know, sodium is attracted to water, so you have a lot sodium in the body and thereby you attract water in the body. That's why you have a higher amount of water compared to sodium. So you have a dilution hyponatremia. Can you end up with a kidney failure? Of course. This is the maximum form of kidney failure in the patients, or of the kidney dysfunction this patient has a kidney failure, which can be due to an acute kidney injury, and the so-called hepatorenal syndrome. Or it can be also through a chronic kidney dysfunction in cirrhosis, which is called the non-acute kidney injury hepatorenal syndrome. Kidney failure is one of the definitions of acute and chronic liver failure as well. Upper gastrointestinal bleeding from esophageal viruses is one of the most serious complications to cirrhosis. Can you talk to us a little bit about this? Yes. This is really a life-threatening complication. The patients, due to portal hypertension, develop varices. These are intraluminal collaterals. 90% of the patients develop them in esophagus. There are some patients who have ectopic varices, especially gastric varices. These patients indeed, when the portal pressure or the pressure into the varices exceeds the wall tension of the varices, then it comes to a rupture and the bleeding. Indeed these patients need acutely help. You need endoscopy in these patients. They need antibiotics, because we know that these patients develop infections very often, and you also need to decrease the pressure, so you need vasoconstrictors in order to decrease portal pressure. Especially the repression is widely used in Europe. Can you prevent bleeding from the varices? If you decrease portal pressure chronically, then you may prevent bleeding. There are several thresholds which have been defined as clinical significant portal hypertensions. This is when the gradient between the pressure in the portal vein and the hepatic vein is more than 10 millimeters of mercury. Then we have a high risk of development of varices. When this gradient between the portal vein and hepatic vein exceeds 12 millimeters of mercury, then you have a high risk of bleeding from varices. If you through different pharmacological interventions, decrease this portal pressure, or decrease this gradient below 12, or below 10, then you may be safe in the follow-up. So these patients will not experience varices bleeding. Are there any other measures that you can take? Of course, if you have patients who are very severe with trial B, or an active bleeding endoscopy or trial C cirrhosis, then you may consider TIPS in this patient. TIPS is the shunt between the portal vein and hepatic vein through a stand. Indeed it decompresses portal pressure and it decreases rapidly the pressure in the varices, and thereby the patients stop bleeding. On the other way around, when you do the TIPS, then you can still embolize the varices through the portal vein because this is a interventional radiologists technique. You are already on the portal vein and then you can just perform embolization of the link between the portal vein and the varices. Hepatic encephalopathy is another serious complication to cirrhosis. Can you tell us about this? Hepatic encephalopathy is a cerebral dysfunction. The patients may have a very different phenotype. It comes from a little bit of slurry language up to coma. It defends on the grade of hepatic encephalopathy, and this is mainly due to hepatocellular dysfunction. If the patients, or if the liver function is severely impaired, then the patients will develop hepatic encephalopathy. Or if there is a very large fainting, in case for example, a very large TIPS or the spontaneous portosystemic shunting, then these patients also will develop hepatic encephalopathy. Is it treatable? Yes. Fortunately it's treatable. In many patients we can control hepatic encephalopathy through different strategies to remove ammonia, which we know, and also to remove or to decrease systemic inflammation. You can give lactulose for example, and this will lead to a lower production of ammonia in the gut. As you may know, the ammonia comes majorly from the gut. You can also give rifaximin, which has a similar mechanism of action. It also decreases ammonia production. But also in the patients with acute or hepatic encephalopathy not responding to lactulose or to lactulose treatments. You may also give L-ornithine L-aspartate IV, which increases the degradation of ammonia in these patients. What happens when the drugs no longer work? This is an important challenge in the medicine. There are several ways or treatment opportunities. One of them is artificial liver support. For example, MARS or other techniques which may remove using extracorporeal circulation, may remove ammonia from the blood. Of course, also liver transplantation is another option. Which patients would be eligible for a transplant. Talking about transplant, it is very important to see that we have very different allocations. So organ allocation policies in different countries in the world. Indeed in Europe, we are MELD-based. That means that MELD or the model for end-stage liver disease , which is a formula based on which you can predict the three months mortality of the patient. This number ranges between 6-40. It is known that with the MELD score of above 50, you are eligible for liver transplantation because then the mortality after liver transplantation will be lower than the patients with an old liver. You can consider the patients with a MELD score of more than 15 to be listed, or to enter in the wait list for liver transplantation. In different countries, there is a different allocation strategy, but usually the allocation is through the MELD score, so the higher the MELD score the more urgent is the liver transplant indication. Thank you very much Jonel. It's a pleasure.
