Thank you cheers, and it's a great opportunity for a parcel and all of us to be here I bring greetings from our as well as from the Institute of liver and biliary sciences I Have nothing to disclose except that we are very young and bright faculty and very good residents I start with a case. This is a 30 year old male chronic alcohol user For last 10 years who was drinking 150 to 200 grams with the last intake 20 days ago Who presented with jaundice for 25 days? distention of abdomen for 10 days and low-grade fever for 4 days The examination revealed he had features of SIRS heart rate of 110 120 by 50 blood pressure and he had edema icterus and pellet Asterexis spider nevi were present. He had a 5 centimeter large liver, which was tender foam Spleen and he had grade 2 he and free fluid The labs came miss bill rubin was 16 AST ALT were high INR was 2.9 and he was diagnosed as alcohol-associated acute and chronic liver failure As in the first talk On hepatitis B. I would reiterate that at least in a parcel and the Asian region Those who present with hepatic insult and liver failure and have underlying chronic liver disease or cirrhosis Are considered as acute and chronic liver failure and dominantly now it is ethanol you heard about hep B these patients have underlying chronic liver disease or cirrhosis diagnosed by endoscopy biopsy or CT and the liver failure with a bilirubin above 5 coagulopathy and ascites which develops within four weeks or hepatic encephalopathy and the main element is of reversibility So there are two definitions predominantly, I am not discussing the American one and There is time to choose the normal if you have an acute insult you get acute liver failure Decompensated cirrhotic who gets an acute insult which leads to further worsening of decompensated cirrhosis Whether it is sepsis or bleed or AKI is that these are two distinct diseases Let's look at chronic liver disease like f2 f3 or even f4 early fibrosis Those who get an acute insult and have liver failure and that liver failure or jaundice leads to ascites This is a distinct group where acute portal hypertension has developed in a patient with cirrhosis If there is a compensated cirrhosis He can present in different manners one manner can be GI bleed Distinctly different one can be HE one can be ascites one can be HRS or sepsis or a combination So, in fact, there are 29 combinations of these of all these only one Combination that is an insult which presents with jaundice followed by ascites Which is a very homogenous group is considered as a CLF why other definitions would include almost the complete spectrum and of course, it is very Comprehensive but when you want to design trials and drugs, you may be needing a small focused group So, let me further revise it in a parcel the patient is picked up in the liver failure scenario While in easel, it will be an extra hepatic organ failure maybe kidney maybe lung brain or circulation or intestine and Sometimes this may be even without liver failure in a simple cirrhotic So these patients will have SIRS or have immunoparalysis sepsis and sometimes present with shock so I'll just give you now some scenarios in our setup a patient who has hepatitis B Will generally be less meld or CTP while in alcohol, which I am discussing there will be a much higher Meld or a CTP score. They are more sick patients in an ACLF. This data is of 3,100 patients you will see that mortality Increases in bay day 28 about 40% mortality in a CLF workers today Arc has a database of about six thousand three hundred cases 52 centers in 17 countries Now my main task is on management challenges in alcohol-associated ACLF How do you assess? Can you predict and is there a dynamic model and how do you manage? Prevent organ dysfunction and failure and how do you improve? transplant outcomes So, let's go back to our case this patient had jaundice 25 days ago Distention came 10 days. So his ACLF what we have is just 10 days old So jaundice to distension was 15 days now It is 10 days old and he has these lab parameters. Please look at it carefully bilirubin of 16 INR of 2.9 HE of grade 2 and Lactate 2.3 and creatinine 1.1 and that is what is the basis of simple arc score, which is a bedside score So if the bilirubin in our patient like is 16, so he gets 2 points He's in grade 2 HE gets 2 points. His INR is 2.9. He gets 3 points His lactate is 2.3 gets 2 points and creatinine is 1.1. He gets 2 points So 2 and 2 4 and 3 7 2 9 and 2 11 He has a score of 11 at presentation. What does it mean? He is in grade C Arc is called liver failure Now this is to show you and this will be presented tomorrow Anyone who has an arc score of more than 10 This patient by day 7 and then it continues he will have a mortality at 19 days of almost 92 So those who have a high arc score They have a high mortality those who have a less than 10 arc score have a low mortality And this has been tested very well as an index of severity of liver failure and this scores far superior Than cliff's sofa or Other scores which are available At ilbs in new delhi. This is a data for last 8 years up to 17 1550 patients of them Those who had ascites mild clinical and those who had liver failure due to alcohol was about 1230 out of 1500. So this is three out of four patients have underlying liver disease How do we manage them? So a patient who has severe alcoholic or alcohol associated hepatitis with a df of more than 32 is a screen for presence of sepsis He will be started on antibiotics and if needed antifungals an aggressive nutritional therapy Which I will come to it in a minute and then will be considered whether he is steroid eligible or steroid ineligible And then the response will be assessed What are our goals of nutrition? first Foremost is liver regeneration nutrition is just not maintaining life immune restoration I don't have data in time positive nitrogen balance and decrease excess ammonia production improve survival and this is achieved By either placing a nasogastric tube and giving 35 to 40 kilo calories IV lipids because patients cannot take is an integral part of our management Most of our patients will undergo indirect calorimetry to assess the calorie debt And this last year we presented as oral in asld those who have omega-3 They decrease their tnf alpha and il-1 beta and increase il-10 and il-6. So IV lipids are useful even with high bilirubin Steroids is the mainstay and the current recommended therapy Patients who are above 35 df but less than 90 are considered in the absence of sepsis or aki Just to show you 78% of our patients are unfit for steroids at presentation 40 milligram per day for seven days the patient responds you continue with or without Antibiotic and non-response is assessed by lil score of more than 0.45 at day seven however This exposes seven days of steroids exposes them to high mortality and infections We have worked hard for last almost six years to identify baseline predictors of non-response to steroids Most important all our patients would undergo a liver biopsy Is the malary body as well as ballooning index mb index, which is more than five I'll show you presence of cholestasis or eosinophilic degeneration a urine metabolome acetyl carnitine of more than 2500 nanogram is a sure-shot marker of having poor outcome and mortality High hepatocyte specific Microvasicles asgp are positive large in size high iron load transfer in saturation of more than 20 And liver transcriptome from biopsy. I don't have time to show you all but just to tell you that if the patient has got cholestasis ballooning degeneration Malory dank bodies eosinophilic degeneration Most of us feel that this patient will need a transplant steroid non-response is a failure of liver regeneration liver has to regenerate despite Injury, so when steroids are given patient does not respond. It is a failure of cholangiocytes to commit to become hepatocytes we tried GCSF in early days and as you can see that even during liver failure ACLF there is CD 34 cell from bone marrow into the liver Giving GCSF it increased to about two and a half times and this led to an improved survival Although the sample size is small Those who do not respond to steroids do we have an option other than transplant We didn't have any we tried GCSF very carefully and Those who received GCSF compared to placebo Non-responders did improve we however have to say that this group of patients is very carefully selected You must ensure and I'll show you in my next slide that it is under a great hospital care and supervision So who are the people whom you will give GCSF therapy those who have severe alcoholic hepatitis But DF is not above 90 and meld and is less than 20 if the patient has higher meld Don't I try to do this? Dosages can be 150 to 300 Microgram for initial five days and then maybe alternate days or every third day for four weeks You have to titrate before giving every dose We do baseline GCSF and GM CSF in our patients we exclude patients who have sepsis or organ failure and TLC leukocyte count is more than 30,000 for them Leukophoresis is important those who have features of HLH low hemoglobin high ferritin For them bone marrow is to be done those who have renal failure Wait for recovery those who have market sarcopenia and osteoporosis so remember GCSF therapy is for a select group of patients and Avoid GCSF if you are not in the trained group This is a picture taken from Slovakia Bratislava, this is a soldier who is in a pit and It is said that if you touch his head your wishes are actually turned into reality and I did it Just to say and feel that what we are doing as fecal microbiota Transplantation works So we have three trials one was done on FMT steroid ineligible the second we completed few years ago is in the process of submission pentoxifilin versus FMT in steroid ineligible now, we got some more confidence. So now the last trial we finished is FMT versus steroid in a steroid eligible group. I'll just show you data of the first one This was an initial pilot study of eight patients and they were compared with patients who had No stool transplant just conservatively managed and there was a significant survival benefit 8 and 18 patients Now I will go into further management of alcohol-associated ACLF how do you prevent organ dysfunction and failure and how do you improve transplant outcomes? I take you to a new new world This is the world of acute portal hypertension in a patient who already has got cirrhosis of liver with raised pressure now he gets a Acute portal hypertension means he gets a situs in 10 days. He has very high cytokines Stellate cells are super active endothelial dysfunction and impaired vascular relaxation these patients very rapidly in two weeks get Development of varices they get HRS and they have GI bleed Two years ago. We had a plenary here to say that if you gave beta blockers in these patients it reduces mortality This paper just got published the second paper which is online is Modest volume paracentesis. We have introduced a concept of MVP The one I'm showing you is under review the one which has been published is this MVP is done patients with ACLF don't have flanks. They are like 10 subdominant anterior-posterior 10 subdominant with very high pressures in Then if you tap 3 liters or 4 liters not the conventional 5 liters That is more than enough if you tap about 3 to 4 liters and do not give albumin Which is a recommendation for more than 5 liters you get 70% patients will have PICD If you give albumin is still 30% will get PICD and this is just to show you that albumin is useful and is required even for modest volume paracentesis I'll go on to the two other Complications one is AKI and one is hepatic encephalopathy. This is very common in alcohol associated ACLF so you have a newly diagnosed AKI you will give some volume. It doesn't work you give albumin if There is a response. It is very good Then it is functional HRS if there is no response and it is functional HRS if it is Responding then you will give fluids and albumin You give vasoconstrictors if it doesn't work, but the response is seen in only one third So you will have two thirds where high bilirubin is there it will not work Therefore you will be ready for giving an early dialysis sled or CRRT these patients Generally would go into CKD So here is a group of patients of AKI in ACLF which requires highly specialized care We differentiate between organ dysfunction and organ failure Grade 1 and 2 is organ dysfunction 3 and 4 is organ failure and ammonia above 143 has high mortality in ALF it is 120 for such patients You can do plasma phoresis and sometimes ammonia targeted therapy if you do plasma phoresis in them Compared to standard therapy as seen here plasma exchange And this is Mars the plasma exchange scores over and above Mars and others and this is under review Now what is it time and I know the next talk is in a very important talk on liver transplant But I will just share with you what the concept wise timing for liver transplant if a patient has Grade 1 ACLF according to us means the ARC score is between 5 and 7 You have a good chance of transplant survival But as the time passes by you will see that these patients develop sepsis they get organ dysfunction and In them once you have that window of 7 to 15 days gone Then it is very rare. They will get organ failure and it's a good time that you will take within first 1 to 2 weeks Let's say how we did an Asian survey of about 78 Centers which answered different things Asian and European survey and this shows you the most important reason for not transplanting a patient is Sepsis this is a survey of 84 transplant centers that one sepsis has developed transplant becomes a problem Therefore we need to work before this develops So this is an algorithm which we propose Sepsis at any time try to optimize and prevent organ failure Patient has a meld above 30 and ARC score above 10. That means 11 or so. He can be taken straight for transplant If the ARC score at day 4 to 7 is Less then you may act and he is improving then you can continue with medical management So from ARC score of 10, he has become 10 9 8 he is better If however, the ARC score is increasing Let's 11 12 He needs an emergency transplant if the patient at presentation has two organ failures or more This patient might go for plasmapheresis if he is stable, then he can go for a transplant However, if he is not improving then you just need to give a supportive care So those who have four organ failures or more or have two organ failures Which are not improving you can immediately say futility of care So at day 0 or day 4 or 7 you can make a decision Where the patient has to go so in our patient which came with an ARC score of 11 that patient would require an Emergency transplant and if he would wait more than seven days the chances are he may not survive I'm not going to discuss liver transplant, but I'm just raising these issues because of alcohol that timing three months one month seven days abstinence and the ethics related to it Development of sepsis which can occur in seven days because you have given steroids in them and the poor outcome. These are challenges Current thinking and I just leave you with this carry home messages Patient has come with severe alcoholic hepatitis and ACLF has a DF of more than 32 aggressive nutrition should be tried which is for liver regeneration and restoration of immunity and If the patient has steroid eligible and if he responds we are okay, we will continue with the steroid therapy However is steroid ineligible IDF or sepsis or he is steroid non-responder. We have few options for them. One option can be GCSF Suppose he does not respond to GCSF or he doesn't want or you don't think he's fit Then you have an option where you can do These patients with plasma exchange and others However, you have to prevent all complications if the patient is fit ethics allows you can take him for transplant however, if not, you can enroll the patient into new trials of FMT IL-22 and Akinna or maybe zinc or liver dialysis or so. So the field is wide open We have very limited choices I've tried to say what is currently recommended and maybe you can come up with new options and therapies for our patients Thank you for your time

alcohol-associated ACLF

liver failure

jaundice

abdominal distention

organ dysfunction

liver transplant