So, thank you, Dr. Lucey. Dr. Lucey, very elegantly, I described the increasing interest and opportunity for patients in liver transplantation for acute alcoholic hepatitis. I must say that it's not going to be a sword fight, however, this afternoon, because instead of having an argument, I think I'm going to take the approach to augment the points that Dr. Lucey has made already. And I'd like to point out that this patient has already failed previous attempt for alcohol rehabilitation and continued drinking, that I think in many of the centers, including those who perform liver transplantation for alcoholic hepatitis, would still not necessarily transplant this patient with our current knowledge of medicine in the United States. But I wanted to come back to the point that was highlighted in the case presentation, that this patient has variants in the PLPLA3 gene. So perhaps it's reasonable to look into what we understand about progression of alcoholic liver disease. And it's known that with continued alcohol use, heavy alcohol use, steatosis progresses to fibrosis and cirrhosis in patients. However, if you look at the percentages, that's relatively low percent of patients who develop the liver disease in the setting of chronic excessive alcohol use. We also don't understand what is the trigger and which patients will present with the acute alcoholic hepatitis that we are seeing in this patient. Some factors have been identified that include gender, the amount of alcohol digested, coexisting liver diseases, and obesity. Most of those recent studies identified genes that can predispose to progression of alcoholic liver disease. And that includes PMPLA3 steatosis gene, the fibrotic genes, TM6SF2 and MBOT7 have been identified with progression to fibrosis and cirrhosis in alcoholic liver disease as well as in non-alcoholic fatty liver disease. So PMPLA3 is a pathogen like phospholipase domain containing protein 3 that has a variant that is strongly associated with hepatic fat content. And this observation came from the Dallas Heart Study. And it was shown that the PMPLA3 variant has a isoleucine to methionine switch at the position of 148. And this particular variant of PMPLA3 in various studies was shown to be a modifier in the progression of alcoholic liver disease. So this particular study showed that patients with alcoholic liver disease have a much greater likelihood of having the GG variant compared to normal controls. And that was also true for cirrhotic patients with alcohol. A recent study in nature genetics actually reproduced and found a similar kind of correlation in a European cohort. So in our patient, what is the prognosis then? Based on the MAD score, that's a very good clinical predictor of outcomes in alcoholic hepatitis. We know that the MAD less than 20 that identifies patients in moderate alcoholic hepatitis. The mortality is still about 20% or lower at 90 days. Our current patient has a MAD score of 29, which puts this patient into the very middle of severe alcoholic hepatitis category with a 90-day mortality somewhere about 50%. That's very, very, very poor. At the same time, what we can offer to this patient is very limited. For moderate alcoholic hepatitis, we have no standard of therapy. And the medical therapy for severe alcoholic hepatitis currently is steroids that have a benefit only limited to 30-day survival with various side effects, including infections. And this patient has already proven not to respond to this therapy. So I just wanted to highlight here the emergent need for potential intervention and development of new therapies in alcoholic hepatitis, because this is a really deadly disease, yet we don't have appropriate interventions. This patient with a severe alcoholic hepatitis and MAD score of 29, very likely to develop systemic inflammatory response syndrome, either from the alcoholic hepatitis itself or with a superimposed infection that is a high likelihood in this patient who is somewhat immunocompromised from the alcohol use. The SERS will most likely result in organ failure in this patient that is known to contribute to death. And as we discussed, transplantation may not be necessarily offered for this patient. What we also know is that organ failure increases the risk of mortality. And this particular study is in acute and chronic liver disease in ACLF. However, this particular cohort, about more than 60% of patients actually had alcoholic liver disease history, and alcohol was the precipitant for the ACLF. And as you can see, the multiple organ involvement linearly correlates with the increase in mortality in this patient population. Now, even if the patient survived the initial event, then readmission cost in cirrhotic patients is very high. So if we just look at the post-index total cost, it has been shown that there is higher readmission rate in cirrhotics, who are the base of alcohol use, and continued drinking increases the readmission rates. The annual post-hospitalization cost is higher for those who get readmitted within 30 days after the index case, in the amount of about $73,000 per year. Those who get readmitted greater than 30 days after the initial case cost somewhat less, and those who are not readmitted, then the cost is relatively lower. It has also been noted that at one year, less than 20% of patients readmitted within 30 days were at home, meaning the rest of them, 80%, were dead or in nursing home or hospice services, again, highlighting the very severe kind of outcome and poor outcome of this disease. So the therapeutic options for this patient, in terms of medical treatment, essentially are close to none. We consider that this patient already failed steroid therapy, and the remaining options don't really have any proven medical treatment. So what could we do is to provide excellent supportive care, treat infections, and have low threshold for use of antibiotics in these patients. And I'm going to show you that nutrition and then treating the alcohol use disorder and some emerging therapies may bring hope for these patients. So the importance of nutrition in survival in alcoholic liver disease, and particularly in alcoholic hepatitis, has been studied for quite a while. This VA cooperative study demonstrated a dose-response relationship between nutrition and outcome. So the red line shows that a decrease in protein calorie malnutrition score shows a relation with increased mortality. And the normal score would be 90 to 100, that shows no mortality. But if the protein calorie malnutrition score is lower in the 40 to 49 range, that is associated with a mortality of about 80%. The blue line shows the voluntary calorie intake and shows how that inversely correlates in mortality. So here, if the calorie intake is less than 1,000 calorie per day, that essentially correlates with a greater than 90% mortality, whereas a greater than 3,000 calorie intake per day essentially correlated with no death in this patient population. Nutritional recommendation is about 35 to 40 kilocalorie per day body weight and daily protein intake of 1.2 to 1.5 gram per kilogram body weight in this patient population. Another recent study showed the six-month mortality according to distribution of daily calorie intake. And very briefly, this study showed that patients who had less than 21.5 kilocalorie per kilogram body weight per day calorie intake had significantly higher mortality compared to those who were able to consume larger amounts of calories. So this was roughly translated to about 1,700 kilocalorie per day for those who had improved survival compared to those who had high mortality with less than 1,700 kilocalorie per day intake. Another point that Dr. Lucy very nicely elaborated on is the alcohol use disorder that is a co-founding element in the disease of these patients. So studies show that persistent alcohol intake is associated with increased mortality, while cessation of alcohol consumption improves survival. And medical and surgical treatments for alcoholic liver disease have limited success when patients continue to drink. So this particular study showed the complete abstinence has a superior survival in alcoholic hepatitis patients compared to those who continue to drink or have recidivism in a period of 180-month follow-up. So at this point, it is concluded that the most effective treatment, if you will, for alcoholics with alcoholic liver disease is to achieve total abstinence. However, we all know that this is very difficult to achieve and it takes more effort than what necessarily a hepatologist can provide. So who should kind of participate in this process? Psychiatrists, psychologists, or social workers? And I would make the argument that I think our current understanding is that there should be a provider team of hepatologists with behavioral and psychiatric experts to improve the prevention of relapse by management strategies that includes team approach. And in this team approach, we may want to include the patient and the families because obviously they are the major participants. Treatment of the alcohol use disorder should probably include psychosocial intervention in combination with pharmacological therapy. And however, we have to point out that at this current point, we have limited therapeutic options for alcohol dependence because the disulfiram and naltrexone in various forms have hepatic toxicity in advanced liver disease, leaving us with a composite as a choice amongst the FDA-approved drugs at this time. I would like to point out that the NIAAA has various tools that we can provide to our patients. So the Alcohol Treatment Navigator is a very user-friendly website that actually provides geographically specific information to patients and families on alcohol use treatment options. And the SAMHSA National Helpline is also available 24-7. So finally, I wanted to leave you with the hopeful future that based on science and preclinical studies, now we have multiple potential targets for potential interventions in alcoholic liver disease that obviously is going to take a while to translate to human studies. But targets such as inflammation, the hepatocyte damage, and targeting the gut are all components that are under investigation. And it looks like that my slides are not showing the animations. But essentially, the ones that are highlighted in orange indicate agents and interventions that are either in phase one or phase two clinical trials in humans. And what you don't see here is the, oh, here we go, IL-22 is in early clinical trials in hepatocytes and multiple attempts and potential targets have been identified for the mucosal barrier dysfunction and microbiomes and or intervening at the level of LPS. Thank you.

liver transplantation

acute alcoholic hepatitis

genetic factors

PMPLA3 gene variant

alcohol use disorder