Dr. Karvellas explores current prognostic scores, novel biomarkers, and management of ALF.
we're now going to move on to our Williams. How Brick memorial lecture It is my absolute pleasure to introduce Dean Corvallis. So I um, Dean is a wonderful hepatology pissed. He's a professor of medicine in the department of Critical Care Medicine and division of gastroenterology at the University of Alberta. He's been absolutely stunningly wonderful in management and studies and progression for treatment of acute liver failure. We all know that. Bill how Brick was a wonderful gash neurologist. I'll never forget him. And I had the blessing of being able to be a fellow under his teaching. Um and he was a wonderful man and we're still happy to have his memorial lecture going. So I am happy to now pass it off to Dr Carmelo's to talk to us about acute liver failure. Thank you very much uh carry for the kind introduction. And it's a real pleasure to give this lecture um at this meeting. So my name is Dean Corvallis and I practice hepatology and critical care medicine at the University of Alberta. And I'm going to be talking to you about acute liver failure and I have nothing to disclose. Um The objectives of this talk is to review the definition of acute liver failure and review the current evidence for the management and specifically the the gaps in evidence of LF, specifically focusing on protecting the brain. Um and also some of the newer data regarding the use of extracorporeal therapies such as continuous renal replacement therapy, explore some of the current prognostic scores and the potential opportunity for novel biomarkers explore the challenging role of transplant in acute liver failure. So just uh I know that we all know this, but just to remind us again that liver injury comes in two flavors. There is the more chronic form of fibrosis which which we see in cirrhosis, which leads to portal hypertension, and in contrast to this acute liver injury as a necro inflammatory process characterized by hypotensive necrosis, resulting in a pro inflammatory cascade. These are patients that had no prior liver disease and did not develop portal hypertension. And one of the real differences between acute liver failure versus acute on chronic liver failure is the concerning for the development of intracranial hypertension and cerebral oedema. So I became really interested in A. L. F. And I call it the classic intensive care physicians disease because it's multi system. So LF can can affect the brain with the hepatic encephalopathy. In cerebral oedema, these patients develop a high output cardiac output state. They can develop acute lung injury. Uh We're aware of the hepatic complications such as lactic acidosis, hypoglycemia and in particular hyper um anemia that can develop um they can develop pancreatitis. They can develop adrenal insufficiency, acute kidney injury, bone marrow suppression and sepsis. So, within acute liver failure there are three different prototypes and classically the the most rapid one is hyper acute liver failure and this is acetaminophen toxicity. And generally these are patients that the timing between the development of cattle apathy from initial liver injury is less than a week. They tend to present with the most profound curricula apathy and are more likely to end up in an intensive care setting. And despite the fact that these patients have the highest risk of intracranial hypertension, they have the highest probability of spontaneous survival without transplants. So this is really the population of patients where as clinicians we can have a significant impact on preventing transplant and helping somebody walk out of the hospital. In contrast to this, on the other end of the spectrum, you get sub acute liver failure and this would be your idiosyncratic drug injury, for example, where often these patients may take several weeks to develop liver injury and eventually liver failure. And by the time they meet poor prognostic criteria, there is really little or no chance of the little liver recovering. And often they will just go on to get a liver transplant. So a lot of the data I'm going to present today is possible because of willie founding the USA El FSG back in 1998. And I really owe a great deal to, to will for for advancing this field in my own personal career. So the US acute liver failure study group registry. This is the classic example of of an NIH funded network where often to study an orphan disease, We need to pull data for many different sites. Um, at one point, there were over 20 sites that were part of the A. L. F. Registry that's currently 12 ongoing. We now have over 3000 patients of which some are acute liver failure and some are acute liver injury. And just to give you an example, the most common cause of acute liver failure in the US and Canada is actually acetaminophen toxicity and this makes up approximately about 46% of patients with the second most common being drug induced liver injury from an idiosyncratic form. One thing to mention is that there is still a group of patients that we classify as indeterminant, meaning that we work them up for viral hepatitis, autoimmune, Wilson's uh and drug-induced liver injury. We don't confirm a diagnosis and and previously had been noted that this was about 10%. There's been an ongoing endeavour within the FSG to go back through the causality Committee and try to audit many of these cases With some of the newer technologies we have, for example, including acetaminophen adducts. And what I want to mention is this is probably only about 5% of cases now. So ideology has a significant impact on prognosis in acute liver failure. And one example is acetaminophen or paracetamol as it's known in europe has the highest rate of transplant free survival. Um and only a small minority of patients will go on to receive a liver transplant. In contrast to this, you get poor prognostic ideologies such as idiosyncratic dilly, or, or foreman and hepatitis b. For example, we're only a small minority, less than 20% will survive without transplant. In the vast majority of these people to have a favorable outcome will need a liver transplant. So putting that kind of in combination ideology and if you have the second cap factor of West Haven criteria, hepatic coma, great. Both have a significant impact on prognosis. And you can see whether you have a favorable ideologies such as acetaminophen or hepatitis A or ischemia. The discrimination between having a low coma grade where the patient is talking to you versus a high coma grade where they're quite intended or likely require intubation, uh ends up having a significant difference on on overall transplant free survival. And this also is similar in the case of patients with the poor prognostic ideologies such as hepatitis B. So we're all aware that there is a significant amount of evidence of the use of an a subtle Sistine as an anecdote in acetaminophen induced liver failure. And and this is very well known. One of the questions that comes up is what about the use of acetaminophen in non sort of the use of an asset to assisting to uh to up regulate the glutathione pathway um in non a pAP induced LF. And this was a randomized study that was done through the LFs G. Back in 2000 and nine. And as you can see in this graph that in those patients that either had high or or sort of low coma grade, the use of anecdotal assisting was associated with an improvement in transplant free survival. So the bottom line is generally we will use to settle Sistine in all causes of acute liver failure, really where the question comes up is if somebody is not in telepathic and doesn't technically meet the criteria for acute liver failure and it is not caused by acetaminophen is a much more kind of difficult question. And really here you're doing it based on risk benefit. So the most concerning complication of a. L. F. If you went back about 20 years ago was intracranial hypertension or cerebral oedema. And we see this a lot more commonly in hyper acute liver failure, specifically from acetaminophen. The good news is with advances in Euro critical care and neuro protective strategies that rates of intracranial hypertension are actually going down. And this is data from Britain and I'll show you a little bit later in the talk that we now have data from north America that shows the same thing. There are two mechanisms for the development of intracranial hypertension and cerebral oedema. One is the development of cida toxic Kadima which is classically astrocytes swelling from the rapid accumulation of glutamine in astrocytes because of interruptions in the recycle and hyper um anemia. And really we see this in hyper acute liver failure in particular. And we don't see this in psoriatic patients because of this rapid accumulation of ammonia which the extra sites are not able to compensate by expelling other active Oz mel's the second factor that comes into this is disruption in the blood brain barrier and Visa Jenna Kadima, which can lead to loss of cerebral auto regulation with blood flow. So as I mentioned, while we know that that's uh ceremonial levels don't tend to correlate well with greater and Keppel apathy. In psoriatic patients, Ammonia levels are very important in acute liver failure. And in particular they discriminate those patients that are highly likely to have intracranial hypertension with those that do not. And this was based on this study by will burn all back in 2007. And really if you look at this multi variable mark, multi variable model, which is what they did. All of the other factors that were associated with the development of I. C. H. Kind of reflected this significant pro inflammatory cascade. They were visibly GIC. They had acute kidney injury requiring renal replacement therapy. And the other thing was that they had high grade coma, meaning you're most likely to to only develop intracranial hypertension if the patient is not talking to you. So from this also we tend to use a cut off of an ammonia of 150 with regards to when we make the decision about hooking somebody up to some kind of extracorporeal circuit. So just to remind us basic neural protective strategies and these have been published in a variety of different areas of brain injury. We keep the head of the bed at 30°. Uh we try to minimize coughing and suctioning for the patient. Uh If patients are mechanically ventilated and a lot of them are. We try to maintain the carbon dioxide level within the no low normal range because CO two is a potent cerebral vino dilator. We will use agents like propofol to sedate agitated patients. We know that fever is bad, that hypothermia can precipitate cerebral venous dilatation. Um There have been a couple of studies looking at prophylactic hypothermia and I'll show you some of that data where it can be a bit challenging to try to mitigate the osmotic effect of glutamine. We generally try to maintain the serum sodium on a on a higher level. And one of the simplest uh circuits that we can run in most of our ICU settings is actually continuous renal replacement therapy. Or using him a filtration which most centers that have an intensive care unit will have access to. So the one question that comes up is should we be putting in direct intracranial pressure monitoring. And this is a technique that has has become less and less common over the last several years. We looked at this through the acute liver failure groups registry back in 2014 And what we did is we picked the high the patients that we felt were at highest risk of developing intracranial hypertension. These were 629 patients with high grade hepatic coma. And what we found was that of the 143 patients that had I. c. p. monitors. About half of them had evidence of significant intracranial hypertension and that's the pressure of greater than 25 mm of mercury. If you were listed for transplant you were more likely to have a bold so often they were using these as as a stop sign. If you will to say that if you have uncontrolled then we'll take you off the transplant list because we won't be able to get you through the through the transplant. However, the the monitor itself was not associated with the difference in outcome, which means likely that this is probably to be used in highly selected patients but certainly not for all a lot of patients. So one of the interesting advances has been in the use of non invasive techniques and we've seen this in a lot of different areas of neural critical care. One is using transcranial Doppler, which is an ultrasound technique to look at the pulse utility index of the middle cerebral artery. Another thing that we can do is actually look at using a linear ultrasound probe is looking at the optic nerve or looking behind the eye and looking specifically at the nerve sheath. Um And there I will kind of go over some information about neuro bio markets and show why they essentially they don't work. So this is really what an optic Shirvani optic nerve sheath a diameter. When we measure this what it looks like. And essentially you just put a Essentially tape over the patient's eye and then you'll use an ultrasound probe to look at this nerve sheath. And generally you would this is where you'd be looking at at seeing if this is greater or less than five. And there's five has come from previous publications in in in the general neural critical care literature. Unfortunately with these types of techniques there's a lot of inter observer variability and the biggest study that looked at the use of both transcranial Doppler and optic nerve sheath and acute liver failure patients showed that the area under the curve was somewhere between about 0.5 and and um with T. C. D. S. Up 2.9. So there was a lot of variation and the challenge of this is just between different operators. You can get slightly different results. So this is certainly not standard of care but needs more more information and more study. Um I just wanted to show you some of the underwhelming data with the use of of biomarkers. If we had a blood test to get to to try to discriminate patients that were high and low risk this would be very helpful. Uh But this is just one example of looking at brain type fatty acid binding protein by our group where we weren't able to really show that it discriminated at all between those patients that had evidence retrospectively of cerebral oedema and those that did not. Um I mentioned before that one of the therapies that we will use is um that's been used for example in the cardiac arrest literatures, therapeutic hypothermia and when looking at all comers. And this was at once again high risk patients of cerebral oedema patients with high hypoxic coma grade. Um looking retrospectively at those patients that were actively cooled with a device like the like the arctic sun where they were on an external external cooling device. There was no significant difference in outcome when looking at the registry overall. And also probably a more uh methodologically robust study was this prospective study that was done at King's where they randomized patients to to moderate hypothermia to 34°. And while they were able to demonstrate a difference in temperature, there was no difference in outcome. What I will say though, is twofold, is that uh, this once again is also probably for a select population of patients and not for everyone because cooling people also has risks. Um But what I will say is well is that even when we put people on for example a CRT circuit we give patients a replacement fluid And often we warm this up to body temperature. So often we passively cool patients into kind of the 35-536 range by not rewarming this replacement fluid on a CRT circuit. And unfortunately neither one of these two studies took that into account. Mhm. So one thing to mention is drugs like blacks, yellows and reds maximum do not work in acute liver failure for hyper um anemia. And generally what you need to use some kind of a blood purification circuit. And the simplest one as mentioned is just it's just our standard CRT machines. And the reason why we like continuous uh techniques is their low efficiency. So you have less salute shifts. You don't get changes in I. C. P. And the one benefit is that you can really you can use these devices and very human dynamically unstable patients. And often we start this not for traditional Ak i uh indications but really it's for volume overload lactic acidosis and hyper um anemia. So um I know that depending on where you where you work this this might be done by a critical care physician. It might be prescribed by a nephrologist and it might be prescribed by somebody that doesn't see very many of these patients. So often the question was where is the data to support this? Well we published this study back in 2018 in hepatology that showed here that if you compared uh these were LF patients with serial ammonia levels and we compared patients that either were on continuous renal replacement therapy or those that were not or those that received intermittent hemodialysis, which generally we don't do anymore. There was a statistically significant improvement with CRT that was not seen in the other two groups, and probably the take home slide here. And it probably shows something that we've that in in smaller centres that was known for for the last several years, that after looking at this big model of almost 1200 acute liver failure patients, and we know that we tend to do more invasive things and sicker patients. So, after adjusting for severity of illness and cause That the use of continuous renal replacement therapy was associated with almost a 50% drop in mortality, Which likely partly was because of the neuro protective benefits were. In contrast, if you see here, the use of intermittent dialysis was actually associated with a 50% increase in mortality, and this was likely in patients that were in an earlier time period where we know that diet that dialysis disequilibrium is very common with high blood flow rates. So the take home point here is that CRT is neuro protective and has a significant benefit in LF. But using intermittent dialysis over a three or four hour run can actually be very harmful to the brain. So the next step up is what if your patient is already on CRT and their deteriorating, whether, what other options are there out there? So there is albumin dialysis which is available in some selected centers and this is the molecular absorbent recirculating system, or Mars, which is probably the most widely studied one. This was a study from France that randomized 102 patients over 16 transplant centers and one of the differences in France compared to the U. S. And Canada is that organ donation rates are significantly higher in europe. So one of the confounding factors in this study was that the median time from listing for transplant and a lot of these patients were listed for transplant to getting a transplant was only 16 hours. So of all the patients that were randomized for Mars, 14 out of 53 of them never even completed their first run. So this was a negative study, but the study was heavily confounded by transplant more recently. What we did is we uh within the L. FSG registry, we kind of did the next best thing to a randomized study which was a propensity match study uh where we found that there were three centers, we were one of them that had patients enrolled in the LFs, the registry that had received MARS. And then we attempted to match them to propensity matched contemporaneous controls that were matched on a variety of different factors from the registry. And what we were able to demonstrate in this study that after adjusting for markers of severity of illness, such as the need for vase oppressors, I and our and the propensity score uh that the use of MARS was actually associated with an improved outcome in acute liver failure. So this is something that probably highlights that if you have a patient on CRT and their deteriorating that this might be of some benefit, particularly probably in acetaminophen induced acute liver failure. However, before I would go out and and suggests that you should get one of these devices, it should be noted that plasma exchange, which is significantly cheaper, actually also has significant benefit in um probably in acetaminophen induced LF. And this was a study that was published by Finn Larson that was a collaboration between Denmark uh Kings in London and in Finland, where they demonstrated that in those acute liver failure patients that did not go on to get a liver transplant, those who received high volume plasma exchange had a significantly improved outcome At 90 days compared to those that didn't get plasma exchange. And obviously the biggest question here is that which patients are most likely to get plasma exchange should not be on the transplant list. These are generally acetaminophen induced acute liver failure patients. So in our center General, we will start with CRT and somebody for example that has an ammonia greater than 1 50. That's at high risk of intracranial hypertension. Or somebody that's got profound shock. And if they don't improve, we will do runs a plasma exchange. So what about prognostic scores and biomarkers? So we know that the King's College criteria were initially published in 1989. And they have been uh several follow up studies to uh to assess its validity. One of the challenges in modern hepatology and critical care is that if you look at the acetaminophen criteria, both the creatinine and the ph will be confounded by things like the use of of continuous renal replacement therapy. And you can also see that in more recent analysis, the sensitivity where somebody might not be criteria but not necessarily have a favorable outcome um is significant more recently, the L FSG came out with with our own prognostic score. And really it's to highlight here that we don't use one prognostic score to make a decision about listening LF patients for transplant. And generally we use it on a composite of different factors. But what you can see here is things like coma grade ideology, billy Rubin and I in our common between the FSG prognostic index, as well as the King's College criteria. This one also incorporates vis oppressors. So if you're on high dose pressers that can portend a worse outcome. There are other factors such as lactate, which are which we use at the bedside quite frequently that are not in any of these prognostic scores. And also you need to look at the at the temporal change to see how patients change between, for example, admission to icu and 48 hours later. So with a sub acute liver failure patient generally, this has been going on for weeks and the writings on the wall and similar to a seraphic patient, we know that they need to be listed for transplant. But this is much more important in an acetaminophen patient where there are a lot of patients that have potential for recovery and if we can buy them some time for their liver to recover, it's much more advantageous to avoid a transplant and immuno suppression for life. So, as mentioned, because of these limitations, are there other prognostic biomarkers that could be valuable? And I just show one example that our group, in collaboration with chris rose and Montreal looked at liver type fatty acid binding protein, which is a small side of plastic protein that is abundantly expressed in the fat rich parasites, essentially, this tends to be expressed in response to inflammation and is elevated in the setting of failed to parasite regeneration. And what we were able to demonstrate is that F A B P one and a pap and acetaminophen induced LF discriminated fairly well between survivors and non survivors at both early and late time points and on this multi variable model on the right, it added value. So if you added this, the F. A. B. P. One serum level to the king's criteria or the LFs. G. Uh prognostic index. It added it improved discrimination with that was statistically significant. However, I should caution that when we took a look at the same marker in other causes of acute liver failure, it was not statistically significant. Um So this is just one example more recently. Also with collaboration with colleagues in Britain, we've looked at some micro RNA signatures and this work by Oliver to bobby is very interesting because they were able to demonstrate that micro RNA signatures on admission that were associated with regeneration discriminated very nicely between survivors and non survivors. But when we looked at blood samples between day three and day five, it was actually those that were linked to cell death. That had more useful prognostic information. I'm not to say that any of these in general are standard of care, but it just shows where the field is going and we're potentially we can improve our our prognostic models and LF because there is a definite need. Finally, I want to finish by saying that we are getting better at this and this is a nice study that my graduate student Andrew Macdonald just published, particularly looking at the at acetaminophen induced LF over the last 20 years. And when Andrew stratified patients between two decades, the last decade, the of 2000 and 8 to 2018 versus the previous uh initial decade of the LFs G were able to demonstrate um on the graph on the right that after adjusting for prognostic markers that patients with a pAP LF are doing better now, likely related to improvements in critical care, neuro critical care and medical management. And this also tended to coincide with the higher use of continuous renal replacement therapy. And as mentioned before, one of the other things we noticed in the study is that rates of intracranial hypertension thankfully are going down, which also probably relates to earlier recognition. Finally um uh this uh this study just shows post transplant outcomes was an abstract that was recently presented at A. S. L. D. By Tom Leventhal. And what tom was able to show is that within the L. FSG that transplant outcomes in acute liver failure are generally similar to other causes of LF with a one year survival of around 92%. So in summary transplant free survival and acute liver failure has significantly improved over the last 20 years, rates of intracranial hypertension and death from cerebral oedema have decreased particularly in acetaminophen induced LF, likely due to improved early neuro protective strategies. And I see you care. I want to thank the USa EL FSG and will li as this network, this NIH network has contributed more than 100 studies regarding LF management and particularly to highlight the use of CRT is associated with improved outcomes and ALF prognosis. We need improved prognostic markers and scores. Um and that future markers potentially we'll look at not only um markers of inflammation and necrosis, but things like immune function and finally, post liver transplant outcomes in acute liver failure are similar to all other indications for liver transplant. Once again, I want to thank collaborators through the FSG and chris Rose and our funders um and I thank you very much for your time.
