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Early Liver Transplantation for Severe Alcoholic Hepatitis

Early Liver Transplantation for Severe Alcoholic Hepatitis
hi everybody I apologize for the delay it's like the ultimate stress of being in traffic for an hour and a half running here and then having to give a talk so hopefully I'm still gonna survive this so appreciate that so I've no relevant to scope disclosures so let's just jump right into it since we've lost a little time I'm going to talk to you today about

early

liver

transplantation

for

severe

alcoholic

hepatitis

but I want to talk a little bit about how we got there all right so a little bit about alcoholism alcohol clear disease how that segues into

alcoholic

hepatitis

at times the assessment of severity and these very sick patients the treatment of

alcoholic

hepatitis

and then lastly a concept of

early

liver

transplantation

so like I let's start with a case you know we're all providers so you know to make it more human I think cases that are very useful so let's talk about case a a fella know this case a 40 year old man who presents for his annual physical he feels well generally they'll report some headache and some insomnia recently he has no past medical history and does not take any medications he's been working long hours as a successful attorney and he reports drinking you know a few glasses of red wine with dinner every once in a while more heavily one with clients was a little vague about that you probably look further tells you that he does have a family history of alcoholism so on exam who looks healthy like sort of a...
early liver transplantation for severe alcoholic hepatitis
typical Manhattanite I'm really unremarkable his labs are largely unremarkable and you know we're used to has provided seeing a whole panel of labs and glossing over a few things but if you look a little more carefully perhaps you might notice that he has slight AST alt predominance is G gtp is slightly elevated as well but everything else looks pretty good so you pass them off as being healthy not to worry about too much but you being an excellent provider you start to get a little suspicious about some of his reports so you ask him this cage questionnaire which I think a lot of you are familiar with and so the cage questionnaire is have you ever one felt the need to cut down on your drinking to felt annoyed by the criticism of your drinking three had guilty feelings about your drinking or for taking a morning eye-opener and so it's a screening test it's not a diagnostic test and notice that this questionnaire doesn't talk about at all so the amount of alcohol consumption which is key to this sort of the process in terms of diagnosing alcoholism but if you have at least two you have a high index of suspicion to sort of follow that up with further questioning and four is virtually diagnostic although again it's really meant as a screening tool so I think we can do better though at detecting alcoholism there was a study in the 1990s that demonstrated that about 50% of providers had heard of the cage questionnaire but that only 14% of them actually knew...
early liver transplantation for severe alcoholic hepatitis
all four categories of it a survey of over 800 primary care physicians using case histories similar to case a a demonstrated that only 6% of them accurately put alcoholism in their top five differential number one was irritable bowel disorder low bowel syndrome so it's often mistaken for these other kinds of etiology so I think we can do better in terms of diagnosing and detecting alcoholism so two years ago the American Psychiatric Association came out with the dsm-5 criteria where they lumped together the older terminology of alcohol abuse and alcohol dependence into alcohol use disorder which can be described as sort of the harmful consequences of compulsive alcohol use and are not eleven criteria I didn't put them all down here but if you had fulfilled more of the criteria you have increasing in terms in terms of severity mild moderate or

severe

alcohol use disorders are very common worldwide with almost six percent of all global deaths a Trudel to alcohol in 2012 and there's a study that just came out in JAMA psychiatry that looked at the prevalence of alcohol use disorder with new definition and they found using a large epidemiologic national database that the lifetime prevalence is almost 30 percent in the United States which is astounding the one-year incidence is about 13% so it's something that we need see quite frequently if we look for it so you know alcoholism can be thought of as sort of a self-inflicted kind of disease but it's a really a...
early liver transplantation for severe alcoholic hepatitis
common and complex disease there's a feeling that after three decades of research at least half of the predisposition to alcohol is genetic so I borrowed this from Vanna triple-a but 60% is thought to be genetic currently the remainder environmental greater than a third of

alcoholic

s tend to have at least one

alcoholic

parent in the family but it's also complex in terms of environmental factors such as the

early

first use of alcohol significantly increases the risk for alcohol abuse disorders and so you can see here that by age 15 if you have your first use of alcohol and you have an alcohol parent you have a four times greater risk of developing an alcohol use disorder versus if you do not have a now parents so it's not a very straightforward kind of diagnosis I'm sorry disease and has a complex interaction between genetics and the environment this is a graph demonstrating the cumulative distribution of alcohol consumption in the United States so while the United while you know we're our nation of drinkers relatively speaking compared to the developed world we don't actually have a very high prevalence of alcohol use but if you do drink alcohol you tend to drink a lot of it so men consume more than women and we still run into problems because 73 percent of alcohol is actually consumed by only 10 percent of the population here as you can see so if you do suspect alcohol use your cage questionnaire is positive it's likely that it's not just one...
drink every once in a while but regular drinking and consistent consumption so so how are you doing in terms of the United States this is a depiction of the total per capita consumption of gallons of alcohol in the United States from a couple years ago red being a higher blue being less and you can see here in New York we're not doing so bad we're kind of middle-of-the-road here in New York State but this level of alcohol consumption per capita has increased over the last couple of years here in the earth so worldwide alcohol is actually the third most preventable risk factor for premature death in developed countries won't lagging only behind tobacco's number one and two hypertension so this this particular fact struck me alcohol attributive fraction for death from cirrhosis worldwide is 50 percent higher in the US and even higher in the UK in Eastern Europe in other words if you have cirrhosis the likelihood that you'll die from cirrhosis is going to be highest with alcohol not with other conditions okay this is

liver

related death so while alcohol may be a smaller fraction of the etiology of

liver

it is you're more likely to die from that than other

liver

related causes like

hepatitis

C for example so you can see in the United States we're in the gray kind of middle the middle the road and then in Europe and Eastern Europe the prevalence is higher very few times in medicine you get a nice linear line like this by direct relationship so it's...
been cl

early

shown over in many studies that the rates of

alcoholic

liver

disease are directly related to the amount of consumption so you can see here i duplicate on this graph the standard death related causes from

liver

disease and cirrhosis and the amount of alcohol consumed liters per capita and in high-prevalence countries high consumption countries you see a nice linear alignment fits very well the more you drink the more likelihood that you're gonna die of

liver

disease and cirrhosis so how do we talk about well drink is very common you know a lot of people do okay is there a safe limit to drinking what's moderate consumption this study probably is the the more the best side of studies it's a prospective population study Denmark using the Copenhagen Missy heart study questionnaire 13,000 patients with long follow-up and they found that the while the incidence of

alcoholic

cirrhosis is quite low women tend to have an increased risk of cirrhosis at a given alcohol intake and then again consistent with the previous slide the risk of

alcoholic

liver

disease increases in a dose-dependent manner so you can see here the curve isn't linear it's somewhat asymptotic in the sense that for women in the the pink arrow you can see that about seven drinks per week is where the line starts to curve in terms of increasing the relative risk of alcohol

liver

disease whereas for men the slope tends to curve a little bit later where it's about two drinks a day or...
fourteen drinks per week and so that is the study based on which the National Institutes of alcohol abuse and addiction the amateur ballet defined quote safe drinking or moderate drinking and so this is where it comes from this study this recommendation so for women in terms of binge drinking on a single day less than three drinks and less than seven drinks per week and for men a little bit higher threshold less than four drinks and less than 14 drinks per week and so if you follow these recommendations only about two percent of those who drink this way have an alcohol use disorder so it's likely that you'll be okay so you know all that and you go back to your patient you say all right well why don't you clarify what you mean by drinking a few glasses of wine with dinner and more heavily with clients and he reports that he drinks more precisely about four glasses of wine a night and you know times more than ten on occasion with clients and then it brings you live well what's a glass all right is it this one is it this one is it this one you know I found this on the internet where you can get one glass of wine that was feeling tired 750 milliliters of wine and so you know when you're talking about not knowing that the unit is of the process that leads to injury you're talking about a lot of vague things all right and so it becomes difficult to it so to ascertain risk right so what is a drink okay this is from the NH or police website so many of you may...
not know this but you know we think of sort of a standard drink as a 12 fluid ounces of beer less so with malt liquor even less v fluid ounces of table wine and then 1.5 ounces of spirits okay now we all know that if you go to a bar you have sort of a cheap shot or a generous shot you know these things you know it can be equated as a single drink but is probably not and then you have know the lingo a little bit too when you talk to patients with alcohol use problems they say well I don't know how many drinks that is but you know I drink the four to forties you know a day I drink and you know how many drinks is that that's four point five drinks a nice way to remember this in terms of bottle wine is that equates to about five drinks so oftentimes you hear a patient saying well I split a bottle of wine a night with my spouse or my partner so that puts you at the 2.5 a drink limit if you're a woman that's over the limit for the safe drinking okay a pint of fit a handle do you know what these things are in terms of alcohol use I bet your patients don't either so a pint 11 drinks a fifth which doesn't sound too bad right 17 drinks a handle maybe from college remember this 39 drinks and people have no idea how many drinks there are per sort of you know package essentially so if they don't know it's gonna be hard for you to ascertain that unless you really push them to get an answer all right so let's talk about the natural history of

alcoholic

...

liver

disease histologically and correlating a little bit clinically so we have a normal

liver

here look nice beautiful

liver

with portal tracts with only two weeks of heavy alcohol use this is about what five or six drinks a day you develop simple steatosis without inflammation okay just two weeks that's been shown in sort of volunteer studies let's say you you know that I don't know how you balance here for that but it's been done after for six weeks of abstinence it reverses back to a normal histology so there's a nice you know sort of plasticity to the

liver

that we know about well let's say you continue this ongoing drinking and you change from the simple steatosis and about 10 to 35 percent depending on the degree of severity to a situation where you have

hepatitis

or inflammation of the

liver

okay web and this is a dynamic process you can go from alcohol

hepatitis

back to staples steatosis and remarkably even with many years and decades of heavy drinking only about fifteen percent of patients who have normal

liver

s eventually develop

alcoholic

cirrhosis so there's definitely not a linear relationship there it's very it's much more complicated than that those who had alcohol Kappa Titus is said that up to fifty percent of those patients will eventually develop

alcoholic

cirrhosis however in the

severe

form where you're presented with jaundice and all the sequelae for the hypertension in our experience at least eighty percent of...
these patients already had or at least cirrhosis on biopsy and if you had

alcoholic

hepatitis

a longer lunch - in a study that followed patients out 18 months demonstrated that if you read biopsy these patients some of them go back to normal most have persistent evidence of

alcoholic

hepatitis

and some have already progressed to cirrhosis okay the wide range you'll see why that we were not able to be very precise about that so I'm not gonna you know belabor this point but you you know understand I understand the alcohol injury leads to a

hepatitis

classic two to one ratio that you learn medical school things that you may not know that hepatologist tend to use is that alcohol induces the enzyme GGT different than talc false okay so you can often see a discordance in terms of GGT versus a lacrosse is toxin to the bone marrow leading to increased mean corpuscular volume alcohol leads to increase absorption of iron and the duodenum and the gut leading to increased iron C's these patients not do not all have a macro mitosis and the

liver

biopsy cannot adequately distinguish between ash versus mash now our pathologists are very good in giving us a sense and correlating with history but ultimately that's sort of your call as a provider and in treatment this should be you know its own slide and things like that but honestly it's amazing how much disease you can cure with abstinence it's simple absence and you know really pushing patients to remain abstinent...
can really dramatically change the course of a patient and another that the remarkable thing is that patients regardless of the kind of intervention that you have where it's a motivational enhancement cognitive behavioral therapy steps program they all be two about the same effect in terms of being able to achieve and durable abstinence afterwards so any of them choose them support them for your patients and then a nutritional assessment we'll talk about later which is important okay so we have a patient pee he comes back a year later as you've said that he looked okay for an urgent visit he now has a new sort of symptoms of yellowness extreme fatigue easy bruising a big belly if he reports now that he'd been increasing his drinking to a fifth of vodka every few days now you know what that is on exam he's got a fever and many of the sequelae of this sort of out the

alcoholic

hepatitis

phenotype jaundice by time's a-wasting Spira Amada I've had a megaria attempts abdomen with ascites ten minutes and asterixis on his labs you can see that he has this classic leukocytosis with the neutrophil yeah elevated MCV looks like hyper hyper bulimic hyponatremia mark the elevated G gtp because their recent drinking and so clogged allopathy and if you're not familiar with this AST alt ratio greater than 2 total bilirubin and direct bilirubin 2219 and sort of all markers of hepatic synthetic dysfunction okay so now he has

alcoholic

hepatitis

right there's...
a cute inflammatory syndrome of jaundice and

liver

injury that occurs after decades of heavy use usually at least ten drinks a day the age groups about 40 to 50 they're often so sick they've been absent for a couple of weeks so that's actually not that they're not telling the truth they just they feel that lousy that they stop drinking they have a lot of the signs of cirrhosis on exam laboratory abnormalities we just discussed them but the a SDLT ratio is usually less than 500 there is a rare form of an indirect hyperbilirubinemia called xiv syndrome meeting two related to him alysus from alcohol that you can also see many of them already has cirrhosis when you see them like this mortality rate though can vary from 15 to 80% which is very wide at six months which will just we'll discuss now but you could think about that 40-year old guy mortality array 80% at six months that's we're talking about you know advanced neoplasm kind of rates so how do you assess for whether this patient is going to survive how they're going to do so there are a variety of different well study and published prediction models of severity and

alcoholic

hepatitis

you see some listed here I'm not going to go through all of them but the probably the ones that you're most familiar with would be the MAGIX discriminant function obvious many of you know the marrow of course and then the Leo score which is a newer one you can see that they a lot of them share the same...
characteristics that are very familiar to us in terms of

liver

is synthetic function bilirubin I&R creatinine in you know very analyses things like age and albumin and white count have also been important in terms of predicting outcomes the magic store is sort of the tried and true one derived from a clinical trial in 1978 it uses bilirubin and INR the Mel can be useful as well spent I spend a little time with the Leo score and that it captures the same a lot of what the Melo score captures Billy urban INR creatinine it captures age paying patients who are younger they tend to do better and they're likely if they're not cirrhotic quite yet and there's a dynamic component to that would be allele score which is that there's a you measure the change in Billy movement from day 0 to day 7 so if there is an improvement in the building movement it's likely that they're going to survive and this is from the original wheel paper the other graph you're showing a capital marker survival probability versus time and days after 200 days and if you have a low wheel score with the decline in bilirubin good other sort of markers that suggest that you have an eighty-five percent chance of survival at six months versus a so 30% chance to survival if you're a real score is a greater than 0.45 and remember the change in bilirubin is in relation to the initiation of steroids so this is our patient a reminder of his labs and we apply the prediction models to his...
score and presentation he's got a high discriminant function greater than 32 which is the cutoff high milled Glasgow

hepatitis

a big scores which had to go over but these are also very high and we don't have a little score yet because we haven't given it any therapy yet so let's talk about therapies all right so tried and true prednisone has been around for more than almost four decades it's sort of a shotgun approach and inhibits transcription factors and inflammation Madri was a resident at Johns Hopkins when you started this trial a seminal trial where you derive the discriminant function and looked at prednisolone and its effects on mortality we spent almost four decades doing subsequent studies and meta analyses that demonstrated that in this forest plot perhaps cretinous prednisolone may not be very effective so there's a lot of argument about that we had the pleasure of seeing Philippe matheran give a talk here last year regarding some of his work in

alcoholic

hepatitis

and he did sort of a gold standard pooled and meta analyses where he took actually the data points of all of these clinical trials put them all together rather than the medians and found that there was a relative risk reduction of 30% with prednisolone with a number needed to treat a 5 however which is still pretty high and with all this combined a it solely recommends that with these very sick patients prednisone should be considered at the highest level of recommendation and...
this is sort of his meta-analysis here in terms of demonstrating survival note that in the the placebo group the mortality the survival rate was only 65 percent at 28 days so very very lousy pentoxifylline which you may know as Trent all and non-selective phosphodiesterase inhibitor also has been used in alcohol kappa titus inhibitor of TNF alpha but in the trials it improves survival by reducing the incidence of hepatorenal syndrome and it did not affect ena alpha levels so it suggested that while it was a it worked it wasn't a very rational therapy in terms of its putative mechanism of action and so it has a less of a recommendation although I'll show you that that has changed as well this is the original capital Meyer curve as you can see demonstrating improves survival with the Tran tall group this is the one study that showed improved survival but the rest of the studies though high bias demonstrated that the forest plot crossed the one threshold so there's some doubt as to whether that really worked so we got pregnant Prentis a lot and you have proxy filing what about some sort of combination of both right so Alexander the bay works with dileep study well if we have a real score you give prednisolone they fair prednisolone after a week with a with a high high Leal score maybe you could rescue them with toxic filings so he did a study where he matched these patients non-responders she got pentoxifylline there was no survival difference at two months what...
about combination therapy would that be better prednisolone plus pentoxifylline versus prednisolone mono therapy alone this is a JAMA article two years ago that did not demonstrate any survival difference at six months and then another combination therapy how about prednisolone and you add IV and acetylcysteine or mucomyst which is something that us hepatologists are very comfortable using in patients with acetaminophen overdose in a New England Journal trial had demonstrated that this combination therapy prednisone plus nak demonstrated a survival benefit at one month but not six months the primary endpoint was six months so it was touted as a negative trial however I'll show you that this one month is at probably the best end point all right so I think of this as a positive trial something that we should really look at okay so a major landmark trial was just published a couple of months ago called the Stoppa trial the steroids for pentoxifylline for

alcoholic

hepatitis

trial it was a multi center huge trial had this very interesting 2x2 factorial double-blind randomized approach where it was able to I evaluate two different agents versus placebo and in combination over 5,000 patients with

alcoholic

hepatitis

or alcohol clear aziz were screened and then over a thousand were randomized over three years at 65 hospitals in the UK so a huge undertaking you can see the study design here to see both to see about 200 prednisone placebo about 200 placebo plus pentoxifylline and...
then combination therapy so the idea was that we really want to see you whether or not head-to-head prednisolone and kentukcy finding whether it makes a difference so is the outcomes at 28 days in terms of looking at all cause mortality there was a trend to see that prednisolone seems to reduce 28 mortality day mortality versus placebo or pentoxifylline including regiments and at the end of the day the odds ratio for mortality was decreased in those who receive a prednisolone contain regimen either with maitake filing or placebo although the p-value was very close didn't quite match significance and the potox e-filing it was demonstrated that that was basically not useful or equivalent to placebo now some of the limitations to this study is that the the placebo survival rate was higher than expected the patients are typically sicker and that really we're not talking about the impact of prednisolone on survival long term but only short at one month remember I mentioned that the combination therapy of prednisolone and IV knack really should have been used for as the endpoint for one month these are we caught kaplan-meier occurs from the study which really helped us answer this new almost four decades long question about whether prednisolone is useful and you can see pentoxifylline versus not the lines are exactly the same type that the prednisolone graph shows that those of prednisolone containing agents tend to diverge by 28 days but one year survival it doesn't...
really make a difference okay so four decades of intense research boiled down to not very much we haven't gotten very far with this orphan disease so laughs last bit of therapy for

alcoholic

hepatitis

something that's pretty unique to this condition is nutrition there's a famous VA study looking at 300 veterans many of them with mild alcohol capacities 100 percent of them had protein calorie malnutrition on anthropometric testing okay very few things have medicine out of our 100 percent a spanish study randomized his patients to prednisone for 28 days versus a guaranteed sometimes NG tube driven hospitalized patients for 2,000 kilocalories per day there was no difference in mortality suggesting non-inferiority so if we spent four decades saying that prednisolone is only useful to reduce one month survival and infecting is the equivalent to just two feeds you know it suggests that two feeds in these patients being aggressive with them despite the presence of Barrett's and things like that are very important and also V also recommends this kind of intervention for or

alcoholic

hepatitis

all right so let's go back to our case you know that your patient likely needs prednisolone we treat him with Freddie's long you know the day list so you give him some combination therapy as well you keep him in the hospital reinfection his unfortunately though at seven days is high there's new evidence of sirs with acute kidney injury now he's on dialysis many of...
the House staff here are very familiar with this kind of patient and now his metal is 50 so were the options so this is a schematic depicting potential therapeutic targets for alcohol

hepatitis

and you can see here starting at one alcohol leads to a leaky gut increasing government there are various antibiotic type agents that can help neutralize that zinc helps improve mucosal permeability there's immunoglobulin - lipoprotein saccharide but aleko polysaccharide that's playing a role in inflammation if that doesn't work these this bacterial translocation bacteria process leads to a stimulation of toll-like receptor 4 in Cupra cells in the

liver

which then are important mediators of the inflammatory cascade leading to production of bile 1 which is another potential target with anakinra tina alpha we've discussed as an important playing important role in cell mediated death and inflammation and other agents such as enrique immitation can inhibit that a beta colic acid is an agent that is being now studied in PVC and non-

alcoholic

steato

hepatitis

has various effects which you'll be hearing more about there is something called the extracorporeal

liver

assist device which is a little different it's almost like a dial or dialysis or artificial

liver

which you know venous blood like dialysis is put into cartridge we have immortalized parasites that will help sort of do its thing phase two trials have been underwhelming than that and probably more theoretical...
interesting therapy that you'll probably hear more about is using granulite colony-stimulating factor also known as philip Thurston or a new pigeon that has been shown in proof of concept studies to mobilize bone marrow drive stem cells peripheral blood mononuclear cells there's indirect evidence that that will support and enhance the function of neutrophils and hepatic regeneration so it's a different target in terms of therapies compared to reduction of inflammation so I think we'll hear more about that soon okay so for our patient well transplant right through that guy's gonna die without a transplant you can see in pink here try a

liver

disease this ain't very steady over the last decade or so

hepatitis

C which is this blue line up here hopefully will start to decline with the advent of the new antiviral agents putting out there the other or unknown this is probably a lot of this is non-

alcoholic

fatty

liver

disease right so this is our patient he's in big trouble multi-organ failure Nell does 50 this is probably underestimates this mortality at three months you have probably has weeks to live are you going to call the palliative care team what are the options for this patient and so this is where I think providers have looked at can we rescue these patients if they have otherwise fit a low risk profile for things like relapse disease recurrence after transplant so this is

early

liver

transplantation

for these patients

severe

alcoholic

...

hepatitis

believe my Tehran published his landmark paper four years ago to determine whether this approach improves six-month survival rate in patients where they are unresponsive to medical management according to the Leal model evaluate whether these patients have a higher rate of alcohol relapse because they do not have this ability to stay alive long enough to follow the six-month rule of abstinence and then to see will this be to sort of an over transplant patience of just

alcoholic

s essentially in terms of a limited resource of liquors so prospective multicenter study at seven transplant centers in France and Belgium over four years inclusion criteria are very important again non-response which we know based on allele score they all got biopsies these patients had

severe

alcoholic

hepatitis

as their first

liver

decompensating event the fancy way for saying that they really didn't know in these patients of the link between their alcohol use and a

severe

medical problem and then there was a complete consensus of medical team circles that need to be achieved they could not have sort of uncontrolled psychiatric disorders or other sort of medical issues that prevented it from the transplant they did a case controlled matching studies to compare outcomes so we're not they didn't transplant all

alcoholic

s okay one out of ten patients only were eligible to be candidates for transplant they ended up transplant twenty-six of these patients several deaths occurred...

early

related to invasive aspergillosis but many of them did very well and there was a very low burden in terms of all the transplants that were done in via participating centers during the three years for your study period and you can see here in the capital Meyer curve the outcome at two years is you know seventy one percent which is excellent and again snapping the goals who had just my outcome which we know from the previous studies I put this arrow here to remind me to tell you that if you're going to do this you need to do it

early

these patients die within two months all right so you're not gonna they're not going to survive to six months since so that's why it's called

early

liver

transplantation

and why an expedited and intense evaluation needs to be performed so what about relapse right we took a chance on these patients and their study three recipients or about twelve percent of patients relapsed okay and relapse has at various definition but patient number one at two years he went back he or she went back to drinking three drinks a day patient number two at two years post plan he or she went back to more than five drinks today I would consider harmful drinking for sure and then the third patient one drink a week this is France after all so and none of these patients have any kind of graft dysfunction that rats are working just fine so this study showed that

early

liver

transplantation

for

severe

alcoholic

hepatitis

improve 6my survival in...
highly selected non-responder candidates lower burdens lonely low rate of relapse and for the first time it really challenged the notion of a sort of prescribed abstinence period and that you couldn't do medically

transplantation

for these very sick

alcoholic

hepatitis

patients and if you were produced though and up until recently there hasn't been any papers looking at this because it's a big deal all right so I'm here to present sort of our experience here at Mount Sinai with this strategy and only a few months after the paper was published we started a strategy very similar to the the French Belgium protocol with a written guideline change okay these are the methods very similar yeah the alcohol kept it tightest if you respond to medical therapy then you're okay if you do not have a response to medical therapy then you need to have a first step expedited psych associated violation because remember ninety percent of these candidates are to have poor profiles and already decline for transplant then a medic expedited a medical evaluation usually in-house and if the consensus is not achieved and the patient has declined for

early

transplant but still could be a candidate for it sort of a traditional six month rule try the transplant however if consensus is achieved and the patient would then be accepted and listed for

early

liver

transplantation

remember these patients are so sick that their mellow scores are so high they would achieve very high priority on...
the waiting list so we looked at about one hundred and eleven consecutive patients hospitalized for alcohol keppa Tytus very few of them were responders to medical therapy but they did pretty well at six months the vast majority though we're non responders or not eligible for specific therapies with very high melt scores more than half of these patients walked in the door or were outside hospital transfers these OSS ofh patients as the house deaf no not eligible at all for any therapy so we talked in the middle to talk about these therapies half of them are not even eligible for those okay so and they're not even that great anyway so we have nothing really for them 20% of them had favorable psychosocial profiles based on our addiction team profiling because nutritionally it was so high from infection only 60% of them survived actually listing them officially with very high meld scores and then eventually nine patients underwent the very

early

liver

transplantation

here and using a similar approach in terms of matched controls we demonstrated that at one year we had eight out of nine patients surviving at one year versus controls you can see a very rapid decline in terms of the mortality of patients who did not get a

liver

transplant so we were also interested to get next step further as to say what are the characteristics of patients where we felt as a team these patients would be good candidates for transplant and so while we made the decision we sort of tease it out...
a little further to say what are the things that we should emphasize and that other centers can emphasize in their evaluations of patients because you know the psychosocial evaluation is not necessarily as quantitative as a stress test to examine so we looked at the profiles of the 20 accepted candidates with good profiles and then the decline candidates with poor profiles and we found a significant variables as you can see here things like stable employment insight a recent life stressor we had a couple of sandy hurricane sandy victims who that was sort of the last straw in terms of increased drinking whether they were right with collaterals on alcohol use and in the end had a good insight and having this first de

liver

er decompensating event as an empiric criteria we found that to be very useful in terms of our selection process so sorry over three years kind of doesn't like that slide we did almost 300 transplants only three percent of them were for

early

liver

transplantation

and the house that should be happy to know that of the intercoastal of transfers ATM 18 of the 20 provisionally accepted candidates came from in the inter hospital transfers so we appreciate your hard work and include three patients from other

liver

transplant centers who are not doing

early

liver

transplantation

suggesting that we are really a quaternary

liver

transplant center okay so their lives they're doing well two years out eight out of nine no rejection graft dysfunction they all...
enrolled in rehab programs in terms of alcohol relapse we had basically two kinds of relapse events one where they're a slits Pi alpha recipients drinking with the returned to abstinence and then one patient who cl

early

realized who was a 31 year old woman you could look back sort of in hindsight well she didn't really meet the first decompensating event criteria didn't have great insight into her alcoholism there wasn't really something that could be reversed in terms of explaining while she increased her drinking so in retrospect perhaps that was someone that we you know may have fought differently however she is back to work and you know providing some benefit to society so there's some question marks about that so our conclusion we can do it all right let's get this a little bit we can do it but the question is you know should we do it right medically surgically is feasible should we do it so let's talk a little at the end here about the six-month rule because that's something that I think people are thinking of while they're hearing about

early

transplant so the origins are from the 8th 1983 where they excluded

alcoholic

hepatitis

a conference about a decade later than suggested that there's strong consensus that requires most

alcoholic

patients the abstinent for at least six months before they can be listed we work on consensus so the vast majority of centers require this six month rule absence however it's not really a rule...
because further down the paragraph you see exceptional patients with

alcoholic

liver

disease who have not been absent for six months who we feel that it could be otherwise good candidates can be referred for consideration so it's really not a rule and it's really not based on a lot of data so let's go through some of the arguments at the last few minutes here in favor of the six month rule and I'll do sort of a point counterpoint to these things so number one it may allow time for the

liver

to stabilize and obviate the need for

liver

transplant all right so we know that already many of them are non-responders and eligible for therapies yes if they get better then they don't need a transplant that's always better than giving them a transplant but now we've had a real score that we know can identify this patients who have very poor outcomes very high mortality they all die within the first two months they're not going to survive you got to make decisions quickly number two the six-month rule examines the patient's commitment to sobriety while implementing preventive strategies against future relapse so you know you may think that the six-month rule as a hepatologist and a transplant you know you've selected them out very nicely if you're on the wait list they're doing well but there's a study that demonstrated anonymously that 1/4 of your patients with

alcoholic

liver

disease and cirrhosis admitted or are drinking alright at...
least one drink while on the waiting list the rate of relapse after a liberal

transplantation

for

alcoholic

cirrhosis is 20% at 3 to 5 years despite meeting the six-month rule and these patients are doing just fine clinically okay and then the data supporting the utility of a six-month rule in reducing the rate of relapse is actually very conflicting and there are many studies show that you may be penalizing those patients in you know they're dying unnecessarily a lot of the studies that show that the longer absence before transplant the less likelihood of relapse these are patients who have been abstinent for 5-10 years okay which is probably not appropriate either number three this strategy has enabled similar if not better five year survival than other indications but unlikely with active

hepatitis

well they've been three studies that have looked at sort of what I described as the UPS kind of study where you transplant them and actually there's active disease and recent alcohol injury in these single Center chart reviews or you know database searches there was no difference between those who had

alcoholic

hepatitis

on the removed explained of

liver

compared to match controls they did exactly the same suggesting that even if they had some alcohol injury recently before transplant they did just as well as those who were absent for many years and lastly the thing that's sort of more kind of a gut feeling kind of thing is these patients have a self-inflicted...
condition for which they are personally responsible and they you're wasting a

liver

on these patients and the public opinion will therefore reduce organ donation right so but this notion of personal responsibility for alcoholism also applies to other indications for

liver

transplantation

what about the patient with a few Hep B or Hep C from distant intravenous drug use or protective sex with a sex worker ecstasy's induced acute

liver

failure from a rave do these piece of these patients equally less deserving or more deserving what about the patient who knows that they have problems with metabolic syndrome and makes daily decisions that affect their health and still they are not able to make changes related to obesity and non-

alcoholic

fatty

liver

disease so you could also apply those conditions which are no-brainers in terms of transplanting these patients to the

alcoholic

hepatitis

group and if you use the acetaminophen overdose patients that's sort of a surrogate for these page so that they often have psychosocial issues and we're getting the benefit out it's a very clear well accepted indication for transplant very few of these patients after this intervention go back to disease recurrence and self-harm 2% from self-harm we attempt suicide from the UK experience so these patients do well something may change these patients after trying to save their life of transplant so in terms of the public opinion issue I think you could have a strong argument that...
this is not a self inflicted condition in terms of the genetic component surveys of public opinion show that you know their people are less apt to select

alcoholic

s than other indications for transplant however in these studies they these opinions also vary significantly with health care providers usually not supporting those in the fringes of society you know as providers you know these are things that we are trying to non-judgmentally try to treat patients in the best way possible and then there's a famous case of George best - some of you may know very famous footballer Manchester United who had alcohol or disease he had a very colourful life 16 months after his

liver

transplant for

alcoholic

cirrhosis he went back to drinking scene at the pub things like that and there was a public outcry as to whether or not he should have got a transplant and there's

early

indications after that publicity that organ donation declined but after one year it demonstrated subsequently that there was no change in the rates of donation because think about it families who are in a situation where the loved one is going to donate their organs to save other people they're not thinking about this they're thinking about how can we turn this negative situation into something that can be life-saving for many others so when we talk about this in terms of our goals indications for transplant you need to ask ourselves what is our goal of transplant is it preventing disease recurrence...

hepatitis

C 100% of the time causes disease recurrence is it overall survival is it benefits to society these

early

alcoholic

hepatitis

patients in our experience half of them have come back to work it's a complex mix of decision-making so I want to conclude by demonstrating this sort of treatment algorithm

alcoholic

hepatitis

you diagnose it by your precise history you calculate their prediction models if they have my lock lock

hepatitis

then they're probably okay you should follow them better and nutrition the

severe

alcoholic

hepatitis

look for things that precludes them from receiving prednisolone essentially nutrition intravenous knack for five days the days of kentukcy filing are over calculate their little score in terms of response after one week and then continue it or possibly consider them for really

liver

transplantation

so in conclusion alcohol use disorders are common they're harmful consider them think about them we still don't know the factors influencing the natural history of

alcoholic

liver

disease prediction models can be very useful we're going on to prednisolone and possibly not reducing one month mortality that's it nothing long-term and toxify leans over further

liver

transplantation

for these patients is an option in only a very few highly selected patients and the key point is that

alcoholic

hepatitis

cares poor prognosis with almost no treatment so it really goes

early

in terms of prevention which is the key thank you you...
start to talk about the Copenhagen study and in that study actually as I recall there was a decrease incidence of all cause dementia including vascular dementia and Alzheimer's disease and so my thinking is that one or two drinks a day may be okay for the

liver

may be good for the brain and I think everybody would agree is good for the heart so is there any way to tease these people apart we're going to go on is there any risk prediction model that ways the benefits of trying to prevent dementia prevent coronary disease and yet maybe damage your

liver

a little bit all right - so summarize your question a little bit so there has been studies looking at sort of moderate alcohol consumption and its impact on other sort of metabolic syndrome type of disorders such as cardiovascular this stroke risk and things like that it's interesting they mention there was a paper that was just published in Lancet that looked at the impact of moderate consumption of alcohol looking at you know similar number is thirty thousand patients something like that so the Copenhagen study that demonstrated that there was indeed a benefit of in terms of reducing cardiovascular mortality with the use of with moderate consumption of alcohol but that you know sort of the byproduct of that is also increasing the odds ratio of alcohol-related problems such as

liver

disease cl

early

but also things like oral pharyngeal cancers all different kinds of cancers as well so I think that the you know it...
kind of boils down to we have this sort of blunt instruments to try to assess this we have a sense that there's some ways that alcohol can be useful in song and when others and I think this is where this sort of genetic being a little more precise about precision medicine role can can play so fifty-five is if I understand the question correctly it's typically for the age cutoff for a living related donation to be acceptable you know in terms of being a recipient we have we trans we've transplanted to a 78 year old and things like that physiologic age is more important to us than the actual number per se you know when you get to 55 and studies have demonstrated this the older the donors are particularly for an adult to adult type of donation using the the right lobe patients they don't tolerate it well in terms of the donors and so we really want to minimize the risk to the donor to be able to make sure that they survive the surgery otherwise of being a healthy person Milt's Wars daily and I know that there are some papers about the Delta L scores sure that's a great question so you know in those scores it's something that we love as a pathologist probably one of the most validated scoring systems in medicine has been used unlike some of these other prediction models to be you see really you know every day like you say to be able to adequately assess risk in a dynamic way so specific to

alcoholic

hepatitis

a sort of another cheap meal score that we...
often use without pulling out our calculator or our smartphone is what is the medal do it's the Mel going up is it going down the Delta Mel the change in meld is often the first clue to either a new insult that's happening with the patient or a change in the situation that demonstrates that this patient in D is not going to get better especially when they're sort of on the threshold of clinical stability and biologics you know biochemical stability to suggest that these patients need more attention and perhaps we should proceed with transport