Okay by vivi07


									>> Okay. Good afternoon. I think we'll get started. If there any students FAES students who are taking the course for credit and have not filled out one of these evaluation forms, would you let me know so we can give one to you to fill out. There are ten students and we have three forms left so I guess -- you're one? (off mic) >> This is only the FAES students. So the other thing is that next week I believe by next Tuesday the computerized final exam will be on the website and I'll give you the URL for it. Now, the FAES students have to take the exam. Don't lose sleep over it. And those who have attended 50% or more of the sessions can also take the exam and if they really have attended something close to that they'll get a certificate. Anybody can take the exam just for the heck of it. but you only get a certificate if you have been here at least 50% of the time. If anybody has any questions or problems about that, let me know. Okay. So today we're going to do something that is very different from I think anything that we've done before. Usually you know the format of a sort of clinical, major clinical entity from a somewhat clinical perspective, even a patient. And then a kind of state-of-the-art discussion of where research is at and where it needs to go and hopefully what areas maybe of interest to you folks in contributing it. So today we're going to deal with another perspective of human health and the need for more science. This is going to start out with a brief presentation of one of the major cancers of the world, primary cancer of the liver. And then that's going to lead into the application -- the failure of most forms of therapy with the exception of liver transplantation, particularly for early detected tumors. So questions will come up how you detect a tumor when it's early and who do you do it in. And then that will lead into the much broader and critical issue of who gets a transplant. We all recognize that there are many thousands of people on waiting lists. How do you make that decision? This is a science. This isn't just meta physics. So we're very fortunate to have a political scientist who is an expert in this area, Alan worth Heimer who is going to lead the third part of this discussion to give you ideas about the scientific approach to decision making over critical issues like a short supply. Okay.

So I'm going to hit major highlights and try to provide some information that will serve as somewhat of a background for the next two speakers. So primary cancer of the liver, not metastatic cancer, metastatic is what comes from all the other places. This is cancer of the liver that begins in the liver. Once upon a time actually not so long ago by my calendar, like 25 years, when a patient appeared in an American academic center with primary cancer of the liver, invariably the case was presented at grand medical rounds because it was so rare. The counterpoint to that is if you are in a hospital in China or in parts of Japan and somebody came in with an acute myocardial infarction that would be presented at grand rounds because it was quite rare. The world has gotten to be much closer and these areas of geographic distribution of disease certainly can be muddied or changed by transportation and all other obvious things. But even from the beginning primary liver cancer was restricted to an area of the world that I'll show you, mainly sub Saharan Africa, the Far East, and a few other selected areas. It was very rare in industrial Europe and in North America. Nobody knew why. Now, in recent times as we'll show you, there's been like an epidemic of primary liver cancer in the United States. This is I think the most rapidly increasing proportion wise, not numbers, of all major cancers. Now, the other thing is in the beginning when these data were first acquired, this was a disease that was about nine to one occurring in males rather than females. And nobody had any idea about that either. Now the difference has gotten smaller again for reasons we don't know in a way not much has changed in terms of the clinical aspect of this disease because it's a bad disease. By the time it's detected invariably certainly detected clinically it's far too late to do anything. Part of that is because the liver is so big because it doesn't have Payne fibers except on the surface so if the is tumor doesn't invade the surface you hardly know it's there. And by the time it impairs function unless it's in some critical anatomic place to make someone say jaundiced, you wouldn't know it's there either. Lastly, one of the mechanisms responsible for this -- for these phenomena and for the disease. So today we're not going to talk about mechanisms but I listed on the website the reference to last year's program which was on molecular mechanisms of primary liver cancer and also several excellent recent reviews of the subject because a lot has gone on in this area that has really contributed a great deal from the use of array techniques to try and detect susceptibility to all sorts of things. Uh-oh. I'm pushing the right one. >> So to begin with to give you an idea of the variations on the theme, these are not uncommon but these are three patients with different histories but common itologies.

So one is a God mine worker -- gold mine worker in South Africa, a young man consuming about 3 to 4,000-calories a day because you have to be really fit to work a mile and a half down in the mines. He's very healthy. One day he notices a lump over the right side of his abdomen and he's dead within six months to a year. Of primary cancer of the liver. His problem is that he aquired hepatitis B virus infection from his mother. In a perinatal infection, usually in MOZAMBIQUE and in addition it's been shown these individuals, many of them have been exposed to AFLATOXIN, a fun gal product that leads to a hot spot mutation in the P-53 gene, something first described by curt Harris here at the NCI. So this is like a double wammy. So the second is a 55-year-old American female who has had chronic hepatitis for 20 years. Not clear how she got it. And it was discovered by ultrasound because people were scanning, she didn't know there was a mass there and she has primary cancer of the liver. Flower, in her the susceptibility factor or maybe the it logic factor is that she's had hepatitis C virus infection for 20 years, actually has pretty advanced liver disease though she wasn't quite aware of it. The last is one of the reasons why we're seeing a change in the demography. A 70-year-old Chinese gentleman came to the United States 15 years ago. On examination he had a mass and he had primary cancer of the liver. In his case he had chronic hepatitis B infection. So just to clue everybody in because many of you don't look through microscopes but you should have some appreciation, this is what the normal liver looks like the purple stuff are hepatocytes and are separated by sinusoids where the blood flows from this group of structure where is the blood comes in and the bile goes out. Then the blood flows through this sinusOID to this checking vessel where it goes back to the heart. That's the normal organ. Pretty dull looking. No mytosis, the liver is in G zero. The cells divide maybe once a year. You'll never when you look at a slide see a cell in mytosis under normal condition. If there's been damage from anything repetitively, the liver repairs by regenerating. But after a while fibrosis occurs and you get these big scars shown here in the up per right and by scan here in the lower right. In between those scars which have disrupted the blood supply the remaining hepatocytes are proliferating. It's struggle but can't get very far due to the fibrosis. Those cells are capable of a lot of normal function. Now, if someone has chronic hepatitis from hepatitis B or C, there's an infiltration of inflammatory cells most of which are immunocytes between lobules of hepatocytes and they destroy the linkage between them.

The piecemeal necrosis. These cells are invading into the mass of the hepatic lobule and usually by t-cell mediated mechanisms are digesting and destroying cells which partially regenerate and ultimately there's a battle that goes on but eventually this becomes a fibrotic area which leads to more serious disturbance of blood supply. Now, down the line usually 20 years after infection with such viruses, for example, cancer develops. Such as shown here. Frequently it's multi-focal but usually it's a single tumor, it's shown in the son gram up above. Here the malignant cells are on the right and they're pretty well differentiated. They look somewhat like hepatocytes but they're invading into the normal structure on the left. So often this happens what looks like a solid mass even by scan actually these cells are invading locally and they can do various things. The first clue to the geography of the distribution of the disease came with the discovery that hepatitis B surface antigen, a marker of hepatitis B virus is distributed in virtually the same areas where there's high incidents of primary liver cell cancer, this is the orange area. The intermediate areas are shown in green. In a way this was the first epidemiologic clue to the fact that oh, now we have something to link. Partly for this work Barrett lumBerg won the Nobel prize, in recent years that global pattern is changing in two different directions. It's increasing in the countries shown on the left inincluding the United States. It's increasing because of a large Asian influx of patients who had predominantly hepatitis B. It's also increasing because of the increased frequency of hepatitis C virus infection. These two are the major associated it logic factors. Japan is a unique situation we'll dwell on in a moment because that shows some difference. Correspondingly primary liver cancer is decreasing in the countries on the right in large part because of the introduction of vaccination against hepatitis B and also -- that's the main finding. So in man, this is year 2000 data, this is the fifth major global primary cancer in the world. And in women, what is it, the 7th. So this is a disease where we're dealing with hundreds of thousands of people. There's some other interesting epidemiologic data that have come to light. If you adjust the incidence of primary liver cancer by race in the United States, the Caucasians in white. This is a incidence rate. If you look at the white bar it's slowly increased in this period up to 1998. In the population it increased even more rapidly that curve continued over the past several years. The real explanation for this is not clear.

It is believed to be associated with racial differences in the reaction to infection with hepatitis B and/or hepatitis C virus. The other is largely Oriental. You notice in the United States the step wise increase that represents the increased immigration frequency from the orient. So the pattern of demography is changing globally as well as nationally. So these are the major risk factors, the viruses we mention, alcohol is evidence you'll show you an example of obesity and diabetes as being a risk factor. A major one considerably less -- iron storage disease or he ma chrometosis. In Africa where there's exposure to AFLA toxin it's unclear where that gives rise on its own to the ultimate transformation to a tumor but it certainly facilitates it as I showed you in that first case because in all instances AFLA toxin produces this P-53 mutational hot spots which activates this tumor suppressor gene. So if we look at patients with liver cancer in the United States and ask what kind of virus are they infected with, this is what you get. So about 50% have hepatitis C. About 15 have hepatitis B, five have both. Only about 30% where none of the viral markers are positive. Which suggests that there are other things going on. Some of which we know like hemochrometosis, alcohol, diabetes, so forth. There's other differences from a epidemiologic standpoint. There's lots of numbers on here but a couple of points. This is the prevalence of hepatitis B virus marker. The surface antigen, and a hepatitis C virus marker antibody in different parts of the world. So you notice for example let's look here in Japan most of the cases have hepatitis C. Only 10% have hepatitis B. Whereas in the United States in Greece and other parts of Asia, hepatitis B is the predominant virus associated with primary liver cancer. I emphasize that because there's an enormous amount of interest in research in hepatitis C and there certainly is a tendency particularly in the public education line to forget a little bit about hepatitis B, after all, we have a vaccine, why can't that just take care of it all? It seems to be pretty obvious that it doesn't probably because people aren't vaccinated. The risk factors in different continents bear out what we were just talking about. In Europe it's mainly hepatitis C. To a lesser extent B, in North America it's about the same. In Asia it's mainly hepatitis B. The one exception being Japan. Now, suppose you have chronic liver disease of any kind but particularly related to chronic viral infection. You have this ongoing fibrotic process leading to a stimulation to growth within the liver. After all, the liver is the only solid organ that regenerates, that's this constant regeneration going on. While death is going on. What are the chances? What are the statistics for developing liver cancer?

So here you see what it is. If you have cirrhosis out's about 2 to 6% per year with hepatitis B, a little less with C. But if you have both viruses then almost regardless of the extent of the pathology the risk from an epidemiologic standpoint is three to five times higher. Now, there are about four recent studies which make it clear that there's an epidemiologic association of primary liver cancer in Dee bettics -- diabetics. Mechanism unknown, unknown from these studies. What's known is these are not virally infected individuals but the extent of their liver disease is not clearly defined in the three studies. Now, here is an interesting scenario. This is the situation in Japan. Where prior to 1990 if you look at the purple bar, the change in itology decreases from 40% hepatitis B, it comes down to about 15% across the board. But the yellow bar prior to 1990 was we don't know because there wasn't any marker or detection for hepatitis C. With that introduction things changed and the unknown drops to 10% but in pink, the hepatitis C contributions. So we don't know what's in the unknown at the moment. Now, what is the normal course of somebody who has the disease, how long do you live? It's not very good. It shows here that from 1977 until 1996 there isn't any real change in the population survival curve. The average survival is somewhere out around maybe year and a half to two years, a little bit longer. There have been many drugs and clinical protocols in all have been introduced to treat the disease. And many techniques try to inject ethanol into the tumor to ablate them by radio waves, microwaves, laser, to embolize material by injecting it into the blood supply. Proton beam radiation and others. And the only one that is really made a difference in the survival of patients so far even bordering in some instances on cure is the application of transplantation of the liver. So the only cures that have been described are basically those in which the tumor is recognized early. I pointed out to you in the beginning, that's not easy. Those effective treatments have been based on removal of the tumor or transplantation of the entire liver. Well, a brief comment. How do you detect primary liver cancer early? There are two general ways. One is to take those who are susceptible, say chronic hepatitis B, C, hemochrometosis, and screen them, either by sonOgram or chemical or biological measurement in blood which has yet to be developed to the extent it's highly effective. The other instance to screen high risk populations for exposure. This was done in China 35 years ago using alpha theta protein as a screen and it led to detection of patients with very small tumors which were helped by surgical resection.

There's a desperate need for serologic measures. This is a long list of markers of primary liver cancer that have been examined generally speaking have been useful but not defin active. In recent years these proteins and the use of microarray and beginning hopefully proteomics as a means of trying to detect in the individual patient particularly those who are chronic viral carriers or hemochrome toeTicCS whether they have signs of a primary liver cancer which would be demonstrated by scanning, and more refined way prior to surgery. Now, all of this as my presentation has been sort of a quick scan through some of the major clinical and epidemiologic features. Most of this disease is asymptomatic. By the time it's symptomatic invariably it's too late. So we haven't talked about the various mechanisms and exciting stuff using gene arrays. These are posted on the website for this year and also you can check the video archive of the presentations from last year which provide this in greater detail. Okay. So now we're going to move on. It uttered the magic word transplantation which is a -- the clue for our next speaker who is Mark downing. Mark is a gastroenterologist, a permanent member of the staff here. He primarily works in the hepatitis branch in the lab headed by Jake LANG and is interested in the development of new therapies for chronic liver disease. So Mark. You're on. Are there any questions about anything that I mentioned? >> So if you'll want to -- can you hear me? Okay. Can y'all hear me now? Okay. So thanks for that wonderful introduction. And my charge is to sort of give a brief overview of liver transplantation. I'm going to highlight some pertinent aspects as they relate to transplantation for liver cancer. So feel free to stop me if you don't understand something that I said or if you have a question. I think I have about 35 minutes or so? Okay. We can certainly talk about transplantation for two days. Okay. So here we go. I would like to just start with a brief historical perspective and the first liver transplantation was performed in 1963 by Dr. Tom STOZLE considered by many to be the father of transplantation. And it actually was in a kid with billry ATRESIA.

The kid died and as a result of that there was a moratorium on transplantation and it wasn't attempted again until 1967. At that time they were successful and that patient survived. One way to look at this is transplantation in three decades. Really there was the early learning decade from '67 to '80 where these were trying times and they were trying to develop a surgical technique. Patients were quite ill. Sophisticated ICU care but not available. There was a lack of adequate immunosuppression. There was only PREDNISONE available at the time and overall high mortality with less than 30% survival at one year. But then came the sun shine years, sun shine decade, 1980 to '90 where we saw significant improvements in the procedure in terms of surgical procedure and in terms of medical management. We saw evolution of the surgical technique, development of the piggy back procedure. Billry reconstruction was improved. This is the Achilles hill of liver transplace. There was a development of venus bypass and better anesthesia care, improvement of innervation solutions to preserve the organ while taking it out of one individual in preparation for putting it into another. Finally improved immunosuppression with development ofcalCIN urine inhibitors. All these improve survival and make liver transplantation a viable option for patients with end stage liver disease. Then that brings us to the next decade, 1990 and onwards where really the procedure has become standard of care for managing end stage disease. As a result of that what's happened is we've had a lot more patients who need a liver transplantation but a shortage of supply of organs. We're going to talk a little bit about this a little later. As a result of that surgeons have become a little creative in that they've started using split livers so where two people can benefit from one liver. And it's also seen the arrival of living donor transplants where a otherwise healthy person can give part of their liver to another individual. This procedure started off initially in areas of the world where there were cultural inhi bigs to donating livers such as in Japan. And was really utilized initially from adults to kids because it was not thought at the time that you could do this procedure from an adult to adult. There wasn't enough hepatocyte mass to sustain the adult. We know it's not true now and you can do adult living donations. So this is the current status of transplantation in the US. The procedure has gotten to the point where we can get 85 to 90% one year survival in most sensors and three year survival is around 75 to 80% with eight year survivals about 60 to 70% so those would be acceptable to most individuals. Here is the reality. Over the last thee years there's only been about 6,000 transplants performed every year. That's remained fixed. Although the number of patients on the liver transplant waiting list continues to uncrease. This number of 17,000 is probably 18,000 now I think based on a 2006 or 7 data.

There are about 1800 deaths each year. Sorry 600 deaths each year on the transplant list and the biggest problem as I mention right now is that demand far outstrips supply. So what I'm going to talk about for the remainder of the talk is to just go through these objectives one by one. Starting with the indications of -- for liver transplantation. One of the criteria that we use to list the patient for transplantation, how we know a patient needs to have a new liver. Organ allocation which perhaps the most contentious issue with regard to liver transplantation. I'm going to spend a brief amount of time going over surgical technique, immunosuppression and end with complication. So while I said transplantation is a viable option for managing patients with end stage liver disease in some regard it's taking one disease and giving the person another disease. Why do I say that? Because there are risks involved with transplantation and there are significant side effects from the immunosuppression that we use that heeds to other problems after transplantation. When assessing a patient for transplantation it's always a risk benefit ratio like most other things that we do in medicine. One has to balance the risk of surgery, the complications of long term immunosuppression with the benefit of improved survival, the prevention of long term complications from the disease being transplanted for and importantly a better quality of life. What are some criteria we use to assess a patient for transplantation. These are accepted indications for transplantation but you have an advanced chronic liver disease with high prediction for death in the next year. Or you have developed acute liver failure with high chance you're going to die in the next weeks to months. You have an unresectable primary liver malignancy or an inherited metabolic liver disease not amenable to other forms of therapy or Yen Rick therapy. There's no alternative form of therapy, no absolute contraindication to transplantation. You'll discuss system of these in more detail a little later. But the individual is willing to comply with the follow-up that's required for managing the graft after transplantation. And that unfortunately you can pay to have the transplant done. What are some of the diseases that get transplanted here in the US? This is data for adults. This pie chart would look different for kids. As you can see here as Dr. AR EAS indicated the major indication by disease for transplantation in the US is chronic viral hepatitis. That accounts for hepatitis C and B for almost 50% of the cases for transplantation. By far and away the largest proportion of patients -- adult patients getting transplanted in the US is for chronic end stage hepatitis C. Alcoholic liver disease accounts for about 12% of cases.

crypto genic cirrhosis a large part which maybe related to fatty -- end stage fatty liver disease or mash may account for system of these cases and colo static liver cases, hepatic liver autoimmune 3% and retransplantation a small percentage. So what about survival after liver transplantation? As I told you that one year survival is greater than 90%, eight year survival is 60%. Survival does vary depending on the disease for which you were transplanted. The best results are obtained with colo static liver disease, primary colongitis. The worst survival used to be for hepatitis B. This is changed with the introduction of better therapy to suppress viral replication post transplantation and survival of hepatitis B approaches that of COLO static liver disease. The worst outcome is for chronic hepatitis C, I apologize this charge is somewhat dated. Transplantation for primary liver cancer is now apreaching that of all other indications for liver transplantation provided you select appropriate candidates. I'll get into that later in the talk. Why don't we move to minimal listing criteria. How do we evaluate a patient and determine that this patient needs a liver transplantation and is a suitable candidate? There are minimal listing criteria for putting the patient on the transplant list. This is liver failure, which is defined a the development of acute hepatitis with the presentation of neurological symptoms. What we term hepatic enreceivelopothy. This is usually increased -- inability to be aware of your surroundings or even Frank coma. And this is a clear indication for transplantation. But it's also somewhat controversial one in that it's it's difficult to determine who is going to survive spontaneously and don't need liver transplantation versus those who have a high likelihood of dying. Then the more definite criteria goes for end stage liver disease. This formerly used to be assessed by a criteria called a child pew score which is no longer used and is replaced by the Mel's score, I'll discuss these momentarily. So the child pew score was developed by two surgeons in Britain, it was developed to predict mortality in patients undergoing surgery for a come mycation of liver disease, esophageal resection. These surgeons impeerically came up with a number of clinical and laboratory parameters they would predict survival. Actually it with stood the test of time. It's been used and been around for over 40 years. It was modified in 1972 by pew who was chief of surgery at university of michigan by removing one of the -- one of the variables which is nutrition and replacing it with the prothrombin time which is a measure of how well your blood clots. Using these two clinical criteria, chronic -- more objective analysis, they're assigned a score of 1, 2 or 3 based on the severity of these parameters. Then they're combined to give you a total score which defines three grades either well compensated, decompensating or decompensated cirrhosis. And based on this classification you are assigned a status which determined your need for transplantation.

But there were problems with this scoring system. I'll get into that when I talk about allocation. How well did child score perform on predicting survival on waiting list? It didn't do too bad. As you can see here on this survival curve you can see there was nice progression between over theall scores and survival such as one year CPT score of six -- I'm sorry, this should be seven or greater discerned survival, one year survival on the waiting list from 90% if you had a child pew score of less than 6 which fell to about 65% if your score was 7 and 40% if your score was greater than 7. So for purely empirical test, I it didn't do too badly. What about patients for transplantation who had hepatocellular carcinoma? Here the criteria adopted is the MILAN criteria. These were developed by surgeons in Italy and prior to development of this, the overall survival rate for transplantation of all patients with hepatocellular carcinoma but generally poor, about 18 to 40%. With the introduction of MILAN criteria, four year survival is about 75% which is the same as that for transplantation -- for all other transplantations. And as Dr. AREAS indicated recurrence free survival if you want to say cure, approaches 85%. That's dramatic when he can you consider the rate of hepatocellular carcinoma untreated where there's over 50% two year mortality. So this is data showing survival of transplantation using the MILAN criteria which is a solitary lesion less than five centimeters in size or up to three lesions all of which are less than 5-centimeters in size. You can see here you have a 75% four year survival which is similar for transplantation for all other diagnoses. As you can see preMILAN criteria, analysis looking at selected patients from 1991 survival actually 18 to 40%. So this has been adopted here in the United States and most other centers in the world for transplantation patients for hepatocellular carcinoma. Not everybody is eligible for transplantation. So what will some of the contra indications? If you have an active bacterial infection HIV is a relative contra indication but should only be done under protocol setting. It's been evaluated right now at two or three centers around the country. I can tell you that while there was some initial thank you because of good results that transplantation for HIV candidates, the results have generally not fared well. Patients have not fared well. Active alcohol or drug abuse is an absolute contraindication. Most require a period of six month sobriety of alcohol use and one year drug abuse prior to listing. Severe co-morbid disease such as uncontrolled diabetes or severe heart disease. Extra hepatic malignancy, irreversible brain damage, multi-organ system failure, severe psychosocial disturbs and inability to comply with the immunosuppression regimen. So what happens when a patient shows up to your door for evaluation?

Well, what you generally do is obtain -- first of all I should say that the evaluation process is a team approach there's no one single physician who determines whether a patient gets transplanted or not. It's based on a committee which consists of hepatoologists, transplant workers, psychiatrists, psychologists and a financial person. Generally when a patient comes they get a battery of lab tests to see if they fulfill the medical criteria. They undergo a cardio pull no mare testing to see whether their heart and lungs can withstand the stress of surgery, the patients with end stage liver disease tend to be sick and in ICU prior to transplantation. And if they have underlying cardio pulmonary disease this can be a relative contraindication to transplantation. They undergo a number of radio logic testing to determine if they have underlying malignancy which may change their listening. And psychosocial evaluation to see are mentally prepared and adjusted to deal with what's involved with undergoing transplantation. This process takes a couple of months to give the patients and families the time to adjust to the process of transplantation. Once the patient is listed for transplantation they wait on the list until an organ becomes available. And while opt list there's some general medical care that's -- that they understood go. Mel scores get updated in a timely fashion and it depends on the severity of the liver disease. The more severe the disease the more often their Mel score gets updated. The healthier they are on the waiting list the longer the duration. They need to be immunized against hepatitis B if they're not immune, against hep A and against other common bacterial infections. Though rates of immunization are lower compared to non-transplant candidates, they need to be tested for tuberculosis, undergo screening for hepatocellular carcinoma, understood go screening for other common cancers that affect the US population. Patients with cirrhosis tend to have bone loss so they need to be screened for bone mass and then undergo treatment for primary disease such as treatment for hepatitis C or hepatitis B. A big part of management for patients prior to transplantation is dealing with complications of liver disease, mostly complications of portal hypertension such as esophageal viruses, hepatic enreceivelopothy, PERITIS and renal and pulmonary complications. Finally dealing with psychosocial issues on the patients on the transplant list. So now I would like to talk about organ allocation. As I said, this is perhaps the most contentious issue with the whole transplant process. How do you decide who gets an organ? And believe me, it's not easy. So what I would like to start with is just how this has evolved historically. Back in the 1980s this was done on a voluntary ad hoc basis.

So patients showed up, you sort of asked around if we had a suitable donor, if there was one the patient gout got it. Then in 1984 Congress got involved and passed the national organ and transplant act which created the organ procurement and transplant network or the OPPN. This network is managed by another organization, the united network of organ sharing or UNOS as it's called. They have been managing the OPTN since its inception in 1984. When this first came along priority was given based on your severity of disease whether you were in the ICU, whether you were hospitalized or whether you were home. So the patients in ICU got first didn'ts on the livers. If you were hospitalized you got it next. If you were home you were way down on the list. But clearly that wasn't adequate. There was gain manship involved. Transplant surgeons would bring patients into hospital, put them in a bed so they would move up on the list when clearly they didn't need a liver. So because of that in 1997 the child pew score which I introduced as minimal listing criteria. You have to have a score of 7 or greater to get object transplant list to try to make things a little bit more fair and equitable. That was superseded by Mel in 2002 and I'll get into that in one moment. So this is sort of a quick overview how the organization is allocated so the organ procurement and transplant network is run by UNOS. UNOS oversees the local organ procurement organization so I think there are 62 of them in the US. Each OPEO is comprised of one to eight transplant centers. How it works when an organ becomes available within an OPEO. The organ must be matched to the recipient with the highest need based on their MEL score and the exception here being status 1 patients. Status 1 patients are the patients in hepatic failure who have a life expectancy of just 7 days or less. These patients get priority over everyone. The way it works when an organ becomes available it's first offered locally within your local transplant network. If the organ can't be used locally it's passed on regionally, if it's not used regionally it's open nationally. So there's 11 region, UNOS divided the country into 11 regions. These aren't based he can tably. There's a lot of politics involved with how these regions were assigned. Maryland, Virginia in region two. And there was a push to try to divide these up based on population. However, that's never taken effect and we have been using this ever since 1984. As I said in the past the organs are based on the child pew score. On your blood type, overall waiting time, and then you're assigned a UNO status. What were these statuses? One I indicated was formal hepatic failure where you had less than seven day anticipated survival.

These patients got the organs first. They still do. In the old system patients with end stage chronic disease were assigned to one of three status, either status 2A, B or C. 2A was patients in the ICU who were hospitalized. 2B were those continuously hospitalized, sort of in and out the ICU, and 3 were mostly at home. You can imagine if you have 18,000 people on a waisting list, they can only go into one of three categories that -- how do you determine who gets an organ? In the old days what determined priority was waiting time on the list. Clearly that was not equitable. And there are also problems where the child pew score. There were a limited number of categories, only 3. There was limited discriminating ability to see the score. This floor to ceiling effect in a patient with a billion Rubin of 3.5 and a billion Rubin of 25 -- Billy Rubin of 25 kept the same score T. one with a number of 24 had a lore life expectancy than a person with a BILIRUBIN of 3.5 so that's hardly equitable. Because of the subjective parameters involved in the score such as presence of ESAIkES, encephalopathy, people would over estimate the amount of -- it was purely arbitrary based on person who was evaluating the patient. Some of the laboratory parameters in the -- the Albumin were open to laboratory variability. This system has never really been validated. And serum creatinine which the driving force in meld is not included in this score. so there was an impetus for change. This is because as I said waiting time did not reflect medical need. The categorical urgency system failed to prioritize a large number of patients on the waiting list accurately and the TTP score was subjective, not validated and didn't distinguish the sickest patients. So in 1998 HHS got involved, Donna SHELELA came up with the final mandate. This charged UNOS with developing a priority for organ allocation based on objective measurement clinical criteria. They furthermore stated waiting time must be de-emphasized an patients should be ranked based on disease severity and on their predicted mortality on the transplant list. As I said this challenge was presented to UNOS to develop a liver disease severity and next to estimate death in chronic liver disease and it would be validated clinically and statistically. This led to the rise of meld. meld was -- meld comprises of three clinical parameter, BILIRUBIN p INR and CrEATINE. This was developed to predict survival in patients undergoing tips procedure, that's a transjugular intrahepatic shunt so this is where you create intrahepatic shunt to divert blood in patients with portal hypertension to decome press the system. And this was replacing surgery for which the child pew score had been developed. And these investigators came up with this logistic regression model which accurately predicted three month survival in tips.

They found it was independent of itology and independent of some of these complications of portal hypertension. So there are significant advantages of meld over child pew score. A continuous measure of disease severity so as the disease worsens your meld score increased. It was based on objective parameters though some of these parameters are subject to lab variation such as testimony measurement of serum CREATINE. It is a accurate predicter to of three month mortality on the waiting list, independent of complications of portal hypertension. It's independent of itology of liver disease. It performs better than child turket pew score. Shown here is a study conducted in about 3,000 patients on the waiting list waiting transplantation. Of which there are about 400 deaths. And the investigators looked at correlated meld score with mortality. As you can see here, there's a nice direct proportional correlation with meld score and mortality on the the waiting list. From a low of about 2.9% if your meld score but less than 9 to about 81% if your meld score but greater than 40. Currently this is the meld score which you would get a transplant between 20 and 29. It varies depending on where you live geographical and from center to center. And this study also showed the meld score was a better predictor than the child pew score. This is a operating curve which is noting sensitivity of one minus specificity. If the curve falls on the die I can't gonal here, this is a 50/50. This is a useless test. The test you might as well toss a coin. Curves in the northwestern quadrant have the best accuracy for predicting what you want your test to do, in this case to predict mortality on the waiting list. And you can see here it was .83 for Mel and .76 for child pew score. Generally a good operating curve is .7 or higher. So meld performed well, performed better than the child pew score and therefore was adopted by UNOS as the criteria where buy patients were listed and where organs were allocated. So there was this concern when meld was introduced by the transplant community that meld was going to lead to transplanting patients who were sicker and that overall results of trans plantation were going to be poorer. So there was a need to show that meld was associated with better transplant outcomes. There was a study conducted where the investigators looked at the meld scores, looked at the -- sorry transplant survival, one year prior to introduction of meld and one year after introduction of meld. What this study showed was after the introduction of meld there was a reduction in new listings primarily in patients with more meld scores so what was happening here is that this was one of the benefits that we wanted to get from meld. Patients were being put on the list who didn't need to be put on the list.

There was a reduction in waiting list deaths so people were getting -- the sickest patients were getting transplants in a more timely fashion. There was increase in cadaverIC transplans. Post importantly there was no difference in early post ORT survival. So this fear that because we were going to transplant sicker patients outcomes were going to be worse was not realized. But there are problems with meld and there have to be exceptions because meld does not fit all indications for transplantation here I'll focus on exceptions for hepatocellular carcinoma. Many hepatocellular carcinoma patients don't have decompensated liver disease when diagnosed with their cancers. we just use the meld criteria to allocate organs they would have much lower meld scores and wouldn't get a transplant. So the people who were at UNOS realized this and made exceptions for meld. So if you had a cancer and you met criteria for transplantation then you got extra points. So in fact most people who have hepatocellular carcinoma come to transplantation have a meld score in the range of 11 to 17. So these patients would not get a transplantation and what would happen is the disease would progress while waiting for their liver disease to worsen and they would die of the cancer while on the waiting list so meld made an exception and allowed the patients extra points because HCC patients were felt to be disadvantaged. So there was some ebb and flow on this and the pendulum officially swung too far to the right. So initially they gave patients who had hepatocellular carcinoma a meld score of 29. So what do you think happened? So more patients with hepatocellular carcinoma were being transplanted than patients who didn't have cancer. That cheerily but not fair. So the pendulum is swung back to the a little bit more to the other side now, now if you develop a cancer and you have a small çûƒWügÆ@ • ƒ ¸v +ÿóPd ð—bË%è9 ±.¸¨ ÎpÉr² a transplant list is low and a patient with a lesion of less than two centimeters has less than a 15% three month mortality, so you get no extra points. And if you have a T-2 lesion defined as a single tumor greater than 2-centimeters, or multiple tumors none of which are greater than 5 you get a meld of 22. So if you meld otherwise would be about 11, 12, you jump up to 22. Every three months you get extra points for being on the list. So by the time -- so most patients with cancers are getting transplanted after an average waiting time of about 6, 7 months. These lead to actually very good results. So moving on to surgical technique. The operation has become standardized now and conceptually we can think of the operation in three phases. The hepatotectomy phase where you remover the liver from the recipient. The anti-hepatic phase where the liver is gone. That's where there's the highest risk of death during the operation.

Because of major fluid shifts that are occurring. Then finally the post implantation phase. So the operation is relatively straight forward. There are basically four vascular (indiscernible) that have to be made and the billry duct. So the vascular ANASTOMOSES, the superhepatic IVC, infear your vena cava, the inferior vena CAVA. The hepatic ATRIA ANASTHIMOSIS. The liver is unique in that it has two blood supplies. It has hepatic archoring which brings oxygenated blood and the portal brain which brings the majority, three quarters of the blood from the intestin which is rich in nutrients to the liver. So these three vascular ANASTHEMOSES are performed first, finally the bile duct is done. And the bile duct is the Achilles hill of this operation. Most complications that arye are due to billry track problems. Most surgeons attempt what's called a primary end to end ANASTHEMOSIS on the bile duct and after the operation a T-2 was replaced to allow and observe drainage. However if for surgical reasons a primary ANASTHEMOSIS cannot be done the next is to do a -- where a loop of bowl is brought up and the bile duct is ANASHEMOSED directly to the intestin. That's all I really wanted to say about the surgical operation. Now just a few words on immunosuppression. There are four classes of drugs used for immunosuppression. cortical steroids have been the main stay. Calcium inhibitors of which the two primary agents used CAPILIVIS and Cyclosporine. Anti-proliferative agents. And RAPAMYCIN and anti-lymphocyte anti-guys such as anti-lymphocyte anti-CD-3 agents. As I mentioned at the beginning of the talk a major problem after transplantation is side effects from immunosuppression. Surprisingly rejection after transplantation is not such a big issue as it is with other solid organ transplantation. And the main problem that physicians dealing with post transplantations have to contend with is adverse events, adverse effects, sorry, of the medications. And listed here on this table are the major side effects associated with these medications, hypertension, renal insufficiency, diabetes, hypercholesterolemia, hypertriglycerideemia and osteoporosis. Complications from immunosuppression are a significant contributor to mortality after transplantation. Most patients who undergo liver transplantation do not die from the disease for which they were transplanted or from rejection. The majority of deaths are related to cardiovascular complications or the development of cancer, associate somewhat due to the immunosuppression that these patients are on after transplantation. Now finally I will just like to spend a few words on complications after transplantation.

I'll sort of group them into early complications, sort of middle to early complications and then late complications. So what are the early complications? The early complications are mostly surgical. And can be looked at a post-operative gastro intestinal bleeding. Vascular complications, hepatic thrombosis or portal vein thrombosis both requiring immediate retransplantation otherwise death ensues within 7 to 10 days. Then as I said billry complications. And we've gotten a lot better at managing billry complications but about 30 to 40% of transplant patients develop pilary complications, these can be obstruction or bioleaks. So early or intermediate complications occur within two weeks to about four months post praytively. These are mostly related to infections. Wound and systemic infections bacterial fun gal or viral. Plenary complications, fusions, and then early rejection which is fairly easy to manage. Most parents are place on an antibiotic and anti-fungal prophylaxis to prevent these infections. Late complications. What are the late complications? Renal dysfunction, this is largely due to complications of the CALCIN neuron inhibitors the main stay of immunosuppression. Mall nourishment and nutritional deficiencies. ZINC and magnesium deficiencies. Metabolic bone disease, it takes about a year to reverse in transplantation. In the 6 to 12 month period these patients are at risk for fractures. Recurrent disease occurs and I'll speak about that in a few moments. And cancer T. most common cancer that develops post transplantation is determine to logical. So these patients need to be followed by a dermatologist once a year. The next on the list, lung, colon and breast cancers. So the cancers that effect the non-transplant population a well. So patients should be screened for these. And then cardiovascular disease. And the ones that are highlighted in orange actually account for most of the mortality in the transplanted patients. So more about recurrent disease. There are many diseases that recur after transplantation, they are listed here. hepatitis B and C, I should say hepatitis B recurrence occurs in 50% of patients now. It used to be universal prior to introduction of hyperimimmunoglob Lynn and nucleoside analogs. This has been significantly diminished. Hepatitis C, it's almost universal. 100%. And this is actually a major cause of morbidity post transplantation, trying to deal with recurrent hepatitis C. Post transplantation, the disease is accelerated in a proportion of individuals.

And treatment of hepatitis C post transplantation is difficult. Primary billry cirrhosis reoccurs in 20% of individuals over five years. Less amount in colonGITIS. 5 to 10% have autoimmune hepatitis. Tumors can reoccur. Hemochrometosis is reported to recur. Recidivism for patients who are transplanted for alcoholic liver disease is about 7 to 15%. Non-alcoholics deal with hepatitis which is fatty liver disease with inflammation and then (indiscernible) syndrome. So this is my last slide here, I want to just end to give you a perspective of some of the costs associated with this procedure. Costs about 244,000-dollar, this is '99 data. In the managed carer ra, this is reduced about 150 to $180,000 for transplant. And shown here is individual break down of the costs. Evaluation, candidacy and procurement account for 22% of the costs. You can see the bulk of the costs going to the hospital fees associated with transplantation. Physician fees account for 15%. The remainder, the post transplantation follow-up and then immunosuppressive medications. So in general patients the cost of immunosuppressive agents is a thousand to $1,500 a month. To give you an idea of what patient versus to pay off transplantation. If the patients cannot pay up front they're not candidates for transplantation. So I think I'll stop there. Are there any questions? >> Thank you very much, Mark. Go ahead. (off mic) >> Recurrence of hepatitis C. As I recall on an earlier slide where you showed the characteristics of the population the largest had hepatitis C but there was a significant number, was it 33%, who did not have either hepatitis C or hepatitis B by combination >> All others, so 60% were not transplanted. >> So those who did have hepatitis C will -- it will recur for -- I mean, it's not that everyone has transplantation develops hepatitis C. Okay. >> No, these are patient whose are transplanted for hepatitis C. So patients who were transplanted for hepatitis C 100% have reC post transplantation. >> Yeah.

(off mic) >> When -- how many years would they get before they have cirrhosis again? >> Well, it's actual hi variable. You can look at them in thirds. A third will have severe recurrent disease within three years. Some smaller proportion will have an accelerated cost. These patients develop fibrosis colon static hepatitis and in three months can have end stage liver disease. A third develop cirrhosis within three years. A third don't develop any cirrhosis. And a third will require -- sorry, about 10% of patients will require retransplantation for hepatitis C. Now, the issue of retransplantation for hepatitis C is very complicated. Some sites will say because of the shortage of organs if your disease reoccurs rapidly and we can't control it with anti-viral treatment, you're not going to get another transplant. Whereas others will say we'll give you another liver so it's very variable from center to center. >> I think we have to go on because we're running late. Just want to bring two things to your attention that Mark mentioned which are a real challenge to basic scientists. One we don't know how to determine whether the liver is regenerating or not except in a rather gross way. If a person wakes up and looks fine that's one thing but the determine whether you really need a transplant are one of the most difficult kind of decisions that you have to make literally at a bedside so we don't know despite all this tremendous biological activity that's going on in the liver we don't know. So it's really very difficult to make those decisions. The second thing to throw in some drama, last year there was ten transplant patient whose ran and completed the Boston marathon. Now we're going to proceed to Alan worthheim who is patiently waiting. Alan is professor emeritus of political science at the university of Vermont. His main interest is in this decision making an has given a great deal of thought to it which we'll benefit from.

>> This okay? >> When -- he said I was a political science, it's true I was in a political science department but I'm not really a scientist, I'm not a scientist, not even a political scientist. I'm really a political philosopher who works on ethical issues. So for me the issues that I have some competence in are not really how people do make decisions but how they ought to make decisions.

That's what I spend my life thinking about and hopefully I'll be able to shed light on this. Maybe because I was in aneth Is department and not a science department we begin our talks with a disclaimer. Shouldn't say they don't represent the views of anyplace else just that if they do it's by coincidence. They're not meant to represent anybody's views. What I have to say today is based on some work that I have done with zeke Emanuel, the chair of my department and a quite brilliant predoctoral fellow in our department. We have an article coming out soon in the lansett on the general issue of allocating scarce healthcare resources of which organs are one but not the only kind of healthcare. That's possible the principles that ought to govern the allocation of resource also vary a bit from resource to resource and perhaps even from organ to organ. I got into this problem, this isn't why I got into NIH I was working on other things because Zeke and I got interested in the allocation of vaccines and anti-virals in the case of a flu pandemic. We wrote an article on that which appeared in science a little while ago. Recently we have just tried to generalize the issue and not just talk about flu vaccines but now try to talk about the principles how should we allocate scarce medical resources. And I'm going to skip over a lot of the factual basis because they have been covered well here. In the area of organs, in some context of healthcare resources in principle we could spend a lot more money to reduce scarcity such that ICU beds wouldn't be scarce if we built enough of them. Might be good reason not to build enough of them. But in principle there's no scarce and necessary scarcity of some resources but in the case of organs it seems inevitable there's going to be a scarcity of organs, we're not going to have enough organs. Even if we got organs from everyone who was a potential donor of livers we would not have enough. At a more general level it's worth noting two issues. One, issues of procurement. How do we go about getting organs or more organs? In general in the United States right now we tend to use what we could call an opt in system. We take organs from people only if they or their proxies or surrogates their family have chosen to say, okay, you can take it. Now, there is some thinking that -- in some countries working with the idea of an opt out system where the default position is that if a person dies his organs are available for transplantation unless there is a specific decision on the part of that person prior to death or the family to say no, so by changing the default position there's the possibility of generating more organs. It won't solve the problem but goes some way towards ameliorating it. There's also the possibilities of financial incentives. One way of possibly getting people to donate organs is to pay them. And you could pay them now. You could say look, if you agree to have your body used for organs when you die we'll give you now a certain amount of money.

There's a lot of resistance to people to the idea of using financial incentives in this context but in principle it's a possibility. Then of course there are also issues in directed donation. This is particularly arisen in the case of kidneys where people have particularly people with considerable means have found ways of advertising, publicizing their stories and tried to get some people to say look, here it is. I'm needY. Could you give me an organ? And for the most part UNOS is quite opposed to that system. Procurement is one issue. The issue I want to talk about today is the issue of allocation. Because in an ideal world in which all brain dead potential donors back actual donors the demand for organs remain constant rather than increasing supply of organs from brain dead donors could not meet the needs of all of the patients on waiting lists. It's worth noting, note that she et al. cxfc refer to brain dead donors. There's controversy about the issue. For the most part in the United States we operate on a dead donor rule. That is to say we only take organs from people who are dead, right? That's actually somewhat controversial. Once you decide that you have opted for a dead donor, only take an organ from somebody who is dead, there's a lot of pressure to define death in a way that lets us take the organ. Okay? So we say okay, you're brain dead, you're dead, or you have cardiac dead. You're dead. Okay? So now we can have the dead donor rule yet although the person may not be dead by some views about what death really is, we can take the organ. Now, members of my department have actually suggested maybe the better way to think about this, at least the more honest way to think about it is to reject the dead donor rule. And say we will accept organs from those who were not dead but where we would respect in those cases a valid decision to withdraw treatment and the surrogate consent. So in the case of brain dead donor, don't say the person is dead, they're not dead yet but this is a case where we would accept a valid decision to withdraw treatment and the surrogate consents to withdraw treatment so go ahead and take the organ. I won't go into that but want to note there's some controversy about this issue. Well, who should get organs? Mark explained quite well the existing some of that UNOS uses. The issues that I'm interested in as a ethicist and a philosopher is not actually how it's done but how maybe it ought to be done. Are they using the right principal? If we were to think about the principle the issue from a more general ethical perspective, how would we think about it? And -- well, we would start with principles and think about principals that we might use on a one by one principal.

I would suggestion when we think about principles we can think about principles as being either flawed or being insufficient. What do I mean by that? A flawed principle is a principle that really shouldn't be used at all. It's morally not the right principle to use in a -- one context or another. And insufficient principle is a principle that is of -- it's a relevant ethical criterion for the allocation of a resource but by itself we might think it's not sufficient. That the best ethical approach would therefore combine nonflawed insufficient principles hopefully into a system which gives us the best possible result. No system is going to be perfect here. What we're trying to do is to see if we can figure out what the most defensible or plausible approach from an ethical perspective would be. And it seems to me that there are -- seems to us I should say because this really is work that's grown out of collaborative work. Of four major sort of values that we could think about as underlying the allocation of scarce resources including liver. One is equality. Everybody likes to talk about equality. That there should be equal opportunity some might say. Or we might say we should help -- it's a view sometimes called pry your tearian, give scarce resources to people who are worse off or the worst off. I'll say more about each of these principles. Or we might say let's do it in a way that maximizes bench let's treat organs as a scarce resource and distribute them in a way that gives you the biggest bang for the buck. Okay? And that's a possible criterion as well. Then another one finally this actually I think turns out to be more than issue with flu vaccine and anti-virals than it does with organs than it is with organs. But some notion of promoting and rewarding social use -- social usefulness. So you have for example the issue of desert. Do some people deserve a resource more than others? Mark mentioned alcoholism. Note, he talked about the survival I take it of people with alcoholism and -- but one might say one could say look, somebody who is an alcoholic and now -- forget about whether they'll do well, forget about whether they're now off alcohol and likely to survive. The fact is because they were an alcoholic they now need a liver, right, that they wouldn't otherwise have needed had they been, quote, -- they behaved better in the past someone might say, right? So they -- someone might say, I'm not defending this now, someone might say well, they deserve it less than someone else. It's because of their past behavior that they're now are in a of need. Whereas someone whose need is generated simply by bad genetic luck, bad environmental luck of one kind or another, maybe they should be higher. In fact actually we reject that view. But what I'm trying to outline here are the kinds of possible views that one might have about how to allocate a scarce resource. Let's talk about equality.

The problem of course is there are some resources which ready visible but many medical resources are not divviable. If you have a certain amount of money you can distribute it equally but with a medical resource you can't. You can't divide a heart in two or two people on dialysis at the same time or give a dose of penicillin or flu vaccine to two people. If there's anything to the notion of equality it's not going to be distributing something equally but giving people an equal opportunity. Some people might say, well, look, we do believe in equal opportunity. Why shouldn't that apply to the distribution of scarce resources like organs? Why should somebody be lower down just because? So some might argue we actually reject this, but I just want to note that in some important moral context we do use a lottery device. For example, military service was once decided in this country when we had conscription on the basis of a lottery. You might say we didn't say well, who would be the best soldier. There was a point that said no, the fairest way is for people to have an equal chance. Hotrys are in some context not a bad idea. They're hard to corrupt. Mark talked about the gaming of the system and the use of some principle. Lotteries are hard to corrupt. You draw the right number or you don't. It protects people from complaints. Why him and not me? Well, you got a number, okay. It's easy to apply. The problem of course with lotteries is that they're blind to relevant -- numerous moral considerings like a person's prognosis. It seems in the case of organs lotteries is probably not the way to go. You could have it's a kind of -- it's almost like a natural lottery. First come first serve. To some extent we still do use first come first serve because a waiting list is essentially first come first serve. To the extent you give people credit for how long they have been waiting, you're basically working on a first come first serve, even if it's not the only principle, it's a part of the principle. And in some context there are -- there's a lot to be said for first come first serve. It tends to preserve the doctor/patient relation. For example, somebody is on a respirator and placed on a respirator and somebody else let's say needs it more or would have a better prognosis with that respirator, we don't say oh, okay we the respirator away from you and give to it the other person. First come first serve allows us, once you're on you're on and it gets to preserve the doctor/patient relationship. One of the problems with first come first serve in come context, I don't know it's a problem with liver is it often tends to favor the well connected and the well off who find ways of getting themselves on a list or getting themselves on multiple lists.

So that's an ethical difficulty with first come first serve. Let's talk about helping the worst off. We can define that in a couple of ways. Seems to me the most natural way is to think of worst off as those who were sickest. And there's a lot to be said. Those who are suffering now, it's hard not to be compassionate toward those -- the thickest. One of the problems is that it ignores what appear to be morally relevant criteria. It ignores prognosis. Which is often worse among the sicker patient. In some context it doesn't -- it doesn't consider whether a person -- if we say the person is sickest, if we say they're sickest right now there are some context, I don't know that this is an issue with livers where though a patient may not be sickest right now we can predict they will be the sickest. So sometimes with give it to sickest right now it might be a resource like organ for somebody likely sicker in a relatively short period of time. One of the reasons I think historically treating the sickest first was viewed ads plausible, it was like let's treat the people sickest now and by the time that others need something maybe more will come along. So we'll be able to help everybody. Get the sickest now, we'll assume the scarcity is temporary and by the time somebody else is that sick maybe we'll be able to help them all. The problem is that's basically based on a kind of denial. The scarcity is not temporary. So given that there's actually some reason -- this maybe some reason to value sickest first but for the most part I think it's probably not the most morally relevant cry tieria. Interestingly we think that as Emanuel and worth Heimer think, another way to think about those worst off is in terms of age. And there's a sense in which the youngest are the worst off. A sense in which. In the sense that they have had the least life. They are less well off than others in the sense they have less of something valuable than others which is to say years of life. And so given everyone is interested in living a long life up to a certain point anyway, we think there's some reason -- and we have argued this where we think it's more relevant in the case of flu vaccine than in the case of livers. But there is some reason, we actually think quite persuasive reason, to favor the youngest when other things are equal. I should go back. Let me figure out how to go back here. Let me go back for a minute to the issue of the youngest to helping the youngest. Somebody might say that helping the youngest first or giving people preference on the basis of age is discriminatory in a certain way, a kind of ageism. We think that complaint against using age as a relevant variable is unsound. Okay?

It is not discriminatory in the way that discriminating against people on the basis of race or religion or gender is discriminatory. The fact is that everybody goes through the same age, you live long enough, everybody who is 50 was once 15. Everybody who is African American was not once white and vice versa. So it is discriminatory in a technical sense but it isn't discriminatory in a pernicious sense. So we think that age is as a criterion is not vulnerable to some of the criticisms that could be used against other kinds of discrimination. One of the problems with using the youngest first is it like other some other variables ignores prognosis which we think is a mistake. Another criterion, let's maximize the benefit. Let's use a scarce resource in a way that saves the most life. This is based on the principle that each life is valuable and therefore the more saved the better. One of the difficulties with the save the most lives principle is that it could be note there's a difference between saving the most lives through the use of a scarce resource like an organ, and saving the most life years. Because a younger person other things being equal, if we can expect a younger person to live more life years without taking sides right now, suppose you had let's say for some scarce resource like a liver or some other organ, a person who was 40 who if they got the organ you could expect to live 30 years. And two -- and some scarce resource such that you could keep two other people who were 70 alive so you could save two people or one person but in one case you might be getting 30 or 40 years for your organ, the other case you might be getting a total of maybe 20 years for your organ. Not suggesting that we shouldn't save the most lyes. But suggesting that saying the most lives is not obvious particularly as that some people have lived less than others. They're younger, where -- let me stop for a second. Those who are want working on flu vaccines where the principal of saving the most lives might tilt towards those who are sickest or oldest. Okay? We're saving the most life years might tilt towards giving vax seens to younger people. What's interesting that when the government went out and sort of field tested their model for the -- when they talked about saving the most lives and giving to the people who were sickest, older people say no, give it to my grand kids. I have had a decent -- I have had a reasonably long life. Don't use the scarce resource on me. I say this with somebody who has got his Medicare card. That there was actually among people out there in the field when the government went around to focus groups and talked to people about the principle, considerable sympathy for using age as a -(off mic) >> I'm sorry?

(off mic) >> Save the liver surgeon. >> We're coming to that. We're coming to that because actually because I don't have much time. Did I do something wrong here? What happened? (off mic) >> Pardon? (off mic) >> I got out of -- and we have no help. All right. You'll just talk. I don't quite know what -- one of the -- in the flu vaccine context the government position is that first you have to keep healthcare workers and the manufacturers of the vaccines alive. Out's kind of save the pilot first or save the captain first. If the plane is going down -- I'm sorry, if people on the plane are sick I should say, the first person you want to treat is the pilot. Because if the pilot goes, everybody. So there is actually an ethical case could be -- sorry about that. Could be -- I taught at the university of Vermont 37 years and never used power point. Okay? Now I'm at NIH and I'm told that you can't talk without using power point. So here we talk about the notion of people having instrumental value which we think actually in the case of public health emergencies is something that ought to be taken into account. To give priorities to people who can benefit. Very important to see that the notion of people having instrumental value isn't that they are intrinsically more valuable. The idea isn't that the healthcare worker or the transplant surgeon is a more valuable person in some moral sense and they deserve to be kept alive. It's that if it's the case that keeping one person alife will enable us to keep other people alive, we value their life in this instrumental way. In some context, particularly in the context of healthcare emergency there might be some reason to do that. We talked about promoting social usefulness and the principal of reciprocity, another possible principle for allocating resources, there's this organization called life sharers which some of you maybe familiar with and the idea there is that if you sign up to allow your organs to be taken you will have a call on other people in this organization for their organs.

And it's -- in principle I think a reasonable idea. We think that when you consider these principles, and I now have I guess only five -- we stop at 6, right? Okay. That some of the principles that I discuss should be excluded as what we have called flawed principles. We don't think first come first serve or time on waiting list is a particularly good idea. It's easily manipulated, biased to the rich and the well connected. Sickest first we think should be down on the list of possible criterion. It's inefficient, tends to assume that prognosis was equally good when it's not. And also that the currently sickest may not be worse off when one considers all the ways in which people maybe worst off. Other of the principles that I've outlined we think contain important and morally relevant considerations and should be part of a multi-principle system. However strew mental value we think is probably most relevant in an emergency situation where there are public health worries but not in non-emergency experiments. But we have the thought emperiment. You think it. great minds think alike. Should we give priority to a transplant surgeon who needs an organ? Mark might say yes. Are you a transplant surgeon? All right. I mean but one can ask this question. Look, this is the kind of question as a philosopher I spend the -- it's amazing I get paid to do it but time thinking about. Well, we think that what we have advanced as morally relevant but insufficient principles need to be combined into a multi-principle system since I only have a couple of minutes I'm going skip over the UNOS system which Mark covered, another approach that some people have favored is what are called quality adjusted life years and where we try to maximize not just the number of lives but life years adjusted for the quality of those life years. So we use a scarce resource like a liver or a kidney or a vax seen in a way that doesn't treat all life years on the quality model as comparable. You can look if you want after the slides, we say more about them. Others have the world health organization has advocated a system which they call disability adjusted life years. We -- where they actually take a person not only their contribution to health but their economic productivity into account suggesting that society will be better off if scarce resources like organs goes to those likely to be economically the most productive, we're very skeptical of that approach. We think it's probably not the way to go. Pardon? (off mic)

>> To get the person back to ->> Tax payer status. >> I apologize. I should have said up front I don't hear well. One of my -- I have one hearing aid and other one is in the shop. So I'm at a disadvantage here and by the way not covered by any kind of health insurance, you figured that out. Okay? So the complete live system that we recommend and develop in this article, you can see more on the slides if you want, that we do think other things being equal that youngest first should be included. Prognosis, maximization of number of lives, if we have lottery here as -- that is to say if in fact on some scheme it was -- you had a group, suppose you had a number of people who had roughly comparable meld scores or otherwise in a comparable group eligible for some scarce resource like an organ, we might think at that level you might throw a lottery is a way to choose among them but not a a basic value. Instrumental value we can suggest in the case of public health emergency. But the idea is we think in general the goal in allocating scarce resources should be to try to enable people to live a complete life. Here I'm just going to mention because I only have -- we -- do I have time for two minutes? Okay. I'm pathological about time. This will be the most controversial thing I will say today. Okay? And we find that people -- we think it's correct and that's why I'm saying it. I say that it doesn't represent the views of NIH or the department but represents what we think is the truth. We think that when we say to give preference on the basis of age that you might think that what we would argue is that a one month old infant should have priority over a 15year-old or 20-year-old adolescent. If you were going to the youngest first. Actually we don't think that. We actually have a view that the death of a -- we think that the death of a 20-year-old is more tragic than the death of a 70-year-old but we think it may also be more tragic than the death of a 2-year-old or make it a one month old or a six month old. And the idea that we're working with, and it's -- I -- it is controversial but the idea is that a 15 or 20-year-old has a conception of his or her life, has planned, hoped, interests, ties, connections. There's been investment by others in that person in a way -- by the way, this is not to suggest that others deaths aren't tragic but we're talking about a scarce resource. We're talking about we can't do something for everybody and we have to make choices here. We think that actually there's some reason to think that the badness of death as it were, I have a slide here, looks a little bit like -- I'm not going to defend this now.

But we actually try to defend a view that looks something like this. That the -- that the badness of death as it were tend to go up as age goes up. Maybe peaks at some point and then actual hi goes down a little bit so we actually do think, again, I warned you, this was controversial. That the death of a 60-year-old probably isn't as bad as it were as the death of a 30-yearold or 20-year-old. So my death isn't as bad a the death of some people here. Okay? Some people are in my boat, but so Mark's is probably worse than mine. The badness of Mark's death on this theory would be worst than the badness of my death. What's hard for me to swallow I will say is the badn 't of Mark'ss death is worse than the death of my one-year-old grandson but that is what the view that we're defending commits me to say. I find it hard to swallow. But I actually think it's right. I just tossed a lot at you. What I tried to to is give you a brick, a brief survey of the kinds of ethical considerations that we think should play a role in thinking about the question as to who should receive a scarce resource such as a liver. It is quite possible we think that the principles do need to be tailored to the kind of scarce resource. So not everything needs to be governed by exactly the same principle. So okay? >> Thank you.

[Applause] >> Thank you. The hour is late. If you have questions just come up and ask. >> I think it's actually tend to be governed by the UNOS system that Mark described. There was a time when decisions were made by committees and dialysis was actually made by. They do have to evaluate. They have to evaluate but I think the idea is exactly to try to take some of the pressure off of the individuals in the hospital. Say look, we're not going to ask you to make a decision. We're going have a system that tells you what to do because I think the idea is this is just -- it's too much to ask of people. >> Put anytime a computer. >> In effect, yes.

Have an algorithm spit it out. It's you, not me. All right. What are we going to do? >> Interesting. >> Hi. >> I very much enjoyed and look forward to looking at your slides on line so I can get the ->> When the paper comes out. The paper will be better. The flu vaccine is actually out. You can see sort of the -- that would be a manual. >> Okay. >> Okay? >> Excellent. >> I don't have the data on it but I think it was 2006. >> Ezekiel.

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