PANCREATITIS: MEDICAL AND TRANSPLANT CONSIDERATIONS, DHIRAJ YADAV, MD 1

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1 DHIRAJ YADAV, MD 1 Good afternoon. This is actually an interesting time of the day to do pancreas topic since you just had lunch and this is the time when the pancreas is the most active with a lot of amylase and lipase going into the intestine and probably a sufficient amount of insulin too. So what I'm going to do over the next 25 minutes or so is to talk about the medical and transplant considerations as it relates to pancreatitis. I've organized my talk into two sections. The first is a general section on chronic pancreatitis, especially as it relates to the current epidemiology, management issues and algorithm for treatment of pain. This is a nice segue into the total pancreatectomy and islet autotransplantation or TPIAT where chronic abdominal pain affecting quality of life is the only indication of TPIAT as of now. We'll talk about the procedure, indications, preoperative evaluation, outcomes of interest and review some of the available data. Over the last 20, 25 years our understanding of the natural course of pancreatitis has changed. In the late '80s, early '90s it used to be believed that acute and chronic pancreatitis are two separate disorders with very little or no overlap. But what we are recognizing now is that acute and chronic pancreatitis represent a disease continuum, a subset of patients with acute pancreatitis will have recurrences and a subset will go on to develop chronic pancreatitis. Among all patients with chronic pancreatitis about 75% of them would have had an attack of acute pancreatitis either at the onset or at some time during their disease course. In the left panel you see a figure showing the incidence rates per 100,000 in he U.S. population for these diseases and in the right side you see the burden of disease as it relates to these diseases. Chronic pancreatitis if you use the most stringent criteria there are about 250,000 individuals with the disease in the U.S. currently. That translates to about a population rate of 50 to 60 per 100,000.

2 DHIRAJ YADAV, MD 2 Chronic pancreatitis used to be believed to be a disease of heavy alcoholics and men, but in the last 15 years or so what we are recognizing is that the etiologic spectrum of the disease is much wider, especially when it comes to women. So this is data from two large cohorts: in the top panel the North American Pancreatitis 2 study or the NAPS2 which is a consortium of about 25 centers around the country that have prospectively enrolled 2000 patients with varying stages of pancreatitis and had done a detailed evaluation; and in the bottom panel is data from a multicenter Italian cohort. A few things stand out here. According to physicians alcohol still is the most common cause of chronic pancreatitis accounting for about 50% of all patients. But an important point is that about 1/4 of patients we do not have an identifiable cause. This is specifically relevant to women when compared with men. Secondly the proportion of patients in whom genetic factors are identified is increasing. A couple of examples of this would include CFTR mutations. Some of those used to be considered inconsequential but what we are realizing that some mutations can affect only bicarbonate transport and not chloride transport. What that means is that these patients may not have lung disease, they may have pancreatic manifestations as the only manifestation of CF. Secondly claudin 2 mutation of polymorphisms were identified to play a role in alcoholic pancreatitis in two large genome wide association studies. Chronic pancreatitis profoundly affects quality of life. This is data from the NAPS2 study and you can see here on an SF12 scale a difference of 3 points is clinically relevant. What you see is chronic

3 DHIRAJ YADAV, MD 3 pancreatitis after you control for several different factors profoundly affects physical quality of life as well as mental quality of life. And when you stack the quality of life of CP patients with other chronic disorders or even malignancies it can result in significantly lower quality of life. Chronic pancreatitis also impacts disease survival or long term survival. This is data from a population study in Olmstead County that we did a few years ago showing when compared with age and sex matched individuals chronic pancreatitis patients have significantly poor survival. Patients come to us for treatment for chronic pancreatitis mainly for pain. This could be because of many different reasons, because of an attack of acute pancreatitis, disease flares, it could be chronic pain, it could be complications from chronic pancreatitis, it could be related to organ dysfunction either exocrine or endocrine insufficiency, and it could be related to some other uncommon complications. How prevalent is pain? This is data from the NAPS2 study, if you look in a crosssectional manner 15% of patients with chronic pancreatitis would say they had no pain in the past year. The typical profile of chronic pancreatitis patient is somebody who has chronic unrelenting pain. This is seen in only a small subset of patients. About 50% of patients with chronic pancreatitis have mild to moderate pain with periods of severe pain. When you look at this data by stratifying them based on severity and the temporal nature of pain about half of the patients would say that they have constant pain and two-thirds will say they had severe pain at some time in the past year. 60% of them are on narcotics but only a third need chronic narcotics. And about one-quarter of them are disabled due to their pancreatitis.

4 DHIRAJ YADAV, MD 4 The pain in chronic pancreatitis can be very difficult and challenging not only for management but also to understand the mechanisms. There can be many different mechanisms that are at play in an individual patient and that brings up a question with regard to it is very difficult often for us to determine what exactly is the mechanism in an individual patient which also translates that even if you do endoscopic treatment or surgery not all patients would have improvement in their pain. An important component that we are recognizing is that subsets of patients with chronic pancreatitis have altered sensitization or centralization of their pain because of a faction of the afferent and efferent nerve fibers that supply the pancreas. Understanding the natural history of the disease is very important. This is a rough sketch of a clinical course of a chronic pancreatitis patient. Patients may have episodes of acute pancreatitis, abdominal pain but then have intervening periods when they are completely asymptomatic. A subset of patients may go on to develop chronic pain. There is loss of function over time but this is not inevitable because patients can have advanced atrophy of pancreatic duct dilatation or calcification but then they have no diabetes or malabsorption. I put an 8 to 10 year time line as a rough gauge for patients with alcoholic chronic pancreatitis, but when we are looking at the TPIAT population which is overwhelming, overwhelmingly consistent of patients with nonalcoholic pancreatitis this duration can extend to 2 or 3 decades. So keeping this in mind with regard to where the person is at a particular stage is very important in making decisions. When we see somebody with chronic pancreatitis who has pain what we typically do is to assess their morphology to understand with regard to whether we can find either the cause in the pancreas

5 DHIRAJ YADAV, MD 5 or extrapancreatic region so that we can address accordingly. If we find for example a complication, pseudo cysts or a common bile duct stricture, it can be endoscopically or surgically addressed. If there are extrapancreatic causes like peptic ulcer disease or something we can address it that way. But if we do not find an exact cause a trial of conservative management is typically what we do and the reason for that is that can help us to understand the natural course of the disease in an individual with regard to where they end up because understanding this is very important because you do not want to delay the treatment for too long but you do not want to go into aggressive treatments too early. Now depending upon the morphology of the pancreas if it appears that patients are amenable to endoscopic or surgical treatment which is determined by presence of an obstructive physiology that means pancreatic ductal stone or a structure and pancreatic duct dilatation endoscopic or surgical treatments can be offered. But if patients do not have morphology amenable to these treatments then a conservative treatment is usually recommended. This is the stage where TPIAT comes into play. So Total Pancreatectomy with Islet Auto Transplantation is a procedure that was first developed at the University of Minnesota about 35 years ago and over the past 3 decades the number of centers that are doing this procedure has increased to about 18 or 20 currently in the United States. The procedure in summary is you take out the pancreas completely and then you digest the pancreas so that you can separate out the exocrine and endocrine components. The islets are the endocrine components you separate from exocrine component and basically you infuse the islets into the portal circulation with an anticipation that they will set home in the liver and continue to function and make islets or hormones so that you can control diabetes.

6 DHIRAJ YADAV, MD 6 Typically pancreas is a remote end block along with the duodenum, as well as the spleen and the postsurgical anatomy is fairly similar to what you will see in a patient with Whipple s disease, with Whipple resection where you have a gastrojejunostomy, a jejunojejunostomy and a choledochoduodenostomy. There may be minor differences based on individual patients. Now typically these operations are performed in an open approach but increasingly there are a number of reports for robotic or minimally invasive way in which these procedures can be performed. At UPMC which has one of the largest experience of robotic surgeries, several patients have undergone TPIAT using a robotic approach. Now once the pancreas has been harvested or removed the next step is islet processing which is a very important step. So typically pancreas is removed completely or sometimes they have to remove it in pieces, but the pancreatic duct is supposed to be in tact. And what is done is a solution is infused into the pancreatic duct consisting of collagenase and what it does it breaks up the fibrous tissue of the pancreas and through a dispersion technique helps us to separate the islets from the acinar tissue and the fibrous tissue. The islets can then be harvested, the aim is to harvest as much islets as we can and as pure as we can. Inevitably there is small amount of acinar tissue and fibrous tissue that is in mixture. The importance of this is the lower is the volume that you have at the end, the better it is because once you infuse the islets into the portal circulation the volume determines how much the portal pressure will go up. And if the portal pressure goes up to more than 25 or so, that increases the risk of bleeding complications as well as thrombosis.

7 DHIRAJ YADAV, MD 7 Follow up after TPIAT is very important. The majority if not all of these patients are on narcotic medications before transplantation is performed, so management by a pain specialist is very important because the goal is to taper narcotics over time. Lifelong monitoring of diabetes either development of new diabetes or management of diabetes is important as well as nutritional monitoring and replacement of pancreatic enzymes lifelong. Some results. So the number of TPIATs are increasing over time. This is data from University of Minnesota which was reported about 3 years ago in about 400 patients that have been transplanted since As you can see here in the last 7 or 8 years the number of transplants performed have significantly increased. There are now reports coming from many other centers in the United States and also other countries and it is now we can compare the results of different centers to know whether they got outcomes as well as complications. There are several important considerations during the transplant process. Perhaps the most important is patient selection. Then pre-transplant evaluation, islets processing as we discussed, and the short and long term outcomes. Pain and quality of life is the most important because this is the primary reason why transplant is being performed. Insulin independence is important, correcting malabsorption, knowing the complications from the procedure short term and the long term and then motility issues that can arise. The only indication of total pancreatectomy with islet auto transplantation currently is intractable pain in patients with chronic pancreatitis or recurrent acute pancreatitis that is significantly impairing their quality of life in whom prior medical endoscopic and surgical procedures have failed. The optimum timing as we discussed have been I talked about the

8 DHIRAJ YADAV, MD 8 natural history is very important, because it depends upon how much pain somebody has, what is the severity of their pain, what is the temporal nature of their pain, how much narcotics they are on, how much quality of life is affected, what is the rate of progression, these are all important considerations. There are contraindications to TPIAT which can be grouped into psychological and medical. Active alcohol consumption, substance use or significant psychiatric issues are an absolute contraindication. Poor support network is a relative contraindication because these patients need long term follow up for their medical conditions. Medical contraindications would be established diabetes. Also although there are reports that early diabetes patients can still undergo transplantation, status of portal vein and presence of portal hypertension and significant liver disease, significant cardiac and pulmonary disorders, and known pancreatic cancer. Confirming the diagnosis of chronic pancreatitis is critical. In patients who have obvious morphological evidence of chronic pancreatitis, it is easier than if they have calcifications or significant atrophy or ductal dilatation. But if patient does not have morphological changes consensus is now evolving with regard to having them have 2 tests, a functional test and also either endoscopic ultrasound or MRCP to have definitive changes before TPIAT can be considered. Evaluation by a multidisciplinary team is critical because each of these individuals can individually give an opinion but then make a collective decision with regard to confirming the diagnosis and determining with regard to is this the right patient and the right time for the person to get TPIAT.

9 DHIRAJ YADAV, MD 9 Assessing beta cell mass is important to uncover presence of diabetes as well as to preempt with regard to whether diabetes is going to develop over time or not, or what is the risk, and then assessing the patency of portal vein system is important as is evaluation of chronic liver disease and their immunization status because they are going to get a splenectomy along with it. So who is getting TPIAT? This is data from 4 centers, Minnesota, Cincinnati, MUSC, and our own data from UPMC. If you look at the mean age of patients it s about 30 years or mid thirties which is very different from alcoholic pancreatitis who are usually in their late 40 s or 50 s. In 2 studies that reported age on child patients the mean age was around 11 or 12. The proportion of women is much higher ranger from 50-75%, again very different from traditionally what we think about chronic pancreatitis. And the geology of pancreatitis, a large majority of patients have idiopathic presumed sphincter of Oddi dysfunction, or pancreas divisum. Note that alcoholic pancreatitis forms a very small subset of these patients. In the UPMC subset if you see about half of the patients have genetic causes of pancreatitis. This is data on narcotic use on the X axis is time after transplantation, Y axis is the proportion of patients before the transplant was performed almost all patients are on narcotics and a large majority of them described pancreatic pain. Over time the proportion of patients who reported pancreatic pancreatitis type pain decreased significantly and about 40% were on narcotics. So it s important to remember that a large majority of patients are able to get off narcotics but a significant fraction still may need narcotic medications although at a lower dose.

10 DHIRAJ YADAV, MD 10 Quality of life data. These are subscales of SF-36 showing that after transplantation is performed over a 2 year period there was significant improvement in quality of life in different domains, both in patients who are eventually able to get off narcotics or if they continue narcotics. The improvement was much higher in patients who are insulin independent later on compared to patients who needed insulin. This is data on survival in the Minnesota series the overall 5 year survival was about 90%. A small fraction of patients died during hospitalization and out of 409, 53 died during follow up. Only in a small fraction of patients chronic pancreatitis or surgery was directly the cause of their death. Insulin independence is important. A rough rule of thumb is that 1/3 patients will be insulin independent at about 3 years after transplant, 1/3 will need some insulin and 1/3 will be insulin dependent. Now although a large majority of patients may need some insulin but they still have functioning islets as done demonstrated by presence of c-peptide. And they may need insulin but their hemoglobin A1C are typically less than 7 so they can be controlled easily. What determines insulin independence? It is the islets and yield. What that means is the number of islets equivalent to per kilogram that are being transfused at the time of operation is the most important determinant. On the X axis is the time and the bars show the number of islets that were transfused. So if the islets equivalents are less than 2,500 per kg, the insulin independence is low, as compared to patients who had more than 5,000 islets per kg. In these people, about 75% of these patients are insulin independent at 3 years and in these patients the attrition of islets over time is

11 DHIRAJ YADAV, MD 11 much less. So 75% of them would still be insulin independent 5 years out. And the overall yield as I said over time is also dependent upon the amount of islets that are transfused. There are other factors that also determine islet yield and function. Prior pancreatic surgery is a very important criteria. In the Minnesota series about 20% of patients had prior pancreatic operations and in these patients if they had distal pancreatectomy or Puestow operation the islet yield is very low as you can see only around 2,000 which will be determinant with regard to how much diabetes they will develop over the long run. As compared to that Whipple s patient had relative high islet yield and the reason for that is islets are typically concentrated in the body and tail of the pancreas. And if a person has a Puestow s operation which is a drainage operation it is difficult to infuse the pancreas with the collagenous solution so that the islet yield can be affected. This is an important point because if a patient during the course of the disease has reached a point where they have significant pain issues and quality of life is affected, determining what operation to offer may be important. A partial pancreas resection may not be a good idea because a TPIAT may give more durable response over time. So something to consider about. But there are other factors also that determine islets and yield and function. In the perioperative period, it could be immune related reactions in the blood, hypoxia, yield vascularization can be affected, apoptosis, some of these factors can affect islet yield and islet function. Blood glucose levels also determine with regard to the stress of islets. So typically in the perioperative period and as much as up to 3 months after the transplant, these patients are given insulin to keep their blood sugars very tightly between mg per deciliter because that has been shown to improve islet function.

12 DHIRAJ YADAV, MD 12 It s important to remember the complications in the Minnesota series about 15% patients needed a reoperation during their hospitalization for bleeding, an anastomotic leak, infections or other problems. The bleeding was directly related to the portal pressure in patients in whom the portal pressure were less than 25 the bleeding rate was about 2 or 3 times lower compared to patients in whom the portal pressures were high. What is typically done is the portal pressures are high and not all islets are infused, the surgeons will typically deliver them into the peritoneum where they can actually also are able to function. These are some of the data from the UPMC cohort, this are SF-36 scales in different components. The pink column is the norm for the controlled population, the third column is the pre surgery data and then the data over time. What you see here is there is significant improvement or at least a trend in improvement over time in many of these scales, and the significance may not reach because the sample size is small. This is data on pain and pain medication use. There was a trend towards decrease in the pain medication use over time and also the average pain that the patients reported. A unique data that we have is data on quality of life in adults of children who underwent transplantation. And in these caregivers also we see a trend with regard to improvement in quality of life after the transplantation was performed for the child. So to summarize, the epidemiology of chronic pancreatitis is changing and there are many reasons for that and I can answer questions about that. TPIAT is indicated in a select subset of patients with

13 DHIRAJ YADAV, MD 13 chronic and recurrent acute pancreatitis. Patient selection is critical for TPIAT. Initial results of TPIAT are promising. UPMC results are generally similar to other centers. Prospective registries are needed to understand the long term outcomes in patients undergoing TPIAT and future efforts should also target measures to improve islet cell yield and function. Thank you.