CellR4 2015; 3 (2): e1536 Total Pancreatectomy-Autologous Islet Cell Transplantation (TP-AIT) For Chronic Pancreatitis – What Defines Success? C. S. Desai, K. M. Khan, W. X. Cui Medstar Georgetown Transplant Institute, Washington, DC, USA Corresponding Author : Wanxing Cui, MD, Ph.D; e-mail: [email protected] ABSTRACT 30 per 100,000 in United States according to the Na - Chronic pancreatitis is an inflammatory disease tional Institutes of Diabetes, Digestive and Kidney which is characterized by irreversible morpho - diseases (http://www.niddk.nih.gov). Patients with logic changes that typically causes pain and per - chronic pancreatitis suffer from debilitating pain, manent loss of the functions. The lack of good which progresses to significant narcotic medication treatment options for patients with chronic pan - requirement and deterioration in quality of life. Pa - creatitis is in part is related to any therapy need - tients can undergo multiple endoscopic and surgical ing to address the “3Ps” that are necessary for intervention procedures without significant success. this disorder.1) Pain relief, 2) Prevention of brit - In one report, pain recurs in over 50 percent of pa - tle diabetes mellitus and 3) Prevention of pan - tients after having endoscopic surgical procedures 1. creatic cancer. Total pancreatectomy and Total pancreatectomy may ameliorate the pain of autologous islet cell transplant (TP-AIT) does chronic pancreatitis however the resultant severe offer a definitive therapy while addressing these brittle diabetes makes this a less than desirable op - three; however there has not been a universal tion. Autologous islet cell transplant after total pan - uptake of this treatment to consider it the stan - createctomy (TP-AIT) gives patients with chronic dard of care due to it being considered highly in - pancreatitis the hope of pain relief and reduces the vasive and success being measured mainly by the potential for brittle diabetes. There are multiple re - concept of the length of insulin independence. ports of TP-AIT being done with an emphasis on in - However diabetes is an endpoint of chronic pan - sulin independence at 1 and 2 years or 5 years and creatitis and this procedure offers the possibility also the mean time of insulin independence as defi - of glycemic control albeit with some insulin use nition of success 2-16 . Possibly due to reports of in - and therefore offers the best alternative to a life sulin independence not being a universal outcome of pain, diabetes and cancer. this procedure has received certain criticism being too drastic a procedure 17 . In this review we examine Keywords: Chronic pancreatitis, Autologous islet cell the value of this approach and why it maybe hin - transplantation, Quality of life, Diabetes mellitus, Pancreatic drance to the management of these patients. cancer, Pancreatic surgery, Islet cell. BACKGROUND Patients with chronic pancreatitis typically seek INTRODUCTION medical help for abdominal pain. The pain eventu - Chronic pancreatitis is an inflammatory disease ally becomes intractable with patients not being ad - which is characterized by irreversible morphologi - equately treated even with large does of narcotics. cal changes that causes permanent loss of function. Patients usually do not appreciate other complica - The incidence of chronic pancreatitis is 1.6 to 23 per tions that result from the chronic damage of the pan - 100,000 of the population and the prevalence is 10 to creas until a much later stage. The most striking of 1 2 C. S. Desai, K. M. Khan, W. X. Cui TOTAL PANCREATECTOMY AND AUTO ISLET CELL TRANSPLANT AS A TREATMENT OPTION these is the development of diabetes mellitus (type 3) A procedure originally pioneered by David Suther - due to destruction of the islet cells. Patients do how - land at the University of Minnesota, TP-AIT does ever notice exocrine pancreatic insufficiency though offer a definitive therapy for chronic pancreatitis symptoms may be obscured by the use of narcotics. while addressing our “3Ps” 23,24 . Although it can be Apart from pancreatic (endocrine and exocrine) dys - taken for granted that pain relief will be the main function patients the third most important issue is initial objective the preservation of islet cells will the potential development of pancreatic cancer in ensure at least the presence of glucagon and there - someone with chronic pancreatic inflammation. fore reducing the potential for life threatening swings in glucose control. And the chance of ma - TREATMENT OPTIONS FOR CHRONIC PANCREATITIS lignancy is nullified altogether. Most gastroenterologists would agree that treating pa - While TP-AIT does represent a potentially good tients with chronic pancreatitis is not a rewarding treatment option for chronic pancreatitis there has not proposition. In the few patients that have a pancreatic been a universal uptake of this treatment to consider it duct or sphincter disorder endoscopic therapy may be the standard of care. In part the procedure is considered of use however in reality most patients with chronic to be highly invasive. However this is typically not pancreatitis have multiple procedures with the futile weighed against the impact of no treatment for chronic hope that there is an unrecognized mechanical prob - pancreatitis. Another reason why the validity of the lem in the pancreatic duct that will be amenable to yet procedure has been questioned is the concept of in - another procedure 18 . Non-endoscopic practices have sulin free survival or the proportion of people who re - been mainly aimed at methods to relieve pain the most main euglycemic without insulin support. scientific of which has been the use of pancreatic en - As a major indication of the success of TP-AIT, zymes. As we have previously noted there is theoret - pain relief rate post TP-AIT ranges from 73% to ical basis for the use of antioxidant regimens 19 . In 90% 7,15 . The insulin independence rate ranges from practice the results have been mixed. The conserva - 27% to 64% post TP-AIT 15,25 . The improvement of tive surgical therapies like Puestow’s procedure and patient quality of life has been reported in many dif - Frey’s procedure have some benefit 20,21 however sig - ferent studies 15,26-28 . It is therefore a misconception, nificant numbers of these patients have persistent pain as we have shown that patients almost always have and continuation of endocrine function damage and a significant islet cell loss even prior to TP-AIT as cancer risk 22 . a result of chronic inflammation and fibrosis 29 . And The lack of good treatment options for patients it can be argued that if all patients were insulin free with chronic pancreatitis in part is related to any after TP-AIT then one could question whether the therapy needing to address the, “3Ps” that are nec - original diagnosis was indeed chronic pancreatitis. essary for this disorder. In view of this we reviewed the literature to eval - “Pain relief ” is a paramount and can mean the uate the success of this procedure being addressed difference between a functioning employable per - considering the “3Ps”. son and one requiring constant care themselves. “Prevention of brittle diabetes mellitus ”. Dia - PAIN CONTROL AND QUALITY OF LIFE betes occurs from the disease itself and after re - Many articles did address this issue. Pain control moval of the pancreas to address the pain. The was documented in the form of reduction in the opi - absence of islet cells not only results in a lack of in - ate dosage. Two studies have documented that the sulin but also glucagon which may result in life morphine requirement after surgery is reduced 2,30 . threatening hypoglycemic events and brittle dia - Quality of life was addressed using the SF-36 and betes. Of course exocrine dysfunction by contrast is McGill pain questionnaires, and Visual Analogue relatively easily addressed by enzyme therapy or Scale. Patients were followed with surveys admin - with the use of predigested nutrition. istered at 1 month, 6 months, and 1 year to evaluate “Prevention of Pancreatic cancer ” is the least changes in their quality of life and pain experienced. well appreciated of the potential complication of Significant improvement was reported in all com - chronic pancreatitis and little data exist on mecha - ponents of every questionnaire within a year after nisms involved. Nevertheless over time a chroni - surgery. Furthermore, patient reported mean scores cally inflamed pancreas will clearly be at risk of this on quality of life were found to fall within the range fatal complication. of the general population 7,15,31-33 . 3 Many patients with chronic pancreatitis have re - Total Pancreatectomy-Autologous Islet Cell Transplantation (TP-AIT) peated hospital admission due to pain from acute on chronic pancreatitis. For example, according to the tion of islet yield preoperatively 29,40 , modifying tech - study by Mullady et al 34 > 90% of patients had been niques of surgery to reduce ischemia and surgery in - hospitalized on at least one occasion in their lifetime duced damage during pancreatectomy to improve for pain related to chronic pancreatitis. In addition > islet yield 41 , introduction of minimally invasive sur - 25% of the chronic pancreatitis patients were on dis - gery 42 , availability of standard operating procedures ability benefit and patients with constant pain were of human islet isolation 43-60 , and understanding the more likely to miss over 4 days of work or school per host environment which potentially can effect re - month than patients with intermittent pain. sults 61 . At the same time progress has been made in islet processing technology that have resulted in the PREVENTION OF BRITTLE DIABETES observed improvement of the clinical results and post There are 21 million of patients suffering from type transplant islet fuction 62,63 , use of anticoagulation, and 1 or 2 DM in the United State (National Diabetes Sta - anti-inflammatory strategies to enhance engraft - tistics Report, 2014, www.cdc.gov).