1. Introduction

Surgical management of chronic pancreatitis is in a constant state of evolution.  The trials of management are akin to the inherent complexity of the organ’s function and closeness to neighboring organs.  As the progressive and irreversible process of chronic pancreatitis commences, patients are subjected to varying degrees of endocrine and exocrine loss, as well as pain.  Management of this process is multifaceted.  Endoscopic and surgical drainage procedures can be used to attempt decompression of dilated ducts.  Celiac ganglion blocks, narcotic analgesics, and enteral or parenteral nutrition are therapies directed at the recurring or continuous pain of recurrent acute pancreatitis (RAP) or chronic pancreatitis (CP).  Patients refractory to these therapies frequently find themselves on escalating doses of narcotics due to intractable pain and can be faced with countless days of lost time at school or work, depression, and financial burden.

2. History

Total pancreatectomy was first proposed to relieve pain in patients where other therapies had failed (28).  Islet autotransplantation was added to this procedure to preserve beta-cell mass in an effort to prevent development of brittle diabetes (28,120).  Mirkovitch and Campiche were the first successful investigators to transplant autologous islets in large animals by injecting into the spleens of pancreatectomized dogs (115, 164). The first human total pancreatectomy with islet autotransplantation (TPIAT) in the world was performed at the University of Minnesota in 1977.  This patient was insulin-independent and pain-free until her death 6 years later due to unrelated causes (56,121).  This success helped to shed light on the etiology of antecedent allograft efforts; failure likely resulting from low viability, poor preservation of deceased donor pancreases, or rejection (28,121).  A small number of other centers began utilizing IAT after TP with variable initial success in the 1980s, with modest program expansion occurring in the 1990s-2000s (164).  Complications initially occurred at some centers not using anticoagulation (112,114,173).  The world literature as of 2014 contains reports of over 900 IATs as several centers are developing their programs (9,10,52,68,71,82,86,99,116,162,163,168,183,198).  Advancements in surgical technique, islet isolation, patient selection, and perioperative care are steadily improving outcomes for this therapy. 

3. Patient Selection

Patient selection for TPIAT is difficult.  The primary focus for surgery is to alleviate pain, however, the pathogenesis of pain in chronic pancreatitis is incompletely understood.  There are multiple theories based on observational studies that attempt to explain the multifactorial features of this prominent symptom.  In the presence of strictures, stones, or disrupted ducts; increased intraductal pressure, interstitial hypertension, and ischemia are thought to be the culprits of pain.  The neuropathic theory is based on observation of abnormal intrapancreatic nerves and increased perineural inflammatory cells (124, 88, 176).  Additionally, pain levels do not correlate well with severity of fibrosis or impairment of organ function (18).  These inconsistencies contribute to the complexity of patient selection for TPIAT.  Individualized evaluation is critical for optimal pairing of appropriate therapy.  Patients with dilated large ducts or expanded head may be candidates for endoscopic or surgical drainage procedures.  Those with a focal stricture, disrupted duct, or tail-only disease may find relief when treated with distal pancreatectomy (128). However, there are a growing number of patients not candidates for classical surgical therapy or endoscopic drainage, including small duct pancreatitis and minimal change disease.  Additionally, adults and children with genetic causes of chronic or recurrent pancreatitis should be given special consideration for TPIAT, given the likelihood of persistent disease, and in some patients increased risk for pancreatic malignancy (18).

4. Preoperative Evaluation Criteria

Given the gravity of removing the entire pancreas, the correct diagnosis of CP is paramount to the success of this operation.  Criteria for patient selection has evolved over the years as outcomes and better understanding of the disease process help match patients to the appropriate surgical management.  Patients should be evaluated at a well-established center with a multidisciplinary approach including surgeons, gastroenterologists, endocrinologists, pain management physicians, and nurse coordinators.  Patients should have abdominal pain > six months duration with impaired quality of life such as inability to attend work, school, or ordinary activities; repeated hospitalizations; and a constant need for narcotics.  Their symptoms must have failed to respond to medical or endoscopic therapies. 

The University of Minnesota has developed the following criteria for the diagnosis of chronic pancreatitis (Table 1): 1) Pancreas calcifications on CT scan , or obviously abnormal ERCP including pancreatic stones, strictures and/or main duct/sidebranch abnormalities, or greater than or equal to six of nine criteria on endoscopic ultrasound (EUS); 2) Two of three of the following: ductal or parenchymal abnormalities on secretin stimulated magnetic resonance cholangiopancreatography (MRCP), EUS with four of nine criteria positive, abnormal endoscopic pancreatic function tests with peak bicarbonate < 80 mmol/L).; 3) Histopathologic confirmed diagnosis of chronic pancreatitis from previous operations or biopsy; 4) Hereditary pancreatitis (PRSS1, SPINK1, or CFTR gene mutation) with a compatible clinical history; or 5) History of recurrent acute pancreatitis with greater than three episodes of pain associated with imaging diagnostic of acute pancreatitis and/or elevated serum amylase or lipase three times normal (19,162).  EUS evaluation features include “Rosemount Criteria”: hyperechoic parenchymal foci, strands, hypoechoic lobules, cysts, main duct irregularity, ductal dilation, hyperechoic duct walls, visible side branches, and calcifications or stones (37).  

Contraindications include active alcoholism, pancreatic cancer, illegal drug usage, poorly controlled psychiatric illness, predictable inability to comply with the postoperative regimen, or end stage cardiopulmonary disease (18,162).  Patients with C-peptide negative diabetes also do not benefit from the IAT portion of the procedure, therefore it is not recommended at this time (28).  Additionally, preoperative assessment for liver disease; including portal hypertension, portal vein thrombosis, or cirrhosis is important as these are relative contraindications to any major pancreatic resection or islet embolization into the portal vein (18).

5. Metabolic Testing

After determining that recurrent acute pancreatitis or chronic pancreatitis is the primary diagnosis and the pain is of pancreatic origin, evaluation of metabolic function should be undertaken prior to surgery.  This may include fasting and postprandial blood glucose and HbA1c, glucose tolerance test, and baseline and stimulated C peptide levels.  Studies have demonstrated that fasting and mixed meal test glucose and HbA1c correlated inversely with IEQ/kg, while the other factors have modest correlation with islet isolation outcomes as well (14,16,102). 

6. Other Testing

Immunization status should be assessed and updated to include encapsulated organisms due to the high likelihood of splenectomy associated with removal of the pancreas.  Additionally, assessing nutritional status and for comorbidities that may impact postoperative management, such as gastroparesis, is important.  Exocrine dysfunction is common in preoperative CP patients, however, no routine quantitative preoperative testing is performed at this time.  In patients with cystic fibrosis mutations, pulmonary consult for evaluation and preoperative optimization is appropriate.

7. Technique

TPIAT is most commonly performed via open laparotomy, though increasing reports of laparoscopic and robotic assisted resection are being described (69,106,74,66,65,203).  Surgery involves resection of the entire pancreas, duodenum, distal common bile duct, and typically the spleen.  Pylorus preservation is surgeon dependent.  During mobilization of the pancreas, an important consideration is that the blood supply must be preserved as long as possible to minimize warm ischemia time to the islet cells.  In this way, the gastroduodenal artery and the origin of the splenic artery and splenic vein are ligated only after full pancreatic mobilization.  The distal pancreas should not be separated from the splenic vessels (28).  In cases of difficult mobilization, the body and tail can be resected and sent separately to the islet processing lab while the head is removed and sent later (162,199).  After resection, the specimen is placed in cold preservation solution and prepared for processing by removing non-pancreatic tissue before being sent to the lab (15).  Biliary and enteric reconstruction occur while the islets are being processed.  Choledochojejunostomy is typically performed in the end-to-side fashion.  Gastrojejunostomy or duodenojejunostomy can be performed in the antecolic or retrocolic fashion.  Variations of reconstruction have been described when the patient’s anatomy or sequela of chronic pancreatitis necessitate alternative resections (163).

Spleen resection rates are variable across centers, but is necessary the majority of the time due to disruption of the blood supply (162,183).  After the hilar vessels are taken, the spleen can at times survive off collateral circulation.  Leaving the spleen has its risks, however, including variceal formation, splenomegaly, and both early and late GI bleeding (28,68).

After processing the pancreas for islet isolation, the islets are returned to the operating room for infusion.  The majority of centers perform this infusion through the portal vein with embolization of islets to the liver.  There are multiple options for endovascular access site to the portal vein, such as a recanalized umbilical vein (136), mesenteric vein (3,168,184), or splenic vein (117).  Islets are typically infused intraoperatively, or less commonly by interventional radiology after surgery.  This is done via percutaneous transhepatic access to the portal vein (117,163).  Heparin is administered at 70 U/kg prior to infusion to minimize thrombotic complications from tissue thromboplastin present in the islet preparation (28,112).  Most centers also measure portal pressures before and during infusion.  If there is a persistent increase in portal pressure > 25cm H20 with islet infusion, it is advisable to consider an alternative site such as intraperitoneal, beneath the renal capsule, or the sub-mucosal layer of the stomach (28).

8. Preoperative Care

Continuous insulin infusion is initiated immediately after resection of the pancreas to maintain euglycemia and prevent glucose toxicity to the islets as they engraft (14,199).  This is continued postoperatively until the patient has initiated enteral nutrition and may be transitioned to an outpatient regimen.  A gastric or jejunal feeding tube may be placed at the discretion of the surgeon at the time of operation.  Exocrine supplementation may be administered upon initiation of enteral feeding as well from either route.  At the discretion of the surgeon, prophylactic heparin/lovenox should be initiated in the postoperative period when bleeding risk allows.  It is the practice of the author’s institution to perform a screening right upper quadrant ultrasound at one week postoperatively to evaluate for portal vein thrombosis.  If positive, patients are kept on Coumadin for three months.

9. Islet Isolation

Islet isolation and purification must be performed at a facility that meets good medical practice (GMP) standards and has expertise in islet isolation.  The basic method of islet preparation will be reviewed, however, enzyme type varies across institutions.  First, intraductal infusion of enzyme is performed either manually or via automated pump perfusion.  Interstitial perfusion is performed in cases of severe fibrosis or incomplete enzyme dispersion.  Next, semi-automated digestion at 34-37°C in a Ricordi chamber facilitates tissue dissociation.  Previously, Liberase HI was universally adopted for enzyme digestion from 1994 to 2007.  At this point, it became clinically unavailable and centers now utilize a range of enzyme protocols (5,8).

After digestion, purification is performed to minimize exocrine cell contamination without compromising islet numbers.  Islet purification is performed using isopycnic density gradient centrifugation (5,8). The islets can also be partially purified or transplanted as an unpurified preparation.  The decision to purify is multifactorial, balancing the benefit of avoiding islet exposure to harsh solutions and additional mechanical stress and the desire to minimize increases in portal pressure during islet embolization to the liver.   Currently, the author’s institution allows up to 0.25 ml/kg for intraportal infusion.  Quantities above this are considered for purification (8,197).

Extent of fibrosis plays a large role in enzymatic digestion of the extracted pancreas.  Additionally, age, pancreas weight, and fat infiltration can lead to discrepancies in islet release.  Variations in length of enzyme exposure, enzyme dose, digestion chamber size, temperature, circulation speed, and level of mechanical shaking are needed in order to accommodate the discrepancies found in each organ (8).

10. Outcomes

The majority of TPIATs reported to date have been performed at the University of Minnesota, encompassing over 500 patients (163).  Other reports of current or past TPIAT programs include centers at Leicester, University of Cincinnati, University of Arizona, University of Alabama, Medical University of South Carolina, Digestive Disease Institute Cleveland, and Baylor Research Institute (68,198,71,52,116,183,168).  TPIAT for small numbers of patients with benign and malignant tumors are being performed at San Raffaele Scientific Institute in Italy (9,10) and benign tumors in Korea (82,86,99) and Geneva (24).  

Examining the demographics (Table 2) in the largest series with comprehensive data of TPIAT for CP, patients with mean ages 35 - 44 undergo surgery after suffering symptoms of pancreatitis for a range of 5.4 to 9.2 years (162,68,168).  The most common etiology prior to surgery is idiopathic, followed by alcoholic pancreatitis.  Anywhere from 12-80% of study populations have undergone prior pancreatic resections before TPIAT.  This has been shown in multiple studies (particularly a lateral pancreaticojejunostomy or distal pancreatectomy) to have deleterious effects on islet cell harvest, which in turn may confer decreased success of the transplanted beta cell mass (162,117,15).  With the earliest reports of TPIAT done in the late 1970s, centers such as the

University of Minnesota are amassing follow-up data on patients spanning decades, which helps to continually improve treatment for this patient population.

The predominant goal of surgery is mitigation of intractable pain.  These centers together (Table 3) have demonstrated that TPIAT can successfully alleviate pain in the majority of CP patients (52,68,71,116,162,168,183,198). Nearly all patients undergoing TPIAT are narcotic dependent at the time of surgery and studies show rates of narcotic independence at 1 year postop of 55%-71% (162,68,198,71).  This success shows continued improvement over time likely due to the effect of tapering long-term narcotic users.  Additionally, these same studies demonstrated significant improvement in pain scores postoperatively when compared to their preoperative state.

The addition of islet autotransplantation to attenuate the otherwise complete insulin and glucagon deficiency is also proving positive.  Insulin independence rates range from 10%-47% across studies, though attrition rate increases over time (Table 3).  The patients who become insulin dependent but retain partial islet function demonstrated by C peptide positivity gain a benefit by ameliorating the potentially severe glycemic swings seen in pancreatogenic diabetes, thus improving diabetes management (14).  The centers at Minnesota and Leicester report C-peptide positivity rates of 90% and 100% respectively, demonstrating high success rates in islet autotransplantation (162,68).  Additionally, studies have shown that postoperative insulin use did not negatively impact quality of life scores (49).

11. Postoperative Management

It is important to maintain follow-up with TPIAT patients postoperatively as aspects of their anatomy and physiology may be foreign to centers and practitioners not experienced with this treatment.  Avoidance of corticosteroids is paramount to avoid harm to the islets (129).  In addition, TPIAT patients with infusion of islets into the liver may have abnormal imaging findings.  After infusion, the islets engraft into the hepatic sinusoids.  Subsequent blockage of terminal portal vein branches and local insulin release may result in hepatic structural changes (134).  This in turn may lead to an increase in echogenicity with a nodular appearance on ultrasound.   A UK study showed 25% of patients to have these characteristics, and were stable at 6 and 12 month imaging.  These did not correlate with a significant loss of liver function or increase in insulin requirements (134).  These changes have also been reported as seen on MRI and thought to be associated with periportal steatosis (26).

12. Conclusion

Thirty-seven years after the first procedure was performed for chronic pancreatitis, TPIAT is proving to be a safe and effective treatment strategy for this difficult and complex disease process.  Growing experience is allowing earlier and improved selection of patients for TPIAT, which may improve their postoperative endocrine function, pain relief, and quality of life.  Ongoing research in islet processing, preoperative patient assessment and selection, as well as islet engraftment will likely contribute to refining outcomes for patients in the future.

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