Total pancreatectomy and islet cell autotransplantation: Definitive treatment for chronic pancreatitis

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ABSTRACTIn appropriately selected patients, total pancreatectomy and islet cell autotransplant controls pain and improves quality of life while often minimizing the development of overt diabetes. Multidisciplinary management and lifelong follow-up help to maximize the benefit of this procedure. This review highlights its history, indications, metabolic outcomes, and future directions.


  • Chronic pancreatitis is caused by inflammation and results in progressive, irreversible loss of both exocrine and endocrine function.
  • Total pancreatectomy with islet cell autotransplant is a definitive treatment for chronic pancreatitis, with most patients reporting less pain and better quality of life.
  • Patients who have undergone this procedure need lifelong pancreatic enzyme replacement therapy along with surveillance for and treatment of diabetes.
  • Research in this field is expanding our knowledge, from altered physiology to patient selection to improvement in islet yield and survival.



For some patients with chronic pancreatitis, the best option is to remove the entire pancreas. This does not necessarily doom the patient to diabetes mellitus, because we can harvest the islet cells and reinsert them so that, lodged in the liver, they can continue making insulin. However, this approach is underemphasized in the general medical literature and is likely underutilized in the United States.

Here, we discuss chronic pancreatitis, the indications for and contraindications to this procedure, its outcomes, and the management of patients who undergo it.


Chronic pancreatitis is a progressive condition characterized by chronic inflammation, irreversible fibrosis, and scarring, resulting in loss of both exocrine and endocrine tissue.

According to a National Institutes of Health database, pancreatitis is the seventh most common digestive disease diagnosis on hospitalization, with annual healthcare costs exceeding $3 billion.1 Although data are scarce, by some estimates the incidence of chronic pancreatitis ranges from 4 to 14 per 100,000 person-years, and the prevalence ranges from 26.4 to 52 per 100,000.2–4 Moreover, a meta-analysis5 found that acute pancreatitis progresses to chronic pancreatitis in 10% of patients who have a first episode of acute pancreatitis and in 36% who have recurrent episodes.

Historically, alcoholism was and still is the most common cause of chronic pancreatitis, contributing to 60% to 90% of cases in Western countries.6,7 However, cases due to nonalcoholic causes have been increasing, and in more than one-fourth of patients, no identifiable cause is found.6,8 Smoking is an independent risk factor.6,8,9 Some cases can be linked to genetic abnormalities, particularly in children.10

The clinical manifestations of chronic pancreatitis include exocrine pancreatic insufficiency (leading to malnutrition and steatorrhea), endocrine insufficiency (causing diabetes mellitus), and intractable pain.11 Pain is the predominant clinical symptom early in the disease and is often debilitating and difficult to manage. Uncontrolled pain has a devastating impact on quality of life and may become complicated by narcotic dependence.

The pain of chronic pancreatitis is often multifactorial, with mechanisms that include increased intraductal pressure from obstruction of the pancreatic duct, pancreatic ischemia, neuronal injury, and neuroimmune interactions between neuronal processes and chronic inflammation.12

Treatment: Medical and surgical

In chronic pancreatitis, the aim of treatment is to alleviate deficiencies of exocrine and endocrine function and mitigate the pain. Patients who smoke or drink alcohol should be strongly encouraged to quit.

Loss of exocrine function is mainly managed with oral pancreatic enzyme supplements, and diabetes control is often attained with insulin therapy.13 Besides helping digestion, pancreatic enzyme therapy in the form of nonenteric tablets may also reduce pain and pancreatitis attacks.14 The mechanism may be by degrading cholecystokinin-releasing factor in the duodenum, lowering cholecystokinin levels and thereby reducing pain.12

Nonnarcotic analgesics are often the first line of therapy for pain management, but many patients need narcotic analgesics. Along with narcotics, adjunctive agents such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and gabapentinoids have been used to treat chronic pancreatitis pain, but with limited success.15

In patients for whom medical pain management has failed, one can consider another option, such as nerve block, neurolysis, or endoscopic or surgical therapy. Neuromodulators are often prescribed by pain clinics.15 Percutaneous and endoscopic celiac ganglion blocks can be an option but rarely achieve substantial or permanent pain relief, and the induced transient responses (on average 2 to 4 months) often cannot be repeated.14–17

Surgical options to relieve pain try to preserve pancreatic function and vary depending on the degree of severity and nature of pancreatic damage. In broad terms, the surgical procedures can be divided into two types:

  • Drainage procedures (eg, pseudocyst drainage; minimally invasive endoscopic duct drainage via sphincterotomy or stent placement, or both; pancreaticojejunostomy)
  • Resectional procedures (eg, distal pancreatectomy, isolated head resection, pancreaticoduodenectomy, Whipple procedure, total pancreatectomy).

In carefully selected patients, total pancreatectomy can be offered to remove the cause of the pain.18 This procedure is most often performed in patients who have small-duct disease or a genetic cause or for whom other surgical procedures have failed.11


Islet cell transplantation grew out of visionary work by Paul Lacy and David Scharp at the University of Washington at Seattle, whose research focused on isolating and transplanting islet cells in rodent models. The topic has been reviewed by Jahansouz et al.19 In the 1970s, experiments in pancreatectomized dogs showed that transplanting unpurified pancreatic islet tissue that was dispersed by collagenase digestion into the spleen or portal vein could prevent diabetes.20,21 In 1974, the first human trials of transplanting islet cells were conducted, using isolated islets from cadaveric donors to treat diabetes.19

In the past, pancreatectomy was performed to treat painful chronic pancreatitis, but it was viewed as undesirable because removing the gland would inevitably cause insulin-dependent diabetes.22 That changed in 1977 at the University of Minnesota, with the first reported islet cell autotransplant after pancreatectomy. The patient remained pain-free and insulin-independent long-term.23 This seminal case showed that endocrine function could be preserved by autotransplant of islets prepared from the excised pancreas.24

In 1992, Pyzdrowski et al25 reported that intrahepatic transplant of as few as 265,000 islets was enough to prevent the need for insulin therapy. Since this technique was first described, there have been many advances, and now more than 30 centers worldwide do it.


Interest has been growing in using total pancreatectomy and islet autotransplant to treat recurrent acute pancreatitis, chronic pancreatitis, and hereditary pancreatitis. The rationale is that removing the offending tissue eliminates pancreatitis, pain, and cancer risk, while preserving and replacing the islet cells prevents the development of brittle diabetes with loss of insulin and glucagon.26

Proposed criteria for total pancreatectomy and islet autotransplant

Bellin et al14 proposed five criteria for patient selection for this procedure based on imaging studies, pancreatic function tests, and histopathology to detect pancreatic fibrosis. Patients must fulfill all five of the following criteria:

Criterion 1. Diagnosis of chronic pancreatitis, based on chronic abdominal pain lasting more than 6 months with either at least one of the following:

  • Pancreatic calcifications on computed tomography
  • At least two of the following: four or more of nine criteria on endoscopic ultrasonography described by Catalano et al,27 a compatible ductal or parenchymal abnormality on secretin magnetic resonance cholangiopancreatography; abnormal endoscopic pancreatic function test (peak HCO2 ≤ 80 mmol/L)
  • Histopathologically confirmed diagnosis of chronic pancreatitis
  • Compatible clinical history and documented hereditary pancreatitis (PRSS1 gene mutation)


  • History of recurrent acute pancreatitis (more than one episode of characteristic pain associated with imaging diagnostic of acute pancreatitis or elevated serum amylase or lipase > 3 times the upper limit of normal).

Criterion 2. At least one of the following:

  • Daily narcotic dependence
  • Pain resulting in impaired quality of life, which may include inability to attend school, recurrent hospitalizations, or inability to participate in usual age-appropriate activities.

Criterion 3. Complete evaluation with no reversible cause of pancreatitis present or untreated.

Criterion 4. Failure to respond to maximal medical and endoscopic therapy.

Criterion 5. Adequate islet cell function (nondiabetic or C-peptide-positive). Patients with C-peptide-negative diabetes meeting criteria 1 to 4 are candidates for total pancreatectomy alone.

The primary goal is to treat intractable pain and improve quality of life in selected patients with chronic pancreatitis or recurrent acute pancreatitis when endoscopic and prior surgical therapies have failed, and whose impairment due to pain is substantial enough to accept the risk of postoperative insulin-dependent diabetes and lifelong commitment to pancreatic enzyme replacement therapy.15,26 Patients with a known genetic cause of chronic pancreatitis should be offered special consideration for the procedure, as their disease is unlikely to remit.


Total pancreatectomy and islet autotransplant should not be performed in patients with active alcoholism, illicit drug use, or untreated or poorly controlled psychiatric illnesses that could impair the patient’s ability to adhere to a complicated postoperative medical regimen.

A poor support network may be a relative contraindication in view of the cost and complexity of diabetic and pancreatic enzyme replacement therapy.18,26

Islet cell autotransplant is contraindicated in patients with conditions such as C-peptide-negative or type 1 diabetes or a history of portal vein thrombosis, portal hypertension, significant liver disease, high-risk cardiopulmonary disease, or pancreatic cancer (Table 1).26


The choice of total pancreatectomy and islet autotransplant vs conventional surgery must be individualized on the basis of each patient’s anatomy, comorbidities, symptom burden, presence or degree of diabetes, and rate of disease progression. The most important factors to consider in determining the need for and timing of this procedure are the patient’s pain, narcotic requirements, and impaired ability to function.26

Sooner rather than later?

An argument can be made for performing this procedure sooner in the course of the disease rather than later when all else has failed. First, prolonged pain can result in central sensitization, in which the threshold for perceiving pain is lowered by damage to the nociceptive neurons from repeated stimulation and inflammation.28

Further, prolonged opioid therapy can lead to opioid-induced hyperalgesia, which may also render patients more sensitive to pain and aggravate their preexisting pain.26,28

In addition, although operative drainage procedures and partial resections are often considered the gold standard for chronic pancreatitis management, patients who undergo partial pancreatectomy or lateral pancreaticojejunostomy (Puestow procedure) have fewer islet cells left to harvest (about 50% fewer) if they subsequently undergo total pancreatectomy and islet cell autotransplant.22,26

Therefore, performing this procedure earlier may help the patient avoid chronic pain syndromes and complications of chronic opioid use, including hyperalgesia, and give the best chance of harvesting enough islet cells to prevent or minimize diabetes afterward.11


During this procedure, the blood supply to the pancreas must be preserved until just before its removal to minimize warm ischemia of the islet cells.18,29 Although there are several surgical variations, a pylorus-preserving total pancreatectomy with duodenectomy is typically performed, usually with splenectomy to preserve perfusion to the body and tail.30

The resected pancreas is taken to the islet isolation laboratory. There, the pancreatic duct is cannulated to fill the organ with a cold collagenase solution, followed by gentle mechanical dispersion using the semiautomated Ricordi method,31 which separates the islet cells from the exocrine tissue.32

The number of islet cells is quantified as islet equivalents; 1 islet equivalent is equal to the volume of an islet with a diameter of 150 µm. Islet equivalents per kilogram of body weight is the unit commonly used to report the graft amount transplanted.33

After digestion, the islet cells can be purified or partially purified by a gradient separation method using a Cobe 2991 cell processor (Terumo Corporation, Tokyo, Japan),34 or can be transplanted as an unpurified preparation. In islet cell autotransplant for chronic pancreatitis, purification is not always necessary due to the small tissue volume extracted from the often atrophic and fibrotic pancreas.32 The decision to purify depends on the postdigest tissue volume; usually, a tissue volume greater than 0.25 mL/kg body weight is an indication to at least partially purify.18,35

The final preparation is returned to the operating room, and after heparin is given, the islets are infused into the portal system using a stump of the splenic vein, or alternatively through direct puncture of the portal vein or cannulation of the umbilical vein.32,36 If the portal vein pressure reaches 25 cm H2O, the infusion is stopped and the remaining islets can be placed in the peritoneal cavity or elsewhere.18 Transplant of the islets into the liver or peritoneum allows the islets to secrete insulin into the hepatic portal circulation, which is the route used by the native pancreas.22

Next Article:

Self-monitoring of blood glucose: Advice for providers and patients

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