Reviews

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

Author and Disclosure Information

 

References

CONTROLLING GLUCOSE DURING AND AFTER THE PROCEDURE

Animal studies have shown that hyperglycemia impairs islet revascularization,37 and glucose toxicity may cause dysfunction and structural lesions of the transplanted islets.11,38

Therefore, during and after the procedure, most centers maintain euglycemia by an intravenous insulin infusion and subsequently move to subcutaneous insulin when the patient starts eating again. Some centers continue insulin at discharge and gradually taper it over months, even in patients who can possibly achieve euglycemia without it.

OUTCOMES

Many institutions have reported their clinical outcomes in terms of pain relief, islet function, glycemic control, and improvement of quality of life. The largest series have been from the University of Minnesota, Leicester General Hospital, the University of Cincinnati, and the Medical University of South Carolina.

Insulin independence is common but wanes with time

The ability to achieve insulin independence after islet autotransplant appears to be related to the number of islets transplanted, with the best results when more than 2,000 or 3,000 islet equivalents/kg are transplanted.39,40

Sutherland et al18 reported that of 409 patients who underwent islet cell autotransplant at the University of Minnesota (the largest series reported to date), 30% were insulin-independent at 3 years, 33% had partial graft function (defined by positive C-peptide), and 82% achieved a mean hemoglobin A1c of less than 7%. However, in the subset who received more than 5,000 islet equivalents/kg, nearly three-fourths of patients were insulin-independent at 3 years.

The Leicester General Hospital group presented long-term data on 46 patients who underwent total pancreatectomy and islet cell autotransplant. Twelve of the 46 had shown periods of insulin independence for a median of 16.5 months, and 5 remained insulin-free at the time of the publication.41 Over the 10 years of follow-up, insulin requirements and hemoglobin A1c increased notably. However, all of the patients tested C-peptide-positive, suggesting long-lasting graft function.

Most recently, the University of Cincinnati group reported long-term data on 116 patients. The insulin independence rate was 38% at 1 year, decreasing to 27% at 5 years. The number of patients with partial graft function was 38% at 1 year and 35% at 5 years.42

Thus, all three institutions confirmed that the autotransplanted islets continue to secrete insulin long-term, but that function decreases over time.

Pancreatectomy reduces pain

Multiple studies have shown that total pancreatectomy reduces pain in patients with chronic pancreatitis. Ahmad et al43 reported a marked reduction in narcotic use (mean morphine equivalents 206 mg/day before surgery, compared with 90 mg after), and a 58% reduction in pain as demonstrated by narcotic independence.

In the University of Minnesota series, 85% of the 409 patients had less pain at 2 years, and 59% were able to stop taking narcotics.18

The University of Cincinnati group reported a narcotic independence rate of 55% at 1 year, which continued to improve to 73% at 5 years.42

Although the source of pain is removed, pain persists or recurs in 10% to 20% of patients after total pancreatectomy and islet cell autotransplant, showing that the pathogenesis of pain is complex, and some uncertainty exists about it.26

Quality of life

Reports evaluating health-related quality of life after total pancreatectomy and islet autotransplant are limited.

The University of Cincinnati group reported the long-term outcomes of quality of life as measured by the Short Form 36 Health Survey.42 Ninety-two percent of patients reported overall improvement in their health at 1 year, and 85% continued to report improved health more than 5 years after the surgery.

In a series of 20 patients, 79% to 90% reported improvements in the seven various domains of the Pain Disability Index. In addition, 60% showed improvement in depression and 70% showed improvement in anxiety. The greatest improvements were in those who had not undergone prior pancreatic surgery, who were younger, and in those with higher levels of preoperative pain.30

Similarly, in a series of 74 patients, the Medical University of South Carolina group reported significant improvement in physical and mental health components of the Short Form 12 Health Survey and an associated decrease in daily narcotic requirements. Moreover, the need to start or increase the dose of insulin after the surgery was not associated with a lower quality of life.44

OFF-SITE ISLET CELL ISOLATION

Despite the positive outcomes in terms of pain relief and insulin independence in many patients after total pancreatectomy and islet cell autotransplant, few medical centers have an on-site islet-processing facility. Since the mid-1990s, a few centers have been able to circumvent this limitation by working with off-site islet cell isolation laboratories.45,46

Whether and when to consider this procedure must be individualized

The University of California, Los Angeles, first reported on a series of nine patients who received autologous islet cells after near-total or total pancreatectomy using a remote islet cell isolation facility, with results comparable to those of other large institutions.45

Similarly, the procedure has been performed at Cleveland Clinic since 2007 with the collaboration of an off-site islet cell isolation laboratory at the University of Pittsburgh. A cohort study from this collaboration published in 2015 showed that in 36 patients (mean follow-up 28 months, range 3–26 months), 33% were insulin-independent, with a C-peptide-positive rate of 70%. This is the largest cohort to date from a center utilizing an off-site islet isolation facility.47

In view of the positive outcomes at these centers, lack of a local islet-processing facility should no longer be a barrier to total pancreatectomy and islet cell autotransplant.

PATIENT CARE AFTER THE PROCEDURE

A multidisciplinary team is an essential component of the postoperative management of patients who undergo total pancreatectomy and islet cell autotransplant.

For patients who had been receiving narcotics for a long time before surgery or who were receiving frequent doses, an experienced pain management physician should be involved in the patient’s postoperative care.

Because islet function can wane over time, testing for diabetes should be done at least annually for the rest of the patient’s life and should include fasting plasma glucose, hemoglobin A1c, and C-peptide, along with self-monitored blood glucose.26

All patients who have surgically induced exocrine insufficiency are at risk of malabsorption and fat-soluble vitamin deficiencies.48 Hence, lifelong pancreatic enzyme replacement therapy is mandatory. Nutritional monitoring should include assessment of steatorrhea, body composition, and fat-soluble vitamin levels (vitamins A, D, and E) at least every year.26 Patients with chronic pancreatitis are at increased risk for low bone density from malabsorption of vitamin D and calcium; therefore, it is recommended that a dual-energy x-ray absorptiometry bone density scan be obtained.26,49

Patients who undergo splenectomy as part of their procedure will require appropriate precautions and ongoing vaccinations as recommended by the US Centers for Disease Control and Prevention.26,50,51

WHAT TO EXPECT FOR THE FUTURE

The National Institute of Diabetes and Digestive and Kidney Diseases has reviewed the potential future research directions for total pancreatectomy and islet autotransplant.15

The more islet cells transplanted, the better the chance of insulin independence

Patient selection remains challenging despite the availability of criteria15 and guidelines.26 More research is needed to better assess preoperative beta-cell function and to predict postoperative outcomes. Mixed meal-tolerance testing is adopted by most clinical centers to predict posttransplant beta-cell function. The use of arginine instead of glucagon in a stimulation test for insulin and C-peptide response has been validated and may allow more accurate assessment.52,53

Another targeted area of research is the advancement of safety and metabolic outcomes. Techniques to minimize warm ischemic time and complications are being evaluated. Islet isolation methods that yield more islets, reduce beta-cell apoptosis, and can isolate islets from glands with malignancy should be further investigated.54 Further, enhanced islet infusion methods that achieve lower portal venous pressures and minimize portal vein thrombosis are needed.

Unfortunately, the function of transplanted islet grafts declines over time. This phenomenon is at least partially attributed to the immediate blood-mediated inflammatory response,55,56 along with islet hypoxia,57 leading to islet apoptosis. Research on different strategies is expanding our knowledge in islet engraftment and posttransplant beta-cell apoptosis, with the expectation that the transplanted islet lifespan will increase. Alternative transplant sites with low inflammatory reaction, such as the omental pouch,58 muscle,59 and bone marrow,60 have shown encouraging data. Other approaches, such as adjuvant anti-inflammatory agents and heparinization, have been proposed.15

Research into complications is also of clinical importance. There is growing attention to hypoglycemia unrelated to exogenous insulin use in posttransplant patients. One hypothesis is that glucagon secretion, a counterregulatory response to hypoglycemia, is defective if the islet cells are transplanted into the liver, and that implanting them into another site may avoid this effect.61

Next Article:

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

Related Articles

  • Medical Grand Rounds

    Managing severe acute pancreatitis

    Progress in managing this disease has been disappointing, but clinicians are learning to recognize it and treat it supportively better than in the...