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- Materials and Methods
Chronic pancreatitis is an irreversible inflammatory condition of the pancreas associated with severe pain, malabsorption and endocrine dysfunction . Total pancreatectomy and islet autotransplantation (TPIAT) may be performed to relieve intractable pain and improve quality of life in patients with severe chronic pancreatitis [2-4]. While the goal of islet autotransplantation is to preserve endocrine function to reduce or prevent postsurgical diabetes mellitus [1, 3], much uncertainty surrounds the diabetes outcome for an individual patient, and optimal timing for TPIAT—balancing preserved islet mass while not proceeding to surgery too early in the disease course—can be difficult to determine. Thus, better tools are needed to determine likelihood of a successful islet isolation for patients considering this surgery.
Overall, about one-third of adult IAT recipients are insulin independent, with another one-third using minimal insulin (often once-daily basal insulin). However, the remaining third of patients require a standard basal-bolus insulin regimen, and approximately 10% are C-peptide negative and may have a more labile postpancreatectomy diabetes. The likelihood of success depends largely on the number of islets that are isolated for transplant from the diseased pancreas. In a recently published cohort of 409 TPIAT patients at the University of Minnesota, islet yields of <2500 islet equivalents (IEQ)/kg resulted in insulin independence in only 12% of cases at 3 years, compared to 22% with 2501–5000 IEQ/kg and 72% if >5000 IEQ/kg. Perhaps more importantly, regardless of insulin use, the vast majority of patients with at least a moderate islet yield ≥2500 IEQ/kg have a favorable metabolic outcome. Nearly all of these patients demonstrate islet graft function (C-peptide positive), and the majority maintain hemoglobin A1c levels in the American Diabetes Association goal range of <7% .
Unfortunately, potential islet yield is currently unknown until pancreatectomy is performed. Prior pancreatic surgery (particularly surgical drainage by lateral pancreaticojejunostomy) and atrophy on MRI have been shown to negatively correlate with islet yield, but a wide range of islet yields has been found in patients with these risk factors [3-6]. Preoperative predictors of islet yield could provide more patient-specific information to aid in counseling patients about the risk of diabetes after TPIAT.
Published literature from human cadaveric donor pancreas isolations and porcine isolations suggests a significant correlation between tests of insulin secretion—particularly the acute insulin response (AIR) to arginine or glucose—and the islet yield at isolation [7, 8]. The AIR to arginine or glucose and the glucose-potentiated arginine-induced insulin secretion posttransplant correlate well to transplanted islet mass . However, the relationship between preoperative islet functional testing and isolation outcomes in chronic pancreatitis undergoing TPIAT remains largely unexplored. Preliminary data from 10 pediatric patients suggested a relationship between C-peptide on mixed meal tolerance testing (MMTT) and islet yield . TPIAT is performed more frequently in adult patients, yet presently there is no published literature examining the relationship between preoperative metabolic testing and islet yield in this population.
At our institution, TPIAT recipients enrolled in clinical trials undergo intravenous glucose tolerance testing and MMTT immediately prior to surgery. Herein, we examined the potential of preoperative metabolic testing to predict islet isolation outcomes in a large cohort of adult patients undergoing TPIAT for chronic pancreatitis. While such tests are clearly useful for establishing preoperative baseline for islet function, we hypothesized that these results may also aid in individualized counseling regarding the likelihood of a successfully isolation.
- Top of page
- Materials and Methods
Total pancreatectomy and islet autotransplant may be considered for patients with severe chronic pancreatitis. The goal of the IAT is to ameliorate or reduce the severity of postoperative diabetes, and optimistically, we can achieve this goal in about two-thirds of patients. While 30–40% of patients are completely insulin-free, another 30% maintain normoglycemia on minimal insulin, typically once-daily basal insulin. The remaining one-third of patients have a more severe form of postpancreatectomy diabetes mellitus [23, 24], which may be labile and difficult to control. The risk and severity of diabetes are determined in large part by the viable islet mass transplanted . Historically, those with <2500 IEQ/kg transplanted remain insulin dependent in the vast majority of cases and may be unable to safely achieve the American Diabetes Association goal of hemoglobin A1c <7%.
Because one of the major patient and physician concerns going into TPIAT is the risk for labile postpancreatectomy diabetes mellitus, it is essential that we develop meaningful protocols for preoperative assessment of islet mass and diabetes risk in these patients. We found a relationship between stimulated insulin and C-peptide secretion and the isolated islet mass in adult patients with chronic pancreatitis undergoing TPIAT. The acute insulin and C-peptide responses to an intravenous glucose tolerance test correlated modestly with islet mass. While these tests did not precisely predict islet mass for an individual patient, in those without prior surgical drainage procedures (lateral pancreaticojejunostomy), a normal fasting glucose along with a mixed-meal stimulated C-peptide >4 ng/mL accurately identified recipients highly likely to have a successful isolation outcome.
For the TPIAT recipient, metabolic testing is an important component of the presurgical evaluation. Such tests could serve two purposes: (1) to document baseline function prior to complete (and irreversible) removal of the pancreas; and (2) potentially to improve our preoperative counseling of potential TPIAT recipients. The latter is not yet established.
Previously published studies suggest a correlation between (1) postoperative intravenous stimulation tests and islet mass transplanted in IAT recipients , (2) arginine or intravenous glucose stimulation tests and islet isolation results in cadaveric pancreas donors and porcine pancreas isolations [7, 8] and (3) metabolic testing and morphologic assessment of beta cell mass in animal models [25-27]. In a prior analysis, glucose-potentiated arginine stimulation (GPAIS) and intravenous glucose tolerance testing performed after IAT in a small group of recipients correlated well with transplanted islet mass . However, preoperative metabolic tests have never previously been studied in relation to TPIAT isolation outcomes in chronic pancreatitis patients undergoing this procedure.
We found a modest correlation (r value 0.3–0.4) between the acute insulin response (AIRglu) and C-peptide response (ACRglu) on IV glucose tolerance testing and the islet mass isolated. While insulin and C-peptide measures correlated best with total islet mass (IEQ), glycemic measures (HbA1c and glucose on MMTT) were better predictors of relative islet mass (IEQ/kg body weight), with lower glucose levels and lower HbA1c associated with better outcomes. While IVGTT measures provided a reasonable correlation with islet mass at a population level, these measures could not predict islet isolation outcomes for an individual patient.
Notably, we were able to identify the patients likely to receive a moderate or high islet mass of ≥2500 IEQ/kg based on prior surgical history, fasting glucose and stimulated C-peptide after a mixed meal. Those patients with a stimulated C-peptide >4 ng/mL on MMTT had nearly eight times the odds of receiving at least 2500 IEQ/kg compared to the patients with low C-peptide. In patients without a prior surgical drainage procedure (lateral pancreaticojejunostomy, or Puestow), those patients with both normal fasting glucose and a stimulated C-peptide ≥4 ng/mL prior to surgery received ≥2500 IEQ/kg in 94% of cases, with a notably high yield of ≥5000 IEQ/kg in 50%. In contrast, in patients with a prior lateral pancreaticojejunostomy, or with impaired fasting glucose and/or stimulated C-peptide <4 ng/mL, fewer than half received ≥2500 IEQ/kg.
The majority of TPIAT recipients who receive a moderate islet mass of ≥2500 /kg are C-peptide positive and maintain goal glycemic control, with hemoglobin A1c <7% . Thus, this is a clinically relevant threshold for identifying those likely to perform well metabolically after islet transplant. The mixed-meal test is relatively easy to perform in the clinical setting.
Our results showed a weaker correlation between insulin secretory measures and the islet mass than one might expect based on the published literature [7, 8, 25]. Previous studies in animals and a limited number of studies in human partial pancreatectomy and islet transplant recipients reported correlation between AIRglu and beta cell mass, with correlation coefficients of 0.6–0.8. This difference may relate to (1) variability inherent in our particular model—particularly the variations in the effectiveness of the islet isolation or islet count; or (2) a need for more sensitive measures of beta cell mass in this population. In particular, patients with chronic pancreatitis may not mimic the other populations in which these tests have been performed. It is possible that the chronic inflammatory environment present in chronic pancreatitis may impair beta cell function in response to oral and intravenous stimuli, thus reducing the reliability of such tests to adequately assess beta cell mass in this population .
Because there are inherent variabilities in the islet isolation process, there is not likely to be any test that correlates perfectly with islet yield using currently available technologies and enzyme solutions. The recovery of beta cells from the native pancreas, while presumed high, is <100% of the pancreatic islet mass, and varies depending on the condition of the pancreas and digestion of the pancreatic parenchyma. Pancreas digestion may be more successful in some cases than others. Second, islet counts are subjective, relying on a manual assessment of islet size and number in a small aliquot; thus, inherent errors in estimation of islet number may account for the imprecision around the regression line. Third, when comparing beta cell functional tests to isolated islet mass, we are making the assumption that all islets contain a similar proportion of functional beta cells, and that, in fact, islet mass accurately reflects beta cell mass. This may or may not be true in patients with chronic pancreatitis. Stimulated insulin secretion is a measure of beta cell function, and it has been proposed that some patients with chronic pancreatitis have a deficit in beta cell function, which precedes the loss of islet mass . Ultimately, the clinical challenge is to (1) estimate the true availability of islet mass in the pancreas, (2) efficiently liberate those islets into free suspension and (3) engraft the islets with high efficiency into the patient.
There are a number of factors that are proposed to impact outcomes via islet mass, islet viability or islet engraftment, and which were not the focus of this particular analysis. We noted that a smaller pancreas or more fibrotic pancreas is associated with a lower islet mass, although these variables were assessed postpancreatectomy. The approach to pancreatectomy (ischemic time) may affect islet viability, while intraportal inflammation, the instant blood mediate inflammatory reaction and efficacy of revascularization may all affect posttransplant islet survival and function. While recognizing this complexity of the islet transplant situation, we attempted to identify preoperative predictors for one important piece of the puzzle—islet mass available for transplant. It will additionally be important to follow these patients for long-term islet graft function and correlate preoperative testing directly with long-term outcome. At this point, recipients remain engaged in a randomized treatment trial and metabolic outcomes are collected as a component of the clinical trial.
Although we could separate those likely to do well from those at high risk for poor isolation outcomes, we lacked in this study the ability to precisely measure islet mass, which would be highly valuable for longitudinal follow-up of recipients to determine the timing of TPIAT. GPAIS measures insulin secretory response to an intravenous arginine bolus during hyperglycemia; because this test elicits a maximal insulin secretory response, it may be more sensitive for measuring early deficits in beta cell mass. Notably, GPAIS has been suggested as a superior measure of beta cell mass compared to either AIRglu or AIRarg [9, 25]. GPAIS can be incorporated into future studies and evaluated as a potential predictor of islet mass in this model.
In summary, we found that in adult patients with chronic pancreatitis, stimulated insulin and C-peptide levels and glycemic measures obtained prior to surgery were weakly correlated to the number of islets subsequently isolated from the diseased pancreas. While a stimulated C-peptide and normal fasting glucose could help identify those recipients at low versus high risk for low islet yield and thus more severe postoperative diabetes, such tests lacked utility for accurately predicting islet mass within individual recipients in this population. Future research should investigate additional metabolic tests to determine measures that may be more sensitive in precisely predicting islet mass prior to TPIAT, to aid in preoperative counseling of recipients and, potentially, to aid in determining the timing of TPIAT.