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BACKGROUND: In total pancreatectomy with islet autotransplantation (TPIAT), a greater number of islets transplanted produces more favorable outcomes. We aimed to determine predictors of islet isolation outcomes. METHODS: We investigated factors associated with islet isolation outcomes expressed as islet number (IN), islet equivalents (IEQ; standardized to an islet with 150 µm diameter), IN/kg, or IEQ/kg using data from the multicenter Prospective Observational Study of TPIAT. Single-predictor linear regression was used to estimate the association of individual patient and disease characteristics with islet isolation outcomes, and augmented backward elimination was used to select variables to include in multivariable analyses. RESULTS: In multivariable analyses, only elevated hemoglobin A1c was associated with worse outcomes for all measures (Pâ <â 0.001 for all). Total IEQ obtained for transplant was higher for participants with Hispanic ethnicity (Pâ =â 0.002) or overweight status pre-TPIAT (Pâ <â 0.001) and lower with non-White race (Pâ =â 0.03), genetic pancreatitis (Pâ =â 0.02), history of lateral pancreaticojejunostomy (Pâ =â 0.03), and presence of atrophy (Pâ =â 0.006) or ductal changes (Pâ =â 0.014) on imaging. IEQ/kg was higher in females (Pâ =â 0.01) and Hispanic participants (Pâ =â 0.046) and generally lower with older age (nonlinear association, Pâ <â 0.001) and pancreatic atrophy (Pâ <â 0.001) on imaging. Total IN and IN/kg showed trends similar, but not identical, to IEQ and IEQ/kg, respectively. CONCLUSIONS: Patient demographics and certain pancreatic disease features were associated with outcomes from islet isolation. Hemoglobin A1c before TPIAT was the metabolic testing measure most strongly associated with islet isolation results.
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Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (ß-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor ß-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or ß-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor ß-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.
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Antagonistas Adrenérgicos beta , Estudios Cruzados , Diabetes Mellitus Tipo 1 , Técnica de Clampeo de la Glucosa , Hipoglucemia , Trasplante de Islotes Pancreáticos , Fentolamina , Propranolol , Humanos , Femenino , Masculino , Diabetes Mellitus Tipo 1/metabolismo , Persona de Mediana Edad , Adulto , Trasplante de Islotes Pancreáticos/efectos adversos , Hipoglucemia/inducido químicamente , Hipoglucemia/metabolismo , Método Doble Ciego , Antagonistas Adrenérgicos beta/farmacología , Fentolamina/farmacología , Propranolol/farmacología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Insulina/metabolismo , Glucagón/metabolismo , Glucagón/sangre , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismoRESUMEN
BACKGROUND & AIMS: Acute pancreatitis (AP) is increasingly recognized as a risk factor for diabetes mellitus (DM). We aimed to study the association of pancreatitis genes with pancreatic endocrine insufficiency (pre-DM and DM) development post-AP in children. METHODS: This was an observational cohort study that enrolled subjects ≤21 years with their first episode of AP and followed them for 12 months for the development of pancreatic endocrine insufficiency. Pancreatitis risk genes (CASR, CEL, CFTR, CLDN2, CPA1, CTRC, PRSS1, SBDS, SPINK1, and UBR1) were sequenced. A genetic risk score was derived from all genes with univariable P < .15. RESULTS: A total 120 subjects with AP were genotyped. Sixty-three subjects (52.5%) had at least 1 reportable variant identified. For modeling the development of pancreatic endocrine insufficiency at 1 year, 6 were excluded (2 with DM at baseline, 3 with total pancreatectomy, and 1 death). From this group of 114, 95 remained normoglycemic and 19 (17%) developed endocrine insufficiency (4 DM, 15 pre-DM). Severe AP (58% vs 20%; P = .001) and at least 1 gene affected (79% vs 47%; P = .01) were enriched among the endocrine-insufficient group. Those with versus without endocrine insufficiency were similar in age, sex, race, ethnicity, body mass index, and AP recurrence. A model for pre-DM/DM development included AP severity (odds ratio, 5.17 [1.66-16.15]; P = .005) and genetic risk score (odds ratio, 4.89 [1.83-13.08]; P = .002) and had an area under the curve of 0.74. CONCLUSIONS: In this cohort of children with AP, pancreatitis risk genes and AP disease severity were associated with pre-DM or DM development post-AP.
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Whole-organ pancreas, pancreatic-kidney and islet transplantation are surgical therapeutic options for the treatment of type 1 diabetes. They can enable effective glycemic control, improve quality of life and delay/reduce the secondary complications of type 1 diabetes mellitus. Radiologists are integral members of the multidisciplinary transplantation team involved in these procedures, with multimodality imaging serving as the mainstay for early recognition and management of transplant related complications. This review highlights the transplantation procedures available for patients with type 1 Diabetes Mellitus with a focus on the imaging appearance of transplantation-related complications.
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OBJECTIVES: Total pancreatectomy and islet autotransplantation (TPIAT) for pancreatitis may induce risk for essential fatty acid deficiency (EFAD) due to exocrine pancreatic insufficiency and intestinal alterations. The prevalence of EFAD post-TPIAT is currently unknown. METHODS: We abstracted essential fatty acid (EFA) profiles (n = 332 samples) for 197 TPIAT recipients (72% adult, 33% male). Statistical analyses determined the prevalence of, and associations with, EFAD post-operatively. EFAD was defined as a Triene-to-Tetraene ratio ≥0.05 if <18 years old, or ≥0.038 if ≥18 years old. RESULTS: Prevalence of EFAD was 33%, 49%, and 53.5% at 1, 2, and ≥3 years. At 1-year post-TPIAT, older age at transplant ( P = 0.03), being an adult versus a child ( P = 0.0024), and obstructive etiology ( P = 0.0004) were significant predictors of EFAD. Only 6% of children had EFAD 1-year post-TPIAT versus 46% of adults. The alpha-linolenic acid levels were lower with lower body mass index at transplant ( P = 0.011). EFAD was associated with the presence of other intestinal diseases ( P < 0.0001). CONCLUSIONS: One-third of individuals had EFAD 1-year post-TPIAT, highlighting the need for systematic monitoring. Older age at transplant increased risk and adults were more affected than children. Other diagnoses affecting intestinal health may further increase risk for EFAD.
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Ácidos Grasos Esenciales , Trasplante de Islotes Pancreáticos , Pancreatectomía , Trasplante Autólogo , Humanos , Masculino , Pancreatectomía/efectos adversos , Pancreatectomía/métodos , Femenino , Trasplante de Islotes Pancreáticos/efectos adversos , Trasplante de Islotes Pancreáticos/métodos , Adulto , Ácidos Grasos Esenciales/deficiencia , Niño , Trasplante Autólogo/efectos adversos , Adolescente , Persona de Mediana Edad , Adulto Joven , Prevalencia , Factores de Riesgo , Preescolar , Pancreatitis/etiología , Insuficiencia Pancreática Exocrina/etiología , Insuficiencia Pancreática Exocrina/epidemiología , Insuficiencia Pancreática Exocrina/diagnóstico , Factores de EdadRESUMEN
OBJECTIVE: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). METHODS: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. RESULTS: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CONCLUSION: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.
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Citocinas , Pancreatitis Crónica , Humanos , Proyectos Piloto , Enfermedad Aguda , Estudios Transversales , Quimiocinas , Interleucina-6RESUMEN
BACKGROUND: Total pancreatectomy with islet autotransplant (TPIAT) can improve quality of life for individuals with pancreatitis but creates health risks including diabetes, exocrine insufficiency, altered intestinal anatomy and function, and asplenia. METHODS: We studied survival and causes of death for 693 patients who underwent TPIAT between 2001 and 2020, using the National Death Index with medical records to ascertain survival after TPIAT, causes of mortality, and risk factors for death. We used Kaplan Meier curves to examine overall survival, and Cox regression and competing-risks methods to determine pre-TPIAT factors associated with all-cause and cause-specific post-TPIAT mortality. RESULTS: Mean age at TPIAT was 33.6 years (SD = 15.1). Overall survival was 93.1% (95% CI 91.2, 95.1%) 5 years after surgery, 85.2% (95% CI 82.0, 88.6%) at 10 years, and 76.2% (95% CI 70.8, 82.3%) at 15 years. Fifty-three of 89 deaths were possibly related to TPIAT; causes included chronic gastrointestinal complications, malnutrition, diabetes, liver failure, and infection/sepsis. In multivariable models, younger age, longer disease duration, and more recent TPIAT were associated with lower mortality. CONCLUSIONS: For patients undergoing TPIAT to treat painful pancreatitis, careful long-term management of comorbidities introduced by TPIAT may reduce risk for common causes of mortality.
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Causas de Muerte , Trasplante de Islotes Pancreáticos , Pancreatectomía , Humanos , Pancreatectomía/efectos adversos , Pancreatectomía/mortalidad , Femenino , Masculino , Trasplante de Islotes Pancreáticos/efectos adversos , Adulto , Factores de Riesgo , Persona de Mediana Edad , Trasplante Autólogo , Adulto Joven , Estudios Retrospectivos , Medición de Riesgo , Factores de Tiempo , Adolescente , Resultado del Tratamiento , Pancreatitis/mortalidad , Pancreatitis/etiología , Pancreatitis Crónica/cirugía , Pancreatitis Crónica/mortalidadRESUMEN
The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3 months post-TPIAT. Here, we report 2-year diabetes outcomes and peri-operative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90 mg/kg IV x6 doses, n = 13), etanercept (50 mg then 25 mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2 years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucose-potentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFα differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2 years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period.
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Diabetes Mellitus , Trasplante de Islotes Pancreáticos , Humanos , Etanercept/uso terapéutico , Autoinjertos , Trasplante Autólogo , Insulina , Inflamación , Citocinas , ADN , Pancreatectomía , Resultado del TratamientoRESUMEN
OBJECTIVES: We aimed to estimate the incidence of new-onset diabetes (NOD) and identify risk factors for NOD in patients with necrotizing pancreatitis (NP). METHODS: Necrotizing pancreatitis patients were reviewed for NOD, diagnosed >90 days after acute pancreatitis. Baseline demographics, comorbidities, clinical outcomes, computed tomography (CT) characteristics of necrotic collections, and CT-derived abdominal fat measurements were analyzed to identify predictors for NOD. RESULTS: Among 390 eligible NP patients (66% men; median age, 51 years; interquartile range [IQR], 36-64) with a median follow-up of 400 days (IQR, 105-1074 days), NOD developed in 101 patients (26%) after a median of 216 days (IQR, 92-749 days) from NP. Of the NOD patients, 84% required insulin and 69% developed exocrine pancreatic insufficiency (EPI). Age (odds ratio [OR], 0.98), male sex (OR, 2.7), obesity (OR, 2.1), presence of EPI (OR, 2.7), and diffuse pancreatic necrosis (OR, 2.4) were independent predictors. In a separate multivariable model assessing abdominal fat on CT, visceral fat area (highest quartile) was an independent predictor for NOD (OR, 3.01). CONCLUSIONS: New-onset diabetes was observed in 1 of 4 patients with NP, most within the first year and requiring insulin. Male sex, obesity, diffuse pancreatic necrosis, development of EPI, and high visceral adiposity identified those at highest risk.
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Diabetes Mellitus , Insuficiencia Pancreática Exocrina , Insulinas , Pancreatitis Aguda Necrotizante , Humanos , Masculino , Persona de Mediana Edad , Femenino , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Pancreatitis Aguda Necrotizante/epidemiología , Grasa Intraabdominal/diagnóstico por imagen , Enfermedad Aguda , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Insuficiencia Pancreática Exocrina/diagnóstico , Obesidad/complicacionesRESUMEN
OBJECTIVE: This pilot study seeks to identify serum immune signatures across clinical stages of patients with chronic pancreatitis (CP). METHODS: We performed a cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies-study. CP subjects were categorised into three clinical stages based on the presence/absence of metabolic complications: (1) CP with no diabetes and exocrine pancreatic dysfunction (EPD), (2) CP with either diabetes or EPD, and (3) CP with diabetes and EPD. Blinded samples were analysed using an 80-plex Luminex assay of cytokines/chemokines/adhesion molecules. Group and pairwise comparisons were performed to characterise immune signatures across CP subgroups. RESULTS: A total of 135 CP subjects (evenly distributed between clinical stages) and 50 controls were studied. Interleukin-6 (IL-6), interleukin-8 (IL-8), and soluble intercellular adhesion molecule 1 (sICAM-1) were significantly elevated in CP subjects compared to controls. The levels of IL-6 and IL-8 increased with advancing disease stages, with the highest levels observed in CP with diabetes and EPD (clinical stage 3). Furthermore, hepatocyte growth factor and macrophage-derived chemokine were significantly increased in clinical stage 3 compared to controls. CONCLUSION: Our study reveals a progressive elevation in pro-inflammatory cytokines and chemokines with advancing clinical stages of CP. These findings indicate potential targets for the development of disease-modifying interventions.
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Diabetes Mellitus , Pancreatitis Crónica , Humanos , Interleucina-8/análisis , Interleucina-6 , Proyectos Piloto , Estudios Transversales , Citocinas , Pancreatitis Crónica/diagnóstico , QuimiocinasRESUMEN
For children with diminished quality of life and chronic pain caused by acute recurrent or chronic pancreatitis who are undergoing total pancreatectomy with islet autotransplantation, postoperative nutrition support has several unique characteristics. Surgical complications may lead to delays in nutrition support initiation or require modifications to the regimen. Early postoperative dysmotility requires the use of temporary enteral nutrition until this improves. The resultant complete exocrine pancreatic insufficiency necessitates lifelong pancreatic enzyme replacement therapy and fat-soluble vitamin supplementation. A low-oxalate diet is recommended to prevent kidney stones. Carbohydrate counting is needed for the provision of short-term insulin dosing and possibly long-term as well, depending on the transplanted islet yield. Children should have careful nutrition assessment and monitoring at several follow-up visits during the first year, then annually, and at any time with concerns.
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Trasplante de Islotes Pancreáticos , Pancreatitis Crónica , Humanos , Niño , Pancreatectomía/efectos adversos , Trasplante Autólogo , Calidad de Vida , Pancreatitis Crónica/cirugía , Pancreatitis Crónica/complicaciones , Resultado del TratamientoRESUMEN
Background: Although diabetes after total pancreatectomy and islet autotransplantation (TP-IAT) is one of the biggest concerns for TP-IAT recipients and physicians, reliable prediction of post-TP-IAT glycemic control remains unestablished. This study was conducted to identify early predictors of insulin independence and goal glycemic control by hemoglobin A1c (HbA1c) ≤ 6.5% after TP-IAT. Methods: In this single-center, retrospective study, patients who underwent TP-IAT (nâ =â 227) were reviewed for simple metabolic markers or surrogate indices of ß-cell function obtained 3 mo after TP-IAT as part of standard clinical testing. Long-term metabolic success was defined as (1) insulin independence and (2) HbA1c ≤ 6.5% 1, 3, and 5 y after TP-IAT. Single- and multivariate modeling used 3-mo markers to predict successful outcomes. Results: Of the 227 recipients, median age 31 y, 30% male, 1 y after TP-IAT insulin independence, and HbA1c ≤ 6.5% were present in 39.6% and 72.5%, respectively. In single-predictor analyses, most of the metabolic markers successfully discriminated between those attaining and not attaining metabolic goals. Using the best model selected by random forests analysis, we accurately predicted 1-y insulin independence and goal HbA1c control in 77.3% and 86.4% of the patients, respectively. A simpler "clinically feasible" model using only transplanted islet dose and BETA-2 score allowed easier prediction at a small accuracy loss (74.1% and 82.9%, respectively). Conclusions: Metabolic testing measures performed 3 mo after TP-IAT were highly associated with later diabetes outcomes and provided a reliable prediction model, giving valuable prognostic insight early after TP-IAT and help to identify recipients who require early intervention.
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Objective: Immediate type I, type III, and delayed type IV hypersensitivity reactions to insulin are rare, but potentially serious complications of exogenous insulin administration required for the treatment of type 1 diabetes (T1D). Methods: We present four cases of insulin hypersensitivity reactions occurring in youth with T1D and a literature review of this topic. Results: Insulin hypersensitivity reactions included types I, III, and IV with presentations ranging from localized urticaria, erythematous nodules, and eczematous plaques to anaphylaxis with respiratory distress. Reactions occurred in youth with newly diagnosed T1D and in those with long-standing T1D who were using both injection and insulin pump therapy. Multidisciplinary care involving pediatric endocrinology and allergy/immunology utilizing trials of many adjunct therapies yielded minimal improvement. Despite the use of various treatments, including antihistamines, topical therapies, immunosuppressant medications, desensitization trials, and intravenous immune globulin, cutaneous reactions, elevated hemoglobin A1c levels, and negative effects on quality of life remain persistent challenges. One patient became one of the youngest pancreas transplant recipients in the world at age 12 years due to uncontrollable symptoms and intolerable adverse effects of attempted therapies. Conclusion: Although rare, insulin hypersensitivity reactions negatively affect glycemic control and quality of life. These cases demonstrate the varying severity and presentation of insulin hypersensitivity reactions along with the limited success of various treatment approaches. Given the life-sustaining nature of insulin therapy, further studies are needed to better understand the underlying pathophysiology of insulin hypersensitivity and to develop targeted treatment approaches.
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Diabetes Mellitus Tipo 1 , Hipersensibilidad a las Drogas , Urticaria , Niño , Humanos , Adolescente , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Calidad de Vida , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/etiología , Insulina/efectos adversos , Urticaria/inducido químicamente , Urticaria/complicaciones , Urticaria/tratamiento farmacológicoRESUMEN
Clinical studies on the treatment of type 1 diabetes with device-encapsulated pancreatic precursor cells derived from human embryonic stem cells found that insulin output was insufficient for clinical benefit. We are conducting a phase 1/2, open-label, multicenter trial aimed at optimizing cell engraftment (ClinicalTrials.gov identifier: NCT03163511 ). Here we report interim, 1-year outcomes in one study group that received 2-3-fold higher cell doses in devices with an optimized membrane perforation pattern. ß cell function was measured by meal-stimulated plasma C-peptide levels at 3-month intervals, and the effect on glucose control was assessed by continuous glucose monitoring (CGM) and insulin dosing. Of 10 patients with undetectable baseline C-peptide, three achieved levels ≥0.1 nmol l-1 from month 6 onwards that correlated with improved CGM measures and reduced insulin dosing, indicating a glucose-controlling effect. The patient with the highest C-peptide (0.23 nmol l-1) increased CGM time-in-range from 55% to 85% at month 12; ß cell mass in sentinel devices in this patient at month 6 was 4% of the initial cell mass, indicating directions for improving efficacy.
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Chronic pancreatitis is a progressive and irreversible process of pancreatic inflammation and fibrosis that can lead to intractable abdominal pain and severely impaired quality of life (QoL). Often patients are refractory to standard medical or endoscopic treatments. Total pancreatectomy (TP) and islet auto-transplantation (TP-IAT) can offer pain relief to patients by removing the entire pancreas and the auto-transplant component ameliorates the resulting diabetes. QoL is significantly improved after TP-IAT when insulin independence is present. Recent data support offering TP-IAT rather than TP alone and treating with exogenous insulin for patients with debilitating chronic pancreatitis.
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Trasplante de Islotes Pancreáticos , Pancreatitis Crónica , Humanos , Pancreatectomía/métodos , Calidad de Vida , Resultado del Tratamiento , Pancreatitis Crónica/cirugía , Trasplante de Islotes Pancreáticos/métodos , Insulina , Trasplante Autólogo , Insulina Regular HumanaRESUMEN
Children with intractable chronic pancreatitis may require total pancreatectomy with islet autotransplantation (TPIAT) for pain relief. The IAT reduces the severity of post- pancreatectomy diabetes. We analyzed 635 mixed meal tolerance tests (MMTT) in 134 children undergoing TPIAT to determine whether superior survival of islet grafts explains higher rates of insulin independence previously reported in young children (n = 52, age 3-11 years) versus adolescents (n = 82, age 12-18 years). For MMTT, children consumed Boost HP and we sampled C-peptide and glucose repeatedly over 2 h. The trajectory of outcomes before and after TPIAT was compared between children and adolescents using data from pre-TPIAT and 3, 6 months, 1, 2, 3, and 4 years post-TPIAT and mixed linear models with a random effect for child. Cox regression was used to analyze time outcomes (e.g., time to first off insulin). Islet mass transplanted, measured as islet equivalents (IEQ), was higher in adolescents (p = .003) but IEQ/kg was higher in young children (p < .001) because of their lower weight. AUC C-peptide in young children increased somewhat over 4 years, but was stable in adolescents (p = .0013). AUC glucose increased more in adolescents over time post-TPIAT (p = .0024). Islet function by AUC C-peptide:AUC glucose ratio was better preserved in young children (p < .001). Adolescents were less likely to wean off insulin (hazard ratio .44 [95% CI .28, .69]). These data support an advantage of young age in islet graft survival after TPIAT. The greater likelihood of insulin independence in young children may be driven by better islet survival after transplant.
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Trasplante de Islotes Pancreáticos , Niño , Adolescente , Humanos , Preescolar , Trasplante Autólogo , Pancreatectomía , Péptido C , Insulina , Glucosa , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. METHODS: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. RESULTS: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. CONCLUSIONS: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies.
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Trasplante de Islotes Pancreáticos , Pancreatitis Crónica , Adulto , Niño , Humanos , Masculino , Femenino , Pancreatectomía/efectos adversos , Trasplante Autólogo/efectos adversos , Trasplante de Islotes Pancreáticos/efectos adversos , Vitamina A , Delgadez , Pancreatitis Crónica/cirugía , VitaminasRESUMEN
BACKGROUND & AIMS: Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis. METHODS: Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57). RESULTS: A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status. CONCLUSIONS: Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.