Endocrinology and Metabolism / Inserm U1190
Lille University Hospital
Post-transplantation CA19-9 levels correlate with islet purity and long-term metabolic results after islet transplantation in type 1 diabetes
Kanza Benomar1,2, Clara Leroy1, Robert Caiazzo2,3, François Pattou2,3, Julie Kerr-Conte2, Marie-Christine Vantyghem1,2.
1Endocrinology and Metabolism, Lille University Hospital, Lille, France; 2INSERM U1190, European Genomics Instititute for Diabetes, Lille, France; 3Surgery, Lille University Hospital, Lille, France
Diaménord and G4 group.
The carbohydrate antigen 19.9 (CA19.9), a mucin circulating glycoprotein, is a proliferation marker of the liver and pancreatic duct cells. Used as a marker of pancreatic adeno-carcinoma, it also increases in unbalanced diabetes, cholestasis, liver fibrosis and renal insufficiency. Besides beta cells, preparations for islet transplantation include ductal cells. The percentage of these ductal cells is inversely correlated to the purity of the preparation. CA19.9 is thought to be a biomarker of these cells, fate of which is poorly understood: destruction, neogenesis, favorable impact on islet implantation or even tumorigenesis.
Therefore, the aim of this prospective study was to describe the evolution of CA19.9 in a cohort of islet-transplanted type 1 diabetic patients and to determine the factors influencing its variation.
Patients: 43 C-peptide negative type 1 diabetic patients (15 islet-after-kidney transplantation (IAK), 28 islet transplantation alone (ITA), transplanted between 2003 and 2013 in a single center were included with a median follow-up of 6 (2-10) years (clinical.gov NCT00446264 and NCT01123187). All patients had normal CA19-9 level before islet transplantation. Induction was performed with thymoglobulin or anti-interleulin2 receptor antibody and maintenance with tacrolimus and either sirolimus or mycophenolate.
Methods: Blood CA19-9 and alphafoetoprotein levels, metabolic, renal and liver parameters, betascore and daily insulin need were measured before and yearly after transplantation. The mean purity and viability of the 2 or 3 islet preparations received by each patient was calculated. The percentage of liver steatosis assessed with MRI, and a score of liver fibrosis assessed with Fibroscan were prospectively recorded. The linear mixed model taking the effect time into account was used to compare the kinetics of CA19-9.
Results: The 10-year percentage of insulin independence was 22% and of detectable C-peptide of 75%. After transplantation, CA19.9 levels increased above the normal threshold in 30% of the patients (26%: IAK - 32% ITA), especially during the first 3 years, without clinical or morphological evidence of exocrine pancreatic disease. At 10 years, CA19.9 levels were significantly correlated with liver enzymes (ASAT and ALAT) (OR=0.20;p<0.0001), the degree of purity of islets (OR=-1.25;p=0.0001), the daily insulin dose (OR=-0.15;p=0.03) with a tendency for the βscore (OR=0.2;p=0.07). CA19.9 levels were correlated neither with the liver fibrosis evaluation nor to the alphafoetoprotein level, a liver carcinoma marker, which both remained normal throughout the follow-up), nor to HbA1c or renal parameters.
In conclusion, Ca19-9 increases in a third of the patients after islet transplantation. This increase was strongly and inversely correlated with the islet purity and to a lesser extent to the quality of the metabolic results. These results suggest that the presence of ductal cells in islet preparations could have a beneficial effect through environmental factors or neogenesis, which nevertheless remains to be demonstrated. Otherwise no liver tumorogenesis, steatosis or fibrosis was observed on the long term after intraportal islet transplantation demonstrating that the liver is a safe localization for islet transplantation.
 Dombrowski F, Jost CM, Manekeller S, Evert M. Cocarcinogenic effects of islet hormones and N-nitrosomorpholine in hepatocarcinogenesis after intrahepatic transplantation of pancreatic islets in streptozotocin-diabetic rats. Cancer Res. 2005;65:7013?22.
 Ryan EA, Paty BW, Senior PA, Lakey JRT, Bigam D, Shapiro AMJ. Beta-score: an assessment of beta-cell function after islet transplantation. Diabetes Care. 2005;28:343?7.
 Street CN, Lakey JRT, Shapiro AMJ, Imes S, Rajotte RV, Ryan EA, et al. Islet graft assessment in the Edmonton Protocol: implications for predicting long-term clinical outcome. Diabetes. 2004;53:3107?14.
 Gmyr V, Bonner C, Lukowiak B, Pawlowski V, Dellaleau N, Belaich S, et al. Automated digital image analysis of islet cell mass using Nikon’s inverted eclipse Ti microscope and software to improve engraftment may help to advance the therapeutic efficacy and accessibility of islet transplantation across centers. Cell Transplant. 2015;24:1?9.
 Kim SH, Baek C-O, Lee KA, Park TS, Baek HS, Jin HY. Clinical implication of elevated CA 19-9 level and the relationship with glucose control state in patients with type 2 diabetes. Endocrine. 2014;46:249?55.
11:00 - 12:30
|Pancreas and Islet Transplantation: Imaging, Biopsies, and Biomarkers||Post-transplantation CA19-9 levels correlate with islet purity and long-term metabolic results after islet transplantation in type 1 diabetes||Room 110|