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Design Flaws in the Study of Distinguishing Diabetes Associated With Chronic Pancreatitis and Type 2 Diabetes Mellitus

Liu, Yu MD1,2; Wang, Dan MD1,2; Li, Zhao-Shen MD1,2; Hu, Liang-Hao MD1,2

Clinical and Translational Gastroenterology: November 2019 - Volume 10 - Issue 11 - p e00097
doi: 10.14309/ctg.0000000000000097
CORRESPONDENCE
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1Department of Gastroenterology, Gongli Hospital, The Second Military Medical University, Shanghai, China;

2Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.

Correspondence: Liang-Hao Hu, MD. E-mail: lianghao-hu@hotmail.com.

Online date: November 01, 2019

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

We read with great interest the recent published study on distinguishing diabetes mellitus associated with chronic pancreatitis (CP-DM) and type 2 diabetes mellitus (T2DM) based on the genetic risk score (1), and we found that the study design should be improved.

First, the author mistook patients with diabetes mellitus (DM) and recurrent acute pancreatitis (RAP) for CP-DM. In fact, RAP is a disease different from chronic pancreatitis (CP). RAP is defined as a syndrome of multiple distinct acute inflammatory response originated from the pancreas in individuals with 2 or more episodes of acute pancreatitis, separated by at least 3 months (2). It is reported that RAP was featured with increasing frequency of monocyte chemoattractant protein 1 G allele and cystic fibrosis transmembrane conductance regulator gene mutation, whereas CP had no statistical association with these gene mutations (3). A meta-analysis revealed that 36% RAP could progress to CP (4). Thus, patients with DM and RAP should not be enrolled in the CP-DM group because they may have different mechanisms for DM.

Second, patient selection bias could lead to the inaccuracy of this study. Patients with CP were selected from the North American Pancreatitis Study 2 (NAPS2). There were 1,195 patients with CP and 569 patients with RAP in NAPS2 studies published in 2016 (5) in which 930 patients with CP and 579 patients with RAP had undergone genome-wide genotyping (6). However, only 734 patients with CP and 438 patients with RAP were enrolled in the present study. Why were not all patients with CP undergone genome-wide genotyping included in the present study? Was there patient selection bias? What is more? Follow-up data for patients were never reported in series studies involving NAPS2, and patients with pancreatic cancer were not excluded. For most researches concerning CP, patients diagnosed with pancreatic cancer within 2 years after CP diagnosis were excluded, and some studies even used 5 years to avoid misdiagnosis. Therefore, patient selection bias may exist in this study.

Third, the conclusion that “CP-DM may be a subtype of T2DM” is inappropriate. CP-DM is considered as DM caused by CP in this study, which is actually postpancreatitis diabetes mellitus (PPDM). PPDM belongs to diabetes of the exocrine pancreas, which is independent from and cannot coexist with other types of diabetes (7). Moreover, not all cases of diabetes in patients with CP should be regarded as PPDM. Thus, the CP-DM group is actually composed of patients with PPDM and patients with T2DM as a comorbidity of CP.

Mix of PPDM and T2DM in the CP-DM group weakened the difference in the genetic risk score between CP-DM and T2DM. Although the author tried to exclude patients with T2DM in the CP-DM group by removing patients with preexisting diabetes (diagnosed 2 years before CP), patients with family history, or overweight or obese patients from the CP-DM group separately, the analysis was insufficient. Patients with the aforementioned features should be excluded simultaneously in analysis.

In conclusion, the aforementioned study design flaws may cause inaccuracy of the results and conclusion.

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CONFLICTS OF INTEREST

Guarantor of the article: Liang-Hao Hu, MD.

Specific author contributions: Yu Liu, MD, and Dan Wang, MD, contributed equally to this work. Y.L. and D.W. participated in the analysis and interpretation of data and in the manuscript drafting. Z.-S.L. contributed to the conception. L.-H.H. contributed to the conception and data interpretation and revised the manuscript for important intellectual content.

Financial support: None to report.

Potential competing interests: None to report.

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REFERENCES

1. Goodarzi MO, Nagpal T, Greer P, et al. Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus. Clin Transl Gastroenterol 2019;10(7):e00057.
2. Guda NM, Muddana V, Whitcomb DC, et al. Recurrent acute pancreatitis: International state-of-the-science conference with recommendations. Pancreas 2018;47(6):653–66.
3. Cavestro GM, Zuppardo RA, Bertolini S, et al. Connections between genetics and clinical data: Role of MCP-1, CFTR, and SPINK-1 in the setting of acute, acute recurrent, and chronic pancreatitis. Am J Gastroenterol 2010;105(1):199–206.
4. Sankaran SJ, Xiao AY, Wu LM, et al. Frequency of progression from acute to chronic pancreatitis and risk factors: A meta-analysis. Gastroenterology 2015;149(6):1490–500.e1.
5. Wilcox C, Sandhu B, Singh V, et al. Racial differences in the clinical profile, causes, and outcome of chronic pancreatitis. Am J Gastroenterol 2016;111(10):1488–96.
6. Whitcomb DC, LaRusch J, Krasinskas AM, et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44(12):1349–54.
7. Petrov MS, Yadav D. Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol 2019;16(3):175–84.
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology