Original Article
Pancreas, Biliary Tract, and Liver
Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort

https://doi.org/10.1016/j.cgh.2020.03.047Get rights and content

Background & Aims

Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early onset ICP (EO-ICP; median age, 19.2 y) and late-onset ICP (LO-ICP; median age, 56.2 y). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, and ACP.

Methods

We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal–Wallis test was used to compare continuous variables across groups and based on genetic variants.

Results

Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P = .04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P = .001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P = .001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP.

Conclusions

We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared with approximately one quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.

Section snippets

North American Pancreatitis Studies

NAPS2 is a set of 3 studies (the original NAPS2 study, NAPS2 continuation and validation study, and NAPS2 Ancillary Study) that prospectively enrolled 1195 patients with CP from 26 centers in the United States from August 2000 to December 2014.18, 19, 20 The diagnosis of CP was based on definitive changes on abdominal imaging studies, specifically endoscopic retrograde cholangiopancreatography, contrast-enhanced computed tomography, magnetic resonance imaging, endoscopic ultrasound, or

Study Cohort

The final sample size for this study was 663 patients with CP. Of these, 130 (19.6%) were lifetime alcohol abstainers placed in 1 of the 2 ICP groups, 308 (46.5%) were light to moderate alcohol drinkers with CP, and 225 (33.9%) were heavy to very heavy alcohol drinkers placed in the ACP group (Figure 1). Among the 130 patients with ICP, 61 (46.9%) had EO-ICP and 69 (53.1%) had LO-ICP.

Demographics, History of Smoking, and Age at Onset of Symptoms

The age at onset of pancreatitis symptoms and pancreatitis diagnosis in patients with ICP followed a bimodal

Discussion

The NAPS2 cohort allows for the reevaluation of prior descriptive studies of cohorts of CP in light of newer insights into etiopathogenesis, including genetics. We confirmed the existence of 2 types of ICP, EO-ICP and LO-ICP, with a nearly identical bimodal age distribution to the previously published series.7 We also confirmed several other clinical features that characterize patients with EO-ICP and LO-ICP, suggesting that they represent 2 distinct populations of patients with overlapping

Acknowledgments

Presented at Digestive Disease Week, Chicago, IL, May 5–9, 2017.

The authors acknowledge contributions from Kimberly Stello and Danielle Dwyer for laboratory management, Michael O’Connell, PhD, for the Epidemiology Data Center, and Lisa Kennard, PhD, Tian Ye, and Stephen R. Wisniewski, PhD, for data management.

Current affiliations of J.T.: Department of Medicine, A1A Hospitalists, Phoenix, Arizona; DLC: Department of Medicine, The Ohio State University, Columbus, Ohio; G.A.C.: Department of

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    Conflicts of interest This author discloses the following: David C. Whitcomb serves as a consultant for AbbVie, Regeneron, and Ariel Precision Medicine, and is a cofounder of Ariel Precision Medicine and may have equity. The remaining authors disclose no conflicts.

    Funding This research was supported in part by National Institutes of Health grants DK061451 (D.C.W.), DK077906 (D.Y.), U01 DK108306 (D.C.W., D.Y.), and UO1DK108320 (C.E.F.). This publication was made possible in part by grants UL1 RR024153 and UL1TR000005 from the National Center for Research Resources, a component of the National Institutes of Health, and the National Institutes of Health Roadmap for Medical Research (University of Pittsburgh). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the National Center for Research Resources or the National Institutes of Health.

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