Multifactorial genesis of pancreatitis in primary hyperparathyroidism: evidence for "protective" (PRSS2) and "destructive" (CTRC) genetic factors

Objective: A relationship between primary hyperparathyroidism (pHPT) and pancreatitis has long been debated and remains a rare epiphenomenon. In a cohort of patients with pHPT and pancreatitis mutations in the serine protease inhibitor Kazal type I (SPINK1) and cystic fibrosis transmembrane conductance regulator (CFTR) genes, that increase the risk for pancreatitis have already been detected. Among the identification of additional pancreatitis-associtated mutations in the Chymotrypsin C gene (CTRC) it became clear that also protective genetic variants exist in the anionic trypsinogen gene (PRSS2) that decrease susceptibility for pancreatitis. Our aim was to detect either protective or inducing genetic factors in a large cohort of pHPT patients.

Methods: Among 1,259 patients with pHPT, 57 patients were identified with pancreatitis (4.5%). DNA was available from 31 patients (16 acute pancreatitis/15 chronic pancreatitis). These individuals and 100 patients with pHPT without pancreatitis were analysed for CTRC (p.R254W and p.K247_R254del) and PRSS2 (p.G191R) mutations using melting curve analysis and DNA sequencing or PCR and gel electrophoresis (in case of p.K247_R254del CTRC).

Results: 2 of 31 patients with pHPT and pancreatitis carried the CTRC p.R254W missense mutation (6.5%), while all 100 pHPT controls without pancreatitis showed no CTRC mutation (P=0.055). No further SPINK1 p.N34S (n=4) mutations were detected but the probability of either CTRC or SPINK1 mutations in pHPT patients with pancreatitis is high (P<0.05). 1 patient was trans-heterozygous ( SPINK1: N34S/ CTRC p.R254W). CTRC p.K247_R254del was not detected in both groups. PRSS2 (p.G191R) mutation was present in 1 patient with pancreatitis (3.2%) and in 6 pHPT controls (6%) (P=1).

Conclusion: This study underlines the relevance of a genetic background in pHPT related pancreatitis. However, it only indicates that the CTRC (p.R254W) mutation might also contribute to the panel of mutations ( SPINK1 and CFTR) that have been formerly reported to elevate pancreatitis susceptibility in pHPT. Besides it suggests that protective genetic variants, i. e., p.G191R PRSS2, may contribute to the low prevalence of pancreatitis in pHPT patients.