trypsinogen and Hyperparathyroidism--Primary

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.. 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).. 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).. 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.

Topics: Aged; Chymotrypsin; Databases, Factual; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hyperparathyroidism, Primary; Male; Middle Aged; Pancreatitis; Polymerase Chain Reaction; Trypsin; Trypsinogen

Primary hyperparathyroidism (pHPT)-related hypercalcemia is considered to represent a risk factor for the development of pancreatitis. We therefore explored whether mutations in genes that were previously identified to increase the risk for pancreatitis coexist in a cohort of 826 patients with pHPT prospectively studied between 1987 and 2002.. Among 826 patients with pHPT, 38 patients were identified with pancreatitis (4.6%). DNA was available from 25 patients (13 women/12 men, 16 acute pancreatitis/9 chronic pancreatitis). These individuals and 50 patients with pHPT without pancreatitis were analyzed for mutations in the serine protease inhibitor Kazal type I (SPINK1) gene (N34S) and the cationic trypsinogen gene (PRSS1) (N29I, R122H) by melting curve analysis and DNA sequencing. Sequence analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was carried out for the detection of 36 mutations and the Tn polymorphism.. Four of 25 patients with pHPT and pancreatitis carried the N34S missense mutation in the SPINK1 gene (16%), while all 50 controls (pHPT without pancreatitis) showed no mutation in SPINK1 or PRSS1 genes (P < 0.05 vs controls, P < 0.001 vs general population). CF-causing CFTR mutations were present in four patients (P < 0.05 vs general population), while one patient carried a 5T allele. One patient was transheterozygous (SPINK1: N34S/CFTR: R553X). Mean serum calcium levels in pancreatitis patients (3.1 mmol/L) did not differ significantly from the mean of the entire cohort (3.0 mmol/L) or pHPT patients without pancreatitis (3.1 mmol/L).. Pancreatitis risk is approximately 10-fold elevated in pHPT, but pancreatitis occurs infrequently. This indicates an existing but minor impact of pHPT-related hypercalcemia. If pancreatitis occurs, it seems associated with genetic risk factors such as mutations in the SPINK1 and CFTR genes. In contrast, a combination of both hypercalcemia and genetic variants in SPINK1 or CFTR increases the risk to develop pancreatitis in patients with pHPT.

Topics: Carrier Proteins; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Hyperparathyroidism, Primary; Male; Middle Aged; Mutation; Pancreatitis; Risk Factors; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen