Pancreatitis Risk in Primary Hyperparathyroidism: Relation to Mutations in the SPINK1 Trypsin Inhibitor (N34S) and the Cystic Fibrosis Gene

Felderbauer, Peter; Karakas, Elias; Fendrich, Volker; Bulut, Kerem; Horn, Tilman; Lebert, Rainer; Holland-Letz, Tim; Schmitz, Frank; Bartsch, Detlef; Schmidt, Wolfgang E.
February 2008
American Journal of Gastroenterology;Feb2008, Vol. 103 Issue 2, p368
Academic Journal
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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 S PINK1 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.


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