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

• Published in: The American journal of gastroenterology Vol. 103; no. 2; pp. 368 - 374
• Main Authors: FELDERBAUER, Peter, KARAKAS, Elias, FENDRICH, Volker, BULUT, Kerem, HORN, Tilman, LEBERT, Rainer, HOLLAND-LETZ, Tim, SCHMITZ, Frank, BARTSCH, Detlef, SCHMIDT, Wolfgang E
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing 01.02.2008; Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins
• Subjects: Biological and medical sciences; Carrier Proteins - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Endocrinopathies; Errors of metabolism; Female; Gastroenterology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Hyperparathyroidism, Primary - complications; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Metabolic diseases; Middle Aged; Miscellaneous hereditary metabolic disorders; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Other diseases. Semiology; Pancreatitis - etiology; Pancreatitis - genetics; Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases); Risk Factors; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen - genetics; Endocrinopathy; Serine endopeptidases; Enzyme; Respiratory disease; Pancreatitis; Metabolic diseases; Cystic fibrosis; Genetic disease; Peptidases; Trypsin; Parathyroid diseases; Risk factor; Hydrolases; Digestive diseases; Mutation; Hyperparathyroidism; Pancreatic disease
• ISSN: 0002-9270; 1572-0241
• DOI: 10.1111/j.1572-0241.2007.01695.x

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.