Dataset Information

Natural history of SPINK1 germline mutation related-pancreatitis.

ABSTRACT:

Background

The aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP).

Methods

All SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected.

Findings

209 and 302 patients were included in the SPINK1 and control groups (median follow-up: 8.3 years (3.7-17.4) vs 5.3 (2.5-8.8)). The median age at onset of symptoms was 20.1 years (17.5-22.8) in the SPINK1 group versus 41.2 (35.2-45.2). The age of exocrine pancreatic insufficiency (EPI) onset in the SPINK1 group was 49.5 (44.5-54.6) years vs. 65.2 (62.1-68.3), p < 0.001. SPINK1 patients with EPI were 5.3%, 14.7%, 28.3% and 52.4% at 20, 30, 40 and 50 years. Diabetes occurred 37.7 (33.3-42.1) years following the onset of symptoms in the SPINK1 group vs. 30.6 (17.3-43.8) (p?=?0.002). SPINK1 patients with diabetes were 7.8%, 13.4%, 26.3% and 43.4% at 30, 40, 50 and 60 years. Seven patients (3.3%) developed pancreatic cancer in the SPINK1 group (versus 3 (0.99%), p?=?0.1), at a median age of 60 vs 66 years. The cancer risk was 0.8% before 50 years, 11.9%, 27.7%, 51.8% at 60, 70 and 80 years and was 12 times higher than in controls (Cox HR 12.0 (3.0-47.8), p < 0.001).

Interpretation

SPINK1 related pancreatitis is associated with earlier onset and pancreatic insufficiencies. p.N34S SPINK1 may well be associated with cancer.

SUBMITTER: Muller N

PROVIDER: S-EPMC6838417 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Natural history of SPINK1 germline mutation related-pancreatitis.

Muller Nelly N Sarantitis Ioannis I Rouanet Marie M de Mestier Louis L Halloran Christopher C Greenhalf William W Férec Claude C Masson Emmanuelle E Ruszniewski Philippe P Lévy Philippe P Neoptolemos John J Buscail Louis L Rebours Vinciane V

EBioMedicine 20191015

<h4>Background</h4>The aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP).<h4>Methods</h4>All SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected.<h4>Findings</h4>209 ...[more]

PMID: 31628023

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Project description:Acute pancreatitis is a common disease with an annual incidence of between 5 and 80 people per 100,000 of the population. The two major etiological factors responsible for acute pancreatitis are alcohol and cholelithiasis (gallstones). The proportion of patients with pancreatitis caused by alcohol or gallstones varies markedly in different countries and regions. The incidence of acute alcoholic pancreatitis is considered to be associated with high alcohol consumption. Although the incidence of alcoholic pancreatitis is much higher in men than in women, there is no difference in sexes in the risk involved after adjusting for alcohol intake. Other risk factors include endoscopic retrograde cholangiopancreatography, surgery, therapeutic drugs, HIV infection, hyperlipidemia, and biliary tract anomalies. Idiopathic acute pancreatitis is defined as acute pancreatitis in which the etiological factor cannot be specified. However, several studies have suggested that this entity includes cases caused by other specific disorders such as microlithiasis. Acute pancreatitis is a potentially fatal disease with an overall mortality of 2.1%-7.8%. The outcome of acute pancreatitis is determined by two factors that reflect the severity of the illness: organ failure and pancreatic necrosis. About half of the deaths in patients with acute pancreatitis occur within the first 1-2 weeks and are mainly attributable to multiple organ dysfunction syndrome (MODS). Depending on patient selection, necrotizing pancreatitis develops in approximately 10%-20% of patients and the mortality is high, ranging from 14% to 25% of these patients. Infected pancreatic necrosis develops in 30%-40% of patients with necrotizing pancreatitis and the incidence of MODS in such patients is high. The recurrence rate of acute pancreatitis is relatively high: almost half the patients with acute alcoholic pancreatitis experience a recurrence. When the gallstones are not treated, the risk of recurrence in gallstone pancreatitis ranges from 32% to 61%. After recovering from acute pancreatitis, about one-third to one-half of acute pancreatitis patients develop functional disorders, such as diabetes mellitus and fatty stool; the incidence of chronic pancreatitis after acute pancreatitis ranges from 3% to 13%. Nevertheless, many reports have shown that most patients who recover from acute pancreatitis regain good general health and return to their usual daily routine. Some authors have emphasized that endocrine function disorders are a common complication after severe acute pancreatitis has been treated by pancreatic resection.

Project description:BackgroundThe role of mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene in chronic pancreatitis is still a matter of debate. Active SPINK1 is thought to antagonize activated trypsin. Cases of SPINK1 mutations, especially N34S, have been reported in a subset of patients with idiopathic chronic pancreatitis. However, the inheritance pattern is still unknown. Some cases with N34S heterozygosity have been reported with and without evidence for CP indicating neither an autosomal recessive nor dominant trait. Therefore SPINK1 mutations have been postulated to act as a disease modifier requiring additional mutations in a more complex genetic model. Familial hypocalciuric hypercalcemia (FHH) caused by heterozygous inactivating mutations in the calcium sensing receptor (CASR) gene is considered a benign disorder with elevated plasma calcium levels. Although hypercalcemia represents a risk factor for pancreatitis, increased rates of pancreatitis in patients with FHH have not been reported thus far.MethodsWe studied a family with a FHH-related hypercalcemia and chronic pancreatitis. DNA samples were analysed for mutations within the cationic trypsinogen (N29I, R122H) and SPINK1 (N34S) gene using melting curve analysis. Mutations within CASR gene were identified by DNA sequencing.ResultsA N34S SPINK1 mutation was found in all screened family members. However, only two family members developed chronic pancreatitis. These patients also had FHH caused by a novel, sporadic mutation in the CASR gene (518T>C) leading to an amino acid exchange (leucine->proline) in the extracellular domain of the CASR protein.ConclusionMutations in the calcium sensing receptor gene might represent a novel as yet unidentified predisposing factor which may lead to an increased susceptibility for chronic pancreatitis. Moreover, this family analysis supports the hypothesis that SPINK1 mutations act as disease modifier and suggests an even more complex genetic model in SPINK1 related chronic pancreatitis.

Dataset Information

Natural history of SPINK1 germline mutation related-pancreatitis.

Background

Methods

Findings

Interpretation

Publications

Natural history of SPINK1 germline mutation related-pancreatitis.

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