Review Article
An overview of hereditary pancreatitis

https://doi.org/10.1016/j.dld.2011.08.003Get rights and content

Abstract

Hereditary pancreatitis is a rare cause of chronic pancreatitis. The prevalence was evaluated to 0.3/100 000 in Western Countries. Genetic disorders are due to mutations of the PRSS1 gene on the long arm of the chromosome 7, encoding for the cationic trypsinogen. The inheritance pattern is autosomal dominant with an incomplete penetrance (80%). Since 1996, more than 30 mutations were found. The three more common mutations are R122H, N29I and A16V. First symptoms begin since childhood, mainly before 10 years old. Main symptoms are pancreatic pain and acute pancreatitis (>70%). CP morphological changes as pancreatic calcifications are diagnosed at a median age of 22–25 years. Exocrine and endocrine pancreatic insufficiency occurred in 34% and 26% at a median age of 29 and 38 years. No clinical differences exist according to the mutation type. No excess of mortality in hereditary pancreatitis population compared to general population was found, despite a real risk of cancer. The cumulative risks of pancreatic cancer at 50, 60 and, 75 years are 10%, 18.7% and, 53.5%, respectively. The relative risk of cancer increases in smokers and is evaluated to 8.55. Hereditary pancreatitis diagnosis permits to propose an adapted management in expert centres.

Introduction

Hereditary pancreatitis (HP) is a rare cause of chronic pancreatitis (CP), first described by Comfort and Steinberg in 1952 [1]. Authors reported the pedigree of four definite and two probable patients over three generations with hereditary chronic relapsing pancreatitis. Patients had recurrent pancreatitis with destroyed pancreas. The age of onset was 5–23 years and differed from non-hereditary chronic pancreatitis. In 1996, Le Bodic et al. reported an exceptional HP genealogy concerning 249 members of a family covering eight generations born between 1800 and 1993 [2]. According to customary criteria, 63 had definite and 17 probable HP. Description of the family confirmed an autosomal dominant inheritance pattern with incomplete penetrance (80%). Blood samples were taken from 146 subjects to facilitate genetic research and in 1996, the same team found an association between HP and the long arm of chromosome 7 (7q35) described by genetic linkage analysis with microsatellite markers [3]. Results were confirmed by three independent teams [4], [5]. Within months, Whitcomb et al. identified a first genetic defect of the cationic trysinogen gene (PRSS1) through mutational analysis of candidates genes within the newly mapped region [6]. The affected subjects were found to carry a G to A transition in exon 3 of the cationic trypsinogen gene (PRSS1), leading to the substitution of arginine by histidine in codon 122. This first R122H mutation was independently confirmed by Férec et al. [7]. Few months later, the second most common mutation, the N29I mutation in exon 2 of the PRSS1 gene, was described [8]. Since 1996, many other types of mutations (more than 30 different PRSS1 mutations), such as N29I, A16V, R116C, E79K, R116C, R122C and PRSS1 triplication have been identified subsequently [8], [9], [10], [11], [12], [13], [14], [15]. In the literature, HP diagnosis is defined by the presence of a detected cationic trypsinogen gene mutation (with or without clinical or radiological manifestations of CP) (genetic criterion) or by the presence of a CP with a familial history (genealogical and clinical criteria). A familial history is defined by recurrent acute pancreatitis or CP occurring in two first degree relatives or three or more second degree relatives, in two or more generations in the absence of precipitating factors after negative work-up for known CP aetiology.

Section snippets

Genetic features

In 1996, sequencing of the 7q35 chromosome region revealed a strong association of the R122H mutation of PRSS1 gene encoding cationic trypsinogen with HP [6], [16]. Since 15 years, multiple mutations, nucleotide changes (>30) of this gene were discovered (www.uni-leipzig.de/pancreasmutation) in patients with hereditary or idiopathic pancreatitis. In vitro, PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin. This enzymatic cascade explains recurrent acute

R122H mutation

The R122H mutation was the first PRSS1 mutation found in 1996 through mutational analysis of candidate genes. Whitcomb theory on physiopathological mechanisms was that Arg122-Val123 autolytic peptide bond in trypsin plays an important role in the degradation of activated trypsin [6]. In case of R122H mutation, this firewall fails and intrapancreatic trypsin activity increases disturbing the protease antiprotease balance. R122H mutation results in increased trypsin and zymogen stability and

N29I mutation

The second mutation associated to HP was identified within the N-terminal region of the cationic trypsinogen molecule: c.86A > T mutation or N29I [22], [23], [24]. No effect on trypsin or trypsinogen stability was found but an increased autoactivation [20]. N29I mutation is the second most common PRSS1 mutation worldwide and is regularly reported in published series.

A16V mutation

The A16V mutation is the third most common PRSS1 mutation and is significantly associated with pancreatitis [25], [26]. It contrasts with R122H and N29I in that it was first identified in patients with idiopathic pancreatitis and is the most commonly detected PRSS1 mutation in that group [27]. More than 10 affected families were reported [28]. A16V lies at the edge of the signal peptide of trypsinogen and has previously been considered to influence secretion. Secretion failure is still

Others rare PRSS1 mutations

The majority of these mutations were reported in once (−28delTCC, D19A, D22G, K23R, N29I + N54S, P36R, V39A, G83E, K92N, D100H, L104P, A121T, V123M, C139F) or in only a few families (N29T, E79K, R116C, R122C). However, physiopathological mechanisms of some mutations in the pancreatitis process were described and analysed.

K23R, D22G and D19A mutations could increase autoactivation modifying trypsinogen properties. In vitro analysis of E79K mutation revealed unaltered catalytic activity, autolysis,

Prevalence

HP is a rare entity and the precise prevalence of HP is still unknown. Main publications reported small series. The European registry EUROPAC including more than 550 patients relies on spontaneous declaration by GI specialists and did not allow establishing HP prevalence [32]. In 2006, the prevalence in Germany was estimated to 1/800 000 from the German registry (100 patients). In the French cohort on a National basis, the HP prevalence was 0.3/100 000 [33]. The exact value is probably higher

R122H and N29I mutations

Clinical features of HP patients have been described, mostly in families with a known genetic mutation or only in case reports or in small series of patients (n < 15). Main series reported clinical data about the two main PRSS1 mutations: R122H and N29I. In 1978, Sibert reported HP clinical features in 7 families (n = 72 patients) in England and in Wales [36]. Symptoms began during childhood (mean age of onset, 13 years). Symptoms decreased when patients approached middle age or after a severe

Penetrance

Comfort et al., Sibert and Le Bodic et al. reported an estimated penetrance of 80% [1], [2], [36]. These 3 studies did not make use of genetic analysis to confirm their data because they were published before 1996. The penetrance was calculated by comparing the estimated number of patients with mutations considering autosomal dominant inheritance and the number of those with clinical manifestations. Morphological explorations were not systematic and, therefore, patients with only morphological

Risk of pancreatic adenocarcinoma

Independently of its cause, chronic pancreatic is a risk factor for pancreatic adenocarcinoma. In 1993, a first series included patients from six countries, from 1946 to 1989 with a median follow-up of 7 years. The cause of CP was known in 83%. The second study was monocentric and inclusion period was between 1973 and 1997. Median follow-up was 9 years. All patients were alcoholics and had proven CP using validated criteria. An increased risk of pancreatic cancer was found in both studies, with

Survival analysis

Physicians in charge of patients with HP are very often questioned about the risk of HP complications and mortality excess. Thanks to the description of the natural history of the disease, HP complications and potential causes of death are now well known. Several studies dealing with mortality were already published in the setting of alcoholic chronic pancreatitis. The crude mortality rate was 28.8–35% with a similar observation time (median 6.3–9.8 years). All series reported that alcoholics

Pathological data

Increased risk of pancreatic adenocarcinoma has been attributed to the long duration of exposure to inflammatory process since the birth. A progression model of pancreatic tumorigenesis has already been extensively described for sporadic pancreatic ductal carcinoma. Subsequent morphological and genetic studies have demonstrated that non-invasive dysplastic intraductal lesions, called pancreatic intraepithelial neoplasia (PanIN), were precursors of infiltrating ductal carcinoma. PanINs are

Cancer screening of HP patients

The ultimate goal of the prevention of pancreatic cancer in this specific population is the early identification of advanced precursor lesions. The high prevalence of PanIN lesions might thus have clinical implications for the management of patients with HP in order to prevent the development of cancer. Brune et al. reported PanIN lesions in 10.7% of the patients with a strong familial history of pancreatic adenocarcinoma without chronic pancreatitis. Endoscopic ultrasonography was a useful

Treatment

Numerous types of treatment have been proposed to modify chronic pain, attacks number and to decrease fibrosis progression. All results were limited and no clear relevant treatment exists at this point. No experimental data were published about gene therapy. In the French cohort, at least one period of chronic use of analgesics was necessary in 10% of the patients. Specific treatments, including endoscopic procedures (16%) or surgical interventions (24%) were required in 40% of the patients [33]

Endoscopic treatment

Data on therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in children and adolescents with CP were reported. The mean follow-up period of time was 61.4 (range: 24–132) months and the post-ERCP complication rate was 17.3%. 37 patients received therapeutic ERCP alone. Abdominal pain improved in 81.1% and was completely relieved in 64.9% of the patients during the period of follow-up [61]. Another study included 21 patients with HP. Patients were followed-up for a period of 5

Surgical treatment

Surgical intervention in childhood has been shown in one longitudinal study to reduce pain in patients with both HP and ICP and it has been suggested that surgery may modify disease progression, but this potential benefit remains unproven [63].

Medical treatment

Negative feedback regulation of pancreatic enzyme secretion by proteases has been subject to randomised controlled trials with variable efficacy. A meta-analysis failed to show any benefit [64]. Studies about the use of Octreotide and Somatostatin showed disappointing results [65], [66].

In 2007, calcium-channel blockers (Amlodipine) were proposed to 9 HP patients with chronic pain [67], [68]. The rationale of this pilot study was that mutations cluster in the calcium-associated regulator

Genetic testing: indications and counselling

Before performing molecular analysis in case of HP suspicion, a genetic counselling should be proposed. The patient has to be advised, that genetic findings do not change the management of the disease because of lack of specific treatment. The main interests of such determinations are to confirm HP diagnosis and to propose appropriate HP management: prevention of smoking, avoidance of alcohol, and contact with clinical and research groups for their follow-up and screening trials for early

Perspectives

Knowledge's about HP genetic data and HP natural history really increased since 15 years. However living with HP could remain very difficult for the patients. Despite discoveries of new PRSS1 mutations every year, 20–30% of the patients with epidemiological HP criteria do not present known mutations and HP diagnosis is still frequently delayed because of low prevalence of the disease and lack of physician's knowledge about. Physician's role is limited to the management of HP chronic symptoms

Conflict of interest statement

None declared.

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