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Hereditary chronic pancreatitis

https://doi.org/10.1016/j.bpg.2007.10.019Get rights and content

Hereditary chronic pancreatitis (HCP) is a very rare form of early-onset chronic pancreatitis. Apart from young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. Diagnostic criteria and treatment of HCP also resemble those of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile-duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, the disease is mild in most patients. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation, disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes—such as the anionic trypsinogen (PRSS2), the serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR)—have also been found to be associated with chronic pancreatitis (idiopathic and hereditary). Genetic testing should only be performed in carefully selected patients by direct DNA sequencing, and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications such as pseudocysts and bile-duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. The risk of pancreatic cancer is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.

Section snippets

Definition

In 1952 Comfort and Steinberg were the first to recognise that chronic pancreatitis may accumulate in selected families, suggesting a genetic background.1 Thereafter, hereditary chronic pancreatitis (HCP) was defined as an autosomal dominant disease with a penetrance of approximately 80%. However, in the daily clinical setting, the inheritance pattern cannot be determined in some cases. In 1996 several groups mapped a gene for HCP to chromosome 7.2, 3, 4 In the same year, Whitcomb and

Diagnostic criteria

Diagnosis of chronic pancreatitis is made by clinical findings, a typical medical and family history, imaging methods, and pancreatic function tests. The use of invasive function tests (secretin test, pancreozymin–secretin test) has been declining over the years. In recent reviews it was stated that invasive function tests in combination with pancreatic calcification are still the gold standard in the diagnosis of chronic pancreatitis, but these tests are laborious and costly.23, 24, 25, 26

Epidemiology

There are no data regarding the incidence or prevalence of chronic hereditary pancreatitis or of chronic pancreatitis in children. The incidence of chronic pancreatitis of any cause is expected to be about 3.5–10 per 100,000 inhabitants per year in Europe and the USA.28, 29

Clinical characteristics

Alcoholic chronic pancreatitis and HCP exhibit essentially identical clinical laboratory results and histopathological or morphological features. Remarkably, HCP manifests typically at an earlier age, and pancreatic calcification and diabetes mellitus are less frequent complications in comparison to chronic alcoholic pancreatitis. Certainly estimable is the fact that most investigated subjects with the N29I or R122H PRSS1 mutation had mild disease or were asymptomatic.*17, 30

Our investigations

Hereditary chronic pancreatitis and pancreatic cancer

As shown in an investigation of eight patients with pancreatic cancer in a cohort of 246 HCP patients, the life-time risk of pancreatic cancer is about 50-fold higher than in the control population and corresponds with 1 per 1066 person-years. It is only 20-fold elevated in patients with chronic alcoholic pancreatitis.*32, 33 In our cohort of 101 HCP patients (25 N29I carrier, 76 R122H carrier), pancreatic cancer was diagnosed in three patients with the R122H mutation at a median of 23 years

SPINK1 mutations in chronic pancreatitis

Witt and colleagues described an association between mutations of the serine protease inhibitor Kazal type 1 (SPINK1) and chronic pancreatitis.14 SPINK1 is a potent protease inhibitor thought to be a specific inactivation factor of intrapancreatic trypsin activity. During incubation of equimolar quantities of trypsin and SPINK1, the formation of a covalent bond between the catalytic serine residue of trypsin and the lysine carboxyl group of the reactive site of SPINK1 is carried out. After

Molecular diagnostic methods

The recommended ‘gold standard’ method is direct DNA sequencing of both strands. Most laboratories have focused their studies on PRSS1 exons 2 and 3, and until now no unambiguous disease-associated mutation has been identified in the other exons. However, it is still possible that new variants will be identified in exons 1, 4 and 5, or in the intronic and promoter regions. Interestingly, the triplication of a segment containing the PRSS1 gene was recently found in patients with HCP. This

Differential diagnosis

Well-recognised causative factors of chronic pancreatitis are anatomic anomalies, metabolic disorders, trauma, cystic fibrosis, and inflammatory bowel disease. Since HCP manifests predominantly in childhood or early adulthood, alcohol abuse as the most common predisposing condition can generally be ruled out. One of the most important differential diagnoses is cystic fibrosis. Therefore, all patients with onset of the disease in childhood and early adulthood should be screened for a

Genetic counselling and testing

First of all, genetic counselling should be performed in an experienced multidisciplinary clinic that can address the resulting issues. Before genetic testing is performed, the implications of finding HCP-related mutations in the PRSS1 gene for the health and medical care of the patients should be discussed. Moreover, the elevated pancreatic cancer risk and the possible adverse effects for the patient regarding health and life insurance and employment should be discussed. Before performing the

Antenatal diagnosis

As the penetrance of inherited PRSS1 mutations is incomplete, and a highly variable disease manifestation occurs within most affected families, antenatal diagnosis should not be encouraged. Even in recently published guidelines concerning genetic testing in HCP the authors had reservations about antenatal diagnosis, but highlight that they cannot be so prescriptive as to refuse molecular genetic testing in an age of patient autonomy and informed consent.81 Requesting parents should be informed

Management

No prospective randomised trial has been published for any medical or surgical management of HCP, although several case reports (but few systematic studies) have addressed such treatments. Generally, treatment does not differ from that for common forms of chronic pancreatitis.

In most instances treatment of chronic pancreatitis focuses on pain management, maldigestion, diabetes, pseudocysts, bile-duct obstruction, duodenal obstruction, and pancreatic cancer.27, 82, 83, 84 Regarding pain

Prognosis

Today, the individual outcome of HCP is unpredictable. It is not yet possible to predict further episodes of acute pancreatitis, chronic bile-duct obstruction, exocrine or endocrine pancreatic insufficiency, or the occurrence of pancreatic cancer.

Acknowledgements

We gratefully acknowledge the helpful discussion with Professor Miklos Sahin-Tóth, Boston.

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