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Genetic factors in chronic pancreatitis; implications for diagnosis, management and prognosis

https://doi.org/10.1016/j.bpg.2010.02.001Get rights and content

Chronic pancreatitis (CP) is a clinical situation with persisting inflammation leading to destruction of the pancreas ensuing endocrine and exocrine failure. There are 4 subtypes: hereditary, idiopathic, alcoholic and tropical pancreatitis. Genetic factors can explain a significant proportion of CP cases. The PRSS1 gene, encoding cationic trypsinogen, was found to be correlated with hereditary CP. This signalled the extensive search for other candidate genes within the trypsin pathway. Genes like SPINK1 and CTRC are associated with CP and should be considered as important contributing factors rather than causative. The search for candidate genes not part of the trypsin pathway has been less successful and the only gene consistently associated with CP is the Cystic Fibrosis Transmembrane Regulator. In this review we will discuss the various CP subtypes in relation to the respective genetic variants. This review will also address the implications of genetic testing in daily clinical practise.

Introduction

This review aims to give an overview of the genes and mutations that play a role in the pathogenesis of chronic pancreatitis (CP). It has become clear over the past several years that the molecular underpinnings of CP are driven by genetic mutations in the trypsin enzyme cascade. Indeed, the elucidation of genes that are associated with CP has greatly improved our understanding of the disease. This review will provide insight in the historical background that comes with the discovery of these genetic mutations. In addition we will discuss how these genetic mutations contribute to the pathogenesis of the various forms of CP, and lastly we aim to delineate some of the implications these discoveries have for current clinical practise. The mutations will be discussed in context of the different subtypes of CP such as alcoholic (ACP), idiopathic (ICP), hereditary (HCP) and tropical (TCP) CP.

Section snippets

How are genes discovered

The genes involved in CP have been discovered through a mix of genetic approaches. The PRSS1 gene, that has been linked to HCP, was discovered by classical forward genetic linkage analysis. This approach is hypothesis free and assumes no prior knowledge on the pathogenesis of the disease. Here linkage analysis with polymorphic markers is used to detect linkage between markers and a disease locus within a family. Once a locus has been detected, sequencing of the genes from the linked interval is

Historical background

More than a century ago, it was Dr. Chiari who postulated in 1896 that pancreatitis is caused by premature activated trypsin resulting in autodigestion of the pancreas.

An important observation, 65 years later, that contributed to the discovery of the HCP gene was the finding that the disease clustered in families in an autosomal dominant fashion [1]. Indeed, in 1996, the genetic locus for HCP was identified on chromosome 7q35 in a large family [2], and this finding was confirmed in other

Pancreatitis subtypes and their genes

In this section we will outline the different subtypes of CP and the mutations that are the most important in their aetiology (Textbox 1).

Implications for diagnosis, management and prognosis

Diagnosing CP, especially just after the onset of the disease, is a very difficult task. The diagnosis is often made only several years after the first pancreatitis attack when functional and structural abnormalities of the pancreas surface and are detected with laboratory studies and imaging.

But what about genetic testing? Until now genetic testing in CP patients is not part of any standard diagnostic procedure, with the possible exception of PRSS1 mutations in HCP cases.

The presence of a

Summary

We have shown that a variety of genetic variations in genes that are implicated in the trypsin pathway are responsible for a large proportion of HCP, TCP and ICP cases. Apart from genes such as PRSS1, SPINK1, CTRC that have been consistently linked to various CP categories, CFTR is a gene that underlies a significant proportion of ICP, but also ACP patients. Other genes have yielded inconsistent results or are only responsible for a subset of CP patients. The first genes that have been

Conflict of interest

None

Acknowledgement

The authors would like to thank Dr. Richard Szmola for his help and suggestions, especially with the figures. Further they would like to thank Dr. Aura van Esch for her critical appraisal, her suggestions and comments on this review.

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