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The recent genetic discoveries in CP support the hypothesis that inappropriate

intrapancreatic activation of zymogens by trypsin results in autodigestion and

pancreatitis. Two different protective mechanisms prevent activation of the

pancreatic digestive enzyme cascade. First, SPINK1 inhibits up to 20% of

potential trypsin activity and, second, trypsin itself activates trypsin-like

enzymes readily degrading trypsinogen and other zymogens. Pancreatitis may

therefore be the result of an imbalance between proteases and their inhibitors

within the pancreatic parenchyma. The discovery of PRSS1 mutations in families

with CP was the first breakthrough in the understanding of the underlying

genetic mechanisms. Enhanced trypsinogen activation may be the common initiating

step in pancreatitis caused by these mutations. The discovery of SPINK1

mutations underlines the importance of the protease inhibitor system in the

pathogenesis of CP. Thus, gain-offunction in the cationic trypsinogen resulting

in an enhanced autoactivation, or loss-of-function mutations in SPINK1 leading

to decreased inhibitory capacity, may similarly disturb the delicate

intrapancreatic balance of proteases and their inhibitors.

The recent findings of SPINK1, CFTR, and PRSS1 mutations in CP patients

without a family history have challenged the concept of idiopathic CP as a

non-genetic disorder and the differentiation between HP and ICP. There is a

clear mode of autosomal dominant inheritance for some mutations (R122H, N29I,

possibly M1T), whereas the inheritance pattern (autosomal recessive, complex, or

modifying) of other mutations (A16V, N34S) is controverted or unknown. The lack

of mutations in the above-mentioned genes in many patients suggests that CP may

also be caused by genetic alterations in yet unidentified genes. Evaluation of

CP patients without an obvious predisposing factor, e.g. alcohol abuse, should

include genetic testing even in the absence of a family history of pancreatitis.

Finally, identification of further disease-causing genes will create a

better understanding of pathogenesis and may help to develop specific preventive

and therapeutic strategies

Mark E. Armstrong

www.top5plus5.com

NW Chapter Rep

Pancreatitis Association, International