Etiology and Pathogenesis

It is generally held that alcoholism is the most common cause of CP worldwide，accounting for 70-80%of cases.The risk of CP has been related to both the quantity and time of alcohol intake.In 1788，Thomas Cawley（Cawley 1788）first related alcohol to pancreatic disease by reference to the case of a male patient with chronic alcoholism who died of diabetes，and whose pancreas was widely calcified after autopsy.In 1878，Friedrich（Friedrich 1878）proposed that chronic inflammation of the pancreas might be associated with long-term excessive intake of alcohol，coining the phrase“Drunkard's pancreas”.In 1946，Comfort，Gambill and Baggenstoss（Comfort et al.1946）from America's Mayo Clinic described the clinical features of CP，including recurrent abdominal pain，and injury of pancreatic exocrine and endocrine function.These authors reported that 68%of patients belonged to the category of alcoholic CP.On the basis of their surgical specimens and autopsy pathological results，they put forward the theory that pancreatic tissue damage caused by repeated episodes of acute inflammation led to a process of pancreatic tissue necrosis and fibrosis，culminating in CP.This still forms the theoretical basis of research into the biological mechanism of CP.

Clinicians have in the past explained the pathogenesis of alcohol-induced CP in terms of alcohol stimulating the pancreas to produce more enzymes and proteins in the pancreatic juice，forming protein plugs in the small pancreatic duct，thereby causing calcification and pancreatic duct obstruction leading to inflammatory infiltration，acinar atrophy and fibrosis.Recent research suggests that activation of digestive zymogen in cells plays a key role in the pathogenesis of CP.

Apart from alcohol，genetic factors also constitute an important cause of CP.In 1952，Comfort and Steinberg（Comfort and Steinberg 1952）reported a family with hereditary CP.Over the past two decades，investigators have identified several susceptibility genes whose modus operandi involves the premature activation of trypsinogen or failure to inactivate trypsin during pancreatic inflammation；these susceptibility genes include four firmly established loci，namely PRSS1，SPINK1，CTRC and CFTR.In 1996，Whitcomb and colleagues（Whitcomb et al.1996）reported the first gene predisposing to hereditary pancreatitis（PRSS1），encoding cationic trypsinogen and located on chromosome 7q34.In 1998，two simultaneous studies Sharer et al.（1998），Cohn et al.（1998）demonstrated that mutations of the CFTR（cystic fibrosis transmembrane conductance regulator）gene are also associated with CP.Two years later，Witt and coworkers（2000）reported another CP susceptibility gene，termed SPINK1（Kajal type 1 serine proteinase inhibitor），located on chromosome 5q32，and detected a missense mutation in codon 34（p.Asn34Ser）.Molecular biology research has helped us to greatly improve our understanding of the causes and pathogenesis of CP.In 2008，the CTRC gene encoding the trypsin-degrading enzyme chymotrypsin C，located on lp36.21，was reported to be yet another pancreatitis susceptibility gene（Masson et al.2008；Rosendahl et al.2008）.(https://www.daowen.com)

In 1995，Yoshida et al.（Yoshida et al.1995）proposed the concept of autoimmune pancreatitis（AIP），which had a good response to steroid therapy.In 2001，the high serum concentration of immunoglobulins G4（IgG4）was reported as a diagnostic biomarker of AIP（Hamano et al.2001）.In recent years，the concept of AIP as a unique clinical entity has gained increasing recognition as a special cause of CP.

In 1955，Zuideman（Zuideman 1955）first proposed the concept of tropical pancreatitis，mainly encountered in the tropical regions of developing countries，a disease entity which might be associated with inadequate nutrition，involving low protein and fat intake.In 1989，it was shown that high cassava intake with its inherent cyanide toxicity，was involved in the pathogenesis of tropical pancreatitis（Narendranathan et al.1989）.Nowadays，a combination of malnutrition，oxidative stress and inherited genetic mutations are thought to be responsible for tropical pancreatitis.