**4. Pathogenesis**

The exact pathogenesis underlying the chronic pancreatitis is not totally defined. The disease most commonly occurs due to environmental factors such as alcohol and smoking or in patients with genetic abnormalities. However, idiopathic CP affects almost 50% of people with this condition [15]. Some hypotheses for the pathophysiology are proposed to explain the etiologic factors. These can give us ideas about the mechanism about the development of the chronic pancreatitis.

## **4.1 Toxic – metabolic**

Excessive alcohol consumption is responsible for 50% of the chronic pancreatic cases [16]. Alcohol is also the best-known etiologic factor in the world, so that patients can be stigmatized with alcoholism and this leads to lower quality of life. It is shown that alcohol is toxic to acinar cells, pancreatic ducts and its microcirculation [17, 18]. It was supposed that alcohol causes to spasm of the sphincter of Oddi, and it affects the character of pancreatic fluid to favor the formation of protein plugs and stones, which eventually lead to chronic pancreatitis [19]. However, these two theories failed to fully explain the pathogenesis of the alcoholic pancreatitis, scientists focused on the acinar the effect of the alcohol on the acinar cells, which are full of thousands digestive enzyme molecules. Normally, the enzymes are produced as inactive precursors, packed into zymogen granules, and segregated from mainly lysosomal enzymes in order to avoid premature activation [19]. Alcohol leads to destabilization of lysosomes and zymogen granules via by oxidant stress produced by cholesteryl esters (CEs), which accumulate in the pancreas during ethanol consumption; and fatty acid ethyl esters (FAEEs), which are nonoxidative metabolites of alcohol. The enzyme synthesis is increased, but the secretion is also impaired. Therefore, it predisposes the gland to autodigestive injury. The cytokines released during prolonged injury and the ethanol itself via its metabolite acetaldehyde causes activation of the PSC (specific, highly plastic type of myofibroblast) leading to excess deposition of extra cellular matrix and active tissue remodeling

and resulting in fibrosis and replacement of functional tissue [20–23]. Smoking is also common in patients with CP. It is convincingly demonstrated that smoking has an independent from alcohol, dose-dependent effect for developing CP. In addition, it is a facilitating factor for progressing of acute pancreatitis to CP. Furthermore, smoking promotes the fibrosis by inducing the IL-2 [13]. A potent toxic component of nicotine metabolite causes trypsinogen activation and cellular damage leading to pancreatitis [24].
