Tigaro Theory and the New Hypotheses

Toxic and Metabolic Pathway

The most common etiology of chronic pancreatitis involves alcohol. Possible mechanisms of alcohol-related injury include exocrine dysfunction, changes in lipid metabolism, and induction of oxidative stress [2]. However, because pancreatic acinar cells are capable of metabolizing alcohol, it is not proven that alcohol can initiate chronic pancreatitis and/or fibrosis. Oxidative stress may exacerbate chronic inflammation.

Idiopathic Pathway

Some patients with chronic pancreatitis have no clear risk factors. However, patients with the idiopathic type may have unknown genetic alterations.

Genetic Pathway

Hereditary pancreatitis (cationic trypsinogen mutation), cystic fibrosis (CFTR mutations), serine proteinase inhibitor Kazal type 1 (SPINK-1) mutations, and alpha1-antitrypsin deficiency have been found [3].

Autoimmune Pathway

Autoimmune chronic pancreatitis (AIP) is a rare condition. The entity known as non-alcoholic duct-destructive chronic pancreatitis may actually represent AIP. AIP may be associated with other autoimmune diseases, such as Sjogren's syndrome, primary sclerosing cholangitis, and inflammatory bowel disease. Recently, a characteristic high concentration of serum IgG4 was found in patients with sclerosing pancreatitis. Histology reveals lymphoplasmacytic infiltration in periductal non-occlusive fibrosis in the pancreatic tissue, and immunohistochemistry a predominant infiltration of CD4+ or CD8+ T cells and IgG4+ plasma cells [4, 5].

Recurrent and Severe Acute Pancreatitis Pathway

Severe acute pancreatitis induces severe fibrosis after repair of acute inflammation. Recurrent acute pancreatitis may produce chronic pancreatitis through a necrosis-fibrosis sequence. However, little evidence of acute pancreatitis, such as scarring, has been histologically observed in chronic pancreatitis.

Obstructive Pathway

Obstruction of the main pancreatic duct reproducibly produces changes in chronic pancreatitis within weeks in several animal models. The pathology of obstructive pancreatitis in humans is somewhat distinct from typical alcoholic pancreatitis, such as inter- and intralobular fibrosis and marked destruction of the exocrine parenchyma in the area of obstruction. However, interlobular fibrosis, which is a characteristic of chronic alcoholic pancreatitis, is also observed in the early stage of obstructive pancreatitis [6].

Primary Duct Hypothesis

In the primary duct hypothesis, the primary pathogenic factor is an attack of the pancreatic duct epithelium leading to inflammation and destruction of the ductal architecture, such as primary sclerotic cholangitis [7]. The target epithelial cells may express specific acquired or genetic antigens attacked by antibodies, such as carbonic anhydrase I and II [8].

Sentinel Acute Pancreatitis Event (SAPE) Hypothesis

The cellular and molecular mechanism of chronic pancreatitis and/or fibrosis is well understood. This hypothesis could explain why many etiologies lead to a final common pathway of chronic inflammation and/or fibrosis in the pancreas. During early acute inflammation in the pancreas, acinar cells and other cells may be induced by necrosis-fibrosis or toxic-metabolic, or oxidative stress. These cells express inflammatory cytokines to recruit inflammatory cells, such as neutrophils, lymphocytes, and macrophages. Then, if the inflammatory stimuli are removed, this inflammatory reaction disappears and the pancreas heals to a normal state. However, if the inflammatory stimuli continue to attack the pancreatic tissue, pro-fibrotic cells such as stellate cells are reactivated and transformed into myofibroblasts, which then synthesize extracellular matrix. Therefore, pancreatic fibrosis may occur through interaction between the cells producing stimulating factors and those synthesizing extracellular matrix, such as collagen type I and III. Recently, stellate cells were found in the pancreas. Also, cytokines may play an important role in fibrogenesis of the pancreas. Both stellate cells and fibrogenesis-related cytokines are briefly reviewed below.

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