A MODERN VIEW ON ETIOLOGY CAUSES AND MECHANISMS OF DEVELOPMENT AND PROGRESSION OF CHRONIC PANCREATITIS

Abstract

The article highlights the significance of several etiological factors in the development of chronic pancreatitis, such as tobacco smoking, excessive alcohol consumption, and their combined effects. The role of trauma, sphincter of Oddi dysfunction, malignant neoplasms, congenital anomalies, IgG4-related diseases, and genetic factors is emphasized — including mutations in the cationic trypsinogen gene (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), and chymotrypsin C. In the mechanisms underlying chronic pancreatitis, attention is drawn to the ductal obstruction theory and the necrosis-fibrosis hypothesis, which postulates that repeated episodes of acute necrotizing pancreatitis play a central role in the pathogenesis of chronic pancreatitis by replacing necrotic tissue with fibrotic tissue. The SAPE hypothesis (Sentinel Acute Pancreatitis Event) is also emphasized, which suggests that an initial episode of acute pancreatitis leads to pancreatic hypersensitivity and recurrent acute episodes, ultimately resulting in chronic inflammation. The authors focus in particular on the role of chronic low-grade systemic inflammation of immune origin. The involvement of cytokine-driven mechanisms and dysbiosis of the small and large intestines is underlined in the development of chronic pancreatitis, exocrine pancreatic insufficiency, as well as in the formation of insulin resistance and obesity. The authors argue that chronic systemic inflammation contributes to persistent disease progression, fibrosis or steatosis of the acinar tissue, negatively affecting not only quality of life but also long-term prognosis due to complications. The article discusses the role of increased intestinal permeability, which facilitates lipopolysaccharide (LPS) translocation from Gram-negative enterobacteria into the systemic circulation. These LPS molecules damage liver and lung tissues, sustaining chronic inflammation and contributing to comorbid conditions. Particular attention is paid to the role of short-chain fatty acids (SCFAs) in maintaining the integrity of the intestinal barrier. SCFAs constitute 95% of biologically relevant fatty acids in the gut. In healthy individuals, intestinal cells use butyrate as the primary energy source. At low concentrations (2 mmol), butyrate enhances the barrier function, while higher concentrations may increase intestinal permeability. Propionate is utilized by the liver for gluconeogenesis, while acetate circulates throughout peripheral tissues and participates in numerous biochemical reactions. The article positively evaluates the detailed analysis of the role of the intestinal mucosa and the mucosa-associated layer of symbiotic bacteria in barrier function in chronic pancreatitis. These adherent bacteria form microcolonies that anchor to the epithelial cell membranes via lectins (special glycoprotein-containing proteins). These colonies are protected by biofilms, which mediate nutrient exchange between the intestinal lumen and adherent bacterial communities. The importance of both mucosa-associated microbiota and luminal microbiota is discussed — the latter being six times less abundant. In cases of pancreatic fibrogenesis, an increased abundance of species such as Streptomyces, Turicibacter, Methylobacterium, Enterococcus, and Candidatus Paenicardinium has been observed.