Advances in understanding the etiology and pathogenesis of chronic pancreatitis

To the Editor: Chronic pancreatitis (CP) is characterized as a recurrent inflammation of the pancreas, and is often complicated by irreversible injury to pancreatic tissue. The etiologies of CP are numerous; common contributors include genetic predisposition and environmental factors such as smoking and alcohol consumption.[1] The role of genetic mutations and hereditary susceptibility in pathogenesis has recently garnered significant attention, resulting in a multitude of high-quality research findings within the basic science domain. This article focuses primarily on summarizing recent advancements in the study of genetic polymorphisms associated with CP, hereditary susceptibility, and the pathogenesis of pancreatic fibrosis, aiming to serve as a reference for both basic and clinical research. Alcohol misuse and tobacco: Alcohol misuse is the most prevalent independent risk factor of CP, affecting 40–70% of cases. The contribution of alcohol to the pathogenesis of CP varies across ethnic and geographic lines. In Western countries, 90–95% of cases are either attributed to alcohol or are idiopathic. With improved socioeconomic conditions in China, the prevalence of chronic heavy drinking has increased, leading to an annual average growth rate of 108.7% of alcoholic CP, resulting in its emergence as the predominant form of the disease.[2] Genome-wide studies have identified susceptibility genes, such as CLDN2, SPINK1, and PRSS1, in which variations can also increase the risk of developing alcoholic CP. Alcohol misuse is associated with the progression of pancreatitis, though it may not necessarily influence the processes of pancreatic fibrosis and dysfunction. Null alleles of the GST-T1 and GST-P1 genes, specifically the valine variant, confer a higher risk of CP. Genotyping these genes may constitute a crucial screening assay for detecting high-risk alcohol abusers. Smoking exhibits a dose-dependent relationship with the risk of CP, and smoking cessation can slow disease progression. Di Leo et al[3] demonstrated that both smoking and alcohol consumption were prevalent risk factors for the progression of CP in an Italian population. Mechanistic studies show that cigarette smoke inhibits the adaptive unfolded protein response signaling pathway, promoting ethanol-sensitized acinar cell death and pancreatic inflammation. It also activates endoplasmic reticulum (ER) stress pathways, contributing to acinar cell death. Polymorphisms and genetic susceptibility:PRSS1, which is an autosomal dominant gene with high penetrance, cause hereditary pancreatitis, affecting approximately 1% of patients with CP. Approximately 90% of families with hereditary pancreatitis carry mutations at the p.R122H, p.R122C, or p.N29I sites that are also observed in sporadic cases of pancreatitis. Copy number variations involving the deletion of the pseudogenes PRSS3P2 and TRY7 adjacent to the PRSS1 chromosomal locus may reduce the risk of CP. The primary function of PRSS1 is to produce protrypsin, which is activated by a duodenal enteropeptidase to form trypsin. Activated trypsin can be inhibited by serine peptidase inhibitor Kazal type 1 (SPINK1) or degraded by chymotrypsin C (CTRC). Mutations in the SPINK1 gene are highly prevalent among Chinese patients with CP, identified in over 50% of cases. Such mutations are linked to an increased susceptibility to CP. Nevertheless, current research does not support that SPINK1 polymorphisms impede its role in protease inhibition, leaving the pathogenicity of these mutations open to further investigation. In European demographic groups, the p.N34S mutation of SPINK1 predominates and is hypothesized to disrupt the protein's interaction with trypsin, potentially underpinning the mutation's pathogenicity. Conversely, the most frequently encountered mutation in the Chinese population is c.194 + 2T >C. This specific mutation leads to exon skipping, resulting in decreased expression and secretion of SPINK1, which might contribute to the onset and progression of CP. Variants of CTRC, specifically at the p.G60 = site, are found in 30% of CP patients, and increase risk by 2.5-fold (heterozyous genotype), or 10-fold (homozygous genotype). Animal studies suggest that CTRC, by mediating protrypsin degradation, reduces cerulein-induced intracellular trypsin activation in acinar cells. Additionally, an inversion at the CTRB1-CTRB2 locus (chymotrypsin B1/B2) provides moderate protection against alcohol-related CP in European cohorts, although such an effect has not been observed in Chinese populations. CPA1 mutations promote the improper folding of the carboxypeptidase A1 (CPA1) protein within the ER, triggering ER stress. This leads to the degradation of excessive enzymatic proteins and a reduction of secreted enzymes, consequently resulting in pancreatitis. Given the significant differences in single-nucleotide polymorphisms across ethnicities, not all CPA1 mutations identified through sequencing contribute to disease progression; functional experiments are required to confirm the pathogenicity of each mutation. CEL is also implicated in the progression of CP. CEL encodes a digestive enzyme, carboxyl ester lipase, which is associated with maturity-onset diabetes and impairs pancreatic exocrine function. Non-allelic homologous recombination between CEL and its neighboring pseudogene CELP can generate a hybrid gene, CEL-HYB. In murine models, variants of the hybrid allele CEL-HYB1 lead to early ER misfolding and stress, followed by autophagy, thereby increasing the risk of CP. Moreover, the p.T221M mutant of PNLIP exhibits protein toxicity, causing protein misfolding and ER stress. Expression of this mutant in murine models can induce CP. The development of murine models that carry genetic risk variants facilitates a deeper understanding of ER stress and the pathogenesis of protein misfolding. CFTR encodes a chloride bicarbonate channel expressed on ductal epithelial cells. It plays a central role in pancreatic fluid secretion by mediating the transmembrane transport of Cl− and HCO3−. Homozygous CFTR mutations (e.g., p.F508del) reduce chloride conductance, leading to cystic fibrosis (CF). The heterozygous carrier state increases the risk of CP. Meta-analyses have suggested that a subset of CFTR variants, characterized by selective bicarbonate conductance defects, may be associated with CP but not CF. Except for p.R75Q, heterozygous CFTR-BD variants can increase the risk of CP by 2-fold to 4-fold. CFTR can also influence ductal function through synergy with other factors. In mice and humans, alcohol and tobacco smoke both cause CF transmembrane conductance regulator (CFTR) dysfunction, explaining the associations of alcohol consumption and smoking with an increased incidence of CP. The TRPV6 encodes a highly calcium-selective ion channel expressed in epithelial cells. Loss-of-function variants have been associated with early onset non-alcoholic CP. TRPV6 mutants have been observed in cohorts from China, Japan, Germany, and France, and increase the risk of CP [Supplementary Tables 1, 2, https://links.lww.com/CM9/C444]. Research on the pathogenesis and therapy of CP: CP pathogenesis has been investigated through studies of autophagy, ER stress, immunological factors, and the activation of pancreatic stellate cells (PSCs). These studies have explored upstream and downstream genes and signaling molecules to elucidate interactions between pancreatic cells and to identify pathogenic processes such as endocytosis and phagocytosis. Treatments for CP are also being developed. Autophagy plays a crucial role in maintaining acinar cell homeostasis, and can be induced by the activation of the sphingosine kinase 1/sphingosine-1-phosphate (SPHK1/S1P) signaling pathway and may involve PSCs in the fibrosis of CP. S1P/S1PR can also promote this process by modulating autophagy and NLR family pyrin domain containing 3 (NLRP3). Trypsinogens secreted by pancreatic acinar cells can be endocytosed by PSCs, influencing PSC activation and the progression of CP; this endocytic pathway is associated with the Rabepl gene. CP features an absence of phagocytosis. Murine models disclose reduced Atp8b1 and lysophosphatidylcholine expressions suppress macrophage phagocytosis, thereby promoting disease progression. PSCs are activated in the inflammatory microenvironment of the pancreas, and contribute to the progression of fibrosis. Pancreatic fibrosis is irreversible, and no targeted drugs are currently available. Therapeutic approaches under investigation include anti-fibrosis, antioxidant, and gene therapies. Pirfenidone, an anti-fibrotic drug used to treat pulmonary fibrosis, has been explored for CP treatment, and has shown potential in alleviating CP in murine models by inhibiting PSC activation and M1 macrophage polarization. Vitamin A demonstrates antioxidant activity, mitigating oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), adenosine monophosphate-activated protein kinase (AMPK), toll-like receptor 3 (TLR3), and toll-like receptor 4 (TLR4) pathways, suggesting its potential utility for CP treatment. Gene therapy research focuses primarily on genes and molecules that influence PSC activation pathways, those suggest its potential as a biomarker of activated PSCs and as a novel therapeutic target. PIWIL1 regulates PSC activation via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling cascade; Hic-5 can induce PSC activation, its knockdown significantly inhibits the transforming growth factor-β (TGF-β)/SMAD family member 2 (smad2) signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. In conclusion, CP has multifaceted etiologies, with factors such as environmental influences, genetic mutations, and hereditary susceptibility contributing to its progression. Current treatment options are limited and focus primarily on managing symptoms and complications rather than curing the disease. Numerous studies are currently devoted to investigating CP risk factors by exploring the interactions and relationships between various factors. These efforts have also facilitated interinstitutional and international comparisons and integration of data. Despite this progress, a comprehensive and mature theoretical framework for the causation and pathogenesis of CP is still lacking. Further research is needed to unravel their complexities.