Background: Alcoholic pancreatitis is a progressive condition characterized by susceptibility to recurrence, progression to chronic pancreatitis, complications, and high morbidity. Summary: The main causes include long-term alcoholism, excessive drinking, the toxic effects of alcohol metabolites, interactions with biliary diseases, and genetic factors. Alcohol is the second leading cause of acute pancreatitis (AP) in the USA, accounting for one-third of all AP cases. A follow-up study on readmission revealed that the readmission rate of alcoholic acute pancreatitis (AAP) patients within 11 months was 43.1%, of which men dominated the admissions and readmissions of AAP. Among this population, 82.3% have alcohol use disorder, over half have tobacco use disorders, 6.7% have tobacco use disorder, 4.5% have opioid use disorder, and 18.5% of patients exhibit signs of potential alcoholic chronic pancreatitis. Numerous animal and clinical studies suggest that alcohol alone does not cause pancreatitis; rather, additional factors such as smoking, endotoxin lipopolysaccharide (LPS), genetic mutations, or other genetic predispositions – are necessary for the disease’s progression. Key Messages: Given the high rates of admission and readmission for alcoholic pancreatitis, it is essential to further investigate its pathogenesis and pathological processes to develop more effective treatment strategies. Therefore, this paper summarizes the current understanding of the pathogenesis and treatment status of alcoholic pancreatitis, drawing on recently published literature and data to provide insights and references for future research and treatment efforts.

Alcoholic pancreatitis is a significant complication associated with alcoholism. Its pathological characteristics primarily include inflammation of pancreatic tissue, which encompasses degeneration and necrosis of pancreatic acinar cells (PACs), as well as proliferation and degeneration of pancreatic duct epithelial cells [1]. Pancreatic fibrosis, resulting from the activation of pancreatic stellate cells (PSCs), is the predominant histological feature of alcohol-induced chronic pancreatitis (ACP) injury [2]. It is now widely accepted that alcoholic pancreatitis initially presents as an acute condition that can progress to chronic, irreversible pancreatic damage due to recurrent acute episodes. The average alcohol consumption over the preceding 10–15 years is approximately 150 grams per day, as alcoholic acute pancreatitis (AAP) rarely occurs following a single binge. If a patient recovers but continues to consume alcohol, chronic illness may develop [3]. Alcohol-related pancreatitis is more prevalent in Western countries and primarily affects middle-aged men. A large clinical study conducted in Europe revealed that patients with alcoholic pancreatitis constituted 71.4% of all pancreatitis cases [4]. Similarly, a clinical study involving data from 13 US centers indicated that alcoholic pancreatitis accounted for 46% of all pancreatitis cases [5]. In contrast, a clinical study in China found that only 10% of cases were attributed to alcoholic pancreatitis [6]. Alcoholic pancreatitis is characterized by a high rate of relapse, a tendency to progress to chronic pancreatitis, a propensity for complications, and elevated mortality rates. The primary contributing factors include chronic alcoholism, excessive alcohol consumption, the toxic effects of alcohol metabolites, interactions with biliary diseases, and genetic predispositions. A follow-up study on readmissions revealed that 43.1% of patients with AAP experienced readmission within 11 months, with men predominating in both admissions and readmissions for AAP. Furthermore, 82.3% of these patients had a diagnosis of alcohol use disorder, and among them, 18.5% had underlying ACP [7].

Due to the high rates of admission and readmission associated with alcoholic pancreatitis, as well as the unclear pathogenesis and lack of specific pharmacological treatments, this paper summarizes the pathogenesis, pathological processes, and current treatment options for alcoholic pancreatitis. This summary is based on recently published literature and data, with the aim of providing methods and references for further research and treatment of alcoholic pancreatitis.

The Role of Inflammatory Factors

In acute pancreatitis (AP), pancreatic cells are damaged by various pathogenic factors, leading to the release of pancreatic enzymes, activation of mononuclear macrophages, and excessive stimulation of neutrophils by metabolites, which results in the production of a large number of cytokines. These cytokines, in turn, trigger a cascade reaction involving inflammatory mediators, forming systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Key inflammatory factors, including interleukins (IL-1, IL-2, IL-6, IL-8, IL-10, IL-18), C-reactive protein, tumor necrosis factor α (TNF-α) and its receptors, and nuclear factor κB (NK-κB), play significant roles in this process [8, 9].

A recent animal study revealed that, that in addition to an increase in inflammatory factors, chemokines, pancreatic tissue necrosis, edema, alveolar accumulation, adenosine triphosphate (ATP) reduction, and decreased Bcl-2/Bcl-xl expression, there was also a significant increase in the expression of protein kinase D (PKD) mRNA in rat acinar cells fed a Lieber-DeCarli ethanol diet. The findings suggest that the amplification of PKD signal transduction may contribute to the enhanced activation of NF-κB in ethanol-fed rats [10]. This study demonstrates, at least in part, that alcohol exacerbates the pathological response of pancreatitis by activating PKD.

Another animal model demonstrated that low-dose CCK-8 can activate PKC-ζ, but this activation is insufficient to trigger NK-κB. In contrast, and ethanol exposure can activate PKC-ε, which subsequently activates NK-κB, thereby mediating inflammation. PAC is not only involved in inflammatory responses but also has functions similar to those of human macrophages and monocytes. Human and mouse acinar cells obtained from LPS-induced alcohol-exposed pancreatitis show elevated levels of IL-1β, IL-6, TNF-β, caspase 1, and other cytokines and chemokines. It has been shown that PAC mediates the inflammatory response induced by LPS-induced alcohol exposure [11]. Additionally, ethanol can induce human PSCs to produce IL-8, while both ethanol and its metabolite acetaldehyde can stimulate PSCs to produce collagen I (Col-1), which a significant role in the inflammatory processes associated with alcohol-induced pancreatic injury [12].

IL-6 is a well-known pro-inflammatory cytokine. Studies have identified a significant presence of IL-6 and IL-6 receptor (IL-6R)-positive macrophages and PSCs in the pancreatic tissues of ACP. Additionally, the expression of macrophages and IL-6R is elevated following alcohol induction. RT-PCR analysis revealed that the mRNA expression levels of IL-6, IL-6R, TGF-β1, α-SMA, and Col-1 were all significantly increased. Furthermore, IL-6-treated HP-1 (human PSCs) cells showed higher mRNA and protein expression levels of TGF-β1, along with increased phosphorylation of Smad2/3. In conclusion, IL-6 promotes the activation of PSCs and the production of Col-1 by upregulating the TGF-β1/smad2/3 signaling pathway [13], which ultimately leading to pancreatic inflammation.

As with alcoholic liver disease, the fibrotic scarring associated with chronic pancreatitis appears to be primarily linked to the activation of stellate cells. Ethanol exposure leads to tissue edema and the presence of spindle cells in pancreatic tissue, which serves as evidence of pancreatic fibrosis. The increased expression of vimentin indicates that PSCs are activated, while the sharp rise in high mobility group box 1, a necrotic marker, further supports this observation. The increase in Ki67 suggests that PACs undergoe regeneration in response to ethanol exposure [14]. These findings represent typical manifestations of an ethanol-induced inflammatory response.

Abnormal Activation of Calcium Ions

Calcium ions (Ca2+) are the most common multifunctional signal carriers involved in the regulation of nearly all cellular functions. Studies have indicated that under physiological conditions, intracellular Ca2+ is crucial for maintaining the secretion balance of intracellular enzymes. When toxic substances are present, they can lead to Ca2+ overload in the body, resulting in damage to acinar cells [1]. Alcoholic pancreatitis, mediated by ethanol and ethyl fatty acids (FAs), causes a continuous increase in Ca2+ concentration within acinar cells, which in turn activates intracellular digestive enzymes, leading inflammation and necrosis of the pancreas [15].

The ranine receptor (RYR) is a Ca2+ release channel located in the endoplasmic and sarcoplasmic reticulum, playing a crucial role in maintaining cellular excitability and physiological function [16]. Research has demonstrated that the RYR receptor expressed in human and mouse PAC and situated in the basal region of these cells, can regulate pathological Ca2+ signaling and mediate the effects of PAC injury [17]. Further studies have indicated that RYR can promote the onset and progression of pancreatitis induced by bile acids following pathological activation. The application of RYR inhibitors has been shown to reduce the peak of pathological Ca2+ overload and significantly mitigate acinar cell damage [18].

Gerasimenko et al. [19] showed that Ca2+ is released by type 2 and type 3 IP3 receptors stored in acidic granular Ca2+, leading to the activation of intracellular proteases and subsequent pathological reactions. This process is proposed to be a key step in the pathogenesis of alcoholic pancreatitis. Lipoethyl palmitate (POAEE) is one of the most potent metabolites of ethanol, capable of inducing the release of Ca2+ from the endoplasmic reticulum (ER) and the secretory epithelium (AS) of the apical membrane, which activates intracellular trypsinogen and triggers an inflammatory response. AS represents an early activation step and is a primary contributing factor. The RYR inhibitor significantly effects on alcohol-induced Ca2+ release. By introducing the natural defense mechanism calmodulin (CaM) into PAC, it is possible to significantly inhibit ethanol-induced intracellular Ca2+ release and trypsinogen activation. Furthermore, we can enhance this effect by using a CaM activator, which can mitigate pancreatic necrosis induced by a larger dose of POAEE [20].

A recent report found that the concentration of ethanol-enhanced protease activation was reduced following the addition of a RYR inhibitor. This suggests that ethanol increases the sensitivity of PAC to enhanced protease activation through RYR receptor mediation. Furthermore, the effect of ethanol on Ca2+ acceleration waves is entirely abolished after the application of the RYR inhibitor, which proves that this process is also mediated by RYR [21].

A recent study demonstrated that the expression of cystic fibrosis transmembrane conductance regulator (CFTR) is diminished in the presence of ethanol. This reduction is sufficient to disrupt Ca2+ homeostasis by inhibiting the activity of the plasma membrane calcium pump (PMCA), leading to decreased Ca2+ extrusion and a consequent sustained increase in intracellular Ca2+ concentration. This elevation in Ca2+ levels subsequently impairs mitochondrial function and promotes apoptosis, potentially exacerbating the severity of the associated pancreatic disease [22]. In conclusion, Ca2+ plays a crucial role in alcoholic pancreatitis, contributing to alcohol-induced damage to PACs and tissue inflammation; however, the specific mechanisms warrant further study.

Autophagy Disorder

Autophagy abnormalities are closely linked to the pathogenesis of ethanol-induced tissue damage [23]. Autophagy is a highly dynamic cellular process characterized by complex regulatory mechanisms. Its main function is to degrade damaged organelles, misfolded proteins, and invading pathogens. In pancreatic cells, autophagy plays a crucial role in preventing the accumulation of damaged organelles and in mitigating pancreatic inflammation. The combination of alcohol and lipopolysaccharide (LPS) will leads to the depletion of lysosomal-associated membrane protein 2 (LAMP-2) and other lysosomal proteins. This depletion results in the failure of autophagosome-lysosome fusion, accumulation of autophagosomes, and inhibition of the cytoprotective autophagy induction mechanism. The disruption of this process ultimately leads to mitochondrial energy depletion. In cases of severe ATP deficiency, acinar cells are prone to necrosis, which exacerbates local inflammation and further damages tissue damage [24].

Quantitative transmission electron microscopy revealed a significant increase in the number of autophagic lysosomes in acacine cells of mice fed with alcohol combined with LPS. However, the number of autophagolysosomes did not increase, indicating that the final step of fusion between autophagosomes and lysosomes was inhibited. In addition, in mice with endotoxemia, there was a depletion of LAMP-2, along with a reduction in the expression of another lysosomal protein, GRAMP-92 [25]. Another study reported similar findings, showing that both LAMP-2 and GRAMP-92 were severely reduced following induction by ethanol and LPS [24]. These observations suggest that a general disturbance in lysosomal membrane proteins, although the mechanism underlying LAMP-2 depletion remains unclear. In a recent experiment, slow acute ethanol exposure (Gao-binge) significantly increased the number of GFP-LC3 fluorescent dots targeting the autophagic membrane in mouse PAC, indicating enhanced autophagic flux. However, lysosomal biogenesis was impaired following alcohol induction, resulting in an insufficient number of lysosomes available for fusion. Consequently, autophagic lysosomes could not be fully formed, leading to autophagic insufficiency and progression to alcoholic pancreatitis [26].

SIRT2 is a deacetylase that, under the influence of ethanol, interacts with PFKP (phosphofructokinase-platelet subtype). It deacetylates PFKP at mouse lysine 394 and promotes its ubiquitination and degradation. In addition, the phosphorylation and activation of autophagy-associated protein 4B (ATG4B) are inhibited, leading to reduced LC3-I activity, impaired LAP, inhibited glycolysis, and damage to acinar cells [27]. This study suggests that inhibiting SIRT2 expression may improve the survival rate of mice with sepsis, presenting a potential treatment strategy for alcohol-induced sepsis. Micro-tubule-associated protein LC3-I and LC3-II are two forms of the LC3 protein family. LC3-I is typically found in the cytoplasm, while LC3-II predominantly resides on the membranes of autophagic lysosomes, playing an important role in autophagy formation. A recent study indicated that in cases of experimental alcoholic pancreatitis, ethanol upregulates the expression of ATG4B protein by inhibiting its degradation, which reduces the formation of autophagosomes and exacerbates acinar cell damage due to the accumulation of damaged cells, ultimately inducing pancreatitis. Conversely, knocking down ATG4B enhances autophagy formation in pancreatic cells. Alleviating alcohol-induced acinar cell damage may provide a theoretical basis for developing new therapeutic options [28]. The study also found that SNAP23 knockout blocks the binding of autophagosomes to lysosomes; however, the downstream processes of mature autophagolysosomes that have already formed, such as cathepsin processing and trypsin activation, remain unaffected [29].

By observing the immunofluorescence staining of the autophagy marker LC3-II and the lysosomal membrane marker LAMP-2 in mice treated with alcohol and blue protein, it was found that the proportion of positive cells in those mice was higher than that in the AP group. Additionally, the expression of autophagy-related homologous LC3A/B and the autophagy cargo protein SQSTM1/P62 were also elevated [9]. This indicates that the already defective autophagy function is further deteriorated under the influence of alcohol, thereby clarifying the impaired autophagy flux caused by alcohol. Furthermore, the activated AMP-activated protein kinase (AMPK) pathway, induced by alcohol, negatively impacts PAC autophagy flux, which enhances autophagy and increases inflammation. The experimental results demonstrated that the use of the AMPK inhibitor BML-275 could significantly inhibit AMPK activation and reverse the reduction in cell viability. By assessing the expression of autophagy-related proteins, it was observed that the expression of SQSTM1/P62 was significantly decreased, thereby improving the impaired autophagy flux [9]. This finding aligns with previous studies, which have shown that alcohol and its metabolites (such as acetaldehyde and FAEE) can significantly reduce the oxidative stress levels of the upstream kinase AMPKα, while the downstream signaling protein P-ACC1, regulated by AMPKα, is also diminished, exacerbating pancreatitis [30]. In vitro studies have indicated that non-oxidized ethanol metabolites can impair lysosomal membrane function, leading to the inhibition of autophagic lysosome formation. Additionally, endoplasmic reticulum ER stress may further inhibit lysosomal function by disrupting the folding and transport of lysosomal proteases and LAMP-2 [31].

Genetic Mutations

A meta-analysis showed that cytochrome P450 2E1 (CYP2E1) is an ethanol-induced microsomal enzyme that can catalyze the oxidative metabolism of ethanol to produce acetaldehyde and reactive oxygen species (ROS). In experiments with mice subjected to chronic alcohol feeding, it was found that chronic ethanol exposure increases the expression of CYP2E1, which in turn increases ROS production and exacerbates pancreatic tissue damage. The C1C2 and C2C2 genotypes of the CYP2E1-Rsai/Pstl polymorphism are significantly associated with alcoholic pancreatitis in the Asian population [32]. Two mutated genes of CTRC, Arg254Trp, and 180C > T, are highly correlated with the risk of developing AP. The CTRC polymorphic T allele 180C > T is identified as a risk factor for the development of alcoholic pancreatitis. The Arg254Trp allele has been reported in one study, and the number of related studies is limited. Consequently, it is difficult to ascertain its impact on the incidence of alcoholic pancreas [33].

Originating from the crossover between the CEL and its neighboring pseudogene CELP, a hybrid allele known as CEL-HYB was identified. Significant enrichment of CEL-HYB was detected in alcohol-associated chronic pancreatitis [34]. This finding may prove that CEL-HYB may one of the relatively few genes known to contribute to the risk of ACP. However, the results should be interpreted with caution, as they have not yet been confirmed by more studies.

SPINK1 is a specific trypsin inhibitor and serves as the first line of defense against the premature activation of trypsinogen. Research on the mechanisms of the PRSS1 and SPINK1 genes in acute pancreatitis (ACP) suggests that mutations in these genes can easily lead to the early activation of proteases, increasing the risk of AP. Furthermore, these mutations are found to be more prevalent in moderate to severe patients [35]. A study in Poland found that PRSS1 and SPINK1 mutations existed in ACP population, but SPINK1 mutations were not significantly correlated with the clinical course of disease and the frequency of complications [36]. Mutations in PRSS1 and SPINK1 genes were not found to be associated with alcohol consumption in Asian and European ACP populations, or even in healthy people and ACP patients [37]. However, a report from Brazil suggested that the mutation frequency of SPINK1 allele 253C in ACP patients was relatively high, although it was in the noncoding region [38]. The Turkish team also did not find the correlation between SPINK1 and PRSS1, PRSS2, CFTR, and ACP [39]. Overall, the results of the Polish study show a higher rate of genetic mutations than previously reported in other countries. This result may be due to genetic differences between different races and species diversity, but it does not rule out selection bias.

According to previous studies, the inheritance and mutation of the CLDN2 gene have not been found to be associated with human diseases. However, by assessing protein localization in pancreatic surgery cases revealed that half of the cases exhibited high-risk CLDN2 genotypes. Staining acinar cells with claudin-2 particles demonstrated that only the high-risk CLDN2 genotypes showed moderate to strong staining on the basolateral membrane of acinar cells. The combined estimated odds ratio of CLDN2 and PRSS1-PRSS2-positive cases of alcohol-related pancreatitis was then compared to those of negative cases [40]. It was shown that both loci were amplified by ethanol exposure and both appeared to be associated with alcoholic pancreatitis, with the CLDN2 locus being the most significant. Subsequently, a large case-control study confirmed a significant association between rs10273639 T allele variation on chromosome 7 in PRSS1-PRSS2 and ACP, while no association was found in NACP. rs7057398 and rs12688220, located on the X chromosome of CLDN2-MORC4, were significantly associated with ACP in both male and female cases, confirming that the T allele of PRSS1-PRSS2 inhibits ACP [41]. Another study indicated that in ACP patients, the five variants of X-linked CLDN2-MORC4 also showed a significant correlation with ACP, suggesting that this gene locus contributes to susceptibility in ACP. Furthermore, analysis of the interaction between genetic variation and environmental factors also showed that MORC4 has a significant impact on ACP [42].

In recent years, a large cohort study has conducted targeted second-generation sequencing of four genotypes, SPINK1, PRSS1, CTRC, and CFTR, in three subgroups (ICP idiopathic chronic pancreatitis, ACP alcoholic chronic pancreatitis, and SCP smoking-associated chronic pancreatitis). In addition, primer3 technology was used to obtain all exons and exon/intron boundaries of the four genotypes, and the results showed that patients with gene mutations had an earlier age of onset and complications such as pancreatic calculus, diabetes, and fat leakage, among which the patients carrying SPINK1 homozygote had the earliest age of onset. However, the effect of pathogenic genotype on the onset and clinical results of ACP was not as significant as SCP [43]. Although this study only focuses on rare variants, the three subgroups selected are the largest to date and still have important implications for the genetic detection, treatment and prognosis of ACP. CFTR is an ion channel, and when there are gene mutations, the function of this ion channel is weakened, leading to impaired epithelial fluid transport in organs such as the pancreas. Under the influence of ethanol, accelerated channel turnover and abnormal protein folding on the apical membrane can cause a decrease in CFTR expression and PM density [44]. When the wild-type and CFTR-KO mice were induced by ethanol and FAs, the comparison of the HE stained tissue sections and inflammatory indicators of the two groups showed that these inflammatory reactions were more significant in the CFTR-KO group, this indicates that ethanol and its non-oxidative metabolites cause damage to CFTR expression by reducing the expression of CFTR messenger RNA, which decreases the stability of CFTR on the cell surface and disrupts the folding of CFTR in the ER, further exacerbating ethanol-induced pancreatitis [45]. After ethanol treatment or gene mutation, CFTR expression is attenuated, and Ca2+ extrusion is weakened by restriction of PMCA activity, which damages mitochondrial ATP production and causes Ca2+ homeostasis disorder, thus damaging cell viability and leading to pancreatitis [46].

The encoding product of PRSS1-PRSS2T allele is trypsinogen, which has important physiological functions in human body. The mutation of this gene may lead to abnormal expression of trypsinogen and affect normal expression of pancreas. A recent meta-analysis showed that the OR values of common PRSS1-PRSS2 risk related alleles associated with ACP were higher than those of NACP, suggesting an interaction between the PRSS1-PRSS2 haplotype and alcohol consumption in chronic pancreatitis [47]. Therefore, these AP patients should drink less alcohol or abstain completely. Studies have suggested that men who carry the −408CC genotype and drink 29–59 glasses of alcohol per week have an increased risk of AP, and the risk of AP increases with the increase in the amount or time of alcohol consumption per week [47]. As mentioned earlier, SPINK1 is a trypsin inhibitor that prevents pancreatitis. Through gene sequencing, it was found that N34S mutation of SPINK1 was significant in ACP patients, while P55S and CTRC mutations of SPINK1 were not significantly correlated in ACP patients [48]. A recent study examined SPINK1 mutations in samples of AAP, healthy people, and heavy drinkers and found a significant association between SPINK1 mutations and the first episode of AAP, with SPINK1 N34S overexpressed in AAP, but in mild cases. The findings suggest that only a minority of heavy drinkers develop AAP, so it can only partially explain the susceptibility of heavy drinkers to AAP [49]. The study may be useful for assessing risk and interventions, but there are limitations due to the small sample size and lack of additional genetic analysis, and further experiments are needed to confirm the conclusion. Although genetic variation still plays a role in the pathogenesis of ACP, further studies are needed to confirm the specific mechanism.

LPS/Cigarette Extract

LPS, as a component of the cell wall of Gram-negative bacteria, can stimulate the immune response, trigger inflammation, and promote the development of pancreatic fibrosis. Compared with nondrinkers, both long-term drinkers and single heavy drinkers had significantly higher LPS content. Fortunato et al. [50] confirmed that injecting LPS into ethanol-fed rats could lead to pancreatic necrosis and inflammation [51]. Vonlaufen et al. [52] also found that single or multiple injections of LPS resulted in significant pancreatic damage in long-term alcohol-fed rats, and that multiple injections of LPS resulted in pancreatic fibrosis (acinous atrophy and fibrosis), and demonstrated that PSCs play a central role in alcohol-related pancreatic fibrosis. These studies may prove that LPS is a trigger for the development and progression of alcoholic pancreatitis.

Studies have demonstrated significant vacuolation and necrosis of pancreatic tissue induced by LPS following alcohol exposure. The experiment also found that the ADP/ATP ratio increases, indicating that ethanol binding LPS changes the energy balance of cells and promotes cell necrosis [24]. Further in vivo studies demonstrated that in LPS combined with chronic alcohol feeding (ALC) rats, repeated injections of LPS significantly increased collagen deposition in pancreatic tissue, activated PSCs, and elevated the number of Toll-like receptor 4 (TLR4)-positive macrophages (Mψs). TGF-β1 protein levels were significantly increased. BAMBI is a type I receptor belonging to the TGF-β family, can inhibit TGF-β1 signaling. In vitro experiments have demonstrated that LPS and ALC inhibit BAMBI expression and promote PSC activation through the TLR4/MyD88/NF-κB signaling pathway [53]. LPS can induce TNF-α production, which is further enhanced by ethanol exposure. Silencing of TLR4 and MyD88 inhibits the production of TNF-α, indicating that LPS drives the production of inflammatory factors through TLR4 receptors. Acinous cells express TLR4, allowing them to respond directly to LPS [11]. In conclusion, targeting LPS and its downstream mediators may be an effective treatment for ACP.

It is worth noting that most of the pro-inflammatory and anti-inflammatory mediators are produced by acinar cells, and it has been experimentally demonstrated that alcohol exposure can intensify the expression of IL-18, caspase-1, IL-6, and IL-10 produced by LPS-induced PAC, which is more obvious in AP/RAP acinar cells and only slightly increased in CP. In vitro experiments, LPS can be translocated into acinar AR42J cells to initiate intracellular defense response by inducing the expression of pro-inflammatory mediators, and TLR4 signaling promotes LPS-induced inflammation [11]. Lps-induced Caspase-2, Caspase-8, and Caspase-9 activities were inhibited in chronically alcohol-fed rat models, suggesting that alcohol inhibits the activity of various caspase enzymes in response to LPS stimulation [50]. Another animal model experiment found that continuous intake of alcohol and LPS could inhibit PSC apoptosis, leading to permanent damage. Compared with ethanol alone, ethanol combined with LPS could enhance the inhibition of PSC apoptosis, and TLR4 knockdown could reverse this inhibition, proving that this effect was mediated by TLR4 [54]. The ROS levels and IL-6 mRNA expression levels of AR42J cells induced by oxidative stress were significantly increased under the induction of ethanol and LPS [55]. This evidence suggests that exposure to alcohol increases the pancreas’ susceptibility to LPS-induced damage.

In alcoholics who smoke, the combined effects of alcohol and SCE on hPSC behavior may contribute to the progression of pancreatic fibrosis [2]. Phase contrast microscopy showed that cells treated with cigarette extract (CSE) and Etoh exhibited death patterns such as cell contraction and cytoplasmic agglutination. Compared with Etoh or CSE alone, the combined use of the two significantly increased AR42J cell death and led to higher and sustained PERK activation and sustained eIF2α phosphorylation, which suggested that ethanol and cigarette extract induced PAC death by way of ER stress [56]. The apoptosis rate of CSE and ethanol combined treatment was higher than that of CSE or ethanol alone, and CSE/NNK combined with ethanol increased PSCs activation through nAChRs on cells, promoting fibrosis of ACP [57]. So quitting smoking is very important both in terms of treating diseases and preventing complications.

Pathological Exocytosis

Gaisano et al. [58] observed early changes in the actin cytoskeleton of the apical membrane of PAC in CAP, noting “bead-like” alterations. These changes were accompanied by the translocation of Munc18c from the plasma membrane of PAC to the cytoplasm, which rendered the basal membrane prone to translocation exocytosis. The two main steps of exocytosis are vesicle formation and vesicle transport, which occur at the apical pole of acinar cells. CCk-induced apical extosis of PAC is inhibited by alcohol and its metabolites, redirecting the process to the basolateral plasma membrane (BPM). Furthermore, it has been observed that PAC BPM becomes sensitive to CCK-induced Munc18c activation, which promotes SNARE complex assembly. Making restricted BPM sites susceptible to extracellular secretion, eventually leading to alcoholic pancreatitis [59]. Multiple studies [60‒62] corroborated the notion that Munc18c protein on the basolateral PM is activated by protein kinase C (PKC) α-mediated phosphorylation after exposure to clinically toxic levels of alcohol. This protein then enables STX4 to bind to LAMP8 and SNAP23 to form a SNARE complex and open conformation, resulting in basolateral extosis and ultimately pancreatitis.

By observing SNAP23-KD pancreatic sections to trace extosis, it was observed that in the cases of pancreatitis induced by 10 nm CCK, the basolateral plasma membrane had a high abundance of exocytosis, while apicular exostosis was partially inhibited. When the ZG fuses with PM, high fluorescence occurs, a phenomenon known as a high fluorescence. After SNAP23-KD, stimulated basolateral exocytosis hot spots were significantly diminished, and apical exocytosis was further reduced. This indicates that SNAP23-KD mitigates pathological exocytosis by disrupting SNARE complex formation [29], thereby alleviating pancreatitis.

N- ethylmaleimide sensitive factor (STX2) is a soluble adhesion protein receptor that aggregates in significant amounts in PAC. Previous studies have reported that STX2 can mediate apicular exocytosis and plays a crucial role in the molecular mechanism underlying exocytosis [63]. STX2 can bind ATG16L1 and prevent its binding to clathrin. In this study, STX2-KO was simulated using ethanol and supraphysiological dose of CCK. The findings revealed that increased binding of ATG16L1 to clathrin induced autophagy and promoted trypsinogen activation. Moreover, STX2 may act as an inhibitory SNARE, obstructing the formation of the STX3 and STX4 complex SNARE, while STX2-KO can cause exaggerated exocytosis at the basolateral plasma membrane and restore apical exocytosis. These events ultimately contribute to increased susceptibility and severity of pancreatitis [64].

ER Stress

The ER is responsible for protein folding and processing, and PACs have the richest ER network in human tissue, and therefore the highest protein content [65]. However, this specialized function also makes the ER particularly vulnerable to disruptions from external factors such as bacterial or viral infections and ethanol exposure, which can cause proteins to be synthesized in an unfolded or misfolded state, leading to ER stress [66]. Additionally, proteins produced in the ER need disulfide bonds to achieve stable structures necessary for their functions, and the formation of these bonds relies on the help of protein disulfide isomerase (PDI) [67]. In patients with chronic alcoholic pancreatitis, there was a notable decrease in the expression of CFTR membrane in pancreatic ductal epithelial cells (PDEC), while the mRNA expression and cytoplasmic density of CFTR were significantly elevated. This indicates that there is a defect in CFTR protein folding within the ER and that the ER function in PDEC impaired [45].

Previous research indicated that in ADH-deficient mice given a diet containing 3.5% ethanol, exhibited notable apoptotic bodies, along with an expansion and swelling of ER pool, which signifies ER stress. The expression of GRP78, a marker for ER stress, was found to be seven times greater than that of the control group [68]. The formation of fatty acid ethyl esters (FAEE) through the non-oxidative metabolism of alcohol results in the inactivation of AMPKα and subsequent ER stress. Activation of AMPKα by AICAR (5-aminoimidazole-4-formamide ribonucleotide) can significantly decrease FAEE production and alleviate ER stress, while also enhancing the inflammatory response [66]. Following AMPKα activation, there was an improvement in ethanol-induced ER stress and inflammatory signaling in PACs, evidenced by reduced levels of ER stress markers such as GRP78, CHOP, and JNK, as well as a decrease in the secretion of inflammatory factors and chemokines. These findings support the conclusion that AMPKα mitigates ER stress and inflammation. Additionally, increased levels of ER stress markers were noted in islet beta cells cultured with ethanol and in isolated islet tissues [69]. Elevated ER stress markers were also detected in mouse acinar cells exposed to 0.4% alcohol for 6 h [70]. Ren et al. [14] further demonstrated that the expression of various unfolded protein response proteins, including ATF6, CHOP, PERK, and eIF2α, was significantly elevated in mouse pancreatic tissues, along with an increase in inducible nitric oxide synthase, indicating that ethanol exposure can induce oxidative stress and ER stress.

Previous research has indicated that the transcription factor XBP1 is crucial for the development and secretion functions of the ER [71]. Mice that were fed alcohol exhibited notable increases in both mRNA and protein levels of XBP1. Electron microscopy revealed structural abnormalities, significant expansion of the ER, a decrease in zymogenic particles, and an accumulation of autophagy vacuoles, all of which are indicators of ER stress. Furthermore, ethanol exposure leads to the oxidation of PDI, which exacerbates ER stress [72]. Alongside the heightened expression of inflammatory factors and chemokines, there was also a marked increase in ER stress and caspase 12 was activated in the chronic plus binge ethanol mice. Interestingly, caspase is a key mediator in ER stress and induction of fine apoptosis. It can be speculated that ethanol-induced apoptosis may be mediated by ER stress [73]. Addressing the causes of ER stress could be beneficial in treating alcoholic pancreatitis.

Abnormal Mitochondrial Function

A growing body of evidence suggests that mitochondrial damage constitutes a fundamental pathological characteristic of pancreatitis. In instances of alcohol exposure, mitochondrial function is compromised, and the protein synthesis demands of the pancreas require substantial energy, ultimately leading to alcoholic pancreatitis. The effect of ethanol on oxidative metabolic pathway is evidenced by a decreased the ratio of NAD+/NADH, which activates the mitochondrial permeability transition pore (MPTP). This activation results in mitochondrial depolarization and a continuous loss of ΔΨm in acinar cells, ultimately culminating in ATP depletion and pancreatic PAC necrosis [74]. Under conditions of LPS-induction, the ADP/ATP ratio in acinar cells of ethanol-fed rats was consistently higher than that observed in the control group, indicating a pattern of necrotic cell death [50].

The nonoxidizing metabolites of ethanol, FAEE and FAs, disrupt Ca2+ homeostasis. This disruption can result in Ca2+ overload, which subsequently leads to the opening of the mitochondrial permeability transition pore (MPTP), thereby inhibiting mitochondrial function. Ultimately, this process contributes to a reduction in ATP production and induces cell death [75]. Consequently, the application of MPTP inhibitors may offer a potential strategy to prevent the necrosis of PACs.

In both in vivo and in vitro animal studies, it has been demonstrated that ethanol exposure and low phosphate levels constitute a significant risk factor that exacerbates the progression of acute alcoholic pancreatitis (AAP). Research indicates that low phosphate concentrations can lead to pancreatic edema, accompanied by significant elevations in serum amylase, lipase, myeloperoxidase, and other relevant biomarkers. Phosphate serves as a crucial regulator of mitochondrial oxidative phosphorylation and is a key substrate for ATP production. Depletion of phosphate markedly impairs mitochondrial function, resulting in ATP depletion within acinar cells. While phosphate supplementation has been shown to ameliorate the extent of pancreatic damage, this observation has thus far been limited to murine models [76]. Further investigations are required to validate these findings in human subjects, thereby providing a novel experimental framework for the exploration of alcohol-induced pancreatic injury. This may partially elucidate the phenomenon whereby only a minority of individuals with alcohol use disorder develops AP.

Thiamine pyrophosphate (TPP) is a necessary compound for the maintenance of normal cellular biological functions and metabolic processes. Chronic alcohol exposure has been shown to inhibit the expression of the mitochondrial TPP transporter (SLC25A19) and its promoter activity in PAC, thereby impeding the uptake of mitochondrial TPP and contributing to pancreatic injury [77].

In addition, experiments in animal models have found that alcohol has a dual effect on the pancreas, that is, chronic alcohol abuse not only changes the mitochondria and increases the level of ROS, changes the redox state of the ER, and affects protein folding and transport. It was also found that chronic alcohol feeding led to elevated levels of x-box binding protein 1 (XBP1), which restores the level of ER chaperones and oxidoreductase required by the protein folding, transport and degradation (ERAD) pathway and fights the harmful effects of alcohol, demonstrating that XBP1 is a key protective factor against alcohol-induced pancreatic toxicity. Disease occurs when the damaging effect outweighs the protective effect [78].

Effects of Acetaldehyde and FAEEs

Liver and pancreas are the two main organs that metabolize alcohol. Liver mainly metabolizes alcohol through aerobic pathway (ADH) and P450 2E1 (CYP2E1), and the exocrine metabolism of pancreas through this pathway is significantly lower than that of liver. However, lipotropic FAEEs can be produced by pancreatic exocrine metabolism and degradation of alcohol through non-oxidative pathways, which form and accumulate in pancreatic tissues with much higher expression than liver. FAEEs will reach high concentration in the pancreas after exposure to a large amount of alcohol, which is the main pathogen of PAC injury [2]. A recent prospective study showed that the clinical relevance of elevated FAEEs as a biomarker of alcoholic pancreatitis was supported by receiver operating characteristic curve analysis, and that FAEEs residual non-esterified fatty acids (NEFAs) were closely related, but not dependent on ethanol levels. Receiver operating characteristic curve results showed that the area under the curve (AUC) of FAEEs as a diagnostic biomarker for alcoholic pancreatitis was 0.87 (95% CI: 0.78–0.95) (p < 0.01). The sensitivity and specificity of FAEE level >30 nmol/L to AAP were 77.4%, 85.3%, and 5.3 [79].

Chronic alcohol consumption can inhibit ethanol dehydrogenase (ADH) isoenzymes I–III, which appears to promote the formation of FAEE, a nonoxidizing metabolite of ethanol. The continuous formation and accumulation of FAEE is likely a key factor contributing to pancreatic injury. Further studies should be conducted to investigate the distribution and differential inhibition of ADH isoenzymes following long-term alcohol to validate this hypothesis [80]. Interestingly, some research has indicated that ethanol-induced FA levels, similar to FAEE, are significantly elevated in patients with pancreatitis. Moreover, FA can cause an early loss of mitochondrial membrane potential (Ψm), trigger cell death, decrease ATP levels, and continuously increase intracellular calcium (Ca2+), ultimately leading to more severe necrosis of pancreatic tissue than FAEE. This can result in serious complications such as lung injury and kidney failure [81]. Therefore, the conversion of FA to FAEE following alcohol abuse may offer some degree of protection to pancreatic tissue from more severe damage.

Among these compounds, 4-methylpyrazole serves as an inhibitor of ethanol dehydrogenase (ADH), primarily hindering the oxidative metabolism of ethanol while promoting its the non-oxidative metabolism. This shift results in an increased the level of FAEEs in the pancreas. Carboxyl ester lipase (CEL), produced by PACs, also facilitates FAEE production. In contrast, while 3-benzyl-6-chloro-2-pyridone inhibits CEL synthesis, thereby further preventing FAEE formation. The combination of ethanol and palmitoleic acid can induce PAC necrosis and calcium-dependent mitochondrial dysfunction in animal models through a non-oxidative pathway, indicating that alcohol-induced toxicity is primarily mediated by FAEE. Consequently, 3-benzyl-6-chloro-2-pyridone may also mitigate mitochondrial dysfunction and inhibit ATP depletion [82].

Similarly, some scholars have proposed that the cause of pancreatic tissue damage is not ethanol itself, but rather its oxidized (acetaldehyde) and non-oxidized FAEEs metabolites. Among these, mitogen-activated protein kinases (MAPKs) represent is a key pathway in the inflammatory response following oxidative stress. After treatment with ethanol and its metabolites, it was observed that this pathway was significantly upregulated, and the expression levels of the inflammatory factor TNF-α, along with other inflammatory cytokines and chemokines, were markedly increased [30]. In conclusion, alcohol and its oxidative and non-oxidative metabolites can induce acinar cell damage by promoting signal transduction disorders, oxidative stress, and other pathways, making them critical factors in the pathogenesis of acute pancreatitis (ACP). Further studies focusing on the effects of individual FAEEs, the regulation of chronic alcohol metabolism, and the mechanisms of various oxidative stress regulators in acinar cell damage may help identify potential pathogens.

In pancreatic tissues treated with ethanol and its metabolites, the oxygen consumption rate of AR42J cells is significantly reduced, along with a marked decrease in mitochondrial ATP production, leading to damage in pancreatic tissues [30]. Docosahexaenoic acid (DHA), a potent antioxidant, inhibits NADPH oxidase activity, thereby lowering ROS levels, and preventing mitochondrial dysfunction. However, DHA does not affect ethanol/POA-induced Ca2+ shock levels in AR42J cells. Nevertheless, it can inhibit the activation of necrosis regulatory proteins in AR42J cells, further preventing the necrosis of pancreatic tissue [83]. This suggests a promising potential for DHA in the treatment of pancreatitis.

Alcohol and its metabolites, including acetaldehyde, ethyl palmitate, and ethyl palmitate, significantly reduced apical exocytosis induced by CCK-8/cch following the pretreatment of acinar cells. In contrast, basolateral exocytosis was increased. Surprisingly, ethyl palmitate, the primary compound associated with alcoholic pancreatitis, only caused a slight decrease in apical exocytosis. To demonstrate that these phenomena are dependent on Ca2+, the acinar cells were pretreated with a low-concentration Ca2+ medium along with a Ca2+ chelating agent, which prevented these effects. These results confirm that ethyl palmitate reduces CCK secretion by disrupting the Ca2+ peak signaling, thereby affecting apical exocytosis [62].

Cholinergic Receptors

The paraffin staining of mouse pancreatic tissue showed that atropine, a cholinergic receptor antagonist, can significantly reduce AP induced by blue protein and mitigate the histological damage to acinar cells. Under electron microscopy, atropine effectively reduced both the number and size of cavitations caused by alcohol. In vitro experiments have also confirmed that ethanol exposure alters cholinergic signaling in acinar cells, leading to trypsin activation and the pathological consequences of vacuolation. This finding illustrates at least a partial pathological effect of the plasmin inducer on pancreatic exocrine through the cholinergic pathway [84]. Alcohol abuse can modify the characteristics of acinar cells, rendering them more susceptible to pathological responses induced by cholinergic overstimulation. From this experiment, it can be inferred that long-term alcohol consumption may increase the level and duration of acetylcholine action in acinar cells, although this has not been experimentally validated. Currently, there is a limited number of studies on cholinergic receptors in pancreatitis, indicating a need for further research to explore unknown areas and provide a theoretical basis for the pathogenesis and treatment of pancreatitis.

Acute alcoholic pancreatitis is a potentially fatal disease with limited effective treatment options. Quitting smoking and drinking alcohol and maintaining a healthy lifestyle, such as eating more fresh vegetables and high-quality protein, are the most intuitive recommendations. The timeliness and effectiveness of treatment are also important factors affecting prognosis. A retrospective follow-up study suggests that when patients with AAP receive repeated brief interventions during their initial hospital stay, they may still develop RAP, and such patients should be followed up more closely [85]. In ACP patients, due to the activation of external visceral pain neurons of the pancreas, nerve damage, and peripancreatic complications, the quality of life is decreased, and surgical intervention is required, including pancreatic resection and drainage. However, early surgery and complete cessation of smoking are also very important, which can improve the quality of life more lasting [86].

Studies have shown that the PKD inhibitor CID/CRT can significantly alleviate pancreatic cell necrosis, edema, vacuolation, and tissue damage induced by alcohol, thereby reducing the severity of the disease. The pro-survival Bcl-2 protein plays a crucial role in preventing pancreatic necrosis by stabilizing mitochondrial function and averting ATP depletion. However, the expression of the Bcl-2 protein is markedly downregulated in alcoholic pancreatitis, and the application of PKD inhibitors can counteract this downregulation. Additionally, RIP1 levels remain at a relatively stable level during pancreatitis but are significantly reduced following the administration of PKD inhibitors. This suggests that PKD inhibitors may facilitate the degradation of RIP1, indicating their potential as a therapeutic option for alcoholic pancreatitis. Nevertheless, further research is necessary to develop more effective and selective PKD inhibitors, as well as to conduct clinical trials for the treatment of human pancreatitis [10]. Although the symptoms of pancreatic edema did not change significantly after phosphate supplementation, serum amylase and neutrophil infiltration (as measured by myeloperoxidase) were significantly decreased, indicating that phosphate supplementation can effectively prevent ethanol-related cell damage, reduce disease severity, and potentially reverse the ethanol-induced decrease in ATP levels in acinous cells, which may ultimately lower mortality rates [76]. This approach represents a treatment method with clinical value. Furthermore, improving Ca2+ extrusion in epithelial cells may offer a potential novel therapeutic strategy to preserve exocrine pancreatic function in alcoholic pancreatitis [22].

TFEB-mediated lysosomal impairment was found in alcohol-induced mouse pancreas. Injecting adenovirus-TFEB via the tail vein of mice promoted TFEB overexpression, which not only reversed the alcohol-induced reduction of TFEB and its target protein ATP6V1b2 but also partially restored the levels of LAMP1. This intervention significantly alleviated pancreatic tissue injury. These findings suggest that TFEB overexpression may prevent alcoholic pancreatitis, indicating that targeting TFEB-mediated lysosomal biogenesis could be a promising strategy for the prevention and treatment of pancreatitis [26].

In ACP, α-SMA activates PSCs and triggers fibrogenesis in pancreatic tissue. Vitamin E has been shown to reduce fibrosis activation and inhibit the catalytic activity of COX-2 in prostaglandin synthesis, thereby diminishing the inflammatory response. Supplementation of vitamin E in ACP patients can downregulate these pro-inflammatory genes. Additionally, pancreatic amylase (Pap) is a crucial component of the body’s defense mechanism against pancreatic injury, and vitamin E supplementation can also upregulate protective genes. Therefore, vitamin E supplementation is beneficial in the treatment of pancreatitis [87].

MANF can significantly mitigate the inhibition effects of alcohol of cell viability, as measured by MTT assay, and reduce acinar cell apoptosis. The main mechanism involves the inhibition of the P-IRE1-caspase 12-caspase 3 apoptotic pathway, which decreases alcohol-induced cytotoxicity. This finding holds substantial clinical significance for the treatment of alcoholic pancreatitis [70].

It was found that the levels of 25-(OH)D3 in ACP patients were significantly reduced. This deficiency in vitamin D3 may serve as a potential contributing factor to pancreatic fibrosis in ACP, suggesting that vitamin D3 supplementation could be a viable anti-fibrotic strategy. TGF-β1 appears to be the primary regulator of pancreatic fibrosis in ACP. Additionally, carpotriol, as a vitamin D analogue, has been shown to antagonize 16 fibrotic proteins in TGF-β1-induced psc through a dependent mechanism, thereby achieving the goal of anti-tissue fibrosis [88].

As a well-known RYR inhibitor, RR can significantly inhibit bile acid-induced Ca2+ release and improve pathological conditions [89]. RYR inhibitors play a critical role in Ca2+ release and may serve as an effective therapeutic targets in the future. Lycopene is also a potent antioxidant that has been found to inhibit the activity of NADPH oxidase, thereby reducing ROS levels in AR42J cells. Additionally, lycopene inhibits DNA-binding activity of NF-kB as well as IL-6 expression and zymogen activity [90]. Alcoholic pancreatitis can be prevented by dietary lycopene supplementation. However, the experiment revealed that ROS levels in lycopene-treated cells remained higher than those in untreated cells. Therefore, the source of ROS in acinous cells treated with Etoh/POA needs to be further investigation, and additional in vivo studies are required to validate these findings. Lycopene can also upregulate Nrf2 signaling and the expression of its target antioxidant genes, NQO1 and HO-1 in PAC, thereby alleviating the increase of ROS and IL-6 levels, as well as mitochondrial dysfunction caused by Etoh/LPS [55]. SNAP23 depletion seems to improve basolateral exocytosis and pathological autophagosome lysosome fusion, which may protect the body from pancreatitis, and provide a strong theoretical basis for the treatment of alcoholic pancreatitis [29].

Prognosis

Long-term alcoholism and a poor lifestyle are likely to contribute to the recurrence of the disease. Additionally, the prognosis of alcohol-related pancreatitis is influenced by the severity of the condition and its associated complications. Severe alcoholic pancreatitis can lead to serious complications such as pancreatic necrosis, abscess formation, and MODS, all of which can adversely affect prognosis. Research has indicated that cannabis may interact with alcohol in the pancreas through certain mechanism, resulting in a lower incidence of AP among individuals who use cannabis while binge drinking [91]. Patients with AP (CB+) who concurrently use cannabis and alcohol do not exhibit particularly severe clinical symptoms, suggesting that cannabis may enhance the body’s defense mechanisms, mitigate the effects of alcohol through vomiting, and improve the pathological response of the pancreas to alcohol. The findings of this study showed a significant reduction in blood urea nitrogen (BUN), systemic inflammatory response syndrome, Bedside Index for Severity in Acute Pancreatitis (BISAP) scores and other important indicators of disease severity in CB+ patients. However, further prospective studies are warranted [92].

A 9-year follow-up study found that MRI cholangiopancreatography was utilized to observe pancreatic morphological changes in the pancreas of patients admitted for the first time with AAP. Over many years of follow-up, even a single episode of acute alcoholic pancreatitis may cause chronic morphological changes, regardless of severity. Furthermore, the extent of pancreatic morphological changes increases with repeated episodes of AP. During long-term follow-up, 88% of patients with multiple relapses had chronic morphological changes in the pancreas after about 7 years [93]. Consequently, patients with alcoholic pancreatitis often experience pancreatic dysfunction or morphological alterations, such as the development of prediabetes or pancreatic diabetes, which can significantly impact their quality of life. Therefore, routine screening of pancreatic function is essential [94]. Early diagnosis and treatment of the disease are crucial. It is both important and challenging to address the malignant, severe, and chronic tendencies of alcohol-induced pancreatic diseases promptly to improve the success rate of treatment.

The mechanisms contributing to alcoholic pancreatitis discussed in this article are summarized in Figure 1. Some of the mechanisms of alcoholic pancreatitis mentioned are emerging, and the links between these factors are complex. Our current research has a limited understanding of the intricate mechanisms underlying this condition. What specific factors increase susceptibility to alcoholic pancreatitis? The complex pathways involved, as well as the specific mechanisms of gene mutation, remain unanswered questions. Furthermore, most experiments are based on animal models, and there is a lack of studies involving humans. The settings of these animal models are still refined, indicating that more experimental work and clinical studies are necessary to ascertain the validity and scientific basis of these mechanisms and events. However, it is evident that ethanol increases the pancreas's sensitive to damage. Efforts to better understand the mechanisms by which alcohol disrupts normal pancreatic function will aid in treating the disease and mitigating its severity.

Fig. 1.

Mechanisms contributing to alcoholic pancreatitis.

Fig. 1.

Mechanisms contributing to alcoholic pancreatitis.

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The authors have no conflict of interest.

This research did not receive any funding or grants.

Qing Zhang and Xiaoping Tan designed the study. Hanhui Li and Jie Li collected literature. Hanhui Li is the main writer, and Li Jie is responsible for revising the manuscript. Li Jie and Qing Zhang were responsible for the final revision of the manuscript. All reviewers reviewed the manuscript.

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