Predictive value of adipokines for the severity of acute pancreatitis: a meta-analysis

Acute pancreatitis (AP) is a common gastroenterological condition, with approximately 80% of patients developing mild to moderately severe disease (no organ failure > 48 h) and the rest progressing into severe acute pancreatitis (SAP) [1]. The death rate of SAP is as high as 20%, therefore, early assessment of severity in AP is crucial. Despite the large number of studies exploring early prediction of AP severity [2, 3], no ideal multifactorial scoring system and/or biochemical markers have been identified for early assessment of AP severity [4]. Therefore, early identification of the development of severe AP remains a great challenge.

In clinical studies, the components of metabolic syndrome have been found to be associated with the occurrence and deterioration of AP [5, 6]. In particular, obesity is an independent risk factor for the AP morbidity and mortality [7‐10]. Depending on its location, adipose tissue can be divided into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). SAT, accounting for approximately 80% of all adipose tissue, acts as a reservoir for excess lipids. However, once the storage capacity is exceeded, which can only accommodate a limited number of adipocytes with limited expandability, fat begins to accumulate in areas outside the SAT, such as the liver, heart, skeletal muscles, and other sites [11, 12]. Numerous studies have shown that VAT, associated with the occurrence and development of AP [13‐15], is a key site of inflammation and responsible for driving the systemic inflammatory response and exacerbating AP [16, 17], thus serving as an important prognostic indicator of AP severity. Being highly metabolically active, VAT can continuously release adipokines such as resistin, leptin, adiponectin, and visfatin into the portal circulation [18], which may involve in the development and progression of AP by modulating oxidative stress and inflammatory responses and influencing the severity of AP. Furthermore, resistin, leptin, adiponectin, and visfatin are well-known biomarkers for Nonalcoholic Fatty Liver Disease (NAFLD), which is a strong risk factor for AP and SAP.

Resistin has been found to increase the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in mononuclear cells and macrophages [19, 20]. Additionally, it stimulates the production of cell adhesion molecules, including vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein (MCP)-1, as well as chemokine (C-C motif) ligand 2 (CCL 2), which contribute to chemotaxis and leukocyte recruitment to sites of inflammation [21, 22]. Leptin, which is mainly secreted by adipocytes, is a potent chemoattractant for immune cells, causing monocytes and macrophages to accumulate towards adipose tissue, and promoting increased expression of the inflammatory cytokines IL-6 and tumor necrosis factor (TNF) as well as toll-like receptor 4 (TLR4) [23]. At the same time, leptin is required for T-cell development and promotes the production of pro-inflammatory cytokines in CD4[+] T cells [24‐26]. Adiponectin, a hormone mainly produced by white adipose tissue, can inhibit M1 macrophage activation [27, 28], exert anti-inflammatory effects by regulating JmJC family histone demethylase 3, which contributes to M2 polarization [29], and inhibit macrophage infiltration [30]. In animal studies, adiponectin-deficient mice exhibited more severe AP than wild-type mice, and adiponectin overexpression reduced the severity of AP [31]. Administration of exogenous recombinant adiponectin to AP mice significantly reduced NF-kB activity, cytokine levels, and tissue damage [32]. Visfatin has nicotinamide phosphoribose transferase (Nampt) activity, the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage synthesis pathway, and macrophages rely on the NAD salvage pathway to meet their energy requirements and maintain their pro-inflammatory phenotype. Visfatin also promotes the release of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α from peripheral monocytes [33‐35].

Despite many studies that have explored the relationship between adipokines and SAP, the findings have been inconsistent. Furthermore, even though a meta-analysis of the relationship between adipokines and SAP has recently been published [36], it only examined the statistical correlation between resistin and SAP, without addressing the correlation between other adipokines and SAP. Therefore, we performed this meta-analysis, involving such adipokines as resistin, leptin, adiponectin, and visfatin, to explore the correlation between adipokines and SAP.

This study was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.

The results of this meta-analysis showed that increased resistin levels were associated with SAP, whereas leptin and adiponectin levels were not linked to SAP. Only three of the studies included visfatin, not enough to draw any conclusions.

Resistin is a small protein rich in cysteine, with a molecular weight of either 11 or 12.5 kDa. It was first identified in mice in 2001 as a signal molecule produced by adipocytes, and named resistin because it was thought to be involved in the development of insulin resistance [37]. Resistin belongs to the resistin-like molecule (RELM) family, which includes RELM-α, RELM-β, and RELM-γ [38]. Unlike mice, where resistin is produced by adipocytes, humans mainly express resistin in monocytes and macrophages [39]. Despite only sharing 59% of the same amino acids [40], resistin functions similarly in both humans and rodents, even though they are produced from different sources. Resistin has been identified as a molecule that promotes inflammation and regulates various chronic inflammatory, metabolic, and infectious diseases in humans [41‐44]. It modulates many cellular responses in the host, such as recruiting and activating immune cells, promoting the release of pro-inflammatory cytokines, enhancing interferon (IFN) expression, and promoting the formation of neutrophil extracellular trap networks (NETs) [45‐47].

The role of resistin in regulating inflammatory pathways has been demonstrated in the context of AP. Resistin increases the levels of calcium in pancreatic follicular cells, as well as the activity of NADPH oxidase, leading to an increase in the production of reactive oxygen species (ROS) within the cells. Additionally, resistin activates the NF-κB pathway, resulting in the expression of pro-inflammatory cytokines such as TNF-α and IL-6 [48, 49]. Jiang et al. demonstrated in a laboratory model of AP induced by cerulein that resistin increases the production of pro-inflammatory cytokines TNF-α and IL-6 via an NF-κB-dependent pathway. However, the increased mRNA expression levels of TNF α and IL 6 induced by resistin can be significantly reduced by using an NF-κB inhibitor [50]. Furthermore, Wang et al. discovered that the severity of SAP lung injury was positively associated with RELMα levels. Moreover, overexpression of RELMα worsened the release of inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and serum C-reactive protein. This led to an increase in the expression of inflammatory mediators such as phosphorylated (p)-AKT, p-P65, p-P38 mitogen activated protein kinase, p-extracellular regulated kinase, and intracellular adhesion molecule-1, ultimately resulting in lung injury. On the other hand, knocking down RELMα had the opposite effect. It improved the expression of proliferative cellular nuclear antigen, Bcl-2, zonal occludin-1, and Claudin-1 in lung tissue of SAP rats [51]. Furthermore, numerous studies have confirmed the correlation between resistin and the severity of AP. This suggests that resistin may serve as a valuable marker and potential therapeutic target for SAP [52].

Leptin is mainly secreted by fat cells and plays a crucial role in the immune response as an immune modulator [53, 54]. Monocytes treated with leptin increase the production of type 1 cytokines, including IL-1β, IL-6, TNF, and resistin [55, 56]. Adiponectin can inhibit the ROS/NF-κB/NLRP3 inflammatory pathway [57], activate the anti-inflammatory cytokine interleukin-10 (IL-10), and reduce pro-inflammatory cytokines such as interferon-gamma (IFN-γ), IL-6 and TNF-α in human macrophages [58]. The results of this meta-analysis showed that leptin and adiponectin levels were not linked to SAP. However, it is still unclear whether leptin and adiponectin have different effects at different stages of inflammation, or whether an imbalance among leptin, adiponectin and other adipokines may inhibit their regulation of the immune response, or whether there are other possible mechanisms, which need to be confirmed by more studies. Although most studies show that visfatin appears to have pro-inflammatory effects [33‐35, 59‐62], there are some studies that show the opposite [29, 30, 63]. In response to this seemingly contradictory result, the study by Sayers et al. may give us some insight. They found a possible bimodal effect of extracellular Nampt (eNampt) monomer on the stimulation of insulin secretion by β-cells [64]. Whether this bimodal effect is equally reflected in the stimulatory effect of endolipin on inflammatory factors and the modulation of the inflammatory response, and whether it is this bimodal effect that leads to the unstable prediction of SAP by visfatin, remain to be further explored.

Heterogeneity was observed in our pooled analysis. The resistin results were greatly influenced by two studies, while the leptin results were mainly affected by one study. Several factors such as regions, research samples, and detection reagents can affect the outcomes. Small sample sizes can also lead to accidental findings, making heterogeneity between studies inevitable. However, the stability of the results was confirmed even after removing the heterogeneous studies. Furthermore, sample size and mean age of the patients may be associated with resistin heterogeneity. It has been shown that the adverse effects of obesity appear to be reduced in older populations [65]. Khatua et al. suggested that the different visceral triglyceride saturation status could have varying effects on AP severity, explaining the obesity paradox [66]. Based on the results of the subgroup analysis in this meta-analysis, it appears that the mean age of patients has an effect on adiposity factors and resultantly affects AP severity, which may provide a new thought for the obesity paradox.

There are some limitations to this meta-analysis. Firstly, all studies included were case-control studies with inherent selection, information and confounding biases. Secondly, the sample size was moderate for the included studies and a few of the eligible studies had small sample sizes. Thirdly, changes in testing methods and diagnostic criteria over time may have contributed to the different pooled results between publication years in the subgroup analysis.

In conclusion, the results of this meta-analysis suggest high levels of resistin levels are associated with an increased risk of SAP, indicating resistin may be a potential biomarker. Moreover, serum or plasma samples can be easily obtained for resistin detection, and the assay is uncomplicated and can be performed in many laboratories. Since it is often challenging for a single indicator to accurately predict the severity of AP, it may be possible in the future to predict SAP by testing for the levels of resistin in conjunction with other indicators or by incorporating resistin into a scoring system.