Acute pancreatitis (AP) is an inflammatory disease characterized by abnormal activation of pancreatic digestive enzymes, with varying etiologies, that exert digestive effects on the pancreas and peripheral organs. AP mainly manifests as local or systemic inflammation, and its incidence has been steadily increasing worldwide (1). According to the Atlanta classification system, AP can be classified as mild AP (MAP), moderately severe AP (MSAP), or severe AP (SAP) (2, 3). Patients with MAP present with mild symptoms, a short disease course of 1 week, and self-limiting attacks. Approximately 20% of cases progress to SAP, with persistent organ failure (POF), which is the main cause of death in patients with SAP. Considering that the mortality rate of SAP is approximately 20%–40%, early intervention and prediction of AP aggravation are of utmost importance (4–6).

To assess the severity of AP and for early prediction of AP, the Ranson criteria, Acute Physiology and Chronic Health Evaluation II score, bedside index for severity in acute pancreatitis, and Balthazar grades have been reported (7–10). However, scoring is relatively complex and of lower practicality in clinical practice, thereby necessitating simple hematological indicators for predicting AP progression. Procalcitonin (PCT) level, interleukin-6 (IL-6) level, white blood cell (WBC) count, and macrophage migration inhibitory factor level have been successively identified as indicators of AP progression and have shown promising results in small sample size studies, but the effectiveness and practicality of these indicators remain to be explored (11–13). High-density lipoprotein cholesterol (HDL-C), mainly secreted by the liver and small intestine, plays an important role in maintaining cholesterol homeostasis. The relationship between HDL-C level and the occurrence of cardiovascular disease has been widely demonstrated (14, 15). HDLs participate in the immune response of the body via their ability to modulate cholesterol bioavailability in immune cells (16). Therefore, they serve an indispensable role in inhibiting the inflammatory response (17). HDL-C also inhibits the expression of adhesion molecules by transferring miR223 to receptor endothelial cells, thereby achieving anti-infection effects. miR223 is the most abundant miRNA in monocytes and macrophages and plays a key role in the regulation of the inflammatory response (18, 19).

Many recent studies have reported the relationships of HDL-C level with POF and the severity of AP (20–26). However, most of them have focused on HDL-C level within 24 h of admission for the prediction of AP-related patient condition rather than exploring the relationship between subsequent changes in HDL-C level and the occurrence of SAP. Therefore, the present study aimed to investigate the relationship between the lowest HDL-C level of patients with AP during intensive care units (ICU) stay and the progression to SAP and to determine the predictive value of the lowest HDL-C level for AP aggravation.

The study results indicate that HDL-C level higher than the lowest HDL-C level during ICU stay was an independent protective factor for the progression of MSAP to SAP in patients admitted to the ICU. The lowest HDL-C level was negatively correlated with progression to SAP, and an increase of 1 unit in the lowest HDL-C level caused a 0.897-fold change in the probability of progression to SAP. Among different lowest HDL-C levels, patients with lower HDL-C levels have a higher probability of developing SAP, and the incidence rate in the >1.00 mmol/L level is higher than that in the 0.76-1.00 mmol/L level. The reason for this deviation may be attributed to the limited number of patients included, especially in the >1.00 mmol/L range and the 0.76-1.00 mmol/L range. The optimum cutoff lowest HDL-C level for the prediction of progression to SAP was 0.545 mmol/L.

HDL-C is mainly synthesized in the liver and plays a key role in mediating the transport of cholesterol from surrounding tissues to the liver. It also exerts antioxidant, pro-fibrinolytic, and anti-thrombotic effects. A possible mechanism of the negative correlation between the lowest HDL-C level and the progression to SAP is as follows: progression of AP is closely associated with the systemic inflammatory response syndrome (28, 29); when inflammation occurs, the ability of HDL-C to neutralize toxic substances leads to the binding of massive amounts of endotoxins to HDL-C, thereby decreasing the HDL-C level (16, 30). In addition, the inflammatory cytokines IL-6 and tumor necrosis factor-α can inhibit HDL-C synthesis, whereas the acute phase protein secretory phospholipase A2 can accelerate HDL-C degradation (20). HDL-C also participates in innate immunity through innate host defense activity and regulates the participation of miR223 in the anti-infection process at the genetic level by transferring miR223 to receptor endothelial cells, which inhibits the expression of adhesive molecules (18, 19). Research has shown that inhibiting the NLRP3/Caspase-1 signaling pathway can alleviate pyroptosis and inflammatory response in hyperlipidemic pancreatitis models (31). HDL can decrease the expression of NLRP3 and its downstream inflammatory cytokines (32). Therefore, HDL may alleviate pyroptosis and inflammatory response in hyperlipidemic pancreatitis models by inhibiting the NLRP3/Caspase-1 signaling pathway. Studies have shown that activating the NRF2/HO-1-mediated ferroptosis pathway can improve acute pancreatitis, while oxidative stress damage and reduced expression of HDL can accompany the inhibition of the Nrf2/HO-1 pathway (33, 34). Therefore, HDL may alleviate acute pancreatitis by activating the NRF2/HO-1-mediated ferroptosis pathway. Studies have shown that the severity of acute pancreatitis can be improved by inhibiting the PI3K/Akt pathway (35). Inhibiting scavenger receptor class B type I (SR-BI) is sufficient to cause apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling (36). SR-BI is a versatile HDL receptor protein (37). Therefore, HDL may improve the severity of acute pancreatitis by inhibiting the PI3K/Akt pathway.

A study by Peng et al. involving 66 patients in the ICU revealed that the HDL-C level measured at ICU admission was predictive of the occurrence of POF and was negatively correlated with disease severity (24). However, the present study involved a larger number of patients and adopted a wider variety of hematological indicators as covariances, which would lead to greater accuracy in the multivariate analysis results. In another case–control study on the relationship between HDL-C level and severe pancreatitis by Li et al., the HDL-C level within 24 h of hospital admission was negatively correlated with the severity of pancreatitis (20). However, the aforementioned studies merely focused on the relationship between HDL-C level at hospital admission and SAP, without investigating the subsequent changes in HDL-C level during hospital stay.

Our study has the following advantages over these previous studies: (1) a larger number of hematological indicators included in the multivariate analysis; (2) indicator data not limited to the values obtained at hospital admission and consideration of the effects of subsequent changes in indicator values on the analysis results; and (3) a larger number of patients with severe disease included as subjects.

This study also has some limitations. First, it was a single-center study. Second, the study excluded patients with MAP, which may lead to the inapplicability of the study findings to patients with MAP. Therefore, further prospective studies with a larger sample size are required for validation of our results.

The lowest HDL-C level may be an independent predictor of progression to SAP in patients with AP admitted to the ICU. The univariate analysis revealed a negative correlation of the lowest HDL-C level with progression to SAP, and multivariate analysis revealed that HDL-C level was an independent protective factor for the aggravation of AP. The lowest HDL-C level may provide clinical guidance for the prediction of SAP onset and development, with an optimum cutoff lowest HDL-C level of 0.545 mmol/L. Considering the lack of research on the relationship between the lowest HDL-C level and SAP, further prospective studies are required for validation of our findings.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the Ethics Committee of Shandong Provincial Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The Ethics Committee waived the requirement of obtaining informed consent because of the retrospective study design.

QN: Investigation, Methodology, Writing review & editing, Conceptualization. ZY: Writing-original draft, Data curation. PZ: Data curation, Methodology. HJ: Writing review & editing. FL: Investigation, Methodology, Conceptualization. HC: Investigation, Conceptualization, Methodology, Supervision. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors contributed to the article and approved the submitted version.