Background
Acute pancreatitis (AP) is a life-threatening inflammatory disease involving the pancreas as well as peripancreatic and even distant organs [
1]. The main causes of AP include biliary tract disease, alcohol abuse, congenital anomaly, drugs, etc. [
2]. In recent years, the relationship between hypertriglyceridemia (HTG) and AP has received widespread attention from scholars, and it is generally believed that blood triglyceride (TG) levels greater than 11.3 mmol/L can directly induce AP [
3,
4]. However, HTG-induced AP is uncommon, accounting for only 1-4% of AP cases. On the other hand, HTG is commonly present at the early stage of non-HTG-induced AP, such as acute biliary pancreatitis (ABP), and its clinical significance remains unclear.
It has been reported that more than 50% of non-HTG-induced AP patients demonstrate mild-to-moderate TG elevation [
5]. However, the relationship between the elevated TG level and severity of non-HTG-induced AP is not well documented. Some studies reported that when non-HTG-induced AP was accompanied by TG elevation, the disease course of AP shows a trend for aggravation; in particular, if the serum TG level is reduced under 5.65 mmol/L, the disease condition will be gradually stabilized and improved [
6-
8]. However, some other studies showed that an increased TG level might just represent a symptom associated with AP, and there is no significant relationship between an elevated TG level and the severity and prognosis of AP patients [
9]. This discrepancy may be due to the fact that the AP cases included in these studies were induced by different causes, and HTG might play different roles in AP cases induced by different causes.
Therefore, investigating the clinical significance of an elevated TG level in AP induced by a single homogeneous cause could more accurately illustrate the effects of mild-to-moderate HTG on the severity and prognosis of AP patients. As acute biliary pancreatitis (ABP) remains the main type of AP in China and many other countries, the current study focused on the clinical significance of HTG in ABP patients.
Discussion
In recent years, the relationship between HTG and AP has received widespread attention from scholars, and it is generally believed that a serum TG level >11.3 mmol/L can directly induce AP. However, despite the increasing incidence of AP induced by HTG, this type of AP is not the major type observed in clinical practice. The more common clinical situation is that non-HTG-induced AP patients were complicated with TG elevation, and it has been reported in the literature that approximately 50% of non-HTG-induced AP patients demonstrate mild-moderate TG elevation. However, there have been only limited numbers of studies on the significance of TG elevation in non-HTG induced pancreatitis, such as acute biliary pancreatitis (ABP), and the results were inconsistent.
It also remains controversial whether TG elevation is an associated etiological factor or a concomitant symptom in non-HTG induced AP patients. In alcoholic pancreatitis, alcohol can directly affect the metabolism of TG, causing elevated TG levels, and is therefore directly involved in the occurrence of pancreatitis. Thus, an elevated TG level can be seen as an associated etiological factor of alcoholic pancreatitis [
16], whereas it may be considered as concurrent symptom of biliary pancreatitis [
17]. In addition, the relationships between TG elevation and the severity and prognosis of AP, as reported in the literature, are also inconsistent. For example, studies have reported that when AP induced by non-HTG causes is complicated with TG elevation, the disease course of AP shows a trend for aggravation [
7,
8]. However, other studies show that an increased TG level may only represent a symptom associated with AP, as there is no significant relationship between TG level and the severity and prognosis of AP patients [
9]. The presence of these controversies is likely due to the analysis of different compositions of AP patient, including patients with biliary AP, alcoholic AP, cryptogenic AP, and AP due to other factors, as HTG is known to play different roles in AP caused by different factors.
Therefore, the study of the clinical significance of an elevated TG level in AP due to a single etiological factor could accurately illustrate the effects of mild-moderate HTG on AP disease condition and prognosis. Because biliary tract disease is a major cause of AP in China and other Eastern countries, we chose to study the effects of TG elevation on the disease condition and prognosis of patients with ABP. When selecting cases, we excluded patients with a history of hyperlipidemia and alcoholism, aiming to exclude cases with elevated TG levels before the onset of pancreatitis. During the occurrence of AP, due to the body’s stress response, serum catecholamine and glucagon levels, as well as lipase activity, are increased, leading to accelerated break down of fat tissue and the subsequent release of TG and increase in serum lipid concentrations [
18,
19]. In this study group, the incidence of SAP in ABP patients associated with elevated TG was significantly higher compared to that in patients without elevated TG; in addition, ABP patients with elevated TG levels also showed more severe pancreatic necrosis. These results may be due to the fact that elevated TG might lead to increased blood viscosity, which further promotes blood circulation disorders of the pancreas. In addition, large quantities of free fatty acids released from TG breakdown damage the pancreatic acinar cells and capillaries, leading to a higher likelihood of SAP [
20,
21]. Furthermore, this result might also be related to the participation of cholecystokinin, as some studies have shown that in the presence of TG elevation, free fatty acids produced in the body can strengthen the stimulation of cholecystokinin on the excretion function of pancreatic acinar cells, which subsequently activates the endoplasmic reticulum stress phenomenon and thereby damages pancreatic acinar cells [
22].
This study also found that ABP patients with elevated TG levels were more prone to organ failure, particularly respiratory failure. In the AP disease course, respiratory complications primarily include hypoxemia, acute respiratory distress syndrome, atelectasis, and pleural effusion. Respiratory failure is largely due to the large number of toxic cytokines produced during the AP disease course, mainly including platelet-activating factor, TNF-α, IL-1, IL-6, IL-8, NO, P substance, and macrophage-secreted cytokines, which can cause systemic inflammatory response syndrome and respiratory dysfunction. The reason why ABP patients with elevated TG levels were more likely to experience respiratory failure is related to the functions of free fatty acids. In the presence of elevated TG, serum TG is broken down under the action of lipoprotein lipase in the lung, leading to the production of large quantities of free fatty acids. Subsequently, free fatty acids dissociate from albumin in the blood, enter the alveolar capillary membrane, and destruct the pulmonary blood microcirculation, leading to respiratory failure [
23,
24].
It remains unclear why some ABP patients show elevated TG levels while others have normal TG levels, and why the degree of elevated TG varies among patients. We believe that this difference may be related to a number of factors. First, the local or whole body fat distribution of patients may be associated with elevated TG levels and the degree of such elevation. When the body has high levels of fat, under the same level of stress and level of lipase activity, the amount of involved fat tissue is increased, and the amount of TG release is increased. In the present study, the BMI of ABP patients with elevated TG levels was significantly higher than that in patients with normal TG levels. Indeed, previous studies have shown that obesity is closely associated with AP aggravation, and some scholars have suggested that obesity should be considered an independent risk factor of AP aggravation, which is consistent with the results of this study. In addition, in recent years, some scholars have found that genetic polymorphisms are associated with the pathogenesis of AP with HTG [
25]. For example, Chang and his colleagues [
26] first reported that in HTG-induced AP patients, lipoprotein lipase gene mutation was significantly increased, and the probability of AP was 77.8% in patients with hyperlipidemia caused by the mutation in this gene. In short, there may be a mutually reinforcing cycle between elevated TG levels and pancreatitis, such that the occurrence of pancreatitis leads to elevated TG levels, which further increase the severity of pancreatitis. This cycle may represent another important vicious cycles in AP pathogenesis, and timely blockade of this cycle may hold important significance for reducing the degree of AP aggravation and improving the efficacy and prognosis for patients with SAP.
The general treatment protocol of ABP was similar to AP induced by other causes. At the outset, all patients were treated in a conservative manner, and subsequently so-called step-up approach was carried out [
27,
28]. Meanwhile, ERCP and EST were selectively performed in some ABP patients, especially for patients with jaundice and cholangitis. However, there were still controversies on the indications and outcomes of ERCP and EST in ABP treatment [
29,
30]. In the current study, no significant difference of the frequencies of ERCP/EST was observed between normal TG group and elevated TG group. For patients with MSAP/SAP, the frequencies of ERCP/EST were also not significantly different between normal TG group and elevated TG group, but more patients in elevated TG group underwent PCD and open necrosectomy. These results indicated that the ABP patients with TG elevation might be liable to undergo PCD and open necrosectomy. However, as the patients were divided into two groups according to the highest TG level within 72 h of disease onset, we presumed that the raised TG level might be responsible for the liability of PCD and open necrosectomy.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LC contributed to the design of the study and direction of its implementation. FZT and LJT conceived and designed the experiments and supervision of the field activities. LC and ZLL carried out the prepared the Materials of patient and prepared the literature review as well as the Discussion sections of the text. JDR, KX and ZH conducted the data analysis. All authors read and approved the final version of the manuscript.