Hypertriglyceridemic pancreatitis: perspectives from China

Abstract

Purpose of review

This review aims to summarize the recent developments in hypertriglyceridemic acute pancreatitis (HTG-AP) research in China, focusing on its increasing prevalence, pathophysiology, prognosis, and novel treatment strategies, emphasizing the relevance of these findings in clinical practice and research.

Recent findings

Recent studies have highlighted a rising incidence of HTG-AP in China, especially among young males, linked to dietary and lifestyle changes. Key research has identified lipoprotein metabolism abnormalities and genetic factors as predictors of recurrence. Advances in treatment include the combination of low-molecular-weight heparin, insulin, and plasma exchange, showing improved outcomes compared to traditional methods. Additionally, the use of traditional Chinese medicine has shown promise in managing inflammation and improving patient recovery.

Summary

These findings emphasize the importance of early diagnosis, personalized treatment strategies, and integrated approaches in managing HTG-AP. Chinese research has made significant strides in understanding the pathophysiology and treatment of HTG-AP, which may influence both national healthcare strategies and global management of the condition.

INTRODUCTION

Hypertriglyceridemic acute pancreatitis (HTG-AP) has emerged as a significant cause of acute pancreatitis globally, with a particularly rising prevalence in China [1,2]. It is closely associated with metabolic disorders such as obesity, diabetes, and hyperlipidemia, reflecting broader shifts in dietary habits and lifestyle patterns [3,4]. Compared to other causes, HTG-AP presents distinct clinical features, including a higher risk of severe disease, organ failure, and recurrence [5–7].

Recent research in China has focused on the epidemiological trends, pathophysiology, genetic predispositions, and therapeutic strategies for HTG-AP. Advances in lipid metabolism studies and personalized risk assessment models have provided new insights into its progression and recurrence [8^▪,9^▪,10]. Moreover, the development of optimized treatment protocols, including the use of low-molecular-weight heparin (LMWH), insulin, plasma exchange, and traditional Chinese medicine (TCM), has expanded clinical management options[11^▪▪,12^▪]. 

Box 1.

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This review summarizes the latest findings from Chinese studies on HTG-AP, emphasizing its epidemiology, prognostic markers, underlying mechanisms, and evolving treatment strategies (Table 1). Understanding these advancements is crucial for improving patient outcomes and refining future clinical guidelines.

Table 1.

Key advances in Chinese HTG-AP hypertriglyceridemic acute pancreatitis research

Research direction	Representative finding	Key literature	Significance
Epidemiological trends	HTG-AP incidence increasing in China; HTG now a leading cause of AP in some regions	[17]	Raises awareness for targeted prevention as lifestyle changes drive disease prevalence
Early risk prediction	Development of early severity prediction models for HTG-AP	[22▪]	Enables identification of high-risk patients and prompt aggressive management
Genetic susceptibility	Identification of population-specific gene mutations (e.g. APOA5) associated with HTG-AP	[29▪]	Improves understanding of hereditary risk factors and informs personalized prevention strategies
Pathophysiology mechanisms	Discovery of novel inflammatory mechanisms (e.g. NETs, microbiota interplay) exacerbating HTG-AP	[33▪▪]	Reveals new therapeutic targets to mitigate pancreatic injury and inflammation
Combined therapy approach	Combined use of insulin, heparin, and plasmapheresis in acute HTG-AP management	[11▪▪]	Achieves faster triglyceride reduction and better short-term outcomes than standard therapy
TCM adjunct treatment	Use of traditional Chinese medicine (herbal decoctions) alongside standard care	[12▪]	Shows additional anti-inflammatory effects and potential to improve recovery and reduce recurrence

AP, acute pancreatitis; HTG, hypertriglyceride; HTG-AP, hypertriglyceridemic pancreatitis; NET, neutrophil extracellular trap; TCM, traditional Chinese medicine.

EPIDEMIOLOGICAL CHARACTERISTICS OF HYPERTRIGLYCERIDEMIC ACUTE PANCREATITIS IN CHINA

Acute pancreatitis is a digestive disorder primarily characterized by intense abdominal pain and elevated pancreatic enzyme levels [13]. HTG-AP is a recognized subtype of acute pancreatitis, defined by elevated serum triglycerides [14].

Recent studies have highlighted significant regional differences in the underlying causes of acute pancreatitis. In Western countries, such as the United States and Europe, biliary and alcohol-related factors dominate as the leading causes of pancreatitis [15]. However, in China, the proportion of HTG-AP among acute pancreatitis cases has been steadily increasing over the past decade. In certain regions, hypertriglyceride (HTG) has surpassed alcohol as the second most common etiology of acute pancreatitis, following gallstone disease [1,2]. This shift is likely attributable to evolving dietary habits, such as increased consumption of high-fat, high-calorie, and processed foods, alongside lifestyle changes like reduced physical activity and rising obesity rates, emphasizing the critical need to address HTG-AP within the Chinese population [3,4]. These trends reflect broader socio-economic changes, including rapid urbanization and the adoption of Western dietary patterns, which have altered traditional Chinese culinary practices.

Epidemiological data from China indicate that HTG-AP accounts for approximately 10–30% of all acute pancreatitis cases [5–7], with some regions, reporting incidence rates as high as 35.9% [16]. This condition is associated with elevated rates of complications, such as organ failure, systemic infections, and higher mortality compared to other acute pancreatitis subtypes [17,18].

HTG-AP patients in the Chinese population are predominantly young men [19], with a median age of approximately 39–40 years old. Studies consistently show that the male proportion ranges from 67 to 72%, significantly higher than women, and the patient age is generally lower than that of acute pancreatitis caused by other causes (such as gallstones or alcohol) [20]. This characteristic may be related to the higher metabolic risks among young Chinese males (e.g. high-fat diet, alcohol consumption, and metabolic syndrome), which lead to abnormally elevated serum triglyceride levels, increasing the incidence of HTG-AP.

Seasonal patterns are particularly striking in China, with a 2022 study documenting a significant surge in HTG-AP incidence during winter months and following major holidays like the Spring Festival [5]. This phenomenon is likely tied to the short-term cumulative effects of high-fat, high-calorie diets consumed during festive periods, often rich in fried foods, red meat, sugary desserts, and alcohol, which temporarily spike triglyceride levels [5]. Such patterns underscore the potential for targeted public health interventions, such as dietary education campaigns and community-based screening programs, particularly during these high-risk periods to mitigate incidence spikes.

Historical data suggest that HTG-AP incidence has risen from less than 5% in the 1990s to its current levels, paralleling China's economic boom and dietary shifts [21]. Collectively, these findings highlight the unique epidemiological profile of HTG-AP in China and the urgent need for region-specific prevention strategies, distinct from global norms heavily influenced by alcohol-related causes and less variable seasonal patterns.

PROGNOSTIC FACTORS AND RISK ASSESSMENT IN HYPERTRIGLYCERIDEMIC ACUTE PANCREATITIS

Recent studies in China emphasize that while elevated triglyceride levels are a critical trigger for HTG-AP, they do not independently predict disease severity with sufficient reliability. Instead, prognostic factors such as patient age, blood glucose levels, white blood cell count, and the presence of pleural effusion have emerged as more robust indicators of clinical outcome [8^▪]. A risk score model incorporating these variables, developed from a cohort of 919 patients across multiple Chinese hospitals, achieved an area under the curve (AUC) of 0.83, enabling early identification of high-risk individuals and guiding timely clinical interventions such as intensive monitoring or aggressive therapy [8^▪]. Moreover, Chinese researchers have underscored the importance of dynamic triglyceride monitoring over static measurements to capture disease progression more accurately. A retrospective analysis from Beijing Anzhen Hospital demonstrated that triglyceride levels measured 48 h after admission, alongside the ‘48 h TG reduction ratio’, effectively predict progression to SAP [2]. Specifically, a triglyceride level exceeding 7.8 mmol/l or a 48 h/0 h triglyceride reduction ratio above 37.7 signals an elevated risk of severe disease, offering clinicians a practical, time-sensitive tool for risk stratification and decision-making [2].

In a comprehensive study of hypertriglyceridemia-induced severe acute pancreatitis (HTG-SAP), clinical data from 266 patients identified C-reactive protein (CRP), lactate dehydrogenase (LDH), calcium levels (Ca²⁺), and ascites as independent predictors of HTG-SAP [8^▪]. The resulting prediction model boasted an AUC of 0.960, outperforming established international scores such as BISAP, modified CT severity index, Ranson score, and the Japanese severity score CT grade [8^▪]. This model's high accuracy, sensitivity, and practicality – owing to its reliance on routinely measured biomarkers – make it an asset for predicting HTG-SAP and facilitating timely interventions in at-risk patients, potentially reducing mortality and morbidity [8^▪]. Building on this, Yi et al. developed an innovative model incorporating neutrophils and apolipoproteins, achieving an AUC of 0.92, surpassing the United States-favored BISAP score (AUC 0.81) and reflecting China's focus on metabolic rather than inflammation-centric approaches, which may align more closely with its patient demographics [22^▪,23].

PATHOPHYSIOLOGY AND POTENTIAL THERAPEUTIC TARGETS OF HYPERTRIGLYCERIDEMIC ACUTE PANCREATITIS

Chinese research has significantly advanced the understanding of HTG-AP pathophysiology, uncovering a complex interplay of mechanisms that drive its onset and progression. Elevated triglyceride levels lead to the formation of chylomicron microemboli and free fatty acid (FFA) toxicity, which initiate pancreatic injury by obstructing microcirculation within pancreatic capillaries and causing direct cellular damage through lipotoxicity [24]. This triggers a cascade culminating in systemic inflammatory response syndrome (SIRS), which exacerbates the condition by amplifying local and systemic inflammation [25]. Multiple pathways contribute to HTG-AP, including lipid metabolism disorders, calcium signaling disruptions, inflammatory mediator storms, endoplasmic reticulum stress, autophagy dysregulation, mitochondrial dysfunction, and oxidative stress, each presenting potential therapeutic targets for mitigating disease severity [24,25].

Genetic susceptibility

Genetic factors are pivotal in HTG-AP susceptibility and progression. Variations in the APOE gene (e.g. APOE2/2) are strongly associated with disease risk and severity among Chinese HTG patients, impairing lipoprotein clearance [26]. A 2018 whole-genome sequencing study of severe HTG patients identified rare variants in genes such as LPL, APOC2, and LMF1, significantly elevating HTG-AP risk, with LPL variant carriers exhibiting an acute pancreatitis incidence rate of up to 30% because of defective triglyceride hydrolysis [27]. A 2022 case study detailed a 28-year-old female HTG-AP patient with variants in APOA5 (p.G185C, p.V153M), APOE (p.R176C), and CFTR (p.T1220I, p.R1453W, and p.V470M), with familial clustering suggesting inherited susceptibility across generations [28]. Liu et al. [29^▪] confirmed that APOA5 mutations are more prevalent in China than in Western cohorts, underscoring population-specific genetic risks that may explain higher HTG-AP rates.

Lipoprotein metabolism

A series of studies conducted by Chinese scholars in 2023 and 2024 have deeply explored the complex relationship between lipoprotein metabolism abnormalities and HTG-AP. These studies revealed several key findings: First, a retrospective analysis by Tang et al. [9^▪] involving 198 HTG-AP patients found that triglycerides, nonhigh-density lipoprotein, and apolipoprotein A1 were independent predictors of HTG-AP recurrence, emphasizing the importance of monitoring these lipid parameters for identifying high-risk patients. Secondly, a study by Li et al. [10] in a southeastern Chinese population identified specific mutations in the lipoprotein lipase (LPL) gene (e.g. p.Asp36Asn and p.Asp250Asn) that were significantly associated with the occurrence of HTG-AP, providing genetic markers for identifying high-risk individuals and offering potential strategies for future personalized treatment. Additionally, Liu et al. [30] found that blood glucose levels significantly influenced the clearance rate of serum triglycerides, suggesting that controlling blood glucose may help improve the condition in HTG-AP treatment. Finally, a multicenter prospective cohort study by Zhou et al. [31^▪] showed that rapid reduction in triglyceride levels might be associated with improved organ failure, providing evidence for clinicians to select the best triglyceride-lowering therapy. These studies collectively emphasize the importance of monitoring lipid metabolism, conducting genetic screening, and taking proactive therapeutic measures in the management of HTG-AP, offering important guidelines for the prevention and treatment of HTG-AP.

Inflammatory response

Inflammation plays a central role in amplifying HTG-AP severity. A 2023 study demonstrated that excessive FFA activates the NF-κB signaling pathway, releasing pro-inflammatory cytokines like IL-6 and TNF-α, with IL-6 levels in HTG-AP models tripling compared to controls, driving pancreatic necrosis and multiorgan dysfunction [32].

Gut microbiota dysbiosis

Emerging evidence points to gut microbiota dysbiosis as a key contributor. A reduction in Bacteroides uniformis abundance impairs taurine production, elevating IL-17 release and neutrophil extracellular trap (NET) formation, which aggravate pancreatic injury by enhancing local inflammation [33^▪▪]. Supplementation with B. uniformis or taurine inhibits NF-κB and IL-17 signaling, reducing NETs and alleviating damage, suggesting a novel therapeutic avenue that leverages microbiota modulation [33^▪▪,34].

Ferroptosis

Ferroptosis, driven by lipid peroxidation and oxidative stress, exacerbates pancreatic damage in HTG-AP. Ferroptosis markers (e.g. decreased GPX4, increased TFR1) are more pronounced in HTG-AP than in other acute pancreatitis subtypes, and inhibitors like liproxstatin-1 significantly reduce inflammation and necrosis, positioning ferroptosis as a promising target for intervention [35,36^▪]. Qiu et al. [25] emphasized microbiota's role, an area underexplored in Europe's alcohol-centric studies, highlighting China's unique mechanistic insights into HTG-AP pathogenesis.

RECENT ADVANCES IN TREATMENT STRATEGIES FOR HYPERTRIGLYCERIDEMIC ACUTE PANCREATITIS BY CHINESE RESEARCH TEAMS

Chinese researchers have prioritized optimizing HTG-AP management, focusing on both conventional and innovative treatment strategies to improve patient outcomes.

Lipid-lowering therapy optimization

Early and aggressive triglyceride reduction is critical for preventing SAP progression. A study combining LMWH, insulin, and plasma exchange achieved a 90.32% effective rate compared to 73.01% in controls receiving only LMWH and insulin (P < 0.001), accelerating triglyceride reduction, relieving abdominal pain, and shortening hospital stays without increased adverse effects [11^▪▪]. This approach leverages LMWH's anticoagulant properties, insulin's lipolysis suppression, and plasma exchange's rapid triglyceride clearance, offering a synergistic strategy.

Novel intervention strategies

TCM has emerged as a complementary approach. The ‘Qingyi Jiangzhi Decoction’, a herbal formula, enhances triglyceride reduction and improves outcomes in moderate-to-severe HTG-AP cases by modulating inflammatory pathways and promoting pancreatic repair [12^▪].

Personalized and early intervention

Predictive models incorporating triglyceride levels and non-HDL cholesterol enable early identification of high-risk patients, guiding tailored interventions such as intensified lipid-lowering therapy or nutritional support [37]. Zhou et al. in 2024, demonstrated that insulin-fibrate therapy reduced SAP incidence to 15% compared to 28% in controls, outperforming US conservative approaches (20%) by combining insulin's metabolic regulation with fibrates’ triglyceride-lowering effects [31^▪,38]. TCM's modulation of NF-κB contrasts with Western reliance on plasma exchange, reflecting China's adaptive and integrative strategies that blend Eastern and Western medical paradigms [12^▪,39]. These advances underscore a shift toward personalized, multifaceted treatment approaches tailored to China's HTG-AP population.

CONTROVERSY OF BLOOD PURIFICATION THERAPY IN HYPERTRIGLYCERIDEMIC ACUTE PANCREATITIS

Blood purification therapies, such as plasma exchange, are employed for severe hypertriglyceridemia (triglycerides >20 to 50 mmol/l) to rapidly remove pathogenic substances like chylomicrons and FFAs [26]. However, their efficacy remains contentious in both Chinese and international contexts. A multicenter prospective cohort study in China found no significant improvement in organ failure outcomes with plasma exchange, alongside a higher ICU admission rate, suggesting limited clinical benefit and increased resource demands that strain healthcare systems [40^▪▪]. In contrast, a study from Soochow University reported that combining LMWH, insulin, and plasma exchange enhanced triglyceride reduction and improved clinical scores, advocating for its use in select patients with extremely high triglyceride levels [41]. Wang et al. found plasma exchange reduced triglycerides by 65% within 24 h but failed to shorten organ failure duration, aligning with US studies reporting a modest 20% triglyceride reduction without broader clinical impact, raising questions about its utility beyond triglyceride lowering [42,43]. This discrepancy fuels global debates over plasma exchange's cost-effectiveness, optimal timing, and patient selection, with China's mixed results calling for refined criteria – such as targeting patients with triglycerides higher than 50 mmol/l and early SIRS – to maximize benefits [44]. International meta-analyses similarly question plasma exchange's routine application, urging further randomized controlled trials to resolve these uncertainties [39].

RECURRENCE RISK AND LONG-TERM MANAGEMENT IN HYPERTRIGLYCERIDEMIC ACUTE PANCREATITIS

HTG-AP exhibits a high recurrence rate, with up to 64.8% of patients experiencing relapse within 1 year, driven by persistently elevated triglyceride levels at discharge and during follow-up [45^▪]. Multivariable analysis identifies poor triglyceride control, a high comorbidity index (e.g. diabetes and hypertension), and inadequate follow-up care as independent risk factors, emphasizing the need for sustained lipid-lowering therapy and lifestyle modifications [45^▪]. Recurrent pancreatitis also heightens the risk of postacute pancreatitis diabetes mellitus (PAPDM), with affected patients showing a significantly elevated incidence due to repeated pancreatic injury [46]. Yang et al. reported that triglyceride levels exceeding 3.1 mmol/l 1-month postdischarge predict recurrence with an odds ratio of 10.3, surpassing US recurrence rates of 32%, where alcohol-related factors often dominate [46,47]. China's emphasis on metabolic management – integrating lipid-lowering agents like statins or fibrates with glycemic control via insulin or oral hypoglycemics – offers a distinct long-term approach, potentially more suited to its HTG-AP population than Western alcohol-centric models that prioritize abstinence and counseling [46,48].

CONCLUSION

HTG-AP has become a significant clinical concern in China, with its increasing prevalence linked to lifestyle and metabolic changes. Chinese research has made important strides in improving prognosis through dynamic triglyceride monitoring, predictive models, and an understanding of its pathophysiology. Treatment advancements include the combination of LMWH, insulin, and plasma exchange, showing improved outcomes in triglyceride reduction and clinical recovery. Additionally, TCM is emerging as a complementary approach, emphasizing integrative care. However, challenges remain, especially regarding the efficacy of blood purification therapies and the high recurrence rate. Continued research and region-specific strategies will be essential for refining treatment approaches and improving long-term patient outcomes in HTG-AP.

Acknowledgements

We acknowledge the contributions of all authors in the study development and execution.

This manuscript has been seen, reviewed, and approved by all contributing authors. Copyright Transfer form completed and signed by all listed authors.

Financial support and sponsorship

This research was funded by the National Key Research and Development Program of China (2024YFA0918504), Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (2024-RW320-01), National Natural Science Foundation of China (grant number 32170788, 82460135), Beijing Natural Science Foundation (grant number 7232123, 7244390, L248074), the National High Level Hospital Clinical Research Funding (grant number 2022- PUMCH-B-023).

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest