Plasmapheresis in Hypertriglyceridemia‐Associated Acute Pancreatitis: Triglyceride Levels of 5000 mg/dL as a Proposed Threshold

ABSTRACT

Severe hypertriglyceridemia‐associated acute pancreatitis is a disease with a high mortality rate, and high triglyceride (TG) levels increase the severity of the disease. Standard treatments include fasting, insulin, and heparin therapy. In severe cases, plasmapheresis such as therapeutic plasma exchange or double filtration plasmapheresis is performed to rapidly lower TG levels. However, studies comparing plasmapheresis with standard treatment have shown inconsistent results regarding its effectiveness, and the usefulness of plasmapheresis remains controversial. The author hypothesized that plasmapheresis would be effective in cases where baseline TG levels are very high and cannot be managed with standard treatment and investigated relevant clinical articles. On April 14, 2026, a literature search in PubMed was performed using the following search queries ((((“acute pancreatitis” [All Fields]) AND (((((“plasma exchange” [All Fields]) OR (“blood purification” [All Fields])) OR (“plasmapheresis” [All Fields])) OR (“double filtration” [All Fields])) OR (“double‐filtration” [All Fields]))) AND (“hasabstract” [text])) AND (“English” [lang])) AND (2015/01:2026/03 [dp]). Thirteen comparative studies and one single‐arm study were selected. Two out of 12 comparative studies with TG levels below 5000 mg/dL showed clinical effectiveness of plasmapheresis, while the other 10 comparative studies showed no clinical effectiveness. In two clinical studies where TG levels exceed 5000 mg/dL, both studies demonstrated the clinical effectiveness of plasmapheresis. One comparative study involving patients with TG levels exceeding 5000 mg/dL showed that the group receiving plasmapheresis had significantly fewer complications and significantly shorter hospital stays. In another single‐arm study, patients were divided into three groups based on the time from diagnosis to the first plasmapheresis administration. The results showed that the group that started apheresis treatment early had a significantly lower incidence of persistent organ failures. In HTG‐AP, plasmapheresis is considered effective when TG levels exceed 5000 mg/dL. However, as the evidence is limited, further research is needed to clarify this hypothesis.

1. Introduction

Acute pancreatitis (AP) is a serious disease with a high mortality rate. The most common causes are alcoholic and gallstones, and hypertriglyceridemia is the third most common cause. When triglyceride (TG) levels exceed 1000 mg/dL (11.3 mmol/L), the risk of developing AP increases. One hypothetical mechanism of hypertriglyceridemia‐associated acute pancreatitis (HTG‐AP) is that pancreatic lipase hydrolyzes excess TG to produce free fatty acids, which are toxic to acinar cells and vascular endothelium [1]. A TG level of 500 mg/dL or higher is considered “very high” [2]. Severe disease conditions are correlated with high TG levels. Standard treatments include fasting, insulin therapy, and heparin therapy. In severe cases, plasmapheresis, such as therapeutic plasma exchange (TPE) or double filtration plasmapheresis (DFPP), is performed to rapidly lower the TG levels. Several comparative studies have been reported comparing “with plasmapheresis” and “without plasmapheresis”. The results regarding the clinical effectiveness of plasmapheresis are inconsistent. Therefore, the 2023 American Society for Apheresis (ASFA) guidelines classify HTG‐AP as a Category III (Optimum role of apheresis therapy is not established. Decision‐making should be individualized), Grade 1C indication for TPE [3]. The Japanese Society for Apheresis (JSFA) clinical practice guideline for therapeutic apheresis classifies HTG‐AP as a Category III, Grade 2C indication for TPE [4]. As the severity of HTG‐AP correlates with TG levels, the author hypothesized that plasmapheresis is necessary when TG levels are too high to be managed with standard treatment alone and investigated the relationship between baseline TG levels and the clinical effectiveness of plasmapheresis.

2. Materials and Methods

2.1. Literature Search Strategy

On April 14, 2026, a literature search in PubMed was performed using the following search queries. The search period was limited from January 2015 to March 2026, and the language was limited to English.

((((“acute pancreatitis” [All Fields]) AND (((((“plasma exchange” [All Fields]) OR (“blood purification” [All Fields])) OR (“plasmapheresis” [All Fields])) OR (“double filtration” [All Fields])) OR (“double‐filtration” [All Fields]))) AND (“hasabstract” [text])) AND (“English” [lang])) AND (2015/01:2026/03 [dp]).

A literature search yielded 399 clinical study articles. All the abstracts were reviewed and selected articles on the clinical effectiveness in HTG‐AP. These include comparative studies of “with plasmapheresis” and “without plasmapheresis”, as well as studies of plasmapheresis single‐arm that contain important clinical information. Studies that did not mention TG levels and studies that did not evaluate clinical outcomes were excluded. Modalities of plasmapheresis were limited to TPE or DFPP. Figure 1 is a flow diagram of the literature screening and assessing. Fourteen relevant articles were selected.

FIGURE 1.

Literature screening and assessing flow diagram.

2.2. Ethics Committee Approval, Informed Consent

The contents in this article are based on citations from published clinical articles. Ethics committee approval and informed consent are not applicable.

2.3. Statistical Analysis

No statistical analysis was performed.

3. Results

3.1. Threshold of TG Levels

From among 399 articles, 14 articles (13 comparative studies and one single‐arm study) were selected as relevant articles. Table 1 shows summaries of each article. When the TG concentration was expressed in mmol/L, it was converted to mg/dL by dividing by 0.0113. When baseline TG levels were examined in 14 selected articles, the results of 12 comparative studies were inconsistent, where TG levels were below 5000 mg/dL. TG levels of 12 comparative studies ranged from 1524 to 4484 mg/dL [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. The weighted mean TG levels of all patients in those 12 studies were approximately 2390 mg/dL. Since TG level of 500 mg/dL or higher is considered “very high”, plasmapheresis has been used on patients with “extremely high” TG levels of 2390 mg/dL. Although plasmapheresis has been used on patients with “extremely high” TG levels, study results were inconsistent. Meanwhile, in the two articles (one comparative study and one single‐arm study) where TG levels exceed 5000 mg/dL, plasmapheresis was effective in both studies. Therefore, in subsequent analysis, the clinical effectiveness was investigated at thresholds of TG levels of 5000 mg/dL to determine whether plasmapheresis was necessary.

TABLE 1.

Characteristics of included 14 articles.

Ref. no.	Author	Year	Country	Modality	Study design	n Baseline TG with plasmapheresis mg/dL (mmol/L)	n Baseline TG w/o plasmapheresis mg/dL (mmol/L)	Outcome
5	Staudacher	2025	Germany	TPE	PSM retrospective cohort study TPE group: patients with at least one TPE Non‐TPE group: all other patients	60 3636	60 3960	TPE was not associated with a better clinical outcome (inhospital mortality and organ failure).
6	Amin	2025	USA	TPE	PSM retrospective cohort study using TriNetX database TPE group: underwent TPE within 3 days of diagnosis Non‐TPE group: did not undergo TPE within 30 days of diagnosis	412 2455	412 2139	TPE does not significantly reduce the risk of end‐organ damage or mortality.
7	Zhen	2025	China	TPE	RCT TPE group: received LMWH, insulin, and TPE Non‐TPE group: received LMWH and insulin	62 1991 (22.5)	63 2079 (23.5)	TPE group demonstrated a significantly higher total effective rate (Defined as proportion of patients showing significant clinical improvement).
8	Qin	2025	China	DFPP	Retrospective study DFPP group: In addition to standard pharmacotherapy, patients underwent DFPP Non‐DFPP group: Patients were primarily treated with fenofibrate, and some received LMWH or insulin once contraindications were excluded.	49 1806 (20.41)	48 1524 (17.23)	DFPP can significantly improve short‐term outcomes, reduce lipid levels, and reduce the incidence of complications such as SIRS.
9	Wang	2024	China	TPE/DFPP	Cohort of patients from a multicenter, prospective, long‐running registry TPE/DFPP group: underwent TPE/DFPP Non‐TPE/DFPP group: received medical treatment	46 2659 (30.05)	76 1846 (20.87)	There was no significant difference in time to organ failure resolution.
10	Zheng	2024	China	TPE	PSM retrospective cohort study TPE group: treated with TPE Non‐TPE group: treated without TPE	116 1576 (17.81)	78 1530 (17.29)	No differences were found in early stage CTSI improvement rate, local complications or mortality between two groups.
11	Su	2023	China	DFPP	Retrospective study Comparisons across tertiles of the interval from diagnosis to completion of one DFPP session (DTD) were analyzed.	89 5159 (58.3)	N/A	DTD were analyzed. The RCS curves displayed a nonlinear relationship between DTD time and the risk of POF. The risk of POF was relatively low and flat until approximately 15 h of DTD time and then started to increase rapidly afterwards.
12	Cao	2023	China	TPE/DFPP	Multicenter prospective cohort study TPE/DFPP group: underwent TPE/DFPP Non‐TPE/DFPP group: treated with conventional medical treatment	47 2053 (23.2)	47 2168 (24.5)	No difference was detected concerning organ failure–free days between patients undergoing plasmapheresis or not.
13	Lin	2022	China	TPE	PSM retrospective study TPE group: treated with conventional treatment and TPE Non‐TPE group: treated with conventional treatment	42 2456 (27.76)	42 2341 (26.46)	There was no significant difference in incidences of complications, and MODS; organ support treatment; surgical rate; mortality; and hospital stay between the groups.
14	Araz	2022	Turkey	TPE/DFPP	Cross‐sectional retrospective study	19 4484	29 1935	Prognosis did not significantly differ between groups.
15	Gubensek	2022	Slovenia	TPE	Randomized, parallel group study	11 2743 (31)	11 2300 (26)	There was no significant difference, but only a trend toward a greater decrease in triglycerides with PE, and the clinical course was also comparable.
16	Webb	2021	USA	TPE	Retrospectively examined clinical data	16 4406	51 4406	When excluding patients with hospital courses complicated by multiple organ dysfunction, there was no significant difference in mortality or hospital length of stay (LOS) between the groups.
17	Lu	2020	China	DFPP	PSM retrospective cohort study DFPP group: treated with DFPP Non‐DFPP group: treated without DFPP	50 3513 (39.7)	50 2752 (31.1)	No differences were found in terms of the majority of the clinical outcomes between the two groups, including persistent organ failure, local complications, hospital stay, and in‐hospital mortality.
18	Chang	2016	Taiwan	DFPP	Nested case–control study DFPP group: treated with DFPP Non‐DFPP group: treated without DFPP	11 16 179	14 8492	When applied to serum TG in excess of 5000 mg/dL, the major complication rate was lower in DFPP group (p < 0.001), and the duration of hospital admission was shorter (p = 0.012).

Abbreviations: CTSI, CT severity index; DFPP, double filtration plasmapheresis; LMWH, low molecular weight heparin; MODS, multiple organ dysfunction syndrome; N/A, not applicable; POF, persistent organ failure; PSM, propensity score matched; RCS, restricted cubic splines; RCT, randomized controlled trial; SIRS, systemic inflammatory response syndrome; TPE, therapeutic plasma exchange; w/o, without.

3.2. TG Levels and Clinical Effectiveness

Of the 12 comparative studies with baseline TG levels below 5000 mg/dL, two studies demonstrated the clinical effectiveness of plasmapheresis, while 10 studies showed no clinical effectiveness. In one of two studies with clinical effectiveness, Zhen et al. reported the results of a randomized controlled trial (RCT) in a TPE group (received Low molecular weight heparin (LMWH), insulin, and TPE) and a non‐TPE group (received LMWH and insulin) [7]. In the TPE group, TG levels decreased from 1991 to 206 mg/dL after treatment, and a statistically significant difference was observed (p < 0.001). Meanwhile, in the non‐TPE group, TG levels decreased from 2079 to 2088 mg/dL after treatment, showing no significant change (p = 0.986). The TPE group demonstrated a significantly higher total effective rate (defined as the proportion of patients showing significant clinical improvement) of 90.32% compared to 73.01% in the non‐TPE group (p < 0.001). Among 10 studies with no clinical effectiveness, Lu et al. evaluated changes in TG levels 24 and 48 h after admission in the DFPP group and the standard treatment group [16]. Baseline TG levels were 3513 mg/dL in the DFPP group and 2752 mg/dL in the standard treatment group. While the DFPP group showed a significantly superior TG reduction after 24 h, the significant difference disappeared after 48 h. In this regard, it was speculated that the conditions of the patients might not be serious to benefit from DFPP. A TG levels exceed 2000 mg/dL is considered “extremely high”. However, based on these results, it can be said that even such “extremely high” TG levels can be managed with standard treatment in some cases. Meanwhile, Chang et al. conducted a comparative study using DFPP [17]. The risks and benefits of DFPP were explained to the HTG‐AP patients, and the patients decided whether or not to undergo DFPP. Chang et al. further conducted a subgroup analysis on patients with TG levels exceeding 5000 mg/dL. Among patients with TG levels exceeding 5000 mg/dL, the median TG levels were significantly higher in the DFPP group (n = 11, 16 179 mg/dL) than in the non‐DFPP group (n = 14, 8492 mg/dL). However, no significant difference was observed between the two groups regarding Ranson scores, a severity index. No major complications were observed in the DFPP group, whereas five patients in the non‐DFPP group developed major complications. The incidence of major complications was lower in the DFPP group (p < 0.001), and the length of hospital stay was shorter in the DFPP group (p = 0.012). The decision to undergo DFPP was made by the patients themselves. Therefore, it is considered that many patients with higher TG levels underwent DFPP, and consequently, TG levels in the DFPP group may have been higher.

In one single‐arm study using DFPP with TG levels exceeding 5000 mg/dL, the mean TG levels were 5159 mg/dL [18]. When patients were divided into three groups based on the time from diagnosis to the first DFPP, the group that started treatment early had a significantly lower rate of persistent organ failure (POF). Logistic regression models and restricted cubic splines analysis revealed that the risk of POF increases sharply if the first DFPP is initiated more than 15 h after diagnosis.

3.3. Modality and Clinical Effectiveness

Of the two articles that demonstrated clinical effectiveness in patients with TG levels below 5000 mg/dL, one modality was TPE and the other was DFPP. Of the 10 articles that did not show clinical effectiveness in patients with TG levels below 5000 mg/dL, six used TPE, one used DFPP, and three used TPE/DFPP. In two studies reporting the effectiveness of plasmapheresis with TG levels exceeding 5000 mg/dL, the modality was DFPP in both studies. In general, when processing the same volume of plasma, the removal rate of plasma components is equivalent to or higher with TPE than with DFPP. Therefore, when using DFPP, the processed plasma volume may be increased to achieve a removal rate equivalent to that of TPE. Yeh et al. conducted a comparative study of TPE and DFPP in patients with HTG‐AP, evaluating the processed plasma volume and the TG removal rate [19]. The TG removal rate was 64.1% in the TPE group (n = 12, processed plasma volume 2.4 L) and 57.5% in the DFPP group (n = 6, 2.6 L). Judging from the TG removal rate, it is unlikely that there is a difference in clinical effectiveness between TPE and DFPP in HTG‐AP patients. When TG levels exceed 5000 mg/dL, TPE may have comparable effectiveness to DFPP, and evaluation using TPE is awaited.

4. Discussion

Plasmapheresis can rapidly lower TG levels and is often used in patients with severe HTG‐AP. However, the results of comparative studies are inconsistent. The author speculated that the reason for the discrepancy might be that plasmapheresis was used in cases where plasmapheresis was not always necessary. Therefore, the clinical effectiveness of the clinical articles was analyzed and classified into those with baseline TG levels below 5000 mg/dL and those with TG levels of 5000 mg/dL or higher. In the 12 articles with TG levels below 5000 mg/dL, the weighted mean TG levels were approximately 2390 mg/dL, which indicates that plasmapheresis was used on patients with “extremely high” TG levels. However, since these TG levels can be managed with standard treatment in some cases, plasmapheresis may not always be necessary. Meanwhile, plasmapheresis is considered effective in most cases when baseline TG levels exceed 5000 mg/dL. Instead of TG levels, it is also possible to use severity scores such as the SOFA score or the APACHE II score for assessment. However, several articles were missing the description of the severity score, and the purpose of plasmapheresis is to directly remove TG; therefore, the author considered that TG levels are the most direct indicator. Araz et al. reported that two patients in the TPE/DFPP group died [13]. One patient had high TG levels of 6060 mg/dL, while the other had TG levels of 1812 mg/dL and presented with severe renal failure, hypotension, and a Glasgow Coma Scale score of 7 at admission. While the author fully understands that factors other than TG levels can influence prognosis, this article investigated the clinical effectiveness of plasmapheresis from the perspective of TG levels and arrived at this hypothesis.

In conclusion, based on these analysis results, the author hypothesized that plasmapheresis is effective in most cases when baseline TG levels exceed 5000 mg/dL. There are only two studies of TG levels exceeding 5000 mg/dL; one is a single‐arm study, and the number of patients in the comparative study is limited. Therefore, the evidence is insufficient to make a definitive conclusion. The author hopes that comparative clinical studies of patients with TG levels exceeding 5000 mg/dL will be conducted soon.

Funding

The author has nothing to report.

Ethics Statement

The contents in this article are based on citations from published clinical articles. Therefore, ethics committee approval does not apply.

Consent

The contents in this article are based on citations from published clinical articles. Therefore, informed consent does not apply.

Conflicts of Interest

The author is a consultant of Asahi Kasei Medical Co. Ltd.

Data Availability Statement

Research data are not shared.