Abstract
Hypertriglyceridemia-associated acute pancreatitis (HTG-AP) requires causal attribution rather than reliance on a single triglyceride (TG) threshold. Early TG measurement and assessment of competing or coexisting causes are essential because fasting, fluids, and correction of metabolic stress can produce substantial early TG decline. Severity should be determined by serial organ-function assessment using revised Atlanta and Modified Marshall criteria rather than TG concentration alone. Acute management should prioritize standard pancreatitis care, moderate crystalloid resuscitation, analgesia, early oral or enteral nutrition, and correction of genuine metabolic drivers. Intravenous insulin is appropriate for diabetic ketoacidosis, uncontrolled diabetes, marked hyperglycemia, or clinically important insulin deficiency, but current evidence does not support routine insulin solely for TG lowering in insulin-sufficient patients. Heparin should not be used for TG lowering. Therapeutic plasma exchange (TPE) produces rapid biochemical TG clearance, but randomized and adjusted observational evidence has not established improvement in organ failure, pancreatic necrosis, hospital stay, or mortality. TPE should therefore not be used as routine or rescue TG-lowering therapy; exceptional multidisciplinary deliberation may occur only in narrowly defined circumstances and should not be interpreted as an evidence-based indication or recommendation. After recovery, phenotype-directed assessment using fasting lipids, apolipoprotein B, evaluation of secondary drivers, and selective genetic testing can distinguish familial from multifactorial chylomicronemia and guide prevention. Hepatic apolipoprotein C-III (apoC-III) inhibition currently has the strongest randomized evidence for reducing pancreatitis events in relevant chylomicronemia populations. Management should prioritize prevention of organ injury during the acute episode and prevention of subsequent pancreatitis rather than the fastest possible TG decline.
Keywords: acute pancreatitis, hypertriglyceridemia, chylomicronemia, insulin, plasma exchange, apoC-III
Introduction
Hypertriglyceridemia-associated acute pancreatitis (HTG-AP) occupies an awkward boundary between pancreatology, critical care, diabetology, and lipid medicine. Prospective international cohorts show a recognizable population—generally younger and frequently obese or diabetic—but a repeat attack remains a possible, not universal, outcome [1, 2]. The magnitude of risk varies sharply with setting and prior disease burden. In a United States (US) claims cohort of 7,119,195 adults, the annualized incidence of a subsequent acute pancreatitis (AP) admission reached 29.98% among those with at least two AP events in the preceding 12 months [3]. In a Spanish primary-care cohort of 2,256,261 individuals followed for a median of 7.78 years, cumulative AP incidence was 7.37% in those with a baseline history of pancreatitis vs 0.42% in those without such a history (0.44% overall) [4]. In a 317-patient prospective cohort after a first HTG-AP episode, cumulative recurrence was 8% at 12 months and 22% at 18 months [5]. These estimates use different populations, denominators, and follow-up windows and should not be treated as interchangeable recurrence rates. Population data demonstrate a continuous rise in pancreatitis risk with increasing triglyceride (TG) concentrations rather than a biologically clean cut-off and show that prior pancreatitis and metabolic context materially modify absolute risk [1–5].
The 2025 joint guideline of the International Association of Pancreatology, American Pancreatic Association, European Pancreatic Club, International Pancreas Society, and Japanese Pancreas Society retains the international two-of-three diagnostic framework for AP—typical pain, pancreatic enzymes at least three times the upper reference limit, and characteristic imaging—whereas World Society of Emergency Surgery guidance recommends considering an early TG concentration >11.3 mmol/L (>1,000 mg/dL) as the etiology when gallstones and significant alcohol exposure are absent [6, 7]. For this review, HTG-AP is operationally defined as AP meeting those diagnostic criteria in which early chylomicronemia is judged the primary trigger or a material co-trigger after sampling time, competing causes, previous TG values, the clinical/metabolic phenotype, and secondary drivers are considered. The guideline value is an aid to causal attribution, not proof of exclusive causality and not a treatment threshold.
The TG ranges used throughout this review are interpretive rather than categorical: <5.6 mmol/L (<500 mg/dL) obtained before substantial treatment makes hypertriglyceridemia alone less likely; 5.6–11.2 mmol/L (500–999 mg/dL) is an intermediate range in which timing, previous values and co-causes are decisive; and ≥11.3 mmol/L (≥1,000 mg/dL) provides stronger support for causal contribution when sampled early. Pancreatitis risk continues to rise across and above these ranges and is shaped by the clinical/metabolic phenotype and secondary factors rather than switching on at a single boundary [1–5].
The biological model has also matured. A prospective human study linked circulating TG fatty-acid composition, lipase activity and non-esterified fatty acids (NEFAs) to organ failure, and used complementary experimental work to test directionality [8]. These data place pancreatic and intravascular lipolysis upstream of acinar injury, endothelial leak, and systemic lipotoxicity. They do not validate every downstream cell-death pathway in humans, nor do they imply that mechanically removing circulating TG after injury has begun will reverse established organ dysfunction.
Biochemical efficacy is not equivalent to clinical efficacy. Faster TG decline or earlier attainment of a protocol target may demonstrate lipid removal, but cannot establish benefit in persistent organ failure, necrosis, hospital course, mortality, or recurrence [9–11]. No isolated TG concentration or visible lipemia has been validated as a stand-alone indication for intravenous insulin in a normoglycemic patient or for therapeutic plasma exchange (TPE).
Long-term evidence has moved in the opposite direction. Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are clinically and genetically distinguishable, although they overlap at presentation [12, 13]. Phase 3 trials of hepatic apolipoprotein C-III (apoC-III) suppression have now reported fewer adjudicated pancreatitis events in FCS and in broader persistent or trial-defined severe chylomicronemia populations [14–16]. The center of gravity is consequently shifting from unvalidated acute lipid-removal rituals toward phenotype-directed prevention.
This critical narrative review addresses six linked questions: how to attribute an attack to hypertriglyceridemia; which mechanisms are supported directly in humans; how severity should be measured and acted upon at the bedside; what primary comparative evidence shows for insulin, heparin, and TPE; how and why persistent chylomicronemia should be phenotyped after recovery; and which interventions have direct evidence for preventing pancreatitis rather than merely lowering TG. The aim is not to create another treatment list, but to identify where evidence is direct, where it is confounded, and where uncertainty should change practice.
Methods
We conducted a structured critical narrative review because the evidence encompassed heterogeneous study designs, including clinical trials, observational cohorts, registry and claims analyses, diagnostic studies, translational research, and rare-disease trials. The review addressed causal attribution and TG kinetics, mechanisms, acute management, recurrence prevention, differentiation of familial and multifactorial chylomicronemia, targeted therapies, and special populations.
MEDLINE (Medical Literature Analysis and Retrieval System Online) via PubMed and Scopus were searched for records dated August 2026. Google Scholar was used for forward-citation tracking and identification of relevant gray literature, but not as the source of effect estimates when a primary report was available. Table S1 provides the complete reproducible database strings, field syntax, and source-specific yields. The searches identified 716 candidate records: 366 from MEDLINE via PubMed, 298 from Scopus and 52 through Google Scholar. After title normalization and digital object identifier (DOI)/PubMed identifier (PMID) matching, 267 duplicates were removed, leaving 449 unique records.
Eligible studies included randomized trials; prospective or retrospective cohorts; diagnostic-score development or validation studies; molecularly defined phenotype cohorts; and relevant human pharmacodynamic or translational studies. Acute-treatment studies were required to report TG kinetics or at least one patient-centered outcome, such as organ failure, mortality, intensive-care use, length of stay, local complications, adverse events, or cost. Long-term studies had to report pancreatitis events, recurrent attacks, persistent chylomicronemia, phenotype discrimination, or clinically relevant treatment safety. Mechanistic studies were included only when directly relevant to circulating TG, lipolysis, NEFAs, or pancreatic and systemic injury.
Screening proceeded in two stages using the eligibility criteria above. Titles and abstracts of 449 unique records were assessed; 284 were excluded, and 165 full-text reports were evaluated. At full-text review, exclusion reasons were recorded before synthesis. Seventy-one full-text reports were excluded because of ineligible design or inadequate reporting (n = 24), sample size below the prespecified threshold (n = 18), cohort overlap (n = 14), absence of defined clinical or biochemical outcomes (n = 10), or insufficient English-language text (n = 5). The final synthesis included 94 primary empirical clinical and translational studies. An additional 24 clinical practice guidelines, international consensus statements, regulatory documents, and clinically focused reviews were used to contextualize recommendations, giving 118 cited sources overall.
For each primary report, we extracted study design, setting, sample size, chylomicronemia phenotype, baseline pancreatitis severity, treatment indication, comparator and co-interventions, treatment timing, TG kinetics, patient-centered outcomes, adverse events, and principal limitations. Because the questions and designs were heterogeneous, no pooled meta-analysis or single global Grading of Recommendations Assessment, Development and Evaluation rating was applied. Evidence weight was instead classified qualitatively as higher, intermediate, or limited according to directness, study design, risk of bias, consistency, and precision. Higher weight was assigned to randomized direct comparisons and well-adjusted prospective comparative cohorts reporting patient-centered outcomes; intermediate weight to prospective or adjusted observational evidence with residual confounding; and limited weight to retrospective uncontrolled series, case reports, mechanistic extrapolation, or studies limited to biochemical surrogates.
For insulin and TPE, randomized comparisons and contemporary adjusted comparative cohorts with organ failure, necrosis, length of stay, mortality, adverse-event, or cost outcomes were therefore privileged over uncontrolled series reporting only TG decline or target attainment. Faster biochemical clearance was treated as evidence of biochemical activity, not clinical effectiveness, and could not override null or imprecise patient-centered estimates. Interpretation also considered confounding by indication, baseline severity, treatment timing, active vs historical comparators, cohort overlap and mechanistic fit, including residual lipoprotein lipase (LPL)-pathway activity; mechanistic plausibility alone was not treated as proof of clinical benefit.
What makes an episode ‘hypertriglyceridemia-associated’?
AP should be diagnosed independently of its cause, using at least two of three criteria: typical abdominal pain, serum amylase or lipase at least three times the upper reference limit, and characteristic imaging findings [6, 7, 17]. Etiological assessment proceeds in parallel because gallstones, alcohol, hypercalcemia, recent interventions, anatomical abnormalities, and pancreatotoxic drugs remain plausible causes even when TG concentrations are markedly elevated. Lipemic interference may produce spuriously low pancreatic-enzyme results in some photometric assays; discordance between the clinical presentation and enzyme concentrations should therefore prompt sample dilution or reanalysis rather than exclusion of pancreatitis.
The designation HTG-AP expresses causal probability rather than an exclusive etiology. Hypertriglyceridemia may be the primary trigger, a cofactor amplifying biliary or alcohol-related pancreatitis, or a transient consequence of diabetic ketoacidosis (DKA) and stress metabolism. Causality is more likely when TG is measured early in the chylomicronemic range and is accompanied by visible lipemia, previous fasting chylomicronemia, prior HTG-AP, or persistent chylomicronemia after recovery. Conversely, a strong alternative cause or complete normalization after correction of a reversible metabolic disturbance weakens attribution. Visible lipemia confirms chylomicronemia but does not independently establish causality, predict severity, or constitute a treatment indication [1–7].
TG should be measured as early as possible, preferably before prolonged fasting, substantial fluid administration, or insulin treatment. In a 22-admission conservatively managed series, mean TG decreased by almost 70% within 48 h, with an estimated half-life of 30.6 h; the decline was similar to fasting and fluids alone and with insulin administered for hyperglycemia [18]. A retrospective comparison of 106 patients likewise found no significant difference between intravenous insulin and conservative management, with TG reductions of 69% vs 63% by Day 2 and 85% vs 79% by Day 4, despite higher baseline TG in the insulin group [19]. In a 2025 secondary analysis of 413 prospectively enrolled patients, 46.5% achieved TG ≤5.65 mmol/L (≤500 mg/dL) by Day 3, but target attainment was not associated with organ failure at Day 14 in the overall cohort; favorable subgroup associations in patients with greater initial severity could not establish a treatment effect [20]. Consequently, a TG concentration of 7.9 mmol/L (700 mg/dL) measured after 24–48 h may reflect a substantially higher concentration at disease onset, whereas the same value obtained at presentation is less specific for causal attribution.
The relationship between TG and pancreatitis risk is continuous rather than threshold-based. In a claims cohort of more than seven million adults, pancreatitis incidence increased across TG categories and rose markedly above 11.3 mmol/L (1,000 mg/dL), although a history of at least two previous attacks was associated with a substantially greater absolute event rate than TG category alone [3]. Similarly, an electronic-health-record study of 1.5 million individuals found an adjusted hazard ratio of 13.55 for pancreatitis at TG >20 mmol/L (∼ 1,770 mg/dL) compared with ≤1.7 mmol/L (≤150 mg/dL), with particularly high relative risk among younger adults [21]. These values describe risk gradients and should not be interpreted as definitive diagnostic or procedural thresholds (Table 1). Accordingly, TG categories can support causal recognition, post-acute phenotyping and preventive intervention, but they must not be used as stand-alone triggers for insulin, TPE or other extracorporeal lipid removal.
Table 1.
Causal interpretation of an early TG measurement.a
| Finding | Interpretation | What must be checked | What it does not justify | Primary evidence |
|---|---|---|---|---|
| TG <5.6 mmol/L (<500 mg/dL) before substantial treatment | HTG alone is an unlikely primary cause; may be a background modifier | Competing etiologies, prior TG, alcohol, diabetes, medicines | Excluding HTG if sampling was delayed; any acute TG-removal procedure | TG kinetics and organ-failure cohorts [18, 20, 22] |
| TG 5.6–11.2 mmol/L (500–999 mg/dL) | Indeterminate: contributory, mixed or treatment-lowered causal exposure | Time from pain to blood draw; fasting/fluids/insulin; historical TG; biliary disease | Calling HTG the exclusive cause from the number alone | Population and registry gradients [3, 21] |
| TG ≥11.3 mmol/L (≥1,000 mg/dL) obtained early | Strong support for causal contribution, especially without a stronger cause; it is a causal-probability marker, not a validated treatment threshold | DKA, alcohol, pregnancy, obesity, renal/endocrine disease, drugs, previous attacks | Automatic insulin in a normoglycemic patient, including one with FCS, or automatic TPE; using the concentration as a stand-alone trigger for any acute TG-lowering procedure | Prospective and registry cohorts [1, 2, 23] |
| Persistent fasting TG ≥10 mmol/L (≥885 mg/dL) after recovery | Ongoing chylomicronemia and increased risk of future AP events | ApoB, secondary drivers, FCS probability, genetics when indicated | Assuming all persistent chylomicronemia is FCS | Molecular and phenotype cohorts [12, 13, 24, 25] |
AP, acute pancreatitis; ApoB. apolipoprotein B; DKA, diabetic ketoacidosis; FCS, familial chylomicronemia syndrome; HTG, hypertriglyceridemia; TG, triglyceride; TPE, therapeutic plasma exchange.
Pathophysiology: from chylomicronemia to pancreatotoxic lipid stress
The initiating substrate is accumulation of chylomicrons and other TG-rich lipoproteins, although their presence does not itself prove pancreatic toxicity. In FCS, near-absent activity of the canonical LPL pathway causes persistent chylomicronemia; in MCS, residual clearance is overwhelmed by polygenic susceptibility, very-low-density lipoprotein overproduction, and secondary factors. Human cohorts associate greater TG-related lipid burden with persistent organ failure and more severe disease and indicate that phenotype-level genetic susceptibility modifies pancreatitis risk [20, 22–26]. By contrast, direct human evidence that particle size, viscosity, or capillary ‘sludging’ initiates pancreatic injury remains limited; these are plausible modifiers rather than established dominant mechanisms.
The most strongly supported mechanistic link is pancreatic or intravascular lipolysis of TG-rich particles, generating NEFAs. In a prospective study of 269 patients with AP, HTG-AP was associated with higher NEFA concentrations, revised-Atlanta severe disease (19% vs 7%) and organ failure (30% vs 10%) [8]. In linked mouse and rat experiments, lipolysis increased NEFA generation and organ injury, whereas pancreatic TG-lipase deletion or pharmacological lipase inhibition attenuated these effects [27, 28]. Causal support for the substrate–lipase–NEFA pathway is therefore strongest in animals, and therapeutic validation in patients is lacking.
Downstream acinar, endothelial, and microcirculatory injury is supported by complementary clinical and experimental evidence. Human cohorts associate higher NEFA and circulating long-chain fatty-acid concentrations with severe AP or persistent organ failure [8, 22]. A small lipidomic study found differences in TG fatty-acid composition [29]. A 2025 HTG-AP cohort also linked ultra-early interleukin-6, D-dimer, and hypocalcemia with moderately severe or severe disease [30]. These findings are consistent with systemic inflammation and metabolic injury but do not directly demonstrate pancreatic microcirculatory failure. Experimental evidence suggests that when NEFA generation exceeds albumin-binding capacity, unbound fatty acids may acidify tissues, disrupt calcium homeostasis and mitochondrial energy production, and injure acinar and endothelial cells [27, 28, 31]. The resulting capillary leak, hypovolemia, acidosis, and local ischemia may further increase tissue exposure to fatty acids.
Inflammatory amplification follows lipotoxic cellular injury through the release of damage-associated signals, recruitment of innate immune cells, and activation of cytokine networks. Pyroptosis, ferroptosis, mitochondrial stress, and the NLRP3–caspase-1–gasdermin D pathway should be regarded as candidate downstream amplifiers supported mainly by cell-culture, acinar/macrophage, and rodent HTG-AP models [32–35]. None has been validated as a therapeutic target in patients.
Finally, total TG concentration is an imperfect surrogate for pancreatotoxic lipid stress. In the prospective human study, NEFA burden reflected the interaction between TG fatty-acid substrate and serum lipase more closely than TG concentration alone [8]. The lipidomic finding cited above reinforces that measured TG does not capture fatty-acid composition [29]; total TG also fails to represent lipase activity, albumin-binding capacity, or the modifying effects of phenotype and metabolic ‘second hits’. Diabetes or DKA, alcohol, pregnancy, obesity or metabolic dysfunction, and TG-raising medications act predominantly as upstream or parallel modifiers by increasing lipid substrate, impairing clearance or reducing physiological reserve (Fig. 1).
Figure 1.
Integrated pathophysiology of hypertriglyceridemia-associated AP.
Clinical phenotype, severity, and natural history
HTG-AP is usually diagnosed in the third to fifth decade, often in patients with obesity, diabetes, fatty liver, alcohol exposure, or previous AP. In the international APPRENTICE cohort and the 716-patient prospective multicenter study, HTG-AP was associated with younger age and metabolic comorbidity [1, 2]; repeat attacks were reported in subsets rather than in all patients. Yet comparisons with other etiologies are inconsistent after adjustment. A 2024 registry analysis of 1,855 consecutive AP cases found that patients with HTG-AP were younger and more likely to require intensive care unit (ICU) care, develop a severe course, and have an acute peripancreatic fluid collection, but its single-center retrospective design limited causal attribution [36]. Other multicenter and population cohorts likewise report more persistent or multiple organ failure with increasing TG [20, 23, 37, 38]. The discrepancy is clinically useful: hypertriglyceridemia identifies a high-risk metabolic population, but does not replace physiological severity assessment.
Recent multicenter cohorts support a graded prognostic association between TG burden and adverse AP outcomes. A 2025 cohort of 919 patients with HTG-AP reported clinically important severity outcomes across the study population [23], while a 2025 common-data-model study evaluated the prognostic impact of serum TG across AP populations [38]. Both were observational and remain vulnerable to exposure timing, coding, and residual metabolic confounding. Such studies establish prognostic association. They do not demonstrate that acute removal of the measured TG modifies the trajectory, because the value may mark cumulative exposure, remnant metabolism, insulin resistance, or an already active lipolytic process.
A repeat attack occurs in a clinically important minority and is consequential when it occurs. A multicenter prospective cohort following first-episode HTG-AP for a mean of 31 months reported repeat admissions in 23% (37/161); age below 40 years and diabetes were independent predictors, and patients with a repeat attack had worse health-state scores [39]. A 317-patient prospective cohort found that post-attack TG ≥5.65 mmol/L (≥500 mg/dL) was associated with twice the cumulative incidence of recurrence (subdistribution hazard ratio 2.00, 95% confidence interval (CI) 1.05–3.80) [5]. A separate 108-patient single-center retrospective study found that poor TG control at 1 month was associated with recurrence [40], although the design and setting limit causal inference and external reproducibility. In another cohort, three or more attacks were associated with markedly higher odds of post-pancreatitis diabetes than no recurrence [41]. A 2025 prospective cohort found a 30.0% 2-year unplanned-readmission rate, with recurrent AP accounting for 77.3% of readmissions [42]. A 2026 three-hospital cohort associated lower admission high-density lipoprotein cholesterol (HDL-C) with recurrence, particularly during the first 12 months, while a 2025 claims study found greater subsequent emergency-department use, hospitalization, and mortality after severe-hypertriglyceridemia-associated AP than after severe hypertriglyceridemia without AP [43, 44]. These are observational associations and adherence is difficult to measure, but they support a prevention pathway that begins before discharge.
FCS and MCS distribute this risk differently. FCS causes near-continuous chylomicronemia from early life and may be accompanied by recurrent abdominal symptoms and a high pancreatitis burden but relatively low apolipoprotein B (apoB) particle numbers. MCS is more prevalent, fluctuates with secondary drivers, and may carry both pancreatitis risk as TG rises into the chylomicronemic range and atherosclerotic cardiovascular risk through very-low-density lipoprotein (VLDL)/remnant apoB particles. Ten-year comparative follow-up and burden studies demonstrate more pancreatitis in FCS, but substantial morbidity in both phenotypes [45, 46]. A high admission TG therefore predicts neither mechanism nor long-term therapeutic response without post-acute phenotyping.
Bedside severity assessment: what to measure, when, and what action follows
Severity assessment is useful only if it changes location of care, monitoring, or support (Table 2). Operationally, calculate and timestamp Modified Marshall at presentation; within 24 h, calculate the Bedside Index for Severity in Acute Pancreatitis (BISAP) and document systemic inflammatory response syndrome (SIRS); repeat Modified Marshall and SIRS every 12–24 h while abnormal or organ support is escalating; at 48 h, assign revised Atlanta severity from the duration of organ failure; and use the Acute Physiology and Chronic Health Evaluation II (APACHE II) only as an optional ICU adjunct. Clinical deterioration overrides a reassuring score. The revised Atlanta classification is an episode-level classification that can be finalized only after the clinical trajectory is known: mild AP has neither organ failure nor local/systemic complications; moderately severe AP has transient organ failure (<48 h) or local/systemic complications; and severe AP has persistent organ failure (≥48 h) [17]. During the first 48 h, document whether respiratory, cardiovascular, or renal organ failure is present and whether it resolves, persists, or worsens; do not use an unqualified admission label of ‘severe’. Admission TG is neither a severity definition nor an ICU criterion, and no TG threshold replaces clinical assessment of organ dysfunction.
Table 2.
Operational severity assessment and linked actions.a
| Time point | Measure and explicit threshold | Interpretation | Required action | Primary support |
|---|---|---|---|---|
| Presentation (0–6 h) | Modified Marshall respiratory, renal and cardiovascular components; score ≥2 in any system | Organ failure is present now; duration is not yet known | High-dependency/ICU assessment; organ-specific support; timestamp the baseline for the 48-h duration | Dynamic organ dysfunction and outcome cohorts [47, 54] |
| First 24 h | BISAP 0–5; score ≥3 flags higher risk but is not organ failure | Early triage and monitoring intensity | Increase observation and reassessment; a low score never overrules clinical deterioration | Derivation, prospective validation and contemporary comparison [48–51] |
| First 24 h; repeat in ICU if useful | APACHE II: 12 physiology variables plus age/chronic-health points; worst values over the chosen window | Global physiological risk; not pancreas-specific and no universal treatment cut-off | Optional ICU context only; do not delay organ support or use it to select insulin/TPE | Contemporary multicenter comparison [51] |
| 6–24 h and after each resuscitation step | BUN, creatinine, hematocrit, urine output, lactate, oxygen need, and signs of overload | Direction of change tests perfusion and fluid tolerance | Continue, slow or stop fluid; investigate a non-improving trajectory; initiate organ support when indicated | Serial BUN cohort; fluid randomized controlled trial [52, 54] |
| Every 12–24 h while any Marshall component is abnormal or organ support is escalating | SIRS (≥2 criteria) and Modified Marshall repeated | Inflammatory trajectory and evolving/resolving organ failure | Escalate monitoring/support for worsening physiology; no TG threshold or score selects insulin/TPE | Prospective/large cohort evidence [22, 47, 53] |
| At 48 h | Modified Marshall score remains ≥2 in any system: yes/no | Persistence for ≥48 h defines severe AP | Classify severe AP and continue organ support; persistent organ failure does not establish benefit from insulin/TPE or create an automatic TPE branch | Revised Atlanta and organ-failure outcome data [17, 47] |
| After 72–96 h or clinical deterioration | Local-complication imaging when it will change care, not routinely at admission | Necrosis/collections are anatomical complications; infection requires clinical corroboration | Contrast-enhanced computed tomography or magnetic resonance imaging when diagnosis is uncertain or the course fails to improve; avoid early intervention on sterile collections | Prospective severity and necrosis studies [55, 56] |
AP, acute pancreatitis; BISAP, Bedside Index for Severity in Acute Pancreatitis; BUN, blood urea nitrogen; ICU, intensive care unit; SIRS, systemic inflammatory response syndrome; TG, triglyceride; TPE, therapeutic plasma exchange.
The Modified Marshall system operationalizes organ failure in the three systems used by revised Atlanta. A score ≥2 in any system denotes organ failure: respiratory PaO₂/FiO₂≤300; renal creatinine ≥1.9 mg/dL (≥170 μmol/L); or cardiovascular systolic blood pressure <90 mmHg that is not fluid-responsive (scores 3–4 add arterial pH <7.3 or <7.2). Record the score and timestamp at presentation and at least every 12–24 h while any component is abnormal or respiratory, vasopressor, or renal support is escalating. New or worsening organ failure, increasing oxygen or vasopressor requirements, or oliguria warrants immediate monitored/ICU escalation; do not wait for the 48-h classification. Resolution before 48 h is transient organ failure; persistence for ≥48 h defines severe AP. In an international analysis, mortality was approximately 4% with one persistently failing system and 33% and 48% with two and three, respectively [47].
BISAP is a 0–5 early risk-stratification tool, not a diagnosis of severe AP. During the first 24 h, assign one point each for blood urea nitrogen (BUN) > 25 mg/dL, impaired mental status, SIRS, age >60 years, and pleural effusion; BISAP ≥3 flags higher risk and should increase observation and reassessment intensity. BISAP and SIRS are triage aids, not discharge rules or treatment triggers; neither establishes organ failure, and clinical deterioration overrides a lower score [48, 49]. In HTG-AP, a 238-patient single-center retrospective comparison reported areas under the curve of 0.83 for BISAP and the Sequential Organ Failure Assessment (SOFA) and 0.88 for Ranson score for severe AP, but only one patient died, precluding a definitive ranking [50]. A 2026 two-center retrospective cohort of 450 patients found mortality areas under the curve of 0.89 for BISAP and 0.82 for APACHE II (P = 0.08), supporting risk stratification but not superiority or treatment selection [51].
APACHE II can contextualize global physiological burden and be repeated in ICU care, but it requires 12 physiological variables plus age and chronic-health points, uses the worst values over a time window, is not pancreas-specific, and has setting-dependent calibration and cut-offs; its calculation burden should not delay support for shock, hypoxemia, or oliguria [51]. Serial BUN and its 24-h change, creatinine, urine output, hematocrit, lactate, oxygen need, and signs of congestion or hypoperfusion provide actionable trajectories [52]. SIRS is present when at least two of four criteria are met: temperature <36°C or >38°C; heart rate >90/min; respiratory rate >20/min or PaCO₂ <32 mmHg; and white-cell count <4 or >12 × 10⁹/L or >10% immature forms. Persistent organ failure during the first week remains one of the strongest predictors of mortality, and determinant-based severity classification also emphasizes the central prognostic role of persistent organ failure and infected necrosis [54–56]. New hypertriglyceridemia-specific nomograms and machine-learning models published in 2025–2026 report promising discrimination, but most are single-center, use retrospectively selected variables, and lack impact analysis; even a recent multicenter model requires external geographical and workflow validation [57]. They may support research stratification, but should not displace repeated organ-function measurement. Accordingly, severity tools determine monitoring and organ support, not lipid-lowering treatment: no TG threshold and no revised Atlanta, Modified Marshall, BISAP, SIRS, APACHE II, SOFA, or research-model value has been validated to identify benefit from insulin or TPE [9, 11, 19].
Acute management: separate pancreatitis care from a metabolic indication
Evidence-based care for AP remains the foundation
All patients require prompt analgesia, assessment of intravascular depletion, electrolyte and glucose management, and early nutrition. The WATERFALL randomized trial showed that aggressive lactated Ringer’s resuscitation increased fluid overload without improving clinical outcomes compared with a moderate, reassessed strategy [58]. This finding is especially relevant in HTG-AP because obesity, renal dysfunction, capillary leak, and DKA can make both under-resuscitation and overload dangerous. A reasonable initial approach is a bolus only when hypovolemia is present, followed by approximately 1.5 mL/kg/h and frequent reassessment; exact rates must be individualized to hemodynamics, urine output, BUN/creatinine trajectory, oxygenation, and congestion.
Oral feeding should resume as soon as pain, nausea, and ileus permit; a multicenter randomized trial supports immediate oral refeeding in mild or moderately severe AP [59]. In patients unable to eat, enteral feeding is preferred. The PYTHON trial found no benefit from routine very early nasoenteric tube feeding compared with an on-demand strategy [60]. During the chylomicronemic phase, conservative management should include early low-fat oral or enteral feeding as tolerated; prolonged fasting solely to ‘normalize’ TG is unnecessary. Prophylactic antibiotics do not prevent infected necrosis: placebo-controlled trials of ciprofloxacin/metronidazole and meropenem failed to show a clinical advantage [61, 62].
Respiratory failure, shock, acute kidney injury, and electrolyte disorders are treated according to physiology, not etiology. Hypocalcemia should be interpreted with albumin and ionized calcium and corrected when symptomatic or otherwise indicated by the critical-care protocol. DKA requires guideline-based insulin, fluids, and potassium management. Biliary obstruction/cholangitis, abdominal compartment syndrome, infected necrosis, and other complications retain their usual indications for intervention. TPE is not a substitute for these priorities and should not be embedded as a routine third tier of acute TG-lowering management.
The untreated comparator is not ‘no treatment’
Fasting, withdrawal of exogenous fat and correction of metabolic stress rapidly reduce chylomicron influx. TG fell by about 70% within 48 h in a small conservative series [18], while a 106-patient comparison found no additional biochemical acceleration with intravenous insulin beyond fasting and intravenous fluids [19]. These data indicate that early TG decline during insulin, heparin, or plasma exchange cannot be attributed to the intervention without a concurrent supportive-care comparator.
Serial TG measurement every 12–24 h can document resolution of chylomicronemia and identify rebound. Values below 5.6 mmol/L (500 mg/dL) or 11.3 mmol/L (1,000 mg/dL) are commonly used biochemical protocol endpoints, but no acute TG threshold has been validated to determine organ recovery or treatment transition. Clinical recovery, enteral tolerance, and correction of the precipitating metabolic driver should guide transition from acute management.
Intravenous insulin: commonly used, not routine TG-lowering therapy
Insulin suppresses adipose lipolysis, reduces hepatic fatty-acid flux and can promote LPL activity only where a functional LPL pathway remains. The metabolic indication is therefore decisive. Intravenous insulin is required for DKA and is appropriate for uncontrolled diabetes, marked hyperglycemia or clinically important insulin deficiency. In MCS, residual LPL makes an adjunctive effect biologically plausible, particularly when persistent chylomicronemia coexists with hyperglycemia or insulin deficiency. By contrast, classic FCS has near-absent canonical LPL activity, so both insulin-mediated LPL activation and heparin-mediated LPL release are less plausible [12, 13]. In an euglycemic, insulin-sufficient patient, TG concentration or lipemia alone does not create an indication. Accordingly, insulin should not be presented as general TG-lowering therapy for normoglycemic FCS or for any other euglycemic, insulin-sufficient chylomicronemia phenotype.
Most insulin evidence is uncontrolled or observational, often combines insulin with dextrose or heparin, and generally lacks a fasting/supportive-care comparator. The direct 106-patient comparison found no additional biochemical acceleration with intravenous insulin [19], while protocol and before–after studies have not demonstrated reductions in organ failure, necrosis, hospital stay, mortality, or recurrence [63, 64]. Comparative insulin–apheresis data are confounded by baseline severity, and the small randomized insulin-vs-TPE trial lacked a fasting-only arm [9, 65]. No randomized trial has directly compared intravenous insulin with otherwise identical supportive care alone. Newer data reinforce the distinction between protocol feasibility and clinical effectiveness. In a 466-patient multicenter before–after cohort, a fixed-dose insulin protocol changed neither ICU stay, hospital stay, nor time to TG <11.3 mmol/L (<1,000 mg/dL); mild hypoglycemia increased from 25.2% to 36.6%, while protocol-defined severe hypoglycemia and hypokalemia were uncommon but still required protocol surveillance [66]. A prospective 54-patient single-arm study linked greater early TG reduction to less deterioration, but cannot establish whether insulin caused either observation or whether lower-risk physiology caused both [67]. These data support implementation safeguards when insulin is clinically indicated; they do not establish routine benefit in euglycemia or definitive effects on organ failure, necrosis, length of stay, mortality, or recurrence. Protocols should therefore be interpreted as safety and implementation tools, not as evidence of comparative clinical efficacy.
When DKA, uncontrolled diabetes, marked hyperglycemia or insulin deficiency is present, regular insulin should follow a validated metabolic protocol with hourly glucose and frequent potassium, phosphate and acid–base assessment. Hypoglycemia and hypokalemia are predictable treatment hazards and may require dose adjustment, electrolyte replacement, and intensive nursing. Dextrose should be added only to prevent or treat hypoglycemia or to permit completion of insulin therapy for a genuine metabolic indication; in an euglycemic patient, carbohydrate delivery may stimulate hepatic TG production and partly counter substrate withdrawal, although this effect has not been quantified in clinical trials. Consistent with this uncertainty, the Endocrine Society suggests against routine insulin infusion in patients without diabetes, advises insulin to normalize glucose when uncontrolled diabetes is present, and advises that any low-dose insulin use be judicious while noting that fasting may account for part of the observed TG decline [68]. In euglycemic, insulin-sufficient patients, intravenous insulin should not be used solely to lower TG; persistent chylomicronemia alone is not an indication (Table 3).
Table 3.
Design-stratified clinical evidence on intravenous insulin in HTG-AP.a
| Study | Design and population | Key results | Interpretation |
|---|---|---|---|
| Berberich et al. [18] | 22 admissions managed with fasting and intravenous fluids; 12 patients also received insulin for hyperglycemia | Mean TG decreased by 69.8% within 48 h; trajectories were similar with and without insulin | Demonstrates a substantial TG decline during conservative care; does not establish a pharmacological TG-lowering effect of insulin in euglycemic patients; mechanistic generalizability is especially limited in classic FCS because the canonical LPL pathway is absent or profoundly impaired [12, 13] |
| Dhindsa et al. [19] | Retrospective comparison: intravenous insulin, n = 51; conservative management, n = 55 | TG decreased by 69% vs 63% on Day 2 and by 85% vs 79% on Day 4; differences were not significant | No additional TG-lowering benefit of insulin was demonstrated. Non-random allocation and higher baseline TG in the insulin group preclude causal conclusions |
| Perez et al. [64] | Before–after evaluation of a standardized intravenous insulin protocol | The protocol shortened the time to the prespecified biochemical target and had manageable safety | Supports protocol standardization when insulin is otherwise clinically indicated; does not demonstrate improvement in organ failure, length of stay or mortality; shorter time to a biochemical target does not establish clinical effectiveness or preferred treatment status |
| Ibarra [63] | Before–after comparison, 20 vs 20 patients | TG <5.6 mmol/L (<500 mg/dL) was achieved in 85% vs 50% of patients | Suggests improved process consistency with a structured order set; the small non-randomized study does not establish pancreatitis-outcome benefit or generalizability |
| Yacine et al. [66] | Multicenter before–after study, n = 466 | No advantage in TG-target attainment, ICU stay or hospital stay; mild hypoglycemia occurred in 36.6% vs 25.2%; hypokalemia was uncommon | Provides a large real-world estimate of protocol feasibility and safety but does not demonstrate patient-centered benefit or superiority over supportive care |
FCS, familial chylomicronemia syndrome; ICU, intensive care unit; LPL, lipoprotein lipase; TG, triglyceride.
Heparin: transient enzyme release is not durable TG clearance
Heparin releases endothelial-bound LPL into plasma, creating a short-lived increase in measured lipolytic activity. Continuous exposure then depletes tissue stores and removes LPL from its physiological endothelial location. In a controlled human kinetic study, continuous intravenous heparin reduced serum lipolytic activity and caused chylomicron accumulation rather than durable clearance [69]. Like insulin-mediated LPL activation, this mechanism requires residual functional LPL and is therefore still less plausible in classic FCS. Transient enzyme release, bleeding risk in inflamed or necrotic tissue, and absence of clinical benefit make heparin unsuitable for TG lowering.
Retrospective comparisons remain difficult to interpret because heparin dose, concomitant drugs, and baseline severity differ. In a 2024 propensity-matched study, insulin and low-molecular-weight heparin (LMWH) plus bezafibrate did not differ significantly in TG-lowering efficiency, complications or persistent organ failure; non-random treatment selection and the composite LMWH–fibrate regimen precluded attribution of any effect to heparin [70]. The definitive modern test is the 13-centre randomized trial of 533 adults with AP and TG 11.3–40.1 mmol/L (1,000–3,550 mg/dL). LMWH plus insulin did not reduce new organ failure or death compared with insulin alone (25.0% vs 28.3%; risk ratio (RR) 0.89, 95% CI 0.67–1.17), and both groups reached TG <5.6 mmol/L (<500 mg/dL) in a median of 2 days [11]. Thus, heparin added neither a clinically meaningful effect nor faster biochemical clearance.
A 2026 latent-class post-hoc analysis reported a statistically significant interaction suggesting benefit in a high-stress subphenotype, but it was not the prespecified primary treatment comparison, used data-driven class formation, and conflicts with the overall null trial [71]. It is appropriate for prospective hypothesis testing, not bedside selection. Anticoagulation remains indicated for ordinary prevention or treatment of venous thromboembolism; it should not be escalated for TG lowering.
TPE: rapid biochemical clearance without established clinical benefit
TPE rapidly removes circulating chylomicrons and VLDLs, but the relevant comparison is with active conservative treatment rather than with no clearance. Fasting, fluid therapy, and correction of metabolic stress also produce a steep early TG decline, while rebound after TPE may result from redistribution and continued lipoprotein production. Evidence must therefore be interpreted according to study design, population, comparator, clinical vs biochemical endpoints, precision, and susceptibility to indication and timing bias (Table 4). The only completed randomized comparison enrolled 22 patients expected to have a non-severe course and compared TPE with insulin. Mean 24-h TG reduction was 67% vs 53% (P = 0.07), and median time to TG <10 mmol/L (<885 mg/dL) was 1 vs 2 days (P = 0.25). A study-defined severe course occurred in 2/11 patients in each group, median hospital stay was nine days in both groups, and no deaths occurred [9]. Randomization minimizes confounding, but the selected population and very small event count preclude claims of clinical equivalence or exclusion of benefit in patients with early organ failure.
Table 4.
Design-stratified comparative evidence on TPE in HTG-AP.a
| Study/evidence tier | Design, population and comparator | Key outcomes | Interpretation and synthesis weight |
|---|---|---|---|
| Randomized: Gubensek et al. [9] | Randomized controlled trial, n = 22; predicted non-severe HTG-AP; TPE vs insulin | 24-h TG reduction: 67% vs 53% (P = 0.07); severe course: 2/11 in each group; hospital stay: 9 vs 9 days; no deaths | Highest causal weight, but severely underpowered for clinical events. Neither biochemical superiority nor clinical benefit of TPE was demonstrated |
| Prospective adjusted: Cao et al. [10] | Prospective 28-center cohort, n = 267; TPE, n = 56; 47 propensity-matched pairs | Organ-failure-free days to Day 14: 12 vs 13; adjusted difference 0.00 (95% CI −1.00 to 1.00; P = 0.94); 60-day mortality: 3/47 vs 2/47 | Strongest direct patient-centered observational evidence; no clinical benefit signal. Residual confounding by indication and ICU allocation remains possible |
| Prospective organ-failure cohort: Wang et al. [73] | Multicenter PERFORM cohort with organ failure, n = 122; TPE, n = 46; medical treatment, n = 76 | No faster organ-failure resolution: adjusted HR 1.07 (95% CI 0.68–1.68; P = 0.777); ICU admission: 97.8% vs 65.8% | Direct evidence in patients with organ failure, but treatment was non-randomized, and the estimate was imprecise |
| Matched multicenter: Staudacher et al. [72] | Retrospective multicenter cohort; 60 matched pairs | Death or organ failure: 8/60 vs 5/60; median hospital stay: 12 vs 9 days | No adjusted clinical benefit signal; interpretation is limited by few events and residual confounding |
| Global database: Amin et al. [75] | Retrospective database study, n = 14,188; 412 propensity-matched pairs | TG <500 mg/dL: 81% vs 40%; organ failure at 1 week: 4.4% vs 3.3%; mortality: 4.4% vs 6.3% at 30 days and 5.3% vs 7.8% at 3 months | Demonstrates greater biochemical target attainment, but coding limitations, a 3-day exposure window and unmeasured bedside severity preclude causal interpretation of the clinical outcomes |
| Single-center matched: Qi et al. [76] | Ten-year retrospective cohort, n = 608; lipid apheresis, n = 123; 65 matched pairs | More rapid TG reduction without additional improvement in severity or inflammatory outcomes | Large contemporary cohort; faster biochemical clearance without improvement in severity or inflammatory outcomes adds to the futility signal for routine TPE. Residual confounding remains, and no treatment-selection TG threshold was validated |
| Earlier retrospective comparisons: Araz et al. [65], Zheng et al. [74], Hutchison et al. [80] | TPE or mixed apheresis vs insulin or standard medical treatment; treatment was influenced by severity, availability and local practice | Apheresis generally accelerated early TG reduction but did not consistently improve organ failure, local complications, hospital course or mortality | Concordant biochemical signal but low causal weight because of small samples, baseline imbalance, mixed apheresis methods, and limited adjustment |
CI, confidence interval; HTG-AP, hypertriglyceridemia-associated acute pancreatitis; ICU, intensive care unit; TG, triglyceride; TPE, therapeutic plasma exchange.
Prospective and multicenter adjusted studies provide more direct clinical evidence but remain non-randomized. In the 28-centre PERFORM analysis, 56 of 267 patients underwent plasmapheresis, with propensity matching generating 47 pairs. Median organ-failure-free days to Day 14 were 12 ves 13, with a median difference of 0.00 days (95% CI −1.00 to 1.00, P = 0.94); 60-day mortality was 3/47 vs 2/47, while intensive-care admission was more frequent after TPE (44/47 vs 24/47) [10]. The PHIP-JuGa-Study similarly reported death or organ failure in 8/60 TPE recipients vs 5/60 matched controls and a median hospital stay of 12 vs 9 days [72]. Among PERFORM participants with organ failure at enrolment, TPE did not accelerate resolution by Day 14 compared with medical treatment (46 vs 76 patients; adjusted hazard ratio (HR) 1.07, 95% CI 0.68–1.68; P = 0.777) [73]. Another retrospective comparison found faster early TG reduction without improvement in computed tomography (CT) severity, local complications, or mortality [74]. Although these studies consistently address clinically relevant outcomes, their nonidentical endpoints and residual treatment-selection and time-dependent confounding limit causal inference.
Large retrospective cohorts improve precision but provide weaker control of treatment allocation and timing. A TriNetX analysis identified 14,188 database-defined cases and compared 412 propensity-matched pairs. TPE was associated with TG <5.6 mmol/L (<500 mg/dL) at 1 week in 81% vs 40%, but organ failure was similar (4.4% vs 3.3%), and neither 30-day nor 3-month mortality differed significantly [75]. A 2026 single-center 10-year cohort included 608 patients, of whom 123 underwent lipid apheresis, and generated 65 matched pairs. Triglyceride-stratified analyses confirmed rapid biochemical lowering but did not establish additional improvement in disease severity or inflammation [76]. Together with the preceding comparative studies, this constitutes a contemporary futility signal for routine TPE: biochemical acceleration has not translated into improved patient-centered outcomes. These cohorts reduce random error but remain vulnerable to coding misclassification, broad treatment windows, incomplete physiological severity data, and residual indication bias.
TPE is invasive and resource-intensive, requiring central vascular access, anticoagulation, an apheresis platform, replacement fluid, trained staff and close hemodynamic, electrolyte and coagulation monitoring. Complications include vascular-access infection or thrombosis, bleeding, hypotension, fluid and electrolyte disturbances, citrate-related hypocalcemia or toxicity, allergic or transfusion reactions, coagulation-factor depletion, and circuit failure [77]. No modality, timing strategy or TG threshold has demonstrated superior patient-centered outcomes. TPE is not a substitute for standard pancreatitis care and should not be embedded as a routine third tier of acute TG-lowering management.
Phenotype-specific evidence remains limited to case reports and small series. Unlike insulin- or heparin-mediated LPL effects, extracorporeal chylomicron removal does not require residual LPL activity and is therefore mechanistically feasible in classic FCS. This distinction may inform discussion of an exceptional intervention when a separate clinical indication has been established, but FCS does not itself establish that indication: chylomicron production continues, and a single-patient report of chronic prophylactic TPE cannot establish prevention of recurrent pancreatitis [78]. Pregnancy alters procedural and pharmacological trade-offs, but a 2024 report of two FCS pregnancies managed with plasma exchange demonstrates feasibility and successful individual outcomes rather than comparative maternal, fetal, or pancreatitis benefit [79]. Conversely, favorable outcomes in a retrospective cohort managed without TPE do not establish equivalence but further illustrate that routine benefit has not been demonstrated [80].
Neither a striking TG concentration, visibly lipemic plasma, failure to reach an arbitrary TG target, metabolic instability, insulin contraindication, pregnancy, nor FCS constitutes an evidence-based indication for TPE. At most, an exceptional, individualized multidisciplinary discussion may be considered in two narrowly defined settings: (i) a selected pregnancy-associated case with maternal–fetal deterioration despite optimized obstetric, metabolic and organ support and constrained alternatives; or (ii) a genuinely refractory, life-threatening presentation with persistent or rapidly worsening organ failure despite documented organ-specific support and correction of shock, hypoxemia, acidosis, DKA, hyperglycemia, electrolyte abnormalities, and other immediately reversible drivers. These scenarios are retained only to describe circumstances in which multidisciplinary clinicians may deliberate on an unproven intervention; they should not be interpreted as evidence-based indications or recommendations. The ongoing PERFORM-R registry-based randomized trial enrols patients with early organ failure and uses organ-failure-free days rather than TG decline as its primary endpoint [81].
Post-acute phenotyping: the purpose is to prevent the next attack
Phenotyping during the inflammatory and fasting phase is unreliable. The definitive assessment should begin once oral intake, glycaemia, and acute organ dysfunction have stabilized, usually with an early post-discharge visit and repeat fasting testing after 4–12 weeks. The clinical question is not merely ‘are TG still high?’ but ‘which particles and which clearance defect are producing the persistent risk?’ At minimum, the assessment should include fasting TG, total cholesterol, HDL-C, directly measured or calculable non-HDL-C, apoB, glycated hemoglobin (HbA1c)/fasting glucose, thyroid and renal indices, liver tests, alcohol history, body-weight trajectory, pregnancy status when relevant, and a complete medication review.
FCS and MCS are distinct biological disorders, with intermediate phenotypes
FCS and MCS share fasting chylomicronemia but should not be described as opposite ends of a single biological continuum (Table 5). Classic FCS is an autosomal-recessive LPL-pathway disorder in which biallelic pathogenic variants in LPL, apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1) or lipase maturation factor 1 (LMF1) abolish or profoundly impair canonical lipolysis. TG is typically persistent, often ≥ 10 mmol/L (≥ 885 mg/dL) despite correction of secondary factors; onset is frequently early; pancreatitis, recurrent abdominal pain, eruptive xanthomata, or lipemia retinalis may occur; and body mass index (BMI) and apoB tend to be lower. Fibrates and prescription omega-3 fatty acids usually produce minimal or inconsistent TG lowering because they cannot restore absent LPL-mediated chylomicron clearance. In contrast, MCS is a complex polygenic/multifactorial disorder in which common TG-raising alleles, sometimes together with one heterozygous rare pathogenic variant, interact with obesity, insulin resistance or type 2 diabetes, alcohol, pregnancy, renal or endocrine disease, or medication exposure. TG fluctuates more, apoB is generally higher because VLDL/remnant particle number is greater, and correction of secondary drivers plus fibrate or prescription omega-3 therapy retains mechanistic plausibility when residual LPL function remains. One heterozygous pathogenic LPL-pathway variant alone indicates susceptibility and does not establish FCS [12–13, 24–26, 82–83]. Even genetically confirmed FCS is not by itself an acute TPE indication; the phenotype-specific procedural evidence remains case-level [78].
Table 5.
| Feature | FCS more likely | MCS more likely | Clinical caveat and evidence |
|---|---|---|---|
| TG trajectory | Persistent, often ≥10 mmol/L (≥885 mg/dL), beginning in childhood or youth and remaining high after correction of secondary factors | Markedly variable; may fall below the chylomicronemia range after control of diabetes, alcohol use, excess weight, or causative medications | Trajectories overlap; assess serial fasting values after recovery [12, 24, 45] |
| Pancreatitis history | May begin early and recur, sometimes before metabolic comorbidity develops | Usually follows one or more secondary ‘second hits’; recurrence remains possible when follow-up TG stays high | Previous AP increases suspicion but is not specific for FCS [5, 24, 39] |
| BMI and diabetes | BMI is often lower; diabetes, when present, may result from recurrent pancreatitis or pancreatic injury | Obesity, insulin resistance, type 2 diabetes, steatotic liver disease and hypertension are common | Neither BMI nor diabetes is diagnostic; variant-positive MCS may have an intermediate phenotype [12, 24, 82, 83] |
| ApoB and particle pattern | Supportive pattern: apoB <1.0 g/L (100 mg/dL) and TG: total-cholesterol ratio >3.5 using mmol/L or >8 using mg/dL | ApoB ≥1.0 g/L and a lower TG: total-cholesterol ratio favor a VLDL/remnant-rich pattern | Supportive, not diagnostic. Calculated LDL-C is unreliable in chylomicronemia; ASCVD risk reflects apoB, remnants, and conventional risk factors [24, 82, 83, 93] |
| Response to conventional TG-lowering therapy | Fibrates and prescription omega-3 usually produce minimal or inconsistent TG reduction | Fibrates and prescription omega-3 may lower TG when residual LPL activity remains and secondary factors are controlled | Drug response is supportive, not diagnostic, and should be verified. No conventional class has validated AP-prevention efficacy [24, 94, 95] |
| Clinical probability scores | Moulin score ≥10: very likely FCS; NAFCS ≥60: definite FCS; NAFCS ≥45: likely FCS | Moulin score ≤9 or NAFCS <30 lowers FCS probability but does not establish MCS; NAFCS 30–44 is indeterminate | These are post-acute probability tools, not acute-severity or treatment-selection rules. Validation populations differ; discordant findings may warrant genetic testing [84–89] |
| Genetics | Compatible biallelic pathogenic variants in LPL, APOC2, APOA5, GPIHBP1, or LMF1 establish molecular FCS | Polygenic susceptibility, with or without one heterozygous rare pathogenic variant; variant-positive MCS may have an intermediate phenotype | A single heterozygous pathogenic variant does not diagnose FCS; interpret findings with phenotype, secondary factors, polygenic burden and family data [13, 25, 26, 82, 83, 93] |
Cohort-specific O’Dea cut-offs—apoB-100 < 0.772 g/L (77.2 mg/dL) and LDL-C < 1.01 mmol/L (39.2 mg/dL)—may provide additional support but should not be treated as universal diagnostic thresholds [24].
AP, acute pancreatitis; APOA5, apolipoprotein A5; apoB. apolipoprotein B; APOC2, apolipoprotein C2; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; FCS, familial chylomicronemia syndrome; GPIHBP1, glycosylphosphatidylinositol-anchored HDL binding protein 1; LDL-C, low-density lipoprotein cholesterol; LMF1, lipase maturation factor 1; LPL, lipoprotein lipase; MCS, multifactorial chylomicronemia syndrome; NAFCS, North American FCS; TG, triglyceride; VLDL, very-low-density lipoprotein.
Intermediate or ‘FCS-like’ phenotypes are clinically important, but they do not erase the fundamental molecular distinction. Variant-positive MCS usually combines a single heterozygous pathogenic variant with polygenic burden and secondary drivers. In the 2024 United Kingdom (UK) registry of 154 patients (74 FCS and 80 MCS), variant-positive MCS had pancreatic and cardiometabolic features intermediate between classic FCS and variant-negative MCS [82]. The 2025 Italian LIPIGEN cohort of 169 patients (57 FCS, 51 variant-positive MCS, and 61 variant-negative MCS) likewise identified heterozygous variants across LPL, APOA5, LMF1, GPIHBP1, and other genes within MCS [83]. In another molecular cohort, 8.8% of patients classified as MCS had sustained refractory hypertriglyceridemia that behaved clinically as an FCS-like phenotype [12]. These observations justify phenotype-sensitive risk assessment and specialist treatment access, but not reclassification of monoallelic disease as FCS: only compatible biallelic canonical-pathway pathogenic variants establish molecular FCS [12, 13, 25, 26, 82, 83].
ApoB is particularly useful because each VLDL/remnant particle contains one apoB molecule, whereas chylomicrons contain apoB-48 and may carry enormous TG mass with relatively few particles. A very high TG concentration with low apoB therefore supports a chylomicron-dominant phenotype, while higher apoB suggests VLDL-rich MCS and greater atherosclerotic cardiovascular disease (ASCVD) relevance. In the O’Dea clinical-profile analysis, study-specific cut-points favoring FCS were apoB-100 < 0.772 g/L (77.2 mg/dL) and ultracentrifugally measured low-density lipoprotein cholesterol (LDL-C) < 1.01 mmol/L (39.2 mg/dL) [24]. These are cohort- and method-specific discriminators, not universal diagnostic limits. There is no universally validated definition of ‘low LDL-C’ for FCS, and calculated LDL-C is unreliable in marked hypertriglyceridemia; the assay or measurement method must therefore be reported. For practical phenotyping, a TG: total-cholesterol ratio >3.5 when both concentrations are expressed in mmol/L or >8 when expressed in mg/dL, together with apoB <1.0 g/L (100 mg/dL), supports FCS over MCS. These findings modify pre-test probability and the need for genetic testing; they are not stand-alone diagnostic or treatment thresholds.
The dominant complication profiles also differ. Classic FCS is characterized principally by recurrent pancreatitis, abdominal pain, chronic pancreatic injury, and the nutritional burden of lifelong fat restriction. MCS more often clusters with obesity, insulin resistance, type 2 diabetes, steatotic liver, hypertension, and a higher apoB/VLDL-remnant burden, making routine ASCVD risk assessment and treatment essential. In the UK registry, adverse cardiometabolic features and unadjusted ASCVD were more frequent in MCS, but the ASCVD difference was no longer significant after adjustment for age, sex, and BMI [82]. LIPIGEN found a 3.4-fold higher risk of AP in FCS but no significant between-group difference in prevalent ASCVD [83]. Therefore, lower observed ASCVD prevalence in some FCS cohorts must not be interpreted as absence of cardiovascular risk [12, 24, 82, 83].
Scores are triage instruments, not diagnostic truth
The European Moulin FCS score is a weighted clinical–biochemical checklist. Its variables are fasting TG >10 mmol/L (>885 mg/dL) on three consecutive measurements; any fasting TG >20 mmol/L (>1,770 mg/dL); any previous TG <2 mmol/L (<177 mg/dL), which subtracts points; absence of a secondary factor; pancreatitis history; unexplained recurrent abdominal pain; absence of familial combined hyperlipidemia; <20% TG reduction with conventional lipid-lowering treatment; and age at symptom onset (<40, <20 or <10 years, with progressively greater weight) [84]. A total score ≥10 means ‘very likely FCS’; ≤9 is classified as unlikely and ≤8 as very unlikely. The instrument estimates pre-test probability and identifies patients for specialist assessment and genetic testing; it does not establish a molecular diagnosis.
The North American FCS (NAFCS) score uses current age and age at hypertriglyceridemia onset, BMI (<25 kg/m² in adults or <85th percentile in children/adolescents), pancreatitis or otherwise unexplained abdominal pain, presence of secondary factors, the recent fasting TG pattern, TG: total-cholesterol ratio and apoB, with interaction terms for strongly concordant features [85]. It is intended for patients aged ≥1 year with TG ≥5.0 mmol/L (≥440 mg/dL); in those aged ≥10 years, the scenarios assume adherent non-response to fibrates and high-dose omega-3 fatty acids. Practical supportive criteria are all recent fasting TG values >9.9 mmol/L (>880 mg/dL), TG: total-cholesterol >3.5 when both concentrations are expressed in mmol/L or >8 when both are expressed in mg/dL, and apoB <1.0 g/L (100 mg/dL). A score ≥60 indicates ‘definite FCS’, ≥45 indicates ‘likely FCS’, 30–44 is uncertain and should prompt consideration of genetic testing, and <30 makes FCS less likely without excluding it. The tool does not provide a score for infants aged <1 year or for pregnancy.
Validation is informative but population-dependent. In the original Moulin development cohorts, the ≥10 threshold had approximately 88% sensitivity and 85% specificity [84]. Independent UK validation included 151 genetically characterized patients (75 FCS and 76 MCS): sensitivity was 96%, specificity 75%, and area under the curve (AUC) 0.88 (95% CI 0.83–0.94) [86]. The NAFCS score was developed with a RAND/University of California, Los Angeles modified-Delphi process and tested against molecularly classified patients; at ≥60, reported specificity was 100%, sensitivity 66.7%, positive predictive value 100% and negative predictive value 95.5%, whereas ≥45 yielded 96.9% specificity and 88.9% sensitivity [85]. In 66 genetically confirmed BALANCE participants, 95.5% scored ≥45, but this positive-only cohort could not estimate specificity in MCS [87]. A Turkish single-center cohort provided external testing [88], and a direct 2026 comparison in persistent chylomicronemia showed differing classification behavior [89]. Thus, the instruments are not interchangeable; performance may shift with ethnicity, genotype, secondary-factor burden and assay timing, and neither a low nor high score replaces clinical judgement.
Neither score replaces genetic confirmation when it is clinically indicated. Genetic testing should include LPL, APOC2, APOA5, GPIHBP1, and LMF1, with copy-number analysis and contemporary variant interpretation. Classic molecular FCS requires compatible biallelic pathogenic variants causing recessive LPL-pathway failure. A single heterozygous pathogenic variant generally supports variant-positive MCS or susceptibility—not FCS—and must be interpreted with secondary factors, polygenic burden, longitudinal TG, apoB, and family segregation [25, 26, 82, 83]. A negative panel does not prove ordinary MCS because structural variants, unrecognized genes, functional defects, or noncanonical diagnoses may remain. Scores, phenotype, family findings, and molecular results must be interpreted together.
Do not miss acquired or syndromic chylomicronemia
Acquired autoimmune chylomicronemia—particularly GPIHBP1 autoantibody syndrome—should be considered when severe chylomicronemia appears abruptly after previously normal TG, accompanies systemic or serological autoimmunity, follows a negative canonical-gene panel, shows unexpectedly low circulating GPIHBP1/LPL, or appears resistant to otherwise appropriate treatment. The original 6-patient study demonstrated that the antibodies block GPIHBP1 binding and endothelial transport of LPL [90]; a subsequent 22-patient characterization confirmed pancreatitis, frequent autoimmune features, low LPL, and possible GPIHBP1 immunoassay interference [91]. Responses to rituximab or other immunosuppression remain case-based. Testing should therefore be performed with specialist lipid/immunology input, and empirical immunosuppression should not precede diagnostic confirmation.
Lipodystrophy-associated chylomicronemia is another distinct differential diagnosis rather than a point on an FCS–MCS continuum. It should be suspected when generalized or regional loss of subcutaneous fat coexists with disproportionate ectopic fat, marked insulin resistance, early or difficult-to-control diabetes, steatotic liver, and severe hypertriglyceridemia. In a 2025 sequencing study, 6 of 182 patients classified as MCS (3.3%) carried heterozygous pathogenic or likely pathogenic PPARG variants compatible with familial partial lipodystrophy type 3 [92]. The mechanism is impaired adipose storage with ectopic lipid and hepatic VLDL overproduction, not biallelic canonical LPL-pathway failure. A compatible phenotype should prompt examination of fat distribution and extension of genetic testing to lipodystrophy genes; treatment should target the specific insulin-resistant and ectopic-fat disorder rather than assume classic FCS. Additional contemporary reports further illustrate the heterogeneity of severe chylomicronemia and the importance of accurate phenotypic and genetic characterization. A Colombian cross-sectional cohort confirmed the clinical variability of FCS in routine practice [93]. Furthermore, phase 2 evidence indicates that angiopoietin-like protein 3 (ANGPTL3) inhibition with evinacumab lowers TG concentrations primarily in patients with residual LPL pathway activity, whereas responses are limited in classical LPL-deficient FCS [94]. A subsequent case report linking successful evinacumab treatment to the identification of a novel pathogenic LPL variant further emphasizes the value of comprehensive molecular diagnosis in patients with persistent chylomicronemia [95]. Familial dysbetalipoproteinemia, nephrotic or renal disease, untreated hypothyroidism, and paraproteinemia remain additional atypical mimics.
Prevention of future attacks: evidence should follow phenotype
The immediate post-discharge interval is a treatment phase
Previous pancreatitis identifies a population at increased risk of subsequent attacks [3, 4]. In HTG-AP, persistence of the underlying metabolic disorder makes structured post-discharge prevention particularly important. Discharge without a prevention plan leaves potentially modifiable risk of a future attack insufficiently addressed (Table 6). Before discharge, the patient should receive a written provisional phenotype-directed nutrition and metabolic plan: very-low-long-chain-fat precautions when FCS is confirmed or strongly suspected, and explicit glycemic, weight, refined-carbohydrate, alcohol, medication, and other secondary-factor actions when MCS is more likely. The plan should also include medication reconciliation and an appointment within 2–4 weeks. The early visit should review symptoms and adherence and remeasure fasting TG and glucose; a second stable-state assessment at 4–12 weeks should complete apoB-based phenotyping and, particularly in MCS, ASCVD risk assessment. Prospective cohorts show that younger patients and those with diabetes have higher risk, while reported repeat attacks often require readmission [5, 39]. Follow-up TG was associated with recurrence in one prospective cohort [5] and one small single-center retrospective study [40], while suboptimal outpatient management was reported among readmitted patients [44]. These studies cannot specify a universally safe TG target, but they make loss to follow-up an identifiable clinical hazard.
Table 6.
Phenotype-directed long-term therapy: dosing, regulatory status and pancreatitis evidence.a
| Strategy | Phenotype and clinical role | Key evidence, regimen and regulatory status | Pancreatitis evidence and contemporary interpretation |
|---|---|---|---|
| Lifelong very-low-long-chain-fat nutrition | Foundation of treatment in classic FCS; temporary fat restriction may be required during marked chylomicronemia in any phenotype | Infant LPL-deficiency cohort and APPROACH baseline data [96, 97]; treatment should be individualized by an expert dietitian | Supported by longitudinal experience, but not by a randomized AP endpoint. In FCS, nutrition must be lifelong and nutritionally complete; persistent TG elevation should not automatically be attributed to dietary non-adherence |
| Weight, glycemia, refined carbohydrates, alcohol, and secondary-factor control | Foundation of MCS management; does not replace substrate restriction in FCS | Prospective recurrence/readmission cohorts and contemporary phenotype registries [5, 39, 40, 44, 82, 83] | Lower follow-up TG was observationally associated with fewer recurrent attacks, but no universal safe TG target has been established. Include apoB, non-HDL-C, and ASCVD risk assessment |
| Conventional pharmacotherapy: fibrate, prescription omega-3 and statin | Fibrate or prescription omega-3 may lower TG in responsive MCS with residual LPL activity; statins are used only when indicated for ASCVD prevention | Phenotype and molecular cohorts and the EVOLVE lipid trial [12, 24, 82, 83, 98]; dosing should follow renal function, interactions, and the applicable product label | No conventional class has adequately powered randomized AP-prevention evidence. Verify the individual TG response; statins reduce cardiovascular risk but do not clear chylomicrons or prevent AP |
| Olezarsen (Tryngolza; APOC3 antisense oligonucleotide) | FCS and trial-defined severe HTG; activity does not require intact canonical LPL function | BALANCE and CORE/CORE2 [14, 16]. US: 80 mg monthly for FCS; 50 mg monthly for severe HTG, with possible escalation to 80 mg. EU: 80 mg monthly for genetically confirmed FCS [108, 109] | BALANCE: 2 vs 11 AP episodes; pooled rate ratio 0.12. CORE/CORE2: 7 vs 22 episodes; mean rate ratio 0.15. Strongest direct phase 3 prevention evidence; no role in acute AP. Monitor hypersensitivity, injection-site reactions, platelets and, where applicable, liver enzymes and hepatic fat |
| Plozasiran (Redemplo; APOC3 small interfering ribonucleic acid) | FCS and persistent chylomicronemia; another APOC3-directed modality rather than a separate therapeutic target | PALISADE and prior-AP analysis; SHASTA-2 provides supportive lipid evidence [15, 104, 105]. Approved US/EU FCS dose: 25 mg every 3 months; 50 mg is not approved [110, 111] | PALISADE: 2 vs 7 AP episodes (4% vs 20%; odds ratio 0.17); prior-AP subgroup: 2/45 vs 5/22 (HR 0.17). Direct phase 3 evidence but based on few events. Monitor glucose/HbA1c, injection reactions, liver enzymes, and LDL-C/apoB |
| Volanesorsen (Waylivra; APOC3 antisense oligonucleotide) | FCS and selected MCS; TG lowering has an LPL-independent component | APPROACH, COMPASS and uncontrolled extension data [100–103]. EU FCS regimen: 285 mg weekly for 3 months, then every 2 weeks [112] | APPROACH: 1 vs 4 AP episodes; COMPASS: 0 versus 5. Findings were exploratory and underpowered for AP. Injection-site reactions and clinically important thrombocytopenia requiring platelet monitoring constrain current use |
| Evinacumab/ANGPTL3 inhibition | Selected MCS with residual LPL activity; poor mechanistic fit for biallelic LPL-pathway loss | Molecularly stratified phase 2 studies and a small phase 2b AP trial [94, 95, 106]; no established AP-prevention regimen | No prevention benefit demonstrated; AP occurred in 3/11 active-treatment vs 1/10 placebo recipients in the phase 2b trial. Phenotype-dependent and not equivalent to APOC3 inhibition |
| Pegozafermin/FGF21 analogue | Investigational option for insulin-resistant, trial-defined severe HTG/MCS | Randomized phase 2 lipid and safety trial [107]; no approved AP-prevention regimen | No completed phase 3 pancreatitis-event trial. It should not be presented as an established alternative to APOC3 inhibition |
ANGPTL3, angiopoietin-like protein 3; AP, acute pancreatitis; apoB. apolipoprotein B; APOC3, apolipoprotein C-III; ASCVD, atherosclerotic cardiovascular disease; FCS, familial chylomicronemia syndrome; FGF21, fibroblast growth factor 21; HDL-C, high-density lipoprotein cholesterol; HTG, hypertriglyceridemia; LPL, lipoprotein lipase; MCS, multifactorial chylomicronemia syndrome; TG, triglyceride.
Diet is essential, but FCS and MCS require different emphases
For classic FCS, lifelong specialist-directed restriction of long-chain fat is the central substrate intervention because dietary fat enters chylomicron production that cannot be normally cleared. This is not a temporary weight-loss diet. It must be individualized by an experienced dietitian to preserve total energy, essential fatty acids, fat-soluble vitamins, protein, growth, and quality of life. Medium-chain TG can sometimes provide calories because they enter the portal circulation rather than chylomicrons, but require clinical supervision. The evidence is mainly physiological and longitudinal rather than randomized: dietary fat modification rapidly controlled chylomicronemia without persistent growth impairment in a 16-patient infant LPL-deficiency series [96], while the 66-patient APPROACH baseline cohort documented persistent biochemical and pancreatic burden despite restrictive diet and frequent conventional drugs [97]. The latter finding cautions against attributing persistent TG elevation to non-adherence when diet cannot compensate for near-absent LPL activity.
For MCS, dietary fat should also be reduced while chylomicronemia persists, but lifelong FCS-level restriction should not be presented as the default after the chylomicronemic phase resolves. Durable management instead targets weight reduction when clinically indicated, glycemic control, restriction of refined or rapidly absorbed carbohydrate, alcohol avoidance, and correction of TG-raising medicines, hypothyroidism, renal disease, and other secondary drivers. Because hepatic VLDL production and residual LPL function remain relevant, a sustainable hypocaloric Mediterranean-style or lower-refined-carbohydrate pattern may be used after TG leaves the chylomicronemic range. MCS also requires routine ASCVD risk assessment and treatment because apoB-containing VLDL/remnant particles coexist with obesity, insulin resistance, type 2 diabetes, steatotic liver, and hypertension more often than in classic FCS [82, 83]. No randomized dietary trial has used repeat HTG-AP events as an endpoint, so precise macronutrient percentages outside FCS should not be presented as validated pancreatitis-prevention thresholds [5, 39, 40, 44].
Conventional pharmacotherapy is phenotype-dependent and has no validated pancreatitis-prevention effect
Fibrates can be useful in MCS with fasting chylomicronemia after renal function, interactions, and pregnancy status are considered: peroxisome proliferator-activated receptor alpha (PPARα)-mediated reduction of hepatic VLDL production and increased LPL expression have a plausible target when residual LPL activity remains. Prescription omega-3 fatty acids can also lower TG in MCS, principally by reducing hepatic TG synthesis and VLDL secretion, with a smaller contribution from facilitated particle clearance. In classic molecular FCS, however, responses to both classes are usually minimal or inconsistent: fibrates cannot restore absent canonical LPL activity, and reduced VLDL production does not correct the fundamental failure of chylomicron clearance. Response should therefore be measured rather than assumed [12, 24, 82, 83]. The randomized EVOLVE omega-3 trial established dose-related lipid effects in severe hypertriglyceridemia, not prevention of AP [98].
Statins should be prescribed according to standard ASCVD risk and apoB/non-HDL-C/LDL-C burden, rather than as treatment for the height of the TG concentration. This distinction is particularly important in MCS, where apoB-containing VLDL/remnant particles and metabolic comorbidities can confer substantial atherogenic risk [82, 83]. Statins do not restore chylomicron lipolysis, do not treat classic FCS or chylomicronemia, and have not been shown to prevent HTG-AP or repeat attacks. Their treatment indication and endpoint are cardiovascular, not pancreatic. A retrospective 2025 HTG-AP study found no additional early TG benefit from evolocumab, likewise illustrating why therapy directed at the low-density lipoprotein receptor should not be repurposed for acute chylomicron clearance [99].
The absence of class-specific AP trials is an important evidence boundary. Observational cohorts linking lower follow-up TG with fewer repeat attacks cannot determine whether a fibrate, prescription omega-3 formulation, weight or glycemic change, alcohol avoidance, statin use, or adherence produced the association [5, 40, 44]. Conventional treatment should therefore be prescribed for a defined phenotype and target: fibrate or prescription omega-3 therapy for TG lowering in responsive MCS; statins for ASCVD risk reduction; and neither class has proven prevention of pancreatitis. In classic FCS, minimal response to conventional therapy should prompt confirmation of phenotype and consideration of eligible targeted treatment rather than indefinite escalation of LPL-dependent drugs.
ApoC-III inhibition has the strongest direct phase 3 pancreatitis-event evidence
ApoC-III inhibits both LPL-dependent lipolysis and LPL-independent hepatic uptake of TG-rich particles. Suppressing hepatic APOC3 can therefore enhance clearance even when the canonical LPL pathway is profoundly impaired. Among targeted approaches, this mechanistic breadth is now reinforced by the most persuasive direct randomized evidence for reducing pancreatitis events across genetically confirmed FCS and broader persistent or trial-defined severe chylomicronemia. Clinical use is no longer limited to emerging compounds: olezarsen (Tryngolza) and plozasiran (Redemplo) are approved APOC3-directed agents, with monthly vs once-every-3-month dosing and distinct jurisdiction-specific indications and monitoring requirements.
First-generation volanesorsen established APOC3 target validity through the marked TG reduction observed in the FCS APPROACH trial, but its pancreatitis evidence must be separated by trial. APPROACH randomized 66 patients with FCS to volanesorsen 300 mg subcutaneously once weekly or placebo for 52 weeks: four AP episodes occurred in three placebo recipients vs one episode in one volanesorsen recipient; in a post-hoc subgroup with at least two attacks in the preceding 5 years, 0/7 volanesorsen recipients vs 3/4 placebo recipients experienced an attack [100]. COMPASS enrolled 114 patients, predominantly with multifactorial chylomicronemia, using the same 300-mg weekly dose for 26 weeks: five adjudicated AP episodes occurred in three of 38 placebo recipients and none in 75 volanesorsen recipients [101]. Two 2023 uncontrolled longer-term reports—the UK Early Access to Medicines Scheme and an open-label extension—documented sustained TG lowering and pancreatitis experience, but cannot establish comparative prevention [102, 103]. These were exploratory or uncontrolled, small-event comparisons rather than adequately powered AP-primary analyses. Frequent injection-site reactions and clinically important thrombocytopenia requiring intensive platelet monitoring constrain the contemporary role of volanesorsen despite substantial TG lowering.
Olezarsen, an N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide, provides direct randomized FCS event evidence. At 6 months, the 80-mg dose significantly reduced TG vs placebo; the 50-mg dose did not meet statistical significance for the primary TG endpoint. BALANCE randomized 66 adults with genetically confirmed FCS to olezarsen 80 mg, 50 mg, or placebo once monthly for 53 weeks. Eleven AP episodes occurred in seven placebo recipients, compared with one episode in each olezarsen group; the pooled event-rate ratio was 0.12 (95% CI 0.02–0.66), corresponding to an approximately 88% relative rate reduction [14]. The absolute event count was small and pooling both doses for the AP analysis was an important analytic choice, but the independently adjudicated clinical signal is substantially more persuasive than a TG surrogate alone.
CORE-TIMI 72a and CORE2-TIMI 72b extended olezarsen to 1,061 adults with trial-defined severe hypertriglyceridemia, randomizing monthly 50- or 80-mg doses against placebo for 12 months. Both olezarsen doses produced substantial placebo-adjusted TG reductions at 6 months. Across the pooled trials, seven AP episodes occurred in five of 705 olezarsen-treated participants vs 22 episodes in 17 of 356 placebo recipients (1.01 vs 6.23 events per 100 patient-years). The reported mean rate ratio was 0.15 (95% CI 0.05–0.40; P < 0.001), an approximately 85% relative rate reduction [16]. Overall adverse-event rates were similar, but liver-enzyme elevations, platelet counts below 100,000/µL, and dose-dependent increases in hepatic fat were more frequent or greater with the 80-mg dose. These trials provide the strongest current direct evidence for AP prevention beyond molecularly confirmed FCS.
Plozasiran uses hepatocyte-targeted ribonucleic acid interference to suppress APOC3 through a small interfering ribonucleic acid (siRNA); it is therefore another modality within APOC3-directed therapy, not a separate therapeutic-target category. PALISADE, rather than the phase 2 SHASTA-2 lipid study, provides the principal clinical-event evidence. PALISADE randomized 75 adults with persistent chylomicronemia to plozasiran 25 mg, 50 mg or placebo subcutaneously once every 3 months for 12 months. At Month 10, median TG fell by approximately 80% and 78% with 25 and 50 mg, respectively, vs 17% with placebo. Two AP episodes occurred in 2 of 50 plozasiran recipients (4%) vs seven episodes in 5 of 25 placebo recipients (20%); the odds ratio was 0.17 (95% CI 0.03–0.94), or approximately 83% lower odds [15]. A 2026 post hoc analysis restricted to 67 PALISADE participants with previous AP reported recurrent AP in 2/45 pooled plozasiran recipients vs 5/22 placebo recipients (HR 0.17, 95% CI 0.03–0.87); because it re-analyzed the same trial, it refines rather than independently replicates the signal [104]. SHASTA-2 supports durable TG and remnant-lipoprotein lowering in severe hypertriglyceridemia but was not designed to establish AP prevention [105]. Hyperglycemia, headache, nausea, and injection-site reactions are relevant product-specific safety signals.
Taken together, phase 3 data establish APOC3 suppression as the targeted strategy with the most convincing direct evidence of fewer pancreatitis events. They do not establish use during an acute attack, eliminate diet or secondary-factor control, or prove equivalent efficacy and safety among agents. Durability of event reduction, long-term hepatic, platelet, glycemic and reproductive safety, availability, cost-effectiveness, broader indications beyond current labels, and phenotype-specific selection between an antisense oligonucleotide and an siRNA remain unresolved.
ANGPTL3 inhibition is LPL-dependent and not equivalent to APOC3 suppression
ANGPTL3 inhibition relieves inhibition of LPL and endothelial lipase and therefore depends materially on residual LPL-pathway activity. In a molecularly stratified phase 2 trial, evinacumab produced heterogeneous responses, did not meet the prespecified primary endpoint in the cohort without LPL-pathway mutations, and produced little clinically meaningful TG lowering in the FCS cohort [94]. Genotype-tracer analysis likewise found TG reductions below 20% with proven or likely biallelic LPL loss [95]. Thus, this strategy was ineffective where the canonical pathway was biallelically disabled and should be considered phenotype-dependent rather than an alternative with evidence comparable to APOC3 inhibition.
The 2025 phase 2b pancreatitis trial enrolled only 21 participants and had substantial discontinuation. Positively adjudicated AP occurred in 3/11 evinacumab recipients and 1/10 placebo recipients; all active-group events occurred at least 58 days after the last dose, when drug concentrations were minimal [106]. That pharmacokinetic observation is hypothesis-generating but cannot overcome an underpowered, directionally unfavorable clinical comparison. Evinacumab may lower TG in selected MCS with residual LPL activity, but it has not demonstrated prevention of pancreatitis and should not be grouped with APOC3-directed agents.
Fibroblast growth factor 21 analogues and other emerging strategies remain investigational
Pegozafermin, a long-acting fibroblast growth factor 21 (FGF21) analogue, reduced TG and improved several metabolic measures in a randomized phase 2 trial of a study-defined severe-hypertriglyceridemia population [107]. The trial was designed for lipid efficacy and safety, not repeat AP events. FGF21 biology may be attractive in insulin-resistant MCS with steatotic liver, but there is no direct evidence in FCS and no completed phase 3 pancreatitis-event trial. FGF21 analogues therefore remain investigational for pancreatitis prevention. Gene replacement/editing, lomitapide and other production-directed approaches likewise remain specialist or trial options rather than established equivalents to APOC3 inhibition.
Approval status, dose, and clinical positioning are jurisdiction-specific
As of 1 August 2026, Tryngolza (olezarsen) is approved by the US Food and Drug Administration (FDA) as an adjunct to diet to reduce TG in adults with FCS at 80 mg subcutaneously once monthly and, after the June 2026 label expansion, to reduce TG and the risk of AP in adults with severe hypertriglyceridemia (TG ≥5.6 mmol/L (≥500 mg/dL)) at 50 mg once monthly, with escalation to 80 mg when tolerated and additional TG reduction is clinically indicated [108]. The European Union (EU) authorization is narrower: 80 mg once monthly for adults with genetically confirmed FCS, without the broader severe-hypertriglyceridemia indication [109]. Hypersensitivity, injection-site reactions and platelet reduction remain relevant; for the US severe-hypertriglyceridemia indication, liver-enzyme and hepatic-fat monitoring is especially important, particularly at 80 mg.
Redemplo (plozasiran) is FDA-approved (18 November 2025) and EU-authorized (19 June 2026) as an adjunct to diet for adults with FCS at 25 mg subcutaneously once every 3 months; the 50-mg dose studied in PALISADE is not an approved FCS regimen [110, 111]. The EU indication does not require genetic confirmation, whereas neither the US nor EU label extends to the broader severe-hypertriglyceridemia population as of the review cut-off. Hyperglycemia (including small mean rises in fasting glucose and HbA1c), headache, nausea, and injection-site reactions were common safety signals; liver enzymes and LDL-C/apoB may also increase and should be interpreted in the full metabolic phenotype. Quarterly dosing is a practical distinction from monthly olezarsen, but there is no head-to-head evidence that one APOC3 modality is clinically superior.
Waylivra (volanesorsen) is authorized in the EU as an adjunct to diet for adults with genetically confirmed FCS at high risk of pancreatitis after inadequate response to diet and TG-lowering therapy. Its EU regimen is 285 mg subcutaneously once weekly for 3 months and then every 2 weeks [112]. Its role is more restricted because clinically important thrombocytopenia requires intensive platelet-guided monitoring and dose interruption. Regulatory authorization, local access, and reimbursement are not interchangeable with trial eligibility, and none of these agents is a treatment for the acute AP episode.
Secondary drivers and special populations
Diabetes and DKA
Insulin deficiency simultaneously increases adipose lipolysis, hepatic fatty-acid delivery, and VLDL production while reducing LPL-mediated clearance (Table S2). DKA may therefore precipitate chylomicronemia and AP, while AP stress may precipitate DKA; temporal direction is often bidirectional. In a 2025 matched cohort of 90 patients with DKA, concomitant AP was associated with higher TG and total cholesterol, and both lipids independently predicted DKA-AP [113]. A 2025 propensity-matched analysis of 289 HTG-AP patients, 23 with DKA, found more persistent organ failure and longer ICU stay in the DKA group but no clear mortality difference [114]. Another 221-patient cohort reported DKA in 14.9%, associated with type 2 diabetes, higher HbA1c, and severe AP [115]. These studies support DKA as a severity-amplifying metabolic phenotype, not an independent indication for TPE.
Treatment priorities are simultaneous: guideline-based DKA insulin and potassium management, moderate reassessment of AP fluids, early organ support and investigation of other etiologies. Lipase may rise in DKA without imaging-confirmed AP; the standard two-of-three diagnostic rule still applies. After recovery, HbA1c, diabetes type, adherence and underlying lipid susceptibility should be reassessed, because normoglycemia alone may not normalize a polygenic MCS phenotype.
Pregnancy
Pregnancy increases VLDL production and progressively raises TG; women with FCS or MCS begin from a susceptible baseline. The strongest contemporary dataset reviewed 116 pregnancies in 49 women with chylomicronemia. At least one gestational AP episode occurred in 42% of women with FCS and 10% with MCS; AP complicated 17% vs 5% of pregnancies, and preterm delivery was more frequent in FCS [116]. A 2025 genetically characterized case further illustrated that heterozygous CREB3L3 variation can coexist with gestational TG above 5,000 mg/dL, AP, and pre-eclampsia, but single-case evidence cannot define comparative management [117].
Management requires maternal–fetal medicine, lipidology, pancreatology, critical care, and dietetics. Very low-fat nutrition with adequate essential fatty acids is first-line; diabetes and hypothyroidism must be treated. Drug decisions depend on gestational age and maternal risk because randomized pregnancy safety data are absent. Insulin is indicated for diabetes/DKA, not automatically for normoglycemic TG lowering. Plasma-exchange reports, including two FCS pregnancies with successful individual outcomes [79], show feasibility and biochemical lowering but provide no comparative evidence that prophylactic or acute TPE improves maternal, fetal, organ, or pancreatitis outcomes. Neither TG concentration, however high, nor visible lipemia alone is an indication. Pregnancy, persistent chylomicronemia, or visible lipemia alone does not identify benefit from TPE. Urgent obstetric and organ-specific critical-care management remains primary. Only a selected pregnancy-associated case with documented maternal–fetal deterioration despite optimized obstetric, metabolic, and organ support and constrained alternatives may prompt an exceptional individualized multidisciplinary TPE discussion. This is a very low-certainty consideration, not routine or prophylactic therapy, and must not delay delivery or established critical-care treatment. Delivery is an obstetric decision, not a lipid procedure.
Alcohol, obesity, and metabolic dysfunction
Alcohol and obesity are not competing labels that make hypertriglyceridemia irrelevant; they can be co-causes. Obesity increases adipose TG substrate and worsens systemic lipotoxicity, as demonstrated in human necrotic material and complementary models [27]. Alcohol increases hepatic VLDL output and sensitizes the pancreas, and was associated with repeat attacks in two observational HTG-AP cohorts [42, 44]. The practical implication is dual attribution and dual prevention: abstinence after an attack, sustainable weight and glycemic management, and repeat TG to reveal the residual phenotype. Calling such cases ‘alcoholic’ or ‘metabolic’ alone loses actionable information.
Propofol and other medicines
Propofol is delivered in a lipid emulsion and can raise TG during prolonged high-dose sedation, but pancreatitis remains uncommon and multifactorial. A 2025 multicenter study included 11,828 ventilated adults; among the 3,922 with TG measured, 21.7% developed TG >4.5 mmol/L (>400 mg/dL) and 1.2% developed AP. AP occurred in 3.2% with vs 0.7% without hypertriglyceridemia, while propofol dose itself was not independently associated; each 1.13-mmol/L (100-mg/dL) TG increment was associated with an 11% higher risk [118]. These data support baseline and serial TG monitoring in prolonged infusion, especially in patients with pre-existing dyslipidemia, and reconsideration of sedation when TG rises substantially. They do not validate a universal discontinuation threshold or prove propofol caused every event.
Other secondary medicines include estrogens, glucocorticoids, retinoids, selected antipsychotics, protease inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and some anticancer therapies. Causality should be assessed by timing, dose, dechallenge, alternative drivers, and baseline phenotype. Removal or substitution is preferred when clinically feasible; a necessary medicine may require tighter metabolic surveillance rather than reflex discontinuation.
Children and adolescents
Fasting chylomicronemia in childhood makes biallelic LPL-pathway disease, autoimmune disease and rare syndromic causes more likely, although obesity and diabetes increasingly produce MCS. The 16-infant LPL-deficiency series showed that a very-low-fat diet controlled chylomicronemia without persistent growth impairment, but biochemical deficiencies occurred and require monitoring [96]. Pediatric acute-treatment evidence is otherwise dominated by small series. Management should prioritize standard AP support, age-appropriate nutrition, family genetic assessment and specialist lipid care; adult insulin or TPE protocols should not be extrapolated solely from body weight, and neither TG concentration, FCS status nor lipemic plasma alone creates a pediatric TPE indication.
An integrated clinical pathway
The pathway in Fig. 2 deliberately separates decisions that are often collapsed. First, confirm AP and obtain TG early while simultaneously searching for biliary, alcohol-related, drug, and metabolic co-causes. Second, use the bedside sequence in Table 2: calculate and timestamp Modified Marshall at presentation and serially, record BISAP and SIRS within 24 h, assign revised Atlanta severity at 48 h, and use APACHE II only as an optional ICU adjunct. Clinical deterioration overrides a reassuring score; AP physiology determines ICU need, not the height of the TG column. Third, provide moderate reassessed fluids, analgesia, early nutrition, and organ support. Fourth, stratify by glycemic status and phenotype: use insulin for DKA, uncontrolled diabetes, marked hyperglycemia, or insulin deficiency. In euglycemic, insulin-sufficient patients, intravenous insulin should not be used solely to lower TG; persistent chylomicronemia alone is not an indication. Do not rank insulin or any other acute intervention by time to a biochemical TG target. In classic FCS, absent or profoundly impaired canonical LPL-pathway function further weakens the TG-lowering rationale for insulin. Do not add heparin for TG lowering. Fifth, do not include TPE as a general third-tier escalation branch. Neither extreme TG, visible lipemia, persistent chylomicronemia, inadequate biochemical response, insulin contraindication, FCS, nor pregnancy alone is an indication. The pathway prioritizes organ-specific and obstetric support; it permits only an off-pathway, exceptional multidisciplinary discussion for a selected pregnancy-associated deterioration or a genuinely refractory, life-threatening presentation.
Figure 2.
Evidence-based pathway for acute care and prevention after recovery. AP, acute pancreatitis; apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; DKA, diabetic ketoacidosis; FCS, familial chylomicronemia syndrome; LPL, lipoprotein lipase; MCS, multifactorial chylomicronemia syndrome; NAFCS, North American FCS score; TG, triglyceride; TPE, therapeutic plasma exchange.
The pathway continues after discharge. Repeat fasting lipids and apoB, correct secondary drivers, and estimate FCS probability with the Moulin score (≥10, very likely FCS) or NAFCS score (≥60, definite FCS; ≥45, likely FCS) [84–89]. Molecular confirmation is pursued when clinical probability is high, scores and phenotype are discordant, or the result would alter management. Prevention is then matched to biology: classic FCS requires lifelong, nutritionally safe, specialist-directed very-low-long-chain-fat nutrition and eligible targeted therapy because fibrates and prescription omega-3 are usually minimally effective; MCS requires weight and glycemic management, restriction of refined carbohydrate, alcohol avoidance and correction of secondary drivers, with fibrate or prescription omega-3 therapy when a measured response is plausible. ApoB/non-HDL-C and standard ASCVD assessment guide statin therapy, particularly in MCS; statins neither treat chylomicronemia nor constitute pancreatitis prevention. An abrupt acquired phenotype, serological autoimmunity, unexpectedly low GPIHBP1/LPL, or a negative canonical-gene panel should prompt specialist assessment for GPIHBP1 autoantibodies. Abnormal fat distribution accompanied by severe insulin resistance, early diabetes, or steatotic liver should prompt evaluation for lipodystrophy. These disorders require cause-specific management rather than reclassification as classic FCS or ordinary MCS. When targeted therapy is considered, APOC3 inhibition is the only class with direct phase 3 pancreatitis-event evidence [14–16]. ANGPTL3 inhibition is not an equivalent alternative: it requires residual LPL-pathway activity and lacks demonstrated pancreatitis prevention [94, 106]. FGF21 analogues remain investigational and are principally relevant to metabolically driven severe hypertriglyceridemia or MCS rather than genetically confirmed FCS [107]. For eligible adults, the prevention pathway distinguishes olezarsen (Tryngolza; 80 mg subcutaneously once monthly for FCS in the US and EU, with a US severe-hypertriglyceridemia regimen of 50 mg once monthly and possible escalation to 80 mg) from plozasiran (Redemplo; 25 mg subcutaneously once every three months for FCS in the US and EU). Selection must follow the applicable label, access conditions and product-specific safety monitoring [108–111].
Evidence gaps and limitations
Evidence for acute treatment remains dominated by small, unblinded or observational studies with inconsistent definitions, variable treatment timing, and substantial confounding by indication. The only completed randomized TPE-vs-insulin trial is underpowered for clinical outcomes, while the most recent 2026 apheresis cohort remains non-randomized [76]. Apheresis studies use different technologies and time origins and incompletely report co-interventions, access complications, and resource requirements. Future acute-treatment studies should use active supportive-care comparators, prespecify metabolic indications, phenotype and organ-failure status, and prioritize organ-failure-free days, complications, mortality, recurrence, harms and resource use. For prevention, phase 3 trials have demonstrated pancreatitis-event reduction with potent APOC3 inhibition in FCS and persistent or trial-defined severe chylomicronemia [14–16]. Unresolved questions concern long-term hepatic, platelet, glycemic, and reproductive safety, durability, adherence, access, cost-effectiveness, selection between approved agents, and broader indications. ANGPTL3-directed treatment and FGF21 analogues still lack phase 3 pancreatitis-event evidence [94, 106, 107].
Conclusions
HTG-AP is a time-dependent clinical diagnosis that requires causal attribution rather than reliance on a single TG threshold. Early measurement of TG and assessment of competing causes support attribution, whereas revised Atlanta classification and serial organ-failure assessment—not TG concentration alone—should determine severity and level of care.
Acute management should prioritize standard pancreatitis care and correction of the metabolic drivers that genuinely require treatment. Intravenous insulin should be reserved for DKA, clinically important insulin deficiency, uncontrolled diabetes, or marked hyperglycemia, rather than used as routine TG-lowering therapy in insulin-sufficient patients. Heparin should not be used for TG lowering. TPE rapidly lowers circulating TG but has not demonstrated established patient-centered benefit and should not be used as routine or rescue TG-lowering therapy. In narrowly defined exceptional circumstances, multidisciplinary clinicians may deliberate on TPE as an unproven intervention, but such scenarios should not be interpreted as evidence-based indications or recommendations.
After recovery, management should shift from acute TG reduction to phenotype-directed prevention. Persistent or recurrent chylomicronemia should prompt structured differentiation of FCS from MCS and other secondary or acquired causes, using clinical phenotype, apoB and related biochemical markers, validated scores as triage tools, and genetic or other targeted testing when appropriate. APOC3 inhibition currently provides the strongest randomized evidence for reducing pancreatitis events in relevant chylomicronemia populations, whereas ANGPTL3- and FGF21-directed approaches remain less established.
The central therapeutic objective is therefore not the fastest possible biochemical normalization of TG, but prevention of organ injury during the acute episode and prevention of subsequent pancreatitis through accurate phenotyping, correction of reversible drivers and evidence-based long-term therapy.
Supplementary Material
Acknowledgements
None declared.
Contributor Information
Serge Chooklin, Surgical Center, Saint Paraskeva Medical Center, Lviv 79000, Ukraine.
Serhii Chuklin, Surgical Center, Saint Paraskeva Medical Center, Lviv 79000, Ukraine.
Supplementary material
Supplementary material is available at Gastroenterology Report online.
Authors’ contributions
Serge Chooklin (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing) and Serhii Chuklin (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing—original draft, Writing—review & editing). All authors read and approved the final manuscript.
Funding
None declared.
Conflicts of interest
None declared.
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