Carmine De Luca (1), Paola Ciciola (1), Guido D'Errico (1), Chiara Caputo (1), Maria Donata Di Taranto (2), Giuliana Fortunato (2), Gabriella Iannuzzo (1), Matteo Di Minno (1), Ilenia Lorenza Calcaterra (1)

(1) Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy.
(2) Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, CEINGE Biotecnologie Avanzate, Naples, Italy.

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Background: Severe hypertriglyceridemia (SHTG), defined by fasting triglycerides (TG) ≥500–1000 mg/dL, is a heterogeneous disorder linked to acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture includes rare biallelic variants causing familial chylomicronemia syndrome (FCS) and the more prevalent polygenic/multifactorial chylomicronemia syndrome (MCS).

Methods: We systematically reviewed PubMed, Embase, Web of Science, and Cochrane CENTRAL (2005–2025) following PRISMA 2020 guidelines. Eligible studies reported genetic data, clinical features, or treatment outcomes in adults with TG ≥500 mg/dL. Data were qualitatively synthesized for genotype, polygenic risk score (PRS), TG levels, metabolic comorbidities, hepatic steatosis, pancreatitis, cardiovascular events, and therapeutic response.

Results: Eleven studies (N > 3,000) were included. FCS due to biallelic LPL, APOC2, GPIHBP1, or LMF1 variants accounted for <5% of cases but showed the highest TG levels (>2800 mg/dL) and pancreatitis prevalence (>70%), confirming its association with a severe, pancreatitis-predominant phenotype. APOA5, APOC3, and APOB variants were associated with intermediate TG elevations, higher prevalence of MAFLD, and variable therapy response. Polygenic hypertriglyceridemia represented ~70–80% of cases, with TG ≈2200 mg/dL and pancreatitis prevalence 15–20%, strongly modulated by metabolic triggers. MAFLD was present in >70% of polygenic cases but rare in monogenic FCS, supporting a “two-hit” model in which hepatic overproduction of TG-rich lipoproteins amplifies systemic TG excess. Interventional trials demonstrated robust TG reductions with APOC3 antisense therapy (−70–80%) and ANGPTL3 inhibition (−50–55%), while GLP-1 receptor agonists significantly reduced hepatic fat (−30–35%) and achieved NASH resolution in up to 59% of patients.

Conclusions: SHTG displays a clear genotype–phenotype gradient: monogenic FCS is strongly linked to recurrent acute pancreatitis, whereas polygenic/MCS forms are tightly associated with MAFLD and metabolic dysfunction. These findings support a precision-medicine approach, where genetic testing and PRS inform therapeutic selection — prioritizing APOC3/ANGPTL3-targeted TG-lowering therapy for FCS and combination strategies (TG-lowering + metabolic agents) for MCS with MAFLD — to reduce pancreatitis recurrence and slow progression of liver disease.