Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed scientific literature up to 2025 for studies reporting genetic data, clinical features, or therapeutic outcomes in adults with triglycerides (TG) ≥ 500 mg/dL. Extracted data were synthesized for genotype, polygenic risk score (PRS), TG levels, metabolic comorbidities, hepatic steatosis, pancreatitis, and treatment response. Results: Ten studies (n = 2521) were included. FCS due to biallelic LPL, APOC2, GPIHBP1, or LMF1 variants accounted for 2800 mg/dL) with pancreatitis prevalence (>70%). APOA5, APOC3, and APOB variants were associated with intermediate TG levels and high rates of metabolic dysfunction-associated steatotic liver disease (MASLD). Polygenic hypertriglyceridemia represented ~70–80% of cases, with TG ≈ 2200 mg/dL and pancreatitis prevalence 15–20%, largely modulated by metabolic triggers. MASLD was present in >70% of polygenic cases, supporting a “two-hit” model where hepatic overproduction of TG-rich lipoproteins amplifies TG excess. Interventional trials demonstrated TG reductions with APOC3 antisense therapy (70–80%) and ANGPTL3 inhibition (50–55%), while GLP-1RA significantly reduced hepatic fat (30–35%) and resolved NASH in up to 59% of patients. Conclusions: SHTG displays a genotype–phenotype gradient: FCS is linked to recurrent pancreatitis, whereas polygenic/MCS forms are closely associated with MASLD and metabolic dysfunction. These findings support a precision-medicine approach integrating genetic testing and PRS-guided strategies—prioritizing APOC3/ANGPTL3 inhibitors for FCS and combined TG-lowering plus metabolic therapies for MCS—to reduce pancreatitis recurrence and liver disease.

Familial Hypercholesterolemia (FH) is a common genetic disorder characterized by elevated LDL-cholesterol levels and an increased risk of premature cardiovascular disease. While pathogenic variants in LDLR, APOB, and PCSK9 are well-established causes, a substantial proportion of clinically suspected FH cases do not carry either pathogenic variants or rare variants of uncertain significance in these genes (FH/V−/USV−). This study aimed to characterize the metabolome/lipidome of genetically confirmed heterozygous FH (HeFH) patients compared to FH/V−/USV−, seeking to identify specific alterations associated with genetic status and phenotypic variability. Untargeted high-resolution mass spectrometry (UHPLC-Q-Exactive-MS)-based lipidomics and nuclear magnetic resonance-based metabolomics were performed on plasma samples of FH patients (n = 20 HeFH and n = 19 FH/V−/USV−) towards healthy controls (n = 22). PLS-DA analysis revealed group-level separation, suggesting differences in the circulating metabolome/lipidome. As expected, most of identified lipid classes were higher in both FH groups compared to normolipidemic controls. Notably, significant lipids (VIP > 1, p < 0.05) showed potential in distinguishing HeFH and FH/V−/USV− patients, particularly sphingomyelins. These data were confirmed by multivariable regression analysis controlling for age, sex, and lipid-lowering therapy as well as by ROC analysis. The evidence of a distinct lipidome signature in the HeFH subgroup may relate to the increased cardiovascular risk of HeFH patients compared to patients without pathogenic variants.