{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:01:08Z","timestamp":1784955668331,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Primary hyperlipoproteinemias represent a heterogeneous group of inherited lipid metabolism disorders characterized by persistent abnormalities in plasma lipoproteins, a markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD) and, in selected phenotypes, acute pancreatitis. Traditionally classified according to the Fredrickson phenotypic system, these disorders are now increasingly understood through a multidimensional framework integrating molecular genetics, intracellular lipid trafficking, inflammatory signaling, and systemic metabolic regulation. Recent advances have identified both monogenic and polygenic determinants underlying disease expression, including pathogenic variants affecting LDLR, APOB, PCSK9, APOE, and lipoprotein lipase pathways, as well as the cumulative contribution of multiple common lipid-associated variants. Furthermore, emerging evidence highlights the role of endoplasmic reticulum stress, oxidative imbalance, adipose\u2013hepatic crosstalk, intestinal lipid absorption, and inflammatory mediators in modulating lipoprotein metabolism and cardiovascular risk. Novel regulators such as angiopoietin-like proteins (ANGPTLs), microRNAs, and pathways involved in cholesterol efflux and remnant lipoprotein clearance have further refined our understanding of disease heterogeneity and therapeutic responsiveness. Familial hypercholesterolemia and familial combined hyperlipidemia exemplify the complex interplay between genetic susceptibility, metabolic dysfunction, and environmental influences that shape phenotype severity and long-term cardiovascular outcomes. Advances in diagnostic strategies, including genetic testing, polygenic risk scores, apolipoprotein profiling, and vascular imaging, have significantly improved risk stratification and personalized management. Simultaneously, innovative therapies\u2014including PCSK9 inhibitors, ANGPTL3-targeted agents, antisense oligonucleotides, and RNA-silencing technologies\u2014are reshaping treatment paradigms and expanding options for high-risk patients. This chapter synthesizes contemporary insights into the pathogenesis of primary hyperlipoproteinemias, emphasizing the transition from traditional lipid-based classification toward precision medicine approaches focused on lifetime cardiovascular risk, molecular characterization, and individualized therapeutic intervention.<\/jats:p>","DOI":"10.3390\/diagnostics16152313","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:05:42Z","timestamp":1784819142000},"page":"2313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding Primary Hyperlipoproteinemias: A Focus on the Pathogenesis and Diagnosis of Familial Hypercholesterolemia and Familial Combined Hyperlipidemia"],"prefix":"10.3390","volume":"16","author":[{"given":"Iris","family":"Bararu-Bojan","sequence":"first","affiliation":[{"name":"Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Vladeanu","sequence":"additional","affiliation":[{"name":"Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Iliescu-Halitchi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5448-7761","authenticated-orcid":false,"given":"Carmen Elena","family":"Plesoianu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Bojan","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5836-1517","authenticated-orcid":false,"given":"Otilia Elena","family":"Frasinariu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2881-3527","authenticated-orcid":false,"given":"Razvan Cosmin","family":"Tudor","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9240-2175","authenticated-orcid":false,"given":"Manuela","family":"Ciocoiu","sequence":"additional","affiliation":[{"name":"Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"Tudor","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Codruta","family":"Iliescu-Hailitchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Bazyani","sequence":"additional","affiliation":[{"name":"Heart Institute GIM Georgescu Iasi, 700503 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9989-1653","authenticated-orcid":false,"given":"Cezar Ilie","family":"Foia","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7050-8430","authenticated-orcid":false,"given":"Oana-Viola","family":"Badulescu","sequence":"additional","affiliation":[{"name":"Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Santulli, G. (2014). Angiopoietin-like proteins: A comprehensive look. Front. 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