シトステロール血症

Sitosterolemia is a rare genetic disease caused by loss of function homozygous or compound heterozygous mutations in either ABCG5 or ABCG8 genes encoding sterols transporters. The net effect leads to an increase in sterols intestinal absorption and a reduction in sterols bile excretion causing sterols accumulation in plasma and tissues. The spectrum of clinical manifestations is variable and sitosterolemia is often misdiagnosed as familial hypercholesterolemia, particularly in patients with tendon or tuberous xanthomas. However, the triad of hematologic abnormalities, good response to ezetimibe therapy and poor response to statins should raise the suspiscion for sitosterolemia. The diagnosis is based on high plasma sterols (sitosterol and campesterol) -the hallmark laboratory feature of sitosterolemia- and confirmed by genetic analysis. The combination of dietary approach and ezetimibe therapy represents the mainstay treatment of sitosterolemia patients. Lipoprotein apheresis could be used as adjunctive therapy. This case illustrates a stepwise approach for the diagnosis of sitosterolemia and summarizes the pathophysiology, clinical presentations and management of sitosterolemia. It raises sitosterolemia awareness among physicians for an early diagnosis and appropriate therapeutic approach.

PURPOSE OF REVIEW: This paper reviews the genetic spectrum underlying the Familial Hypercholesterolemia (FH) phenotype, aiming to improve diagnosis, awareness and understanding of these inherited lipid disorders. RECENT FINDINGS: Although genetic testing for FH has traditionally targeted LDLR, APOB, and PCSK9, the adoption of an expanded eight-gene sequencing panel is now recommended. This broader approach improves diagnostic accuracy by identifying additional lipid disorders that mimic the FH phenotype. Among these, sitosterolemia and the APOE variant p.(Leu167del) appear to be more prevalent than previously recognized. LDLR variants remain the predominant cause of FH, yet the functional significance of approximately half of the reported variants remains undetermined. Recent research efforts are increasing and aimed at resolving these uncertainties through functional characterization studies. Penetrance varies markedly among FH genes, with LDLR variants showing highest penetrance (> 90%), APOB intermediate (~ 50-70%), and PCSK9 is gain-of-function dependent, influencing phenotype severity. Familial hypercholesterolemia (FH) remains widely underdiagnosed and undertreated, increasing preventable cardiovascular risk. Advances in genetic testing with expanded multi-gene panels have enhanced diagnostic precision, but accurate variant classification-using ACMG guidelines and functional assays-is crucial to reduce variants of uncertain significance. Expanded FH genetic testing not only differentiates true FH from phenocopies but also strengthens the individualized management of lipid disorders. By enabling therapy to target the specific affected pathway, it represents an important step toward precision medicine and improved patient outcomes. Data sharing initiatives like PerMedFH further improve variant interpretation and clinical utility.

High levels of low-density lipoprotein cholesterol (LDL-c) have been recognized as the main causal factor of atherosclerotic cardiovascular disease (ASCVD) and are influenced by both genetic and environmental factors. Among genetic determinants, Familial Hypercholesterolemia (FH) is the most common monogenic disorder, caused by rare high-impact variants in genes involved in LDL uptake. Other monogenic causes of hypercholesterolemia include sitosterolemia, cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency (LALD). However, monogenic disorders only account for a small proportion of inherited hypercholesterolemia. In many individuals, increased LDL-c levels are caused by the contemporary presence of different single-nucleotide polymorphisms (SNPs) with a moderate/low impact. These SNPs could be summarized through polygenic risk scores (PRS) that attribute relative weight to each of these. Another genetic determinant of hypercholesterolemic phenotypes is high levels of lipoprotein(a)-Lp(a). Lp(a) is an LDL particle modified by the binding of apolipoprotein(a)-apo(a)-which represents an independent risk factor for ASCVD. Lp(a) levels are mainly genetically determined by variation in the number of kringle IV type 2 (K-IV2) repeats, as well as by several SNPs, and remain stable throughout life. The aim of this narrative review is to report an updated overview of the genetic mechanisms underlying hypercholesterolemia, including monogenic disorders, PRS and Lp(a), focusing on their potential repercussion in clinical practice by the integration into cardiovascular risk stratification beyond traditional clinical assessment. This integration could lead to a more comprehensive and individualized approach to cardiovascular prevention, with emerging perspectives including the possible use of artificial intelligence (AI).