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Published on: September 15, 2018
Past, Present, and Future of Familial Hypercholesterolemia Management
Viviane Z Rocha1, Raul D Santos1,2
1Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil.
Insights
Familial hypercholesterolemia (FH) is a genetic condition causing high LDL cholesterol, increasing atherosclerosis risk. Early diagnosis and treatment, including statins and newer therapies, are crucial but FH remains underdiagnosed and undertreated.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Metabolic Disorders
Background:
- Familial hypercholesterolemia (FH) is a monogenic disorder characterized by severely elevated LDL cholesterol levels.
- Genetic variants impair hepatic clearance of LDL particles, leading to premature atherosclerosis and increased cardiovascular disease (ASCVD) risk.
- FH affects approximately 1 in 300 individuals, posing a significantly higher ASCVD risk compared to normolipidemic or polygenic hypercholesterolemia populations.
Purpose of the Study:
- To review the diagnosis, risk stratification, and management of Familial hypercholesterolemia (FH).
- To highlight the importance of genetic diagnosis and family cascade screening in identifying affected individuals.
- To discuss current and emerging therapeutic strategies for lowering LDL cholesterol in FH patients.
Main Methods:
- Review of existing literature on FH diagnosis, risk factors, and treatment modalities.
- Analysis of clinical scores and genetic testing for FH diagnosis.
- Evaluation of lipid-lowering therapies including statins, PCSK9 inhibitors, and ANGPTL3 inhibitors.
Main Results:
- FH diagnosis typically relies on clinical scores incorporating lipid levels, family history, and physical signs, but genetic confirmation is recommended.
- ASCVD risk in FH is heterogeneous, influenced by LDL cholesterol levels and other biomarkers like age, obesity, diabetes, and hypertension.
- While statins are first-line therapy, many FH patients require additional treatments like PCSK9 or ANGPTL3 inhibitors to achieve LDL-C goals.
Conclusions:
- Despite effective therapies, FH remains significantly underdiagnosed and undertreated, necessitating improved screening and management strategies.
- Personalized risk assessment incorporating multiple biomarkers is essential for optimizing ASCVD prevention in FH.
- Advancements in lipid-lowering therapies offer improved LDL-C reduction for FH patients, but accessibility and cost remain challenges.
Abstract:
Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH derives from genetic variants that lead to inefficient hepatic clearance of low-density lipoprotein (LDL) particles from the circulation. The FH phenotype is encountered in approximately 1 of every 300 people. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with FH than in normolipidemic individuals and in those with polygenic hypercholesterolemia. FH is usually diagnosed by clinical scores that consider hypercholesterolemia, family history of early ASCVD and hypercholesterolemia, and cutaneous stigmata. Genetic diagnosis is important and should be offered to individuals suspected of FH. Family cascade screening is important to identify asymptomatic hypercholesterolemic individuals. Despite the high risk of ASCVD, this risk is heterogenous in heterozygous FH and depends not only on high LDL cholesterol (LDL-C) but also on other risk biomarkers. Risk can be evaluated by considering biomarkers such as male sex, late-onset therapy (> age 40), LDL-C > 310 mg/dL, low high-density lipoprotein cholesterol, elevated lipoprotein(a), obesity, diabetes, and hypertension by using specific risk equations and by detecting subclinical coronary atherosclerosis. Statins are the main therapy for FH and change the natural history of ASCVD; however, most individuals persist with elevated LDL-C. PCSK9 inhibitors provide robust and safe LDL-C lowering in FH, although elevated costs preclude their widespread use. Newer therapies such as ANGPTL3 inhibitors add intensive LDL-C lowering for refractory forms of FH. Finally, while it is possible to normalize LDL-C in people with FH, the disease unfortunately is still severely underdiagnosed and undertreated.
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