This episode is part of a case reports series developed in collaboration with the National Lipid Association and their Lipid Scholarship Program, with mentorship from Dr. Daniel Soffer and Dr. Eugenia Gianos.
A classic finding in patients with familial hypercholesterolemia is the presence of markedly elevated levels of total and low-density lipoprotein cholesterol (LDL-C) with an LDL-C concentration of 190 mg/dL or greater. However, severe hypercholesterolemia is not inevitably present, and many patients who carry this diagnosis may have lower LDL-C levels. This case history describes a young woman whose mother and brother met clinical and genetic criteria for heterozygous familial hypercholesterolemia but who had only a mild elevation in LDL-C, falling to 130 mg/dL after dietary intervention. Despite this finding, genetic testing revealed the presence of the same genetic variants as were noted in her mother and brother. In addition, a second genetic variant predisposing them to cholesterol gallstone formation was identified in all three family members. If genetic testing had not been performed, the diagnosis may have been missed or delayed, resulting in an increased risk for vascular complications associated with familial hypercholesterolemia. This case supports the value of genetic testing of family members of those with familial hypercholesterolemia, even when LDL-C levels are not severely elevated.
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Pearls – Exposing an Unusual Presentation of Familial Hypercholesterolemia – National Lipid Association
Familial hypercholesterolemia (FH) is among the most common autosomal co-dominant genetic conditions (approximately 1:200 to 1:300 for HeFH, 1:160,000 to 1:300,000 for HoFH).
Genetic testing has a role for all first-degree relatives when a family history of FH is strongly suggestive, regardless of LDL-C level.
Heterogeneity in ASCVD risk among individuals with FH is derived from background polygenic risk, clinical risk factors (e.g., timing of lipid-lowering initiation and adjacent risk factors), as well as subclinical atherosclerosis burden.
In clinical or genetically confirmed FH, an LDL-C goal of 55 mg/dL is recommended.
Beyond statins, FDA-approved non-statin therapies for FH include ezetimibe, PCSK9 mAb, bempedoic acid, inclisiran, evolocumab (only HoFH), lomitapide (only HoFH), and LDL apheresis.
Notes – Exposing an Unusual Presentation of Familial Hypercholesterolemia – National Lipid Association
What are the diagnostic criteria for FH?
Dutch Lipid Clinic Network1
Variables: family history, clinical history, physical exam, LDL-C level, DNA (LDLR, APOB, PCSK9)
Simon-Broome1
Variables: total or LDL-C, physical exam, DNA (LDLR, APOB, PCSK9), family history
Emphasis on clinical history and physical exam reduces sensitivity
U.S. Make Early Diagnosis Prevent Early Death (MEDPED) 1
Only one of the three where no genetic testing is required, may work well in cascade screening
Variables: age, total cholesterol, family relative (and degree) with FH
Definite, probable, possible, unlikely
Emphasis on clinical history and physical exam reduces sensitivity
How does FH affect CAD risk?
There is about a 20-fold higher risk of premature CHD in FH without treatment2
For any CHD3
As high as 100-fold greater risk in young men with FH
Risk is lower in women versus men (approximate 10-year age difference in development)
Up to one-half of men and one-third of women with FH will suffer fatal or non-fatal coronary events before age 50 and 60 years old, respectively 4
Despite this high risk, it is important to note heterogeneity in FH that can be attributable to:
Polygenic risk
Timing of lipid-lowering therapy initiation
Adjacent risk factors
Subclinical atherosclerosis burden 567
What is the role of genetic testing in FH?
Clinical value of genetic testing:
Providing prognostic information
Promotes initiation and adherence of lipid-lowering therapies
Serves as a basis for more effective cascade screening
Heterogeneity in FH may be attributable to other genes that regulate LDL-C, but which are not tested as part of the FH gene panel. For example, there are polygenic risk scoring systems to gauge the relative impact on LDL-C; however, this is not routinely done, but potentially impactful
Provide guideline-based recommendations for treatment
Based on the 2022 ACC Expert Consensus Decision Pathway for Non-Statin Therapy, an LDL-C goal of <55 mg/dL is recommended for individuals with a clinical or genetic diagnosis of FH 8
When should a patient be referred to a lipid specialist?
*Based on 2022 ACC ECDP 8
Any patient with ASCVD
Baseline LDL >190 mg/dL
Inadequate reduction of LDL-C (>50% and LDL-C <70 mg/dL or non-HDL-C <100 mg/dL)
Intolerance to at least two statin therapies, with an attempt to initiate FDA-approved lowest dose of statin and a trial of an alternative statin therapy regimen such as every other day dosing
References
Vallejo-Vaz AJ, Ray KK. Epidemiology of familial hypercholesterolaemia: Community and clinical. Atherosclerosis. 2018;277. doi:10.1016/j.atherosclerosis.2018.06.855 Link to article
Austin MA, Hutter CM, Zimmern RL, Humpries SE. Familial hypercholesterolemia and coronary heart disease: A HuGE association review. Am J Epidemiol. 2004;160(5). doi:10.1093/aje/kwh237 Link to article
Watts GF, Lewis B, Sullivan DR. Familial hypercholesterolemia: A missed opportunity in preventive medicine. Nat Clin Pract Cardiovasc Med. 2007;4(8). doi:10.1038/ncpcardio0941 Link to article
Marks D, Thorogood M, Neil HAW, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168(1). doi:10.1016/S0021-9150(02)00330-1 Link to article
Mszar R, Grandhi GR, Valero-Elizondo J, et al. Absence of Coronary Artery Calcification in Middle-Aged Familial Hypercholesterolemia Patients Without Atherosclerotic Cardiovascular Disease. JACC Cardiovasc Imaging. 2020;13(4). doi:10.1016/j.jcmg.2019.11.001 Link to article
Miname MH, Bittencourt MS, Moraes SR, et al. Coronary Artery Calcium and Cardiovascular Events in Patients With Familial Hypercholesterolemia Receiving Standard Lipid-Lowering Therapy. JACC Cardiovasc Imaging. 2019;12(9). doi:10.1016/j.jcmg.2018.09.019 Link to article
Sandesara PB, Mehta A, O’Neal WT, et al. Clinical significance of zero coronary artery calcium in individuals with LDL cholesterol ≥190 mg/dL: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. Published online 2020. doi:10.1016/j.atherosclerosis.2019.09.014 Link to article
Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366-1418. doi:10.1016/j.jacc.2022.07.006 Link to article