Case Reports of FH Patients Without Atherosclerosis Development
Yes, there are case reports of Familial Hypercholesterolemia (FH) patients who do not develop atherosclerosis, although this is uncommon given the strong causal relationship between FH and premature atherosclerotic cardiovascular disease (ASCVD). 1, 2
Understanding FH and Atherosclerosis Risk
- FH is a co-dominant and highly penetrant monogenic disorder characterized by markedly elevated LDL-cholesterol concentrations from birth, which if untreated, typically leads to premature ASCVD 3, 1
- The condition affects approximately 1 in 311 people in the general population, potentially impacting up to 35 million people worldwide 3, 1
- FH results from genetic defects in the hepatic LDL clearance pathway, most commonly involving mutations in LDLR, APOB, PCSK9, or LDLRAP1 genes 3, 1
Variability in Clinical Presentation
- The clinical picture of FH is highly variable, with heterogeneous phenotypes even within a single family 2
- This variability ranges from patients with very early onset of major cardiovascular events to those who do not develop overt cardiovascular disease even at an advanced age 2
- Several factors may explain why some FH patients do not develop atherosclerosis:
Factors That May Explain Absence of Atherosclerosis in Some FH Patients
1. Genetic Factors
- Different mutations in FH-causing genes can result in varying degrees of LDL receptor dysfunction 3
- Some mutations may result in partial receptor function rather than complete loss 3, 4
- Additional protective genetic variants may counteract the effects of FH-causing mutations 1
2. Early Intervention
- Early diagnosis and aggressive treatment with lipid-lowering therapies can significantly alter the natural history of FH 5
- Statins, ezetimibe, PCSK9 inhibitors, and other therapies can effectively lower LDL-C levels and prevent or delay atherosclerosis development 6, 3
- Mendelian randomization studies confirm that lifelong lower LDL-C levels are associated with substantially reduced ASCVD risk 1
3. Lifestyle Factors
- Diet, exercise, and absence of other cardiovascular risk factors (smoking, hypertension, diabetes) may play protective roles 3
- Some FH patients may naturally have healthier lifestyle habits that mitigate their genetic risk 1
4. Diagnostic Considerations
- Some patients diagnosed with FH based on phenotypic criteria alone may not actually have monogenic FH but rather polygenic hypercholesterolemia 3, 7
- Without genetic confirmation, clinical diagnostic criteria may sometimes misclassify patients 7
Clinical Implications
- The existence of FH patients without atherosclerosis highlights the importance of comprehensive risk assessment beyond LDL-C levels alone 2
- Risk stratification should include genetic testing whenever possible to confirm the diagnosis and identify the specific mutation 3
- Regular cardiovascular imaging is recommended to detect subclinical atherosclerosis, even in apparently asymptomatic FH patients 3
- The International Atherosclerosis Society recommends Doppler echocardiographic evaluation of the heart and aorta annually, and computed tomography coronary angiography every 5 years or less if deemed necessary 3, 4
Conclusion
While FH typically leads to premature atherosclerosis, the clinical course is variable, and some patients may not develop overt cardiovascular disease. This variability underscores the importance of early diagnosis, genetic testing when possible, comprehensive risk assessment, and aggressive lipid-lowering therapy to prevent atherosclerosis development in all FH patients.