In this post, I link to and excerpt from Familial Hypercholesterolemia: Early Diagnosis and Treatment is Key for Cardiovascular Prevention, Apr 16, 2020 | Nishant Shah, MD, FACC Expert Analysis, from American College of Cardiology Latest In Cardiology.
All that follows is from the above excellent resource.
Introduction
Familial Hypercholesterolemia (FH) is an autosomal dominant condition that leads to extreme elevations in low density lipoprotein cholesterol (LDL-C).1 It can remain undiagnosed until a catastrophic cardiovascular (CV) event. Thus, without early detection, many patients will remain undertreated and have missed opportunities for CV prevention.
Several tools and screening strategies have been developed to help guide clinicians to earlier diagnosis and treatment. With the widespread use of electronic medical records (EMR) data can now be extrapolated by artificial intelligence and machine learning algorithms to not only identify patients likely to have FH, but also provide better estimates of prevalence, and help understand gaps in care.1
This overview will provide a summary of the genetics, clinical manifestations, detection strategies, and current guideline-based approaches for treatment of FH.
As noted [in the article], FH is an autosomal dominant condition. Thus, most patients are heterozygous, or in other words have one normal allele and one mutated allele.4 The prevalence of heterozygous FH (HeFH) is estimated to be about 1 in 220 based on large genetic studies.5
Homozygous FH (HoFH) where patients have two mutated alleles is much less common, but presents with a more severe clinical phenotype and worse prognosis since patients can manifest with CV events before age 30. The frequency of HoFH is estimated at 1 in 300,000.4,6
Clinical Manifestations
Several clinical criteria have been developed to help clinically diagnose patients with FH. These criteria revolve round LDL-C level, family history, and physical findings.1 The LDL-C level that raises suspicion is typically greater than or equal to 190 mg/dL, though lower levels with strong family histories and/or physical findings can still confer a diagnosis.
Family history is usually focused on first degree relatives with premature CV events (typically men <55; women <65). Physical manifestations include xanthomas (Figure 2) which are pathognomonic for the disease, xanthelasmas (cholesterol deposits in the eye lids or skin), or corneal arcus (Figure 3).20 Of note, clinical criteria do not apply to HoFH; however the diagnosis is strongly suspected if the patient has very high LDL-C (>500 mg/dL untreated or >300 mg/dL if on maximal lipid-lowering therapy), and cholesterol deposits in the first decade of life in the setting of a strong family history.9
Diagnostic and Screening Strategies
Interestingly, these three clinical criteria [cited in the article] have been compared against each other and none were found to outperform the other.25 However, when patients in the “definite” categories in each criteria underwent genetic testing, the mutation detection rate was as low as 30-40%.25 These results suggest that perhaps not all mutations were tested for, and that polygenetic factors may be overlooked. Thus, the phenotype itself may be more important than the genotype to establish a diagnosis and justify treatment. This notion was also endorsed by the International Atherosclerosis Society which placed high emphasis on LDL-C levels and subclinical disease in diagnosing FH.26
Once an individual is identified with FH it is important to also determine who else in the family is at risk. A commonly used screening strategy is known as cascade screening where LDL-C measurement, genetic testing, or both are done in consenting relatives of patients with FH. As more individuals with FH are identified, the process repeats itself. These methods have been widely implemented in Europe and data from there suggests that identifying 9,000 cases in 10 years could prevent 847 coronary events, 203 coronary deaths, and could add 767 quality-adjusted life years.29,30
Guideline Based Treatment
Reducing the LDL-C level is one of the primary goals of treatments. Therefore, the first-line treatment is maximally tolerated statin therapy and should be started as early as possible, especially if LDL-C is ≥ 190 mg/dL (class I).33 In primary prevention, the target LDL-C is typically 100 mg/dL, though the lower the better. If this is not obtained by statin therapy alone, then the addition of ezetimibe is reasonable (class IIa).33 If the goal LDL-C is still not achieved with maximally tolerated statin and ezetimibe, or the patient is statin intolerant, then PCSK9 inhibitor therapy can be considered (class IIb).33
Medical treatment of FH should always be accompanied by lifestyle modifications to help modify other risk factors; however, lifestyle interventions alone only have a modest LDL-C reduction in FH patients.34 In secondary prevention cases, the goal LDL-C should be less than 70 mg/dL.33
In cases where LDL-C does not respond to medical therapy, often seen in HoFH, LDL apheresis can be considered. This procedure can be cumbersome and involves venous access via needle stick, or in a small number of cases via indwelling catheter, with either weekly or biweekly sessions. It is one of the only therapies shown to prolong survival in HoFH patients.35
Other nonstatin therapies such as niacin, bile acid sequestrants, fibrates, or apoB targeting therapies have very little evidence in FH. Emerging new LDL lowering therapies such as bempedoic acid (especially when given in combination with ezetimibe) and inclisiran appear promising.36,37
Guideline Based Treatment
Reducing the LDL-C level is one of the primary goals of treatments. Therefore, the first-line treatment is maximally tolerated statin therapy and should be started as early as possible, especially if LDL-C is ≥ 190 mg/dL (class I).33 In primary prevention, the target LDL-C is typically 100 mg/dL, though the lower the better. If this is not obtained by statin therapy alone, then the addition of ezetimibe is reasonable (class IIa).33 If the goal LDL-C is still not achieved with maximally tolerated statin and ezetimibe, or the patient is statin intolerant, then PCSK9 inhibitor therapy can be considered (class IIb).33
Medical treatment of FH should always be accompanied by lifestyle modifications to help modify other risk factors; however, lifestyle interventions alone only have a modest LDL-C reduction in FH patients.34 In secondary prevention cases, the goal LDL-C should be less than 70 mg/dL.33
In cases where LDL-C does not respond to medical therapy, often seen in HoFH, LDL apheresis can be considered. This procedure can be cumbersome and involves venous access via needle stick, or in a small number of cases via indwelling catheter, with either weekly or biweekly sessions. It is one of the only therapies shown to prolong survival in HoFH patients.35
Other nonstatin therapies such as niacin, bile acid sequestrants, fibrates, or apoB targeting therapies have very little evidence in FH. Emerging new LDL lowering therapies such as bempedoic acid (especially when given in combination with ezetimibe) and inclisiran appear promising.36,37
Conclusion
The US Centers for Disease Control and Prevention has designated FH as a tier 1 genomic application.38 This indicates that FH imposes a significant public health burden. Several novel screening strategies using modern technology are being investigated to help improve identification. Moreover, new lipid lowering therapies are on the horizon. Most importantly, all clinicians should be aware of the clinical red flags that raise suspicion for FH in order to prevent its CV complications.
*Resources for patients and providers are provided by The Familial Hypercholesterolemia Foundation at www.thefhfoundation.org
