US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry

Highlights

• Familial hypercholesterolemia is underdiagnosed in the United States.

• Three FH diagnostic criteria are widely used: Simon Broome, MEDPED, and DLCN.

• In the United States, no one criterion is widely utilized.

• Rather, US lipid specialists often rely on a heuristic “clinical” diagnosis.

Background

In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear.

Objective

To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry.

Methods

We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: “clinical diagnosis,” MEDPED, Simon Broome, DLCN, and other.

Results

Most adults enrolled in CASCADE FH (55.0%) received a “clinical diagnosis.” The most commonly used formal criteria was Simon–Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a “clinical diagnosis,” 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry.

Conclusions

Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.

Introduction

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by severe lifelong elevations in low-density lipoprotein cholesterol (LDL-C).¹ Thus far, mutations in at least three genes have been found to cause the disorder: low-density lipoprotein receptor (LDLR, Online Mendelian Inheritance in Man [OMIM] # 143890), apolipoprotein B-100 (APOB, OMIM # 107730), and proprotein convertase subtilisin-like kexin type 9 (PCSK9, OMIM # 603776). Although affected individuals have a 20-fold increased risk of premature atherosclerotic cardiovascular disease,² early diagnosis and treatment with lipid-lowering drugs reduces the risk of coronary heart disease (CHD) to rates comparable to the general population.3, 4

Three diagnostic criteria can predict FH-causing mutations with >80% sensitivity or specificity: Simon Broome, Dutch Lipid Clinic Network (DLCN), and the US Make Early Diagnosis to Prevent Early Death (MEDPED).5, 6, 7 The Simon Broome Familial Hyperlipidemia Register began in 1980 as an effort to identify all FH patients in the United Kingdom, resulting in the creation of the eponymous diagnostic criteria for FH.8, 9 In the Netherlands, the DLCN criteria were a critical component of a public health strategy to identify patients with FH for genetic testing, early treatment, and CHD prevention.¹⁰ The US MEDPED criteria were created based on the phenotypic presentation of US families living in Utah.⁵

Consistent application of FH diagnostic criteria improves the identification of index cases. For example, in the Netherlands, the consistent application of DLCN criteria resulted in identification of 71% of estimated cases.¹¹

Unfortunately, in the United States, <10% of cases are identified12, 13—despite an estimated prevalence of 1:200 to 1:50011, 14, 15—and little data are available on the use of FH diagnostic criteria in contemporary US practices. To address these issues, the FH Foundation, a nonprofit research, and advocacy organization, established the US CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) Registry.¹³ CASCADE-FH became active in September 2013 and currently has data on FH patients treated at specialty lipid clinics throughout the country.

We queried CASCADE-FH to characterize how US lipid specialists diagnose FH, specifically, which of the established criteria—Simon Broome, DLCN, or MEDPED—are most commonly used.