Current challenges in diagnosing homozygous familial hypercholesterolemia: Insights from the historical evolution of diagnostic criteria

Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by dysfunctional low-density lipoprotein receptors (LDLR) and markedly elevated low-density lipoprotein cholesterol (LDL-C) from birth. Cumulative exposure to elevated LDL-C results in premature atherosclerotic cardiovascular disease (ASCVD) and death, but early effective treatment can restore near-normal life expectancy. Unfortunately, HoFH is severely underdiagnosed and undertreated, perhaps because of a lack of awareness and confusion around diagnostic criteria.

This historical narrative reviews the evolution of HoFH diagnosis, drawing on key milestones in the field.

The HoFH diagnostic journey began in 1939 when Müller linked xanthomas, elevated cholesterol, and coronary heart disease with a dominant inheritance pattern. From here to the 1970s, diagnosis was focused on phenotypic observation. The genetic era (1970s to 2000s) began with a series of studies linking 2 identical pathogenic mutations in LDLR to HoFH. The 1990s to early 2000s saw the emergence of numerous clinical criteria and scoring systems, driven by availability and sensitivity issues around genetic testing. Today's contemporary guidelines recommend that a diagnosis should be made based on a combination of clinical criteria, including LDL-C, physical manifestations, and family history; genetic testing is not required for diagnosis.

As the diagnosis of HoFH continues to evolve, future diagnostic criteria should place less emphasis on genetics and greater emphasis on modern clinical applications. These changes will help ensure that all individuals with HoFH have access to the most appropriate therapies to reduce their risk of premature ASCVD and death resulting from prolonged exposure to elevated LDL-C levels.