Characteristic findings of different genetic causes of hypercholesterolemia
|
Disorder |
Estimated prevalence |
Characteristic lipid levels* |
Clinical features |
Confirmatory studies |
|
|
In adults |
In children |
||||
|
Heterozygous familial hypercholesterolemia |
1/200 to 1/500 |
Elevated TC and LDL-C LDL-C 190 to 450 mg/dL¶ TG usually normal |
Tendon or tuberous xanthomata Xanthelasmas Corneal arcus Premature CHD |
Subclinical atherosclerosis |
Exclusion of secondary disorders of cholesterol |
|
Homozygous familial hypercholesterolemia |
1/1,000,000 |
Markedly elevated TC and LDL-C Untreated LDL-C >500mg/dL TG usually normal |
Extensive xanthomata Severe and progressive atherosclerotic cardiovascular disease |
Cutaneous or tendon xanthomata often in the first year of life Premature CHD occurs in childhood if untreated |
Genetic testing for mutations in the LDLR, APOB, and PCSK9 genes |
|
Familial combined hyperlipidemia (FCHL) |
1 to 2% |
Phenotypically heterogeneous Elevated TC and/or TG LDL-C/apo B ratio <1.2 |
Xanthelasma Corneal arcus Premature CHD |
Clinical manifestations are typically not seen during childhood |
Similar lipid profile in one first- or two second-degree relatives |
|
Familial hyperapobetalipoproteinemia |
<1% Likely a variant of FCHL |
Apo B >135 mg/dL LDL-C <160 mg/dL LDL-C/apo B ratio <1.2 |
Xanthelasma Premature CHD Obesity |
Clinical manifestations other than obesity are typically not seen during childhood |
Similar lipid profile in at least two first- or second-degree relatives |
|
Polygenic hypercholesterolemia |
>25% |
Elevated TC and LDL-C TG usually normal LDL-C 130-250 mg/dL |
Premature CHD Tendon xanthomata are not seen |
Clinical manifestations are typically not seen during childhood |
|
|
Familial dysbetalipoproteinemia |
1/5,000 |
Elevated TC and TG VLDL/TG ratio >0.3 |
Tuboeruptive xanthomata Xanthomata of the palmar creases Premature CHD |
Clinical manifestations are typically not seen during childhood |
Apo E isoform analysis |
TC: total cholesterol; TG: triglycerides; LDL-C: low density lipoprotein cholesterol; apo B: apolipoprotein B; VLDL: very low density lipoprotein; CHD: coronary heart disease; LDLR: LDL receptor; PCSK9: proprotein convertase subtilisin kexin 9; FCHL: familial combined hyperlipidemia.
* Lipid levels presented in this table represent the typical ranges seen in each disorder, primarily in affected adults. In most of these disorders, there is considerable variability in these values and lipid levels alone generally cannot be used to confirm or exclude the diagnosis.
¶ In pediatric patients, an LDL-C cutoff value of ≥190 mg/dL is generally used to establish a diagnosis of heterozygous FH. However, in patients with a concerning family history (ie, first-degree relatives with hypercholesterolemia and/or early cardiovascular disease), it may be appropriate to use a lower cutoff value (eg, LDL of ≥160 mg/dL).
