Table 2 Clinical recommendations on diagnosis of familial hypercholesterolaemia
Clinical recommendations | Class | Level |
|---|---|---|
1. A diagnosis of HeFH or HoFH should be made, whenever possible, using genetic testing that identifies pathogenic variants (such as in LDLR, APOB, PCSK9 or LDLRAP1) that impair the LDL-receptor pathway; such testing is particularly important when phenotypic features are less obvious, such as in children, and for planning long-term care and cascade testing of family members. Conversely, if the phenotype strongly suggests FH and a pathogenic or likely pathogenic variant is not detected, FH should not be excluded | 1 | A |
2. If genetic testing is not feasible, a clinical diagnosis of FH in adults should be made using country-specific or recognized phenotypic criteria (such as the Dutch Lipid Clinic Network, Simon Broome criteria, MED-PED, AHA, Canadian or Japanese criteria) for index cases (Supplementary Material 2) | 1 | A |
3. A phenotypic diagnosis of FH in adults and children requires exclusion of, or correction for secondary causes of, high LDL-cholesterol concentrations (Supplementary Material 3); in the absence of an untreated value, LDL-cholesterol concentration should be adjusted for concurrent use of cholesterol-lowering medication; LDL-cholesterol concentrations should ideally be measured after fasting and on two occasions | 1 | A |
4. Use of imaging-based detection of subclinical Achilles tendon xanthomas may be considered to increase the specificity and accuracy of the phenotypic diagnosis of FH in adults | 3 | B |
5. A clinical diagnosis of FH in children and adolescents should be considered as highly probable in the presence of an untreated LDL-cholesterol concentration >4.9 mmol/l (>190 mg/dl), recorded on at least two occasions (fasting lipid profile, >2 weeks but <3 months apart), and a parental history of high LDL-cholesterol levels, premature ASCVD or a positive genetic test for FH | 2 | B |
6. After exclusion of secondary causes of high LDL-cholesterol levels (Supplementary Material 3), a clinical diagnosis of FH in children and adolescents should be considered as probable in the presence of an untreated (a) LDL-cholesterol concentration > 4.9 mmol/l (>190 mg/dl; recorded on at least two occasions), even in the absence of a parental history of high LDL-cholesterol concentrations or premature ASCVD; (b) LDL-cholesterol concentration > 4.0 mmol/l (>160 mg/dl; recorded on at least two occasions), with a parental history of high LDL-cholesterol concentrations or premature ASCVD; (c) LDL-cholesterol concentration > 3.5 mmol/l (>135 mg/dl; recorded on at least two occasions), with a parent having a pathogenic gene variant for FH; (d) LDL-cholesterol concentration (recorded on at least two occasions) exceeding a country-specific LDL-cholesterol threshold (lower than the above) and a parental history of elevated LDL-cholesterol concentrations or premature ASCVD | 2 | B |
7. Phenotypic criteria developed for making a diagnosis of HeFH in adult index cases (such as the Dutch Lipid Clinic Network criteria) should not be used in children or adolescents, or when undertaking cascade testing | 1 | A |
8. After excluding secondary causes of high LDL-cholesterol levels (Supplementary Material 3), a clinical diagnosis of HoFH (that is, phenotypic HoFH) should be made in children and adults with an untreated LDL-cholesterol concentration > 10 mmol/l (>400 mg/dl; recorded on two occasions) in the presence of (a) physical stigmata (tendon or cutaneous xanthomas, arcus cornealis) before the age of 10 years and/or (b) untreated LDL-cholesterol concentrations consistent with HeFH in both parents; in the absence of genetic testing and a clear history of FH in both parents, sitosterolaemia and hypercholestanolaemia (cerebrotendinous xanthomatosis) should also be excluded | 1 | C |
9. If cascade testing in the family is recommended, the diagnosis of FH in the proband or index case should ideally be confirmed genetically | 1 | A |
10. The diagnosis of FH during phenotypic cascade testing should be made using age-specific, sex-specific and country-specific LDL-cholesterol concentrations, ideally measured after fasting and on two occasions | 1 | A |
