Lathosterol and Noncholesterol Sterols in Routine Use for the Differentiation and Monitoring of Dietary and Drug Induced Treatment of Hypercholesterolemias in Children and Adolescents

Aims: The authors discuss their 15 years of experience with use of noncholesterol sterols (NCS) when diagnosing heterozygous familial hypercholesterolemia (HFH) and the dietary and drug treatment of children and adolescents when lathosterol (Lat) and desmosterol (Des) as cholesterol synthesis precursors, and campesterol (Cam) and sitosterol (Sit) as cholesterol absorption precursors are included.Patients and Methods: 38 children and adolescents (6-18 yrs) with HFH proven by molecular genetic testing of LDL-cholesterol deficit; 107 children patients with clinical and laboratory symptoms of other hypercholesterolemias; 84 healthy school-age children as a control group. Routine lipid spectrum scan—total cholesterol (TCh), LDL-Ch, HDL-Ch, TAG, with additional apo A1, apo B, Lp (a), LDL-receptors, apo E polymorphism; Lat, Des, Cam and Sit in the plasma—was established by means of GC/MS.Results: The HFH patients on a low cholesterol diet (LCHD) who come to our lipid outpatient clinic have elevated levels of Lat and Des, unlike patients with alimentary hypercholesterolemia (p<0, 001). Lat and Des levels are high following interruption of medical treatment during long vacations or when drug treatment is neglected. Administration of statins only in sufficiently high therapeutic doses reduces Lat and Des (p<0, 001). Compensatory elevation of Cam and Sit occurs only in few pediatric patients. Ezetimibe decreases Cam and Sit more efficiently than Lat or Des. Combination of statin with ezetimibe is most efficient in decrease of not only TCh but also Lat and Des, as well as Cam and Sit.Conclusions: Extending the laboratory spectrum by precursors of cholesterol synthesis and absorption improves the differential diagnosis of HFH and makes monitoring and/or treatment of children and adolescents more precise

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life