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. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Homozygous familial hypercholesterolemia in childhood: Genotype-phenotype description, established therapies and perspectives

International audienceFamilial hypercholesterolemia (FH) is a co-dominantly inherited disorder of plasma lipoprotein metabolism. The prevalence of heterozygous FH (HeFH) is between 1/500 and 1/200 whereas that of homozygous form (HoFH) is about 1/1,000,000. Diagnosis is based on cutaneous xanthomas and untreated levels of LDL-cholesterol over 500 mg/dl before 10 years of age. Life expectancy, without treatment, does not exceed 20 years of age. The aim of this study is to characterise in details a cohort of 8 HoFH paediatric patients in order to illustrate all the current therapeutic options and to add some clinical and genetic information about this rare disease. We collected demographic, clinical, biological, imaging and genotype details. Furthermore, clinical and biochemical response to different treatment methods was retrospectively evaluated. All patients had genetically proven HoFH. All patients were subject to a lipid-lowering diet and medical treatment (except one), three patients underwent a liver transplant and one an hepatocytes infusion. Medical treatment was well tolerated with a median reduction of 44% and 47% in LDL-Cholesterol and Total Cholesterol respectively. The hepatocytes transplant produced a further, though slight, decrease in cholesterol levels as opposed to medical therapy alone. Transplanted patients normalized their cholesterol levels. Since the very high cardiovascular risk, HoFH requires immediate diagnosis, treatment and monitoring. Nowadays, the use of statins remains the cornerstone of medical therapy and liver transplantation is the possibly curative therapy. Besides, high hopes are pinned in new drugs (antibody targeting PCSK9, Mipomersen and Lomitapide) and stem cells

Sustained biochemical response to oral antibiotics in pediatric PSC and ASC are correlated to changes in gut microbiota during therapy

Background and aim Concomitant presence of autoimmune hepatitis and primary sclerosing cholangitis (PSC) is labelled as autoimmune sclerosing cholangitis (ASC) in children. Based upon the possible implication of microbiota in the pathogenesis of PSC, oral antibiotics are increasingly being used as a novel therapeutic approach and shown to have benefit in PSC but their role in pediatric ASC is not well evaluated. We prospectively analysed the gut microflora before and after antibiotic therapy in children with ASC or PSC alone, and evaluated whether changes in gut microflora correlated with response to treatment. Methods Patients diagnosed with ASC or PSC on basis of biochemical, liver biopsy and radiology findings were included. They prospectively received metronidazole (MTZ) for 14 days as induction or rescue therapy. Antibiotics were administrated in addition to the standard treatment of UDCA for PSC patients and azathioprine, UDCA and/or steroids for ASC patients. Stool samples were collected before and after antibiotic therapy. DNA isolation, amplification and Illumina sequencing to profile the microbiota composition were performed using the bacterial 16s rRNA. The beta-diversity measured the dissimilarity between each paired stool samples. The outcome parameters to assess the efficacy of antibiotics were reduction liver enzymes and subsequently achievement of sustained biochemical remission. Results Seven children (4 ASC, 3 PSC) were included, of which 5 have a concomitant ulcerative colitis (UC). All patients showed a significant decrease in their AST (-44%, p<0.025), ALT (-56%, p<0.025) and GGT (-41%, p<0.025) under MTZ. Three children relapsed after stopping MTZ while the four others children showed a sustained biochemical remission (liver enzymes below 1.5 times upper limit of normal) after a median follow-up of 375 days. Among these four patients, three exhibited a wide different microbial composition before and after MTZ as expressed by the beta-diversity variation. On the contrary, the microbiota of patients who relapsed remained unchanged pre- and post-MTZ. Conclusions Our study suggests that oral antibiotic could be an effective treatment of ASC and PSC, especially those with a concomitant UC, and that intestinal microflora play a major role in these diseases as sustained biochemical remission is associated with wide changes in gut microbiota communities after taking antibiotics