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

Open-Label, Randomized, Two-Way, Crossover Study Assessing the Bioequivalence of the Liquid Formulation versus the Freeze-Dried Formulation of Recombinant Human FSH and Recombinant Human LH in a Fixed 2:1 Combination (Pergoveris®) in Pituitary-Suppressed Healthy Women

This was a Phase I, open-label, randomized, two-period, two-sequence crossover study [ClinicalTrials.gov NCT02317809 (https://www.clinicaltrials.gov/ct2/show/NCT02317809); EudraCT 2014-003506-32] assessing the bioequivalence of the liquid and freeze-dried formulations of fixed-dose, fixed-ratio (2:1) combination recombinant human follicle-stimulating hormone plus recombinant human luteinizing hormone (r-hFSH/r-hLH). The safety and tolerability of the two formulations were also assessed. Healthy premenopausal women were randomized to one of two crossover dosing schedules. Subjects in Treatment Sequence 1 received a single subcutaneous dose (900/450 IU r-hFSH/r-hLH) of the liquid formulation of r-hFSH/r-hLH on Day 1 of Dose Period 1 and, after a washout period of at least 14 days, a single subcutaneous dose (900/450 IU r-hFSH/r-hLH) of the freeze-dried formulation of r-hFSH/r-hLH (reconstituted in water for injection prior to administration) on Day 1 of Dose Period 2. Subjects in Treatment Sequence 2 received the treatments in reverse order. The primary endpoints were AUC0–t (area under the serum concentration–time curve from time 0 to the time of the last quantifiable concentration) and Cmax (maximum serum concentration) for FSH and LH, both baseline corrected. A total of 34 subjects were randomized, and 22 subjects were included in the bioequivalence evaluation. Overall, the mean observed PK profiles and individual PK parameters were comparable for the liquid and freeze-dried formulations, although a median difference in the tmax (time to reach maximum observed concentration) of FSH of ~4.5 h was observed between the formulations. The calculated 90% confidence intervals of the mean liquid formulation/freeze-dried formulation ratios for Cmax and AUC0–t were within the bioequivalence range (80–125%) for both LH and FSH, confirming bioequivalence between the two formulations. The safety and tolerability profiles of the two formulations were similar. The liquid formulation can, therefore, be expected to provide the same efficacy as the freeze-dried formulation, with no differences in tolerability

Single‐dose pharmacokinetic study comparing the pharmacokinetics of recombinant human chorionic gonadotropin in healthy Japanese and Caucasian women and recombinant human chorionic gonadotropin and urinary human chorionic gonadotropin in healthy Japanese women

Abstract Purpose Recombinant hCG (r‐hCG) was approved in Japan in 2016. As a prerequisite for a Phase III study in Japan related to this approval, the pharmacokinetic (PK) profile of r‐hCG was investigated. Methods An open‐label, partly randomized, single‐center, single‐dose, group‐comparison, Phase I PK‐bridging study was done that compared a single 250 μg dose of r‐hCG with a single 5000 IU dose of urinary hCG (u‐hCG) in healthy Japanese women, as well as comparing a single 250 μg dose of r‐hCG in Japanese and Caucasian women. The Japanese participants were randomized 1:1 to receive either r‐hCG or u‐hCG, while the Caucasian participants were weight‐matched to the Japanese participants who were receiving r‐hCG in a 1:1 fashion. The primary PK parameters were the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and the maximum serum concentration (Cmax). Results The mean serum hCG concentration–time profiles of r‐hCG in the Japanese and Caucasian participants were a similar shape, but the level of overall exposure was ~20% lower in the Japanese participants. For the Japanese participants, r‐hCG resulted in an 11% lower Cmax but a 19% higher AUC0–∞ compared with u‐hCG. No new safety signal was identified. Conclusion This study cannot exclude a potential difference in the PK profile of r‐hCG between Japanese and Caucasian participants. However, this study does not indicate that there are clinically relevant differences in the serum PK of r‐hCG and u‐hCG in the Japanese participants

An essential cell-autonomous role for hepcidin in cardiac iron homeostasis

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain

An essential cell-autonomous role for hepcidin in cardiac iron homeostasis

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain