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Cholesterol metabolism in normal and heterozygous familial hypercholesterolemic newborns
Alpo F Vuorio1, Tatu A Miettinen, Hannu Turtola
1Division of Internal Medicine, Department of Medicine, University of Helsinki, Finland. Alpo.Vuorio@hus.fi
Insights
Diagnosing familial hypercholesterolemia (FH) in newborns is challenging. While cholesterol synthesis is high at birth, low-density lipoprotein (LDL) cholesterol levels at one year are more reliable for FH diagnosis.
Area of Science:
- Biochemistry and Molecular Biology
- Genetics and Genomics
- Pediatric Cardiology
Background:
- Heterozygous familial hypercholesterolemia (FH) often presents with elevated serum low-density lipoprotein (LDL) cholesterol in utero.
- A distinct Finnish FH population (FH-North Karelia) offers a unique model for studying FH diagnostics.
- Early diagnosis of FH is crucial for timely intervention and management of cardiovascular risk.
Purpose of the Study:
- To evaluate the diagnostic utility of cholesterol metabolism markers in newborns with familial hypercholesterolemia (FH).
- To compare cholesterol precursors, plant sterols, and LDL cholesterol levels at birth versus 1-year follow-up for FH diagnosis.
- To investigate potential differences in cholesterol synthesis between newborns of FH mothers versus FH fathers.
Main Methods:
- Lipoprotein lipids, cholesterol precursors (squalene, methyl sterols, demethyl sterols), cholestanol, and plant sterols were analyzed.
- Samples were collected from FH-North Karelia (FH-NK) newborns, non-FH siblings, and controls at birth and at 1-year follow-up.
- Statistical analysis compared marker concentrations and ratios between groups at different time points.
Main Results:
- Methyl sterol and squalene concentrations were higher in FH newborns than non-FH siblings, but overlapped with controls.
- Cord-blood LDL cholesterol was not diagnostically useful, whereas 1-year LDL cholesterol was highly superior for FH diagnosis.
- Elevated methyl sterol and demethyl precursor sterol ratios in cord blood indicated increased cholesterol synthesis at birth in all groups, with a trend in FH mothers' babies.
Conclusions:
- Diagnosis of FH based on cholesterol precursors or cord-blood LDL cholesterol is questionable.
- LDL cholesterol measurement at the 1-year mark is a superior diagnostic tool for familial hypercholesterolemia.
- While cholesterol synthesis is elevated at birth in FH and non-FH newborns, postnatal LDL cholesterol levels are key for diagnosis.
Abstract:
In heterozygous familial hypercholesterolemia (FH), serum low-density lipoprotein (LDL) cholesterol levels are frequently increased in utero. A unique Finnish FH population, FH-North Karelia (FH-NK), has been identified, providing an excellent opportunity to study the diagnostic significance of cholesterol metabolism in FH. For that purpose, we investigated lipoprotein lipids, cholesterol precursors (squalene, methyl, and demethyl sterols), cholestanol, and plant sterols in FH-NK newborns (n = 5), non-FH siblings (n = 7), and controls (n = 20) at birth and after 1-year follow-up in 8 FH-NK and 5 non-FH children. The sum of concentrations (micrograms per deciliter) of methyl sterol (8-monomethylsterol, methostenol, 8-dimethylsterol, 8,24-dimethylsterol, and lanosterol) and squalene was higher in FH newborns than in non-FH siblings but overlapped with one control case. Cord-blood total or LDL cholesterol values could not be used for diagnostic purposes, whereas 1-year LDL cholesterol values were highly superior to those measured at birth. The methyl sterol ratio in cord blood was 29 to 193 10(2) mmol/mol cholesterol and was undetectable in serum at the age of 1 year; those of the demethyl precursor sterols were 1.5 to 8 times higher in cord blood than in serum at the age of 1 year, suggesting that cholesterol synthesis was markedly increased at birth. Plant sterols, not synthesized in human beings, were already present in serum of all the groups at birth, indicating their transfer, apparently with cholesterol, from mother to fetus. Babies born to FH mothers showed a greater tendency toward accelerated cholesterol synthesis than did those born to FH fathers. Despite signs of markedly high but similar synthesis of cholesterol at birth in FH and non-FH newborns, the diagnosis of FH was questionable by measurement of cholesterol precursors or LDL cholesterol in cord blood. The latter measurement, at the 1-year mark, is superior for diagnostic purposes.