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Metabolomic Approach to Screening Homozygotes in Chinese Patients with Severe Familial Hypercholesterolemia
Zhiyong Du1,2, Yunhui Du1,2, Linyi Li1,2
1The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Insights
Metabolomic profiling can identify patients with homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder causing high cholesterol. This cost-effective method aids in screening HoFH cases from severe heterozygous FH patients, improving diagnosis.
Area of Science:
- Biochemistry
- Genetics
- Metabolomics
Background:
- Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder causing extremely high LDL-C and early cardiovascular disease.
- Genetic testing is the gold standard for HoFH diagnosis but is costly and often reserved for suspected cases.
- Overlapping LDL-C levels between HoFH and severe heterozygous FH (HeFH) patients complicate diagnosis.
Purpose of the Study:
- To discover a unique metabolic pattern for screening HoFH patients among those with severe hypercholesterolemia and overlapping LDL-C levels.
- To evaluate the cost-effectiveness of metabolomic profiling as a diagnostic tool.
Main Methods:
- Serum metabolomic profiling was performed on genetically diagnosed HoFH (n=69) and HeFH (n=101) patients.
- Statistical analysis identified differential metabolite profiles between HoFH and HeFH groups.
- A predictive model was developed using key metabolites to differentiate HoFH from HeFH.
Main Results:
- A distinct serum metabolome profile was observed in HoFH patients compared to HeFH patients.
- Twenty-one metabolic alterations independently differentiated HoFH from severe HeFH.
- A combined model using seven metabolites achieved 91.3% corrected diagnosis for HoFH with an AUC of 0.939.
Conclusions:
- Metabolomic profiling is a useful and economical approach for preselecting HoFH patients with severe hypercholesterolemia.
- This method can assist clinicians in selective genetic confirmation and familial cascade screening for FH.
Abstract:
Homozygous familial hypercholesterolemia (HoFH) is a rare inborn-errors-of-metabolism disorder characterized by devastatingly elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. The gold standard for screening and diagnosing HoFH is genetic testing. In China, it is expensive and is always recommended for the most likely HoFH subjects with aggressive LDL-C phenotype. However, the LDL-C levels of HoFH patients and a substantial proportion of heterozygous FH (HeFH) patients overlapped considerably. Here, we performed a cost-effective metabolomic profiling on genetically diagnosed HoFH (n = 69) and HeFH patients (n = 101) with overlapping LDL-C levels, aiming to discovery a unique metabolic pattern for screening homozygotes in patients with severe FH. We demonstrated a differential serum metabolome profile in HoFH patients compared to HeFH patients. Twenty-one metabolomic alterations showed independent capability in differentiating HoFH from severe HeFH. The combined model based on seven identified metabolites yielded a corrected diagnosis in 91.3% of HoFH cases with an area under the curve value of 0.939. Collectively, this study demonstrated that metabolomic profiling serves as a useful and economical approach to preselecting homozygotes in FH patients with severe hypercholesterolemia and may help clinicians to conduct selective genetic confirmation testing and familial cascade screening.
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