High prevalence of increased sitosterol levels in hypercholesterolemic children suggest underestimation of sitosterolemia incidence

Abstract

Background Sitosterolemia is an inherited lipid disorder which presents with elevated serum sitosterol and can result in an increased risk of premature cardiovascular disease. However, sitosterol cannot be accurately measured by routine diagnostic assays, meaning that sitosterolemia diagnosis can often be difficult, especially with many clinical features overlapping with familial hypercholesterolemia. With such complications resulting in increasing reports of misdiagnosis, the prevalence of sitosterolemia is predicted to be much higher than previously reported. Methods Gas chromatography-mass spectrometry was utilized to measure sitosterol levels of normocholesterolemic and hypercholesterolemic children. Subsequently, an epidemiologically determined cutoff level of sitosterol was calculated and applied to estimate the prevalence of children with increased sitosterol and identify potential sitosterolemia patients. Massively parallel sequencing was used to confirm the diagnosis in suspected patients. Results Samples from 109 normocholesterolemic and 220 hypercholesterolemic were tested for phytosterols. Sitosterol and campesterol levels were significantly increased in hypercholesterolemic children (mean 22.0±45.9 μmol/L for sitosterol and 26.0±32.8 μmol/L for campesterol) compared to normocholesterolemic children (mean 12.1±4.9 μmol/L for sistosterol and 14.8±6.7 μmol/L for campesterol). Via application of a cutoff of 35.9 μmol/L, the prevalence rates for increased and overtly increased sitosterol in hypercholesterolemic children were 6.4% and 1.4% respectively. Furthermore, 3 suspected sitosterolemia patients were identified, with 2 patients receiving molecular confirmation for sitosterolemia diagnosis. Conclusions Our findings reaffirm that the prevalence of sitosterolemia is probably much higher than previously reported, which also indicates the significant risk of misdiagnosis of sitosterolemia with familial hypercholesterolemia. Special lipid testing including sitosterol, especially in children with uncontrolled hypercholesterolemia, is recommended in children in order to identify potential sitosterolemia patients that would otherwise be neglected.

Case Report: Next Generation Sequencing in Clinical Practice–A Real Tool for Ending the Protracted Diagnostic Odyssey

“…However, sitosterolemia may be not so rare, as previously believed. Evidence from recent research demonstrates, that misdiagnosis of sitosterolemia with familial hypercholesterolemia may be prevalent ( 11 , 12 ), which is also the case of our patient. The great variety of possible manifestations means that physicians of different specialties, like cardiologists, hematologists, and rheumatologists can deal with this disease.…”

Phytosterol Accumulation Results in Ventricular Arrhythmia, Impaired Cardiac Function and Death

“…Our data indicate that blocking phytosterol absorption through NPC1L1 inhibition can reduce inflammation, cardiac fibrosis, ventricular arrhythmia and death in mice. Given the fact that individuals with phytosterolemia are at risk of being misdiagnosed with hypercholesterolemia, our work underscores the importance of raising awareness of this disorder 37,38 . This is critically important, considering the issues surrounding misdiagnosis, the fact that statins are the first line standard of care therapy for hypercholesterolemia and are known to provide limited clinical benefit for phytosterolemia patients relative to the NPC1L1 inhibitor, ezetimibe 31,39,40 .…”

Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice

“…Our data indicate that blocking phytosterol absorption through NPC1L1 inhibition can reduce inflammation, cardiac fibrosis, ventricular arrhythmia and death in mice. If our observations in mice translate to phytosterolemia patients, then it will underscore the importance of raising awareness of this disorder, considering the issues surrounding misdiagnosis, the fact that statins are the first line standard of care therapy for hypercholesterolemia and are known to provide limited clinical benefit for phytosterolemia patients relative to the NPC1L1 inhibitor, ezetimibe 36 , 41 – 44 .…”