Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease.
In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts.


CONCLUSIONS
Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol GSD.
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
Marcin
M
Krawczyk
Dieter
D
Lütjohann
Ramin
R
Schirin-Sokhan
Luis
L
Villarroel
Flavio
F
Nervi
Fernando
F
Pimentel
Frank
F
Lammert
Juan Francisco
JF
Miquel
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000367:Age Factors; D000368:Aged; D000704:Analysis of Variance; D001692:Biological Transport / Q000502:physiology; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D005006:Ethnicity / Q000706:statistics & numerical data; D005260:Female; D005500:Follow-Up Studies; D042882:Gallstones / Q000208:ethnology* / Q000378:metabolism / Q000503:physiopathology*; D006630:Hispanic or Latino / Q000706:statistics & numerical data; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010840:Phytosterols / Q000097:blood* / Q000378:metabolism; D018570:Risk Assessment; D012720:Severity of Illness Index; D012737:Sex Factors; D018709:Statistics, Nonparametric; D013261:Sterols / Q000032:analysis / Q000378:metabolism; D013997:Time Factors; D044465:White People / Q000706:statistics & numerical data
C416945:ABCG5 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D008074:Lipoproteins; D010840:Phytosterols; D013261:Sterols; D002784:Cholesterol