We elucidated pathophysiology of pediatric gallstone disease by assessing liver expression of bile transporters in relation to bile acids and surrogates of cholesterol absorption and synthesis in serum and gallstones.
RNA expression of canalicular bile transporters in liver biopsies from 32 pediatric gallstone patients and from 6 liver donors (controls) was measured by qRT-PCR (quantitative real-time reverse transcription polymerase chain reaction). Concentrations of cholesterol and precursors, plant sterols and bile acids in gallstones, and in serum of the patients and 82 healthy children were measured. Primary outcomes were the difference in RNA expressions and serum sterol profiles between patients and controls.
Cholesterol stones (CS; n = 15) contained cholesterol >42% and pigment stones (PS; n = 17) <9% of weight. CS patients had markedly lower serum plant sterols (absorption) and higher cholesterol precursors (synthesis) than PS patients or healthy controls. CS contained several times more cholesterol precursors and less plant sterols relative to cholesterol than PS, which were enriched by primary bile acids (12–5.2-fold, P < 0.001). Liver RNA expression of ABCG5/G8 was similarly increased 2.5- to 1.8-fold (P < 0.002) in CS and PS patients, whereas PS patients had higher ABCB11 expression (P < 0.05). In PS bile acid concentration correlated with gallstone plant sterols (R2 = 0.83, P < 0.0001), and ABCG5 expression with ABCB11 expression (R2 = 0.27, P = 0.03).
In CS, upregulation of ABCG5/G8 expression associates with low absorption and high gallstone content of cholesterol. In PS, activation of bile acid transport by ACBC11 interconnects with hepatic upregulation of ABCG5/G8 enriching PS with bile acids and plant sterols.
*Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital
†Department of Internal Medicine at Helsinki University Hospital
‡Clinic of Gastroenterology, Abdominal Centre at Helsinki University Hospital, Pediatric Liver and Gut Research Group, University of Helsinki, Helsinki, Finland.
Address correspondence and reprint requests to Antti Koivusalo, MD, PhD, Children's Hospital, Stenbackinkatu 11, PO Box 281, 00290 Helsinki, Finland (e-mail: firstname.lastname@example.org).
Received 27 November, 2018
Accepted 20 March, 2019
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The study was supported by Research Foundation of Children's Diseases, Foundation of Sigrid Juselius, Helsinki University Hospital Grant.
The authors report no conflicts of interest.