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Altered Bile Transporter Expression and Cholesterol Metabolism in Children with Cholesterol and Pigment Gallstones

Koivusalo, Antti*; Mutanen, Annika*; Nissinen, Markku; Gylling, Helena; Pakarinen, Mikko*

Journal of Pediatric Gastroenterology and Nutrition: May 6, 2019 - Volume Publish Ahead of Print - Issue - p
doi: 10.1097/MPG.0000000000002353
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Objectives.: 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.

Methods.: RNA expression of canalicular bile transporters in liver biopsies from 32 pediatric gallstone patients and from six liver donors (controls) was measured by qRT-PCR. 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.

Results.: 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 2.5-1.8 fold (p < 0.002) in CS and PS-patients, while 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 ACBC11 expression (R2 = 0.27, p = 0.03).

Conclusions. 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, University of Helsinki, Finland

Department of Internal Medicine at Helsinki University Hospital, Pediatric Liver and Gut Research Group, University of Helsinki, Finland

Clinic of Gastroenterology, Abdominal Centre at Helsinki University Hospital, Pediatric Liver and Gut Research Group University of Helsinki, Finland.

Address correspondence and reprint requests to Antti Koivusalo, Children's Hospital, Stenbackinkatu 1, PO BOX 281, 00290, Helsinki, Finland (e-mail: antti.koivusalo@hus.fi).

Received 27 November, 2018

Accepted 20 March, 2019

Grant support: Research Foundation of Children's Diseases, Foundation of Sigrid Juselius, Helsinki University Hospital Grant

Conflict of interests: Antti Koivusalo (none), Annika Mutanen (none), Markku Nissinen (none), Helena Gylling (none), Mikko Pakarinen (none)

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

© 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,