Top

BMC Gastroenterology

Published in:

Open Access 01-12-2015 | Research article

Relation of cholesterol metabolism to pediatric gallstone disease: a retrospective controlled study

Authors: Antti Koivusalo, Mikko Pakarinen, Helena Gylling, Markku J. Nissinen

Published in: BMC Gastroenterology | Issue 1/2015

Abstract

Background

Cholesterol metabolism may be involved in pediatric gallstone disease. We aimed to reveal cholesterol metabolites and phytosterols and their relation to stone composition of sterols in children having black pigment and cholesterol stones.

Methods

We performed retrospective controlled clinical study, in which we examined parameters of cholesterol metabolism and liver function values in serum (n = 28) and gallstones (n = 46) of consecutively cholecystectomized children. Serum values of age-, body mass index- and sex-matched children (n = 82) and adult gallstones (n = 187) served as controls.

Results

Surrogate markers of cholesterol synthesis in serum (squalene/cholesterol, cholestenol/cholesterol and lathosterol/cholesterol) were 26–52 % higher in both stone subclasses compared to controls (p < 0.05 for all). Respectively, cholestanol/cholesterol and plant sterols campesterol/cholesterol and sitosterol/cholesterol (cholesterol absorption markers) had decreasing order in serum: black pigment stone group > controls > cholesterol stone group (p < 0.05 for all). In black pigment stone group, stone cholestanol/cholesterol was associated with serum bile acids (r = 0.620, p = 0.018). In cholesterol stone group, surrogate markers of cholesterol synthesis in serum (e.g., lathosterol/cholesterol) inversely reflected those of absorption (r-range -0.633–-0.706, p-range 0.036–0.015). In cholesterol stone group, serum and stone lathosterol/cholesterol and cholestanol/cholesterol were positively interrelated (r-range 0.727–0.847, p < 0.05 for both).

Conclusions

Gallstone subclasses shared enhanced cholesterol synthesis. Cholesterol stone children were low cholesterol absorbers with intact homeostasis of cholesterol metabolism. Black pigment stone group was characterized by deteriorated cholesterol metabolism, and accumulation of cholestanol, campesterol and sitosterol in serum and stones suggesting their participation in pathogenesis.

Palasciano G, Portincasa P, Vinciguerra V, Velardi A, Tardi S, Baldassarre G, et al. Gallstone prevalence and gallbladder volume in children and adolescents: an epidemiological ultrasonographic survey and relationship to body mass index. Am J Gastroenterol. 1989;84:1378–82.

Walker SK, Maki AC, Cannon RM, Foley DS, Wilson KM, Galganski LA, et al. Etiology and incidence of pediatric gallbladder disease. Surgery. 2013;154:927–33.

Fradin K, Racine AD, Belamarich PF. Obesity and symptomatic cholelithiasis in childhood: epidemiologic and case–control evidence for a strong relation. J Pediatr Gastroenterol Nutr. 2014;58(1):102–6.CrossRefPubMed

Soloway RD, Trotman BW, Ostrow JD. Pigment gallstones. Gastroenterology. 1977;72:167–72.PubMed

Miettinen TE, Kesäniemi YA, Gylling H, Järvinen H, Silvennoinen E, Miettinen TA. Non-cholesterol sterols in bile and stones of patients with cholesterol and pigment stones. Hepatology. 1996;23:274–80.CrossRefPubMed

Marschall H-U, Einarsson C. Gallstone disease. J Intern Med. 2007;261:529–42.CrossRefPubMed

Koivusalo AI, Pakarinen MP, Sittiwet C, Gylling H, Miettinen TA, Miettinen TE, et al. Cholesterol, non-cholesterol sterols and bile acids in paediatric gallstones. Dig Liver Dis. 2010;42:61–6.

Cariati A. Gallstone classification in western countries. Indian J Surg. 2013. doi:10.1007/s12262-013-0847-y.

Wang HH, Portincasa P, de Bari O, Liu KJ, Garruti G, Neuschwander-Tetri BA, et al. Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol. Eur J Clin Invest. 2013;43(4):413–26.

10.

Wang DQ-H. Regulation of intestinal cholesterol absorption. Annu Rev Physiol. 2007;69:221–8.CrossRefPubMed

11.

Ostlund Jr RE. Phytosterols in human nutrition. Annu Rev Nutr. 2002;22:533–49.CrossRefPubMed

12.

Tilvis RS, Miettinen TA. Serum plant sterols and their relation to cholesterol absorption. Am J Clin Nutr. 1986;43:92–7.PubMed

13.

Miettinen TA, Tilvis RS, Kesäniemi YA. Serum cholestanol and plant sterol levels in relation to cholesterol metabolism in middle-aged men. Metabolism. 1989;38:136–40.CrossRefPubMed

14.

Miettinen TA, Tilvis RS, Kesäniemi YA. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol. 1990;131:20–31.PubMed

15.

Simonen P, Gylling H, Miettinen TA. The validity of serum squalene and non-cholesterol sterols as surrogate markers of cholesterol synthesis and absorption in type 2 diabetes. Atherosclerosis. 2008;197:883–8.CrossRefPubMed

16.

Nissinen MJ, Gylling H, Miettinen TA. Responses of surrogate markers of cholesterol absorption and synthesis to changes in cholesterol metabolism during various amounts of fat and cholesterol feeding among healthy men. Br J Nutr. 2008;99:370–8.CrossRefPubMed

17.

Björkhem I, Miettinen TA, Reihner E, Ewerth S, Angelin B, Einarsson K. Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver. J Lipid Res. 1987;28:1137–43.PubMed

18.

Kempen HJM, Glatz JFC, Leuven JAG, van der Voort HA, Katan MB. Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans. J Lipid Res. 1988;29:1149–55.PubMed

19.

Miettinen TA. Cholesterol metabolism during ketoconazole treatment in man. J Lipid Res. 1988;29:43–51.PubMed

20.

Miettinen TA, Koivisto P. Non-cholesterol sterols and bile acid production in hypercholesterolaemic patients with ileal by-pass. In: Paumgartner G, Stiehl A, Gerok W, editors. Bile acids and cholesterol in health and disease. Lancaster: MTP Press; 1983. p. 183–7.

21.

Cetta F. The role of bacteria in pigment gallstone disease. Am J Surg. 1991;213(4):315–26.

22.

Stringer MD, Taylor DR, Soloway RD. Gallstone composition: are children different? J Pediatr. 2003;142:435–40.CrossRefPubMed

23.

Stringer MD, Soloway RD, Taylor DR, Riyad K, Toogood G. Calcium carbonate gallstones in children. J Pediatr Surg. 2007;42:1677–82.CrossRefPubMed

24.

Saari A, Sankilampi U, Hannila M-L, Kiviniemi V, Kesseli K, Dunkel L. New Finnish growth references for children and adolescents aged 0 to 20 years: Length/height-for-age, weight-for-length/height, and body mass index-for-age. Ann Med. 2011;43:235–48.

25.

Krawczyk M, Lütjohann D, Schirin-Sokhan R, Villarroel L, Nervi F, Pimentel F, et al. Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease. Hepatology. 2012;55:1507–17.

26.

Van Erpecum KJ. Pathogenesis of cholesterol and pigment gallstones: an update. Clin Res Hepatol Gastroenterol. 2011;35:281–7.CrossRefPubMed

27.

Buch S, Schafmayer C, Völzke H, Becker C, Franke A, von Eller-Eberstein H, et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet. 2007;39(8):995–9.

28.

Buch S, Schafmayer C, Völzke H, Seeger M, Miquel JF, Sookoian SC, et al. Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition. Gastroenterology. 2010;139:1942–51.

29.

Cariati A, Piromalli E, Morelli N, Bottino G, Andorno E. Indications for laparoscopic cholecystectomy or oral dissolution therapy with ursodeoxycholic acid in symptomatic gallstone disease. Arch Clin Exp Surg. 2014;3:161–5.

30.

Xie M, Kotecha VR, Andrade JDP, Fox JG, Carey MC. Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis. J Physiol. 2012. doi:10.1113/jphysiol.2011.224717.

31.

Sudhop T, Sahin Y, Lindenthal B, Hahn C, Lüers C, Berthold HK, et al. Comparison of the hepatic clearances of campesterol, sitosterol, and cholesterol in healthy subjects suggests that efflux transporters controlling intestinal sterol absorption also regulate biliary secretion. Gut. 2002;51:860–3.

32.

Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3:543–353.CrossRefPubMed

33.

Carter BA, Taylor OA, Prendergast DR, Zimmerman TL, Von Furstenberg R, Moore DD, et al. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res. 2007;62:301–6.

34.

Gylling H, Vuoristo M, Färkkilä M, Miettinen TA. The metabolism of cholestanol in primary biliary cirrhosis. J Hepatol. 1996;24:444–51.CrossRefPubMed

35.

Pakarinen MP, Lampela H, Gylling H, Miettinen TA, Koivusalo AI, Nissinen MJ. Surrogate markers of cholesterol metabolism in children with native liver after successful portoenterostomy for biliary atresia. J Pediatr Surg. 2010;45:1659–64.CrossRefPubMed

36.

Rajaratnam RA, Gylling H, Miettinen TA. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol. 2000;35:1185–91.CrossRefPubMed

37.

Simonen M, Männistö V, Leppänen J, Kaminska D, Kärjä V, Venesmaa S, et al. Desmosterol in human nonalcoholic steatohepatitis. Hepatology. 2013;58:976–82.

38.

Nissinen MJ, Gylling H, Kaski M, Tammisto P, Mieskonen S, Ignatius J, et al. Smith-Lemli-Opitz syndrome and other sterol disorders among Finns with developmental disabilities. J Lab Clin Med. 2000;136:457–67.

39.

Bhattacharyya AK, Connor WE. β-Sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest. 1974;53:1033–43.CrossRefPubMedPubMedCentral

40.

Cariati A, Cetta F. Rokitansky-Aschoff sinuses of the gallbladder are associated with black-pigment gallstone formation: a scanning electron microscopy study. Ultrastruct Pathol. 2003;27(4):265–70.CrossRefPubMed

41.

Cariati A, Piromalli E. Role of parietal (gallbladder mucosa) factors in the formation of black pigment gallstones. Clin Res Hepatol Gastroenterol. 2012;36:e50–1.CrossRefPubMed

Title: Relation of cholesterol metabolism to pediatric gallstone disease: a retrospective controlled study
Authors: Antti Koivusalo
Mikko Pakarinen
Helena Gylling
Markku J. Nissinen
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Gastroenterology / Issue 1/2015
Electronic ISSN: 1471-230X
DOI: https://doi.org/10.1186/s12876-015-0304-4

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Relation of cholesterol metabolism to pediatric gallstone disease: a retrospective controlled study

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial

Chronic constipation in the elderly: a primer for the gastroenterologist

The clinical characteristics of patients with free perforation in Korean Crohn’s disease: results from the CONNECT study

Comparison of medical costs generated by IBS patients in primary and secondary care in the Netherlands

C-reactive protein level at 2 weeks following initiation of infliximab induction therapy predicts outcomes in patients with ulcerative colitis: a 3 year follow-up study

Factors impacting physicians’ decisions to prevent variceal hemorrhage

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page