Gallstones are very frequent worldwide with a prevalence ranging from 10% to 15% in Western countries to <5% in Africa, with the geographic variations being associated with genetic and environmental factors.1 Although asymptomatic in more than 80% of patients, gallstone disease incurs one of the highest health care costs among digestive diseases and hospitalization is frequent as a consequence of its complications

Alvaro, Domenico

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Domenico Alvaro

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Gastroenterology

Gallstones: Bad Company for the Steatotic Liver

ALVARO, Domenico

Archivio della ricerca- Università di Roma La Sapienza

EDITORIALSpatients with chronic hepatitis C and decompensatedcirrhosis. J Hepatol 2016;65:741–747.Reprint requestsAddress requests for reprints to: Alexander J. Thompson, MBBS (hons), PhD,FRACP, Director of Gastroenterology, St. Vincent’s Hospital Melbourne, 35Victoria Parade, Fitzroy, Victoria, Australia 3065. e-mail:alexander.thompson@svha.org.au.1284Conflicts of interestThe authors disclose the following: A. J. Thompson is an Advisory boardmember for Gilead Sciences, Abbvie, Bristol-Myers Squibb (BMS), andMerck; a speaker for Gilead Sciences, Abbvie, Merck, BMS, RocheDiagnostics; and receives research/grant support (to institution) from Gilead,Abbvie. J. Howell discloses no conflicts.Most current article© 2017 by the AGA Institute0016-5085/$36.00http://dx.doi.org/10.1053/j.gastro.2017.03.025Gallstones: Bad Company for the Steatotic LiverSee “Activation of the hypoxia induciblefactor 1a subunit pathway in steatotic livercontributes to formation of cholesterolgallstones,” by Asai Y, Yamada T, Tsukita S,et al, on page 1521.allstones are very frequent worldwide with aGprevalence ranging from 10% to 15% in Westerncountries to <5% in Africa, with the geographic variationsbeing associated with genetic and environmental factors.1Although asymptomatic in more than 80% of patients,gallstone disease incurs one of the highest health care costsamong digestive diseases and hospitalization is frequent asa consequence of its complications.1–3 In Western countries,cholesterol stones largely predominate, and exogenous andgenetic risk factors have been carefully defined, includingfemale sex, age, and number of pregnancies.1,2 Severalepidemiologic studies have definitively demonstrated anassociation between cholesterol gallstones and nonalcoholicfatty liver disease (NAFLD).4 Cholesterol gallstones sharecommon risk factors with NAFLD, including obesity, dia-betes mellitus, hypertension, hyperlipidemia, insulin resis-tance, sedentary lifestyle, and the metabolic syndrome.1–5Other than being more prevalent, gallstones are also moresymptomatic and complicated when they occur in conjunc-tion with NAFLD2,5 and, therefore, they are unwantedcompany. Much less clear are the pathogenetic mechanismslinking NAFLD and gallstones. In the different conditionsleading to NAFLD, one or more of the following mechanismscould predominate: (i) hepatic cholesterol oversecretion inbile as consequence of insulin resistance,6 (ii) supersatu-rated bile and rapid phase transition owing to increasedconcentrations of mucins or other pronucleating agents,7(iii) gallbladder hypomotility, which frequently occurs indiabetics or patients with obesity,8 and (iv) intestinal dys-biosis perturbing the cholehepatic bile salt (BS) circulation.9The article by Asai et al10 in this issue of Gastroenterologyproposes a novel and intriguing pathogenetic mechanismlinking liver steatosis with gallstones. Indeed, the authors10propose that, in steatotic livers, hypoxia up-regulates theexpression of hypoxia-inducible factor 1 alpha subunit(HIF1A), which reduces the expression of aquaporin (AQP)-8 and concentrates biliary lipids by suppressing watersecretion from hepatocytes. In addition, inflammation andmucin deposition in the gallbladder wall, associated withexperimental liver steatosis, was reduced in iHIF knockoutmice. An effect of HIF1A knockdown was that gallstoneformation was markedly decreased. In sum, this article issuggesting that steatotic hepatocytes secreted moreconcentrated bile on the basis of suppressed water secretionand this significantly affects gallbladder wall integrity andfunction, thus favoring gallstone formation.How can more concentrated bile favor gallstone for-mation? Pioneering studies in the field have clearlydemonstrated the importance of bile concentration fornucleation time and cholesterol saturation index.11,12Indeed, nucleation time is shortened if bile is concentratedwhereas, conversely, nucleation time is prolonged by serialin vitro dilution of bile.11 In addition, more concentratedbile may affect gallbladder motility by increasing themovement of biliary compounds into gallbladder epithelialcells, by increasing the permeability of the gallbladderepithelium to cholesterol, and by favoring its accumulationin muscle membranes, thus reducing contraction.13Increased concentration of secondary BS may alter phos-pholipid acyl groups and, therefore, cholesterol solubilitywithin the micelle/vesicle.13 Finally, higher BS concentra-tions reaching the gut lumen may perturb the microbiotaand, as a consequence, the enterohepatic BS circulation.9An emerging novel concept is that steatotic, hypoxichepatocytes (mainly in the centrilobular zone) secrete lesswater in bile as a consequence of HIF1A-mediated sup-pression of AQPs (specifically AQP8), a family of integralmembrane proteins that facilitate osmotically inducedwater transport through cell membranes.14 Bile secretionis an osmotically driven secretory process resulting fromthe flow of water into the canalicular lumen in response toosmotic gradients created by active solute excretion.14 Thecurrent findings, therefore, open new scenarios indifferent and unexplored areas. How do water movementand cell volume regulatory mechanisms change in hepa-tocytes accumulating lipid droplets or in cells where lipidand glucose metabolism is changed? What are the keyregulators of these adaptive mechanisms? The answerscould lie within the HIF family of proteins, where HIF1A isthe most well-established member.15 HIFs act as keymediators of cellular adaptation to changes in oxygentension.15 Under hypoxic conditions, HIF1A up-regulates aseries of genes, which enables cells to adapt to reducedoxygen availability; it is estimated that >800 genes areEDITORIALSdirect HIF targets, including heme oxygenase-1, vascularendothelial growth factor, glucose transporters, andglycolytic enzymes.15 Indeed, increased glycolysis duringhypoxia is a crucial step needed to meet modified cellenergy demands.15 It is now known that HIF1A can beinduced and activated also at physiological oxygentensions in a mitogen-activated protein kinase-dependentmanner.15 Asai et al10 suggest that HIF1A activation is adefensive and survival pathway for hypoxic hepatocytes.However, HIFs can be activated by proinflammatorycytokines, extracellular hyperosmolarity owing to highsodium intake, and also merely as a consequence ofmetabolic cellular changes.15 It remains unclear howoxygen cell tension changes during the different facets ofNAFLD and whether hypoxic hepatocytes reflect onlycertain degrees of oxidative stress, damage, and hepaticFigure 1. Steatotic hypoxic hepatocytes secrete more concentrathe inhibitory effects of hypoxia-inducible factor 1 alpha subuniaffects gallbladder wall integrity and function, thus favoring gaconcentrated bile may simply reflect the dysmetabolic changconsumption is enhanced by metabolic needs and water exosmolarity; at low oxygen tension, all these mechanisms comechanisms involved in the regulation of intracellular pH (pHhyperlactemia.microcirculation impairment, but not simple steatosis;these are key areas of future research. However, inde-pendent of cell damage or hypoxia, HIF1A could be acti-vated to modulate, as consequence of lipid accumulationor fatty liver–associated dysmetabolism, ion transportmechanisms involved in the regulation of cell size/volumeand intracellular pH (pHi; Figure 1).15–18 Indeed, in thefirst signs of hypoxia, the rapid intracellular accumulationof lactate and Hþ implies activation of pHi and cell volumeregulatory ion transport mechanisms, including Naþ/Hþexchange, that are vital for maintaining cell viability andrepresent steps where HIF1A could play a role.15,16Notably, the accumulation of lactate and Hþ, mainly owingto increased whole body rates of nonoxidative glycolysis,may occur in insulin-resistant cells independent of hyp-oxia.19 Indeed, hyperlactemia induced by insulinted bile primarily owing to suppressed water secretion, wheret (HIF1A) on aquaporin 8 (AQP8) play a role. This significantlyllstone formation. As an alternative mechanism, secretion ofes occurring in insulin-resistant hepatocytes, where waterchange with extracellular spaces is adapted to intracellularuld be amplified. HIF1A could also modulate ion transporti) and of cell volume, which are activated by intracellular1285EDITORIALSresistance may modulate HIF1A activity20 being associatedwith profound changes in intracellular glucose meta-bolism, including decreased glycogen synthesis, increasednonoxidative glycolysis, and impaired glucose oxidativemetabolism.19 The hypothesis that increased levels oflactate would be able to activate pHi and cell volumeregulatory ion transport mechanisms, in addition andirrespective of hypoxia, and the exact involvement of HIFsdeserves special attention.In summary, secretion of concentrated bile may simplyreflect dysmetabolic changes occurring in steatotic hepato-cytes where water consumption is enhanced by metabolicneeds and water exchange with extracellular spaces isadapted to the intracellular osmolarity. At low oxygen ten-sion, all these mechanisms could be amplified.DOMENICO ALVAROUniversity Sapienza of RomeDivision of GastroenterologyDepartment of Internal Medicine and Medical SpecialtiesRome, Italy1286References1. Sanyal AJ. AGA technical review on nonalcoholic fattyliver disease. Gastroenterology 2002;123:1705–1725.2. Lammert F, Gurusamy K, Ko CW, et al. Gallstones. NatRev Dis Primers 2016;28:16024.3. Sandler RS, Everhart JE, Donowitz M, et al. The burdenof selected digestive diseases in the United States.Gastroenterology 2002;122:1500–1511.4. Jaruvongvanich V, Sanguankeo A, Upala S. Significantassociation between gallstone disease and nonalcoholicfatty liver disease: a systematic review and meta-anal-ysis. Dig Dis Sci 2016;61:2389–2396.5. Tsai CJ, Leitzmann MF, Willett WC, et al. Centraladiposity, regional fat distribution, and the risk of cho-lecystectomy in women. Gut 2006;55:708–714.6. Biddinger SB, Haas JT, Yu BB, et al. Hepatic insulinresistance directly promotes formation of cholesterolgallstones. Nat Med 2008;14:778–782.7. Lee SP, LaMont JT, Carey MC. Role of gallbladdermucus hypersecretion in the evolution of cholesterolgallstones. J Clin Invest 1981;67:1712–1723.8. Fraquelli M, Pagliarulo M, Colucci A, et al. Gallbladdermotility in obesity, diabetes mellitus and coeliac disease.Dig Liver Dis 2003;35 suppl 3:S12–S16.9. Fremont-Rahl JJ, Ge Z, Umana C, et al. An analysis ofthe role of the indigenous microbiota in cholesterolgallstone pathogenesis. PLoS One 2013;29:e70657.10. Asai Y, Yamada T, Tsukita S, et al. Activation of thehypoxia inducible factor 1a subunit pathway in steatoticliver contributes to formation of cholesterol gallstones.Gastroenterology 2017;152:1521–1535.11. van Erpecum KJ, van Berge Henegouwen GP,Stoelwinder B, et al. Bile concentration is a key factor fornucleation of cholesterol crystals and cholesterol satu-ration index in gallbladder bile of gallstone patients.Hepatology 1990;11:1–6.12. Holan KR, Holzbach RT, Hermann RE, et al. Nucleationtime: a key factor in the pathogenesis of cholesterolgallstone disease. Gastroenterology 1979;77:611–617.13. Hopwood D, Ross PE. Biochemical and morphologicalcorrelations in human gallbladder with reference tomembrane permeability. Microsc Res Tech 1997;38:631–642.14. Masyuk AI, LaRusso NF. Aquaporins in the hepatobiliarysystem. Hepatology 2006;43(2 suppl 1):S75–S81.15. Kumar H, Choi DK. Hypoxia inducible factor pathway andphysiological adaptation: a cell survival pathway? Medi-ators Inflamm 2015;2015:584758.16. Shimoda LA, Fallon M, Pisarcik S, et al. HIF-1 regu-lates hypoxic induction of NHE1 expression and alka-linization of intracellular pH in pulmonary arterialmyocytes. Am J Physiol Lung Cell Mol Physiol 2006;291:L941–L949.17. Benedetti A, Svegliati Baroni G, Marucci M, et al. Regu-lation of intracellular pH in isolated periportal and peri-venular rat hepatocytes. Gastroenterology 1993;105:1797–1805.18. Graf J, Häussinger D. Ion transport in hepatocytes:mechanisms and correlations to cell volume, hormoneactions and metabolism. J Hepatol 1996;24 suppl1:53–77.19. Thorburn AW, Gumbiner B, Bulacan F, et al. Intracellularglucose oxidation and glycogen synthase activity arereduced in non-insulin-dependent (type II) diabetes in-dependent of impaired glucose uptake. J Clin Invest1990;85:522–599.20. Nalbandian M, Takeda M. Lactate as a signaling mole-cule that regulates exercise-induced adaptations.Biology (Basel) 2016;5:E38.Reprint requestsAddress requests for reprints to: Domenico Alvaro, MD, Full Professor ofGastroenterology, University Sapienza of Rome, Division of Gastroenterology,Department of Internal Medicine and Medical Specialties, Viale del Policlinico151, 00161 Rome, Italy. e-mail: domenico.alvaro@uniroma1.it.AcknowledgmentsThe author thanks Prof. Raffaella Buzzetti (Chief of Diabetes Center, SapienzaUniversity of Rome, Italy) and Prof. Stefano Ginanni-Corradini(Gastroenterology Division, Sapienza University of Rome, Italy) for the criticaldiscussion on the content of the present document.Conflicts of interestThe author discloses no conflicts.Most current article© 2017 by the AGA Institute0016-5085/$36.00http://dx.doi.org/10.1053/j.gastro.2017.03.020

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Gallstones: Bad Company for the Steatotic Liver

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