Skip to main content
SpringerLink
Log in
Book cover

Liver Elastography pp 277–295Cite as

Genetic Confounders of Liver Stiffness and Controlled Attenuation Parameter

  • Chapter
  • First Online:

Abstract

Hepatic steatosis and fibrosis are hallmarks of all chronic liver diseases including non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (ALD), as well as viral hepatitis and can be non-invasively detected and followed up by measuring liver stiffness and controlled attenuation parameter (CAP) using transient elastography (TE, Fibroscan). Since the development and progression of liver injury varies remarkably between individuals and only 15% of heavy alcohol abusers develop end-stage cirrhosis, genetic determinants are suspected to play a major role. Using GWAS and population-based studies, important genetic determinants of steatosis, fibrosis as well as HCC development have been identified that are responsible for the progression of all liver disease etiologies. The most important genetic variant which is associated with steatosis, fibrosis, inflammation, and liver injury in ALD and NAFLD is PNPLA3 p.I148M. By studying ALD patients after alcohol withdrawal, it could be shown that patients with the PNPLA3 GG genotype have higher liver stiffness after withdrawal than patients with PNPLA3 CC type due to delayed resolution of inflammation. PNPLA3 GG was also highly associated with inflammation and ballooning. In contrast, MBOAT7 p.G17E is only associated with increased fibrosis but not inflammation. TM6SF2 p.E167K is still controversially discussed. In addition, there are other genetic variants, which seem to play an important role in patients infected with hepatitis C virus, e.g. rs12979860 C/T polymorphism in the IL28B gene. However, the underlying molecular mechanisms and the effects of these amino acid substitutions are not completely understood and require further detailed investigations.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655–69.

    Article  CAS  PubMed  Google Scholar 

  3. Krawczyk M, Mullenbach R, Weber SN, Zimmer V, Lammert F. Genome-wide association studies and genetic risk assessment of liver diseases. Nat Rev Gastroenterol Hepatol. 2010;7(12):669–81.

    Article  PubMed  Google Scholar 

  4. Mueller S, Rausch V. The role of iron in alcohol-mediated hepatocarcinogenesis. Adv Exp Med Biol. 2015;815:89–112.

    Article  CAS  PubMed  Google Scholar 

  5. Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363(2):166–76.

    Article  CAS  PubMed  Google Scholar 

  6. Rausch V, Peccerella T, Lackner C, Yagmur E, Seitz HK, Longerich T, et al. Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M. World J Hepatol. 2016;8(35):1547–56.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Buch S, Stickel F, Trepo E, Way M, Herrmann A, Nischalke HD, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015;47(12):1443–8.

    Article  CAS  PubMed  Google Scholar 

  8. Yang J, Trepo E, Nahon P, Cao Q, Moreno C, Letouze E, et al. A 17-Beta-hydroxysteroid dehydrogenase 13 variant protects from hepatocellular carcinoma development in alcoholic liver disease. Hepatology. 2019;70(1):231–40.

    CAS  PubMed  Google Scholar 

  9. Stickel F, Lutz P, Buch S, Nischalke HD, Silva I, Rausch V, et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology. 2019. https://doi.org/10.1002/hep.30996.

  10. Weber S, Grunhage F, Hall R, Lammert F. Genome-wide association studies in hepatology. Z Gastroenterol. 2010;48(1):56–64.

    Article  CAS  PubMed  Google Scholar 

  11. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology. 2003;37(3):493–503.

    Article  CAS  PubMed  Google Scholar 

  12. Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? Gut. 2010;59(7):861–6.

    Article  PubMed  Google Scholar 

  13. Mueller S, Seitz HK, Rausch V. Non-invasive diagnosis of alcoholic liver disease. World J Gastroenterol. 2014;20(40):14626–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease. Hepat Med. 2010;2:49–67.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bruschi FV, Tardelli M, Claudel T, Trauner M. PNPLA3 expression and its impact on the liver: current perspectives. Hepat Med. 2017;9:55–66.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Krawczyk M, Grunhage F, Zimmer V, Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease. J Hepatol. 2011;55(2):299–306.

    Article  CAS  PubMed  Google Scholar 

  17. Witzel H, Schwittai I, Pawella L, Rausch V, Mueller S, Schattenberg J, et al. Lipid droplet-associated proteins in alcoholic and non-alcoholic steatohepatitis in patients with polymorphisms in PNPLA3. Z Gastroenterol. 2019;57(01):e55.

    Google Scholar 

  18. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012;122(11):4130–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. BasuRay S, Wang Y, Smagris E, Cohen JC, Hobbs HH. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci. 2019;116(19):9521–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015;61(1):108–18.

    Article  CAS  PubMed  Google Scholar 

  21. Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012;15(5):691–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kollerits B, Coassin S, Beckmann ND, Teumer A, Kiechl S, Doring A, et al. Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins. Hum Mol Genet. 2009;18(23):4669–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Krawczyk M, Gruenhage F, Mahler M, Tirziu S, Acalovschi M, Lammert F. The common adiponutrin variant p.I148M does not confer gallstone risk but affects fasting glucose and triglyceride levels. J Physiol Pharmacol. 2011;62(3):369–75.

    CAS  PubMed  Google Scholar 

  24. Palmer CN, Maglio C, Pirazzi C, Burza MA, Adiels M, Burch L, et al. Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant. PLoS One. 2012;7(6):e39362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Stahlman M, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol. 2012;57(6):1276–82.

    Article  CAS  PubMed  Google Scholar 

  26. Rausch V, Mueller S. Suppressed fat mobilization due to PNPLA3 rs738409-associated liver damage in heavy drinkers: the liver damage feedback hypothesis. Adv Exp Med Biol. 2018;1032:153–72.

    Article  CAS  PubMed  Google Scholar 

  27. Hua X, Wu J, Goldstein JL, Brown MS, Hobbs HH. Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13. Genomics. 1995;25(3):667–73.

    Article  CAS  PubMed  Google Scholar 

  28. Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci U S A. 1998;95(11):5987–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107(17):7892–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dubuquoy C, Robichon C, Lasnier F, Langlois C, Dugail I, Foufelle F, et al. Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes. J Hepatol. 2011;55(1):145–53.

    Article  CAS  PubMed  Google Scholar 

  31. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10(11):645–55.

    Article  CAS  PubMed  Google Scholar 

  33. Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet. 2010;42(1):21–3.

    Article  CAS  PubMed  Google Scholar 

  34. Stickel F, Buch S, Lau K, Meyer zu Schwabedissen H, Berg T, Ridinger M, et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology. 2011;53(1):86–95.

    Article  CAS  PubMed  Google Scholar 

  35. Trepo E, Gustot T, Degre D, Lemmers A, Verset L, Demetter P, et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J Hepatol. 2011;55(4):906–12.

    Article  CAS  PubMed  Google Scholar 

  36. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res. 2009;50(10):2111–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109(3):325–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nischalke HD, Berger C, Luda C, Berg T, Muller T, Grunhage F, et al. The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis. PLoS One. 2011;6(11):e27087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology. 2011;53(3):791–9.

    Article  CAS  PubMed  Google Scholar 

  40. Falleti E, Fabris C, Cmet S, Cussigh A, Bitetto D, Fontanini E, et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int. 2011;31(8):1137–43.

    Article  CAS  PubMed  Google Scholar 

  41. Burza MA, Pirazzi C, Maglio C, Sjoholm K, Mancina RM, Svensson PA, et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis. 2012;44(12):1037–41.

    Article  CAS  PubMed  Google Scholar 

  42. Hassan MM, Kaseb A, Etzel CJ, El-Serag H, Spitz MR, Chang P, et al. Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction. Mol Carcinog. 2013;52(Suppl 1):E139–47.

    Article  CAS  PubMed  Google Scholar 

  43. Krawczyk M, Grunhage F, Lammert F. Identification of combined genetic determinants of liver stiffness within the SREBP1c-PNPLA3 pathway. Int J Mol Sci. 2013;14(10):21153–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Caddeo A, Jamialahmadi O, Solinas G, Pujia A, Mancina RM, Pingitore P, et al. MBOAT7 is anchored to endomembranes by six transmembrane domains. J Struct Biol. 2019;206(3):349–60.

    Article  CAS  PubMed  Google Scholar 

  45. Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150(5):1219–30 e6.

    Article  CAS  PubMed  Google Scholar 

  46. Donati B, Dongiovanni P, Romeo S, Meroni M, McCain M, Miele L, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017;7(1):4492.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, et al. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study. J Lipid Res. 2017;58(1):247–55.

    Article  CAS  PubMed  Google Scholar 

  48. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309.

    Article  CAS  PubMed  Google Scholar 

  50. Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015;61(2):506–14.

    Article  CAS  PubMed  Google Scholar 

  51. Petta S, Di Marco V, Pipitone RM, Grimaudo S, Buscemi C, Craxi A, et al. Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: genetic and metabolic risk factors in a general population. Liver Int. 2018;38(11):2060–8.

    Article  CAS  PubMed  Google Scholar 

  52. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138(4):1338–45, 45 e1–7.

    Google Scholar 

  53. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461(7265):798–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lundbo LF, Clausen LN, Weis N, Schonning K, Rosenorn L, Benfield T, et al. Influence of hepatitis C virus and IL28B genotypes on liver stiffness. PLoS One. 2014;9(12):e115882.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Lutz P, Wasmuth JC, Nischalke HD, Vidovic N, Grunhage F, Lammert F, et al. Progression of liver fibrosis in HIV/HCV genotype 1 co-infected patients is related to the T allele of the rs12979860 polymorphism of the IL28B gene. Eur J Med Res. 2011;16(8):335–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ydreborg M, Westin J, Rembeck K, Lindh M, Norrgren H, Holmberg A, et al. Impact of Il28b-related single nucleotide polymorphisms on liver transient elastography in chronic hepatitis C infection. PLoS One. 2013;8(11):e80172.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Jimenez-Sousa MA, Gomez-Moreno AZ, Pineda-Tenor D, Medrano LM, Sanchez-Ruano JJ, Fernandez-Rodriguez A, et al. The IL7RA rs6897932 polymorphism is associated with progression of liver fibrosis in patients with chronic hepatitis C: repeated measurements design. PLoS One. 2018;13(5):e0197115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Nunez-Torres R, Macias J, Mancebo M, Frias M, Dolci G, Tellez F, et al. The PNPLA3 genetic variant rs738409 influences the progression to cirrhosis in HIV/hepatitis C virus coinfected patients. PLoS One. 2016;11(12):e0168265.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol. 2009;51(3):433–45.

    Article  PubMed  Google Scholar 

  60. d’Assignies GRM, Khiat A, Lepanto L, Chagnon M, Kauffmann C, et al. Noninvasive quantitation of human liver steatosis using magnetic resonance and bioassay methods. Eur Radiol. 2009;19:2033–40.

    Article  PubMed  Google Scholar 

  61. Mancini M, Prinster A, Annuzzi G, Liuzzi R, Giacco R, Medagli C, Cremone M, Clemente G, Maurea S, Riccardi G, Rivellese AA, Salvatore M. Sonographic hepatic-renal ratio as indicator of hepatic steatosis: comparison with (1)H magnetic resonance spectroscopy. Metabolism. 2009;58(12):1724–30.

    Article  CAS  PubMed  Google Scholar 

  62. Sasso M, Beaugrand M, de Ledinghen V, Douvin C, Marcellin P, Poupon R, et al. Controlled attenuation parameter (CAP): a novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol. 2010;36(11):1825–35.

    Article  PubMed  Google Scholar 

  63. Arslanow A, Stokes CS, Weber SN, Grunhage F, Lammert F, Krawczyk M. The common PNPLA3 variant p.I148M is associated with liver fat contents as quantified by controlled attenuation parameter (CAP). Liver Int. 2016;36(3):418–26.

    Article  CAS  PubMed  Google Scholar 

  64. Eliades M, Spyrou E. Vitamin D: a new player in non-alcoholic fatty liver disease? World J Gastroenterol. 2015;21(6):1718–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jamka M, Arslanow A, Bohner A, Krawczyk M, Weber SN, Grunhage F, et al. Effects of gene variants controlling vitamin D metabolism and serum levels on hepatic steatosis. Digestion. 2018;97(4):298–308.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang RN, Zheng RD, Mi YQ, Zhou D, Shen F, Chen GY, et al. APOC3 rs2070666 is associated with the hepatic steatosis independently of PNPLA3 rs738409 in Chinese han patients with nonalcoholic fatty liver diseases. Dig Dis Sci. 2016;61(8):2284–93.

    Article  CAS  PubMed  Google Scholar 

  67. Mueller S, Englert S, Seitz HK, Badea RI, Erhardt A, Bozaari B, et al. Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease. Liver Int. 2015;35(12):2514–21.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine and Center for Alcohol Research and Liver Diseases, Salem Medical Center, University of Heidelberg, Heidelberg, Germany

    Vanessa Rausch, Johannes Mueller & Sebastian Mueller

Authors
  1. Vanessa Rausch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johannes Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sebastian Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sebastian Mueller .

Editor information

Editors and Affiliations

  1. Department of Medicine and Center for Alcohol Research and Liver Diseases, Salem Medical Center, University of Heidelberg, Heidelberg, Germany

    Sebastian Mueller

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Rausch, V., Mueller, J., Mueller, S. (2020). Genetic Confounders of Liver Stiffness and Controlled Attenuation Parameter. In: Mueller, S. (eds) Liver Elastography. Springer, Cham. https://doi.org/10.1007/978-3-030-40542-7_27

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-40542-7_27

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-40541-0

  • Online ISBN: 978-3-030-40542-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation