The impact of hepatic steatosis on portal hypertension

English version

Autoři: Georg Semmler ^aff001; Bernhard Scheiner ^aff001; Philipp Schwabl ^aff001; Theresa Bucsics ^aff001; Rafael Paternostro ^aff001; David Chromy ^aff001; Albert Friedrich Stättermayer ^aff001; Michael Trauner ^aff001; Mattias Mandorfer ^aff001; Arnulf Ferlitsch ^aff003; Thomas Reiberger ^aff001
Působiště autorů: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ^aff001; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria ^aff002; Department of Internal Medicine I, Hospital of St. John of God, Vienna, Austria ^aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0224506

Souhrn

Background and aims

Studies in animal models have suggested that hepatic steatosis impacts on portal pressure, potentially by inducing liver sinusoidal endothelial dysfunction and thereby increasing intrahepatic resistance. Thus, we aimed to evaluate the impact of hepatic steatosis on hepatic venous pressure gradient (HVPG) in patients with chronic liver disease.

Method

261 patients undergoing simultaneous HVPG measurements and controlled attenuation parameter (CAP)-based steatosis assessment were included in this retrospective study.

Results

The majority of patients had cirrhosis (n = 205; 78.5%) and n = 191 (73.2%) had clinically significant portal hypertension (CSPH; HVPG≥10mmHg). Hepatic steatosis (S1/2/3; CAP ≥248dB/m) was present in n = 102 (39.1%). Overall, HVPG was comparable between patients with vs. without hepatic steatosis (15.5±7.5 vs. 14.8±7.7mmHg; p = 0.465). Neither in patients with HVPG (<6mmHg; p = 0.371) nor in patients with mild portal hypertension (HVPG 6–9mmHg; p = 0.716) or CSPH (HVPG≥10mmHg; p = 0.311) any correlation between CAP and HVPG was found. Interestingly, in patients with liver fibrosis F2/3, there was a negative correlation between CAP and HVPG (Pearson’s ρ:-0.522; p≤0.001). In multivariate analysis, higher CAP was an independent ‘protective’ factor for the presence of CSPH (odds ratio [OR] per 10dB/m: 0.92, 95% confidence interval [CI]:0.85–1.00; p = 0.045), while liver stiffness was associated with the presence of CSPH (OR per kPa: 1.26, 95%CI: 1.17–1.36; p≤0.001). In 78 patients, in whom liver biopsy was performed, HVPG was neither correlated with percentage of histological steatosis (p = 0.714) nor with histological steatosis grade (p = 0.957).

Conclusion

Hepatic steatosis, as assessed by CAP and liver histology, did not impact on HVPG in our cohort comprising a high proportion of patients with advanced chronic liver disease. However, high CAP values (i.e. pronounced hepatic steatosis) might lead to overestimation of liver fibrosis by ‘artificially’ increasing transient elastography-based liver stiffness measurements.

Klíčová slova:

Liver diseases – Fibrosis – Etiology – Histology – Liver fibrosis – Fatty liver – Steatosis – Portal hypertension

Zdroje

1. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Alimentary pharmacology & therapeutics. 2011;34(3):274–85. Epub 2011/06/01. doi: 10.1111/j.1365-c2036.2011.04724.x 21623852.

2. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138–53. Epub 2017/03/21. doi: 10.1136/gutjnl-2017-313884 28314735.

3. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Journal of hepatology. 2016;64(6):1388–402. Epub 2016/04/12. doi: 10.1016/j.jhep.2015.11.004 27062661.

4. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology (Baltimore, Md). 2012;55(6):2005–23. Epub 2012/04/11. doi: 10.1002/hep.25762 22488764.

5. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249–53. Epub 2011/07/06. doi: 10.1053/j.gastro.2011.06.061 21726509.

6. Berzigotti A, Seijo S, Arena U, Abraldes JG, Vizzutti F, Garcia-Pagan JC, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology. 2013;144(1):102–11.e1. Epub 2012/10/13. doi: 10.1053/j.gastro.2012.10.001 23058320.

7. Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut. 2013;62(11):1634–41. Epub 2012/12/20. doi: 10.1136/gutjnl-2012-304038 23250049.

8. Bucsics T, Mandorfer M, Schwabl P, Bota S, Sieghart W, Ferlitsch A, et al. Impact of acute kidney injury on prognosis of patients with liver cirrhosis and ascites: A retrospective cohort study. Journal of gastroenterology and hepatology. 2015;30(11):1657–65. Epub 2015/05/15. doi: 10.1111/jgh.13002 25967931.

9. Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology (Baltimore, Md). 2003;37(4):902–8. doi: 10.1053/jhep.2003.50133 12668985.

10. Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481–8. doi: 10.1053/j.gastro.2007.05.024 17681169.

11. Reiberger T, Puspok A, Schoder M, Baumann-Durchschein F, Bucsics T, Datz C, et al. Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III). Wien Klin Wochenschr. 2017;129(Suppl 3):135–58. Epub 2017/10/25. doi: 10.1007/s00508-017-1262-3 29063233.

12. Francque S, Wamutu S, Chatterjee S, Van Marck E, Herman A, Ramon A, et al. Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation in vitro and in vivo in a rat model. Liver international: official journal of the International Association for the Study of the Liver. 2010;30(3):365–75. Epub 2009/10/21. doi: 10.1111/j.1478-3231.2009.02136.x 19840249.

13. Pasarin M, La Mura V, Gracia-Sancho J, Garcia-Caldero H, Rodriguez-Vilarrupla A, Garcia-Pagan JC, et al. Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD. PLoS One. 2012;7(4):e32785. doi: 10.1371/journal.pone.0032785 22509248.

14. Francque S, Laleman W, Verbeke L, Van Steenkiste C, Casteleyn C, Kwanten W, et al. Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Laboratory investigation; a journal of technical methods and pathology. 2012;92(10):1428–39. Epub 2012/08/15. doi: 10.1038/labinvest.2012.103 22890552.

15. Van der Graaff D, Kwanten WJ, Couturier FJ, Govaerts JS, Verlinden W, Brosius I, et al. Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats. Laboratory investigation; a journal of technical methods and pathology. 2018. Epub 2018/01/13. doi: 10.1038/s41374-017-0018-z 29326427.

16. Francque S, Verrijken A, Mertens I, Hubens G, Van Marck E, Pelckmans P, et al. Noncirrhotic human nonalcoholic fatty liver disease induces portal hypertension in relation to the histological degree of steatosis. European journal of gastroenterology & hepatology. 2010;22(12):1449–57. Epub 2011/03/11. 21389796.

17. Schwabl P, Mandorfer M, Steiner S, Scheiner B, Chromy D, Herac M, et al. Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with advanced liver disease. Alimentary pharmacology & therapeutics. 2017;45(1):139–49. Epub 2016/12/03. doi: 10.1111/apt.13844 27910154.

18. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898–906. Epub 2005/06/09. doi: 10.1053/j.gastro.2005.03.084 15940625.

19. Kalambokis G, Manousou P, Vibhakorn S, Marelli L, Cholongitas E, Senzolo M, et al. Transjugular liver biopsy—indications, adequacy, quality of specimens, and complications—a systematic review. Journal of hepatology. 2007;47(2):284–94. doi: 10.1016/j.jhep.2007.05.001 17561303.

20. Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. Journal of hepatology. 2009;50(1):1–3. Epub 2008/11/20. doi: 10.1016/j.jhep.2008.10.014 19017551.

21. van Werven JR, Marsman HA, Nederveen AJ, Smits NJ, ten Kate FJ, van Gulik TM, et al. Assessment of hepatic steatosis in patients undergoing liver resection: comparison of US, CT, T1-weighted dual-echo MR imaging, and point-resolved 1H MR spectroscopy. Radiology. 2010;256(1):159–68. Epub 2010/06/25. doi: 10.1148/radiol.10091790 20574093.

22. Lee SS, Park SH, Kim HJ, Kim SY, Kim MY, Kim DY, et al. Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations. Journal of hepatology. 2010;52(4):579–85. Epub 2010/02/27. doi: 10.1016/j.jhep.2010.01.008 20185194.

23. 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 in medicine & biology. 2010;36(11):1825–35. Epub 2010/09/28. doi: 10.1016/j.ultrasmedbio.2010.07.005 20870345.

24. Shi KQ, Tang JZ, Zhu XL, Ying L, Li DW, Gao J, et al. Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy. Journal of gastroenterology and hepatology. 2014;29(6):1149–58. Epub 2014/01/31. doi: 10.1111/jgh.12519 24476011.

25. Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Ledinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. Journal of hepatology. 2017;66(5):1022–30. Epub 2017/01/01. doi: 10.1016/j.jhep.2016.12.022 28039099.

26. de Ledinghen V, Vergniol J, Capdepont M, Chermak F, Hiriart JB, Cassinotto C, et al. Controlled attenuation parameter (CAP) for the diagnosis of steatosis: a prospective study of 5323 examinations. Journal of hepatology. 2014;60(5):1026–31. Epub 2014/01/01. doi: 10.1016/j.jhep.2013.12.018 24378529.

27. de Ledinghen V, Wong GL, Vergniol J, Chan HL, Hiriart JB, Chan AW, et al. Controlled attenuation parameter for the diagnosis of steatosis in non-alcoholic fatty liver disease. Journal of gastroenterology and hepatology. 2016;31(4):848–55. Epub 2015/10/31. doi: 10.1111/jgh.13219 26514665.

28. Ferlitsch A, Bota S, Paternostro R, Reiberger T, Mandorfer M, Heinisch B, et al. Evaluation of a new balloon occlusion catheter specifically designed for measurement of hepatic venous pressure gradient. Liver international: official journal of the International Association for the Study of the Liver. 2015;35(9):2115–20. Epub 2015/01/15. doi: 10.1111/liv.12783 25585656.

29. Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut. 2013;62(11):1634–41. doi: 10.1136/gutjnl-2012-304038 23250049.

30. Reiberger T, Ferlitsch A, Payer BA, Pinter M, Homoncik M, Peck-Radosavljevic M, et al. Non-selective beta-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis. J Gastroenterol. 2012;47(5):561–8. doi: 10.1007/s00535-011-0517-4 22170417.

31. Reiberger T, Ferlitsch A, Payer BA, Pinter M, Schwabl P, Stift J, et al. Noninvasive screening for liver fibrosis and portal hypertension by transient elastography—a large single center experience. Wiener klinische Wochenschrift. 2012;124(11):395–402. doi: 10.1007/s00508-012-0190-5 22699260

32. Schwabl P, Bota S, Salzl P, Mandorfer M, Payer BA, Ferlitsch A, et al. New reliability criteria for transient elastography increase the number of accurate measurements for screening of cirrhosis and portal hypertension. Liver international: official journal of the International Association for the Study of the Liver. 2015;35(2):381–90. Epub 2014/06/24. doi: 10.1111/liv.12623 24953516.

33. Wong GL, Wong VW, Choi PC, Chan AW, Chan HL. Development of a non-invasive algorithm with transient elastography (Fibroscan) and serum test formula for advanced liver fibrosis in chronic hepatitis B. Alimentary pharmacology & therapeutics. 2010;31(10):1095–103. Epub 2010/02/26. doi: 10.1111/j.1365-2036.2010.04276.x 20180785.

34. Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly JP, et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Alimentary pharmacology & therapeutics. 2008;28(10):1188–98. Epub 2008/08/19. doi: 10.1111/j.1365-2036.2008.03831.x 18705692.

35. Nahon P, Kettaneh A, Lemoine M, Seror O, Barget N, Trinchet JC, et al. Liver stiffness measurement in patients with cirrhosis and hepatocellular carcinoma: a case-control study. European journal of gastroenterology & hepatology. 2009;21(2):214–9. Epub 2009/02/13. doi: 10.1097/MEG.0b013e32830eb8d7 19212210.

36. de Ledinghen V, Vergniol J. Transient elastography (FibroScan). Gastroenterologie clinique et biologique. 2008;32(6 Suppl 1):58–67. Epub 2008/12/17. doi: 10.1016/S0399-8320(08)73994-0 18973847.

37. Stift J, Semmler G, Walzel C, Mandorfer M, Schwarzer R, Schwabl P, et al. Transjugular aspiration liver biopsy performed by hepatologists trained in HVPG measurements is safe and provides important diagnostic information. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2019. Epub 2019/03/14. doi: 10.1016/j.dld.2019.01.020 30862438.

38. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. The American journal of surgical pathology. 1995;19(12):1409–17. Epub 1995/12/01. doi: 10.1097/00000478-199512000-00007 7503362.

39. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology (Baltimore, Md). 1996;24(2):289–93. Epub 1996/08/01. doi: 10.1002/hep.510240201 8690394.

40. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology (Baltimore, Md). 2012;56(5):1751–9. Epub 2012/06/19. doi: 10.1002/hep.25889 22707395.

41. Saeed MJ, Olsen MA, Powderly WG, Presti RM. Diabetes Mellitus is Associated With Higher Risk of Developing Decompensated Cirrhosis in Chronic Hepatitis C Patients. J Clin Gastroenterol. 2017;51(1):70–6. Epub 2016/06/17. doi: 10.1097/MCG.0000000000000566 27306942.

42. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology (Baltimore, Md). 1990;11(1):74–80. Epub 1990/01/01. doi: 10.1002/hep.1840110114 2295475.

43. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology (Baltimore, Md). 2006;43(2 Suppl 1):S121–31. Epub 2006/02/01. doi: 10.1002/hep.20993 16447289.

44. Erice E, Llop E, Berzigotti A, Abraldes JG, Conget I, Seijo S, et al. Insulin resistance in patients with cirrhosis and portal hypertension. American journal of physiology Gastrointestinal and liver physiology. 2012;302(12):G1458–65. Epub 2012/04/12. doi: 10.1152/ajpgi.00389.2011 22492691.

45. Petta S, Maida M, Macaluso FS, Di Marco V, Camma C, Cabibi D, et al. The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease. Hepatology (Baltimore, Md). 2015;62(4):1101–10. Epub 2015/05/21. doi: 10.1002/hep.27844 25991038.

46. Petta S, Wong VW, Camma C, Hiriart JB, Wong GL, Marra F, et al. Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values. Hepatology (Baltimore, Md). 2017;65(4):1145–55. Epub 2016/09/18. doi: 10.1002/hep.28843 27639088.

47. Mendes LC, Ferreira PA, Miotto N, Zanaga L, Lazarini MS, Goncales ESL, et al. Controlled attenuation parameter for steatosis grading in chronic hepatitis C compared with digital morphometric analysis of liver biopsy: impact of individual elastography measurement quality. European journal of gastroenterology & hepatology. 2018. Epub 2018/05/05. doi: 10.1097/meg.0000000000001145 29727388.

48. Semmler G, Stift J, Scheiner B, Woran K, Schwabl P, Paternostro R, et al. Performance of Controlled Attenuation Parameter in Patients with Advanced Chronic Liver Disease and Portal Hypertension. Digestive diseases and sciences. 2019. Epub 2019/06/19. doi: 10.1007/s10620-019-05702-7 31209721.