Skip to main content

Advertisement

SpringerLink
Log in

Management of refractory ascites attenuates muscle mass reduction and improves survival in patients with decompensated cirrhosis

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

This study investigated time-course changes in skeletal muscle volume per year with tolvaptan in patients with refractory ascites that was unresponsive to loop diuretics and aldosterone antagonists.

Methods

This retrospective study included 42 patients who received tolvaptan for refractory ascites and/or hepatic edema and underwent computed tomography (CT) before and ≥ 3 months after initiating tolvaptan. The time-course changes in skeletal muscle index per year [ΔSMI (%)] was calculated as follows: ΔSMI (%) = (SMI at final CT scan − SMI at initial CT scan)/SMI at initial CT scan × 100/years between CT scans.

Results

Eligible patients were 23 men and 19 women of median age of 71 years (range 21–94 years). The median follow-up period was 22.7 (range 3.5–54.6) months. ΔSMI (%) was significantly higher in the responders group than in the nonresponder group. Multivariate analysis showed the response to tolvaptan was an independent and significant factor associated with an increase in muscle mass [odds ratio (OR) 20.364; 95% CI 2.327–178.97; P = 0.006]. Overall survival with tolvaptan was significantly higher in the responder group than in the nonresponder group. Multivariate analysis showed that the response to tolvaptan treatment was a significant contributor to good prognosis (OR 3.884; 95% CI 1.264–11.931; P = 0.018). A significant negative correlation was observed between the dosage of furosemide and ΔSMI (%) (P = 0.014).

Conclusions

Treatment of refractory ascites with tolvaptan may attenuate the progression of sarcopenia and improve the prognosis in patients with decompensated cirrhosis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Montano-Loza AJ, Meza-Junco J, Prado CM, et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin Gastroenterol Hepatol. 2012;10:166–73.

    Article  PubMed  Google Scholar 

  2. Hanai T, Shiraki M, Nishimura K, et al. Sarcopenia impairs prognosis of patients with liver cirrhosis. Nutrition. 2015;31:193–9.

    Article  PubMed  Google Scholar 

  3. Yamada Y, Schoeller DA, Nakamura E, et al. Extracellular water may mask actual muscle atrophy during aging. J Gerontol A Biol Sci Med Sci. 2010;65:510–6.

    Article  PubMed  Google Scholar 

  4. Montano-Loza AJ. Clinical relevance of sarcopenia in patients with cirrhosis. World J Gastroenterol. 2014;20:8061–71.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Román E, García-Galcerán C, Torrades T, et al. Effects of an exercise programme on functional capacity, body composition and risk of falls in patients with cirrhosis: a randomized clinical trial. PLoS ONE. 2016;24(11):e0151652.

    Article  CAS  Google Scholar 

  6. Hiraoka A, Michitaka K, Kiguchi D, et al. Efficacy of branched-chain amino acid supplementation and walking exercise for preventing sarcopenia in patients with liver cirrhosis. Eur J Gastroenterol Hepatol. 2017;29:1416–23.

    Article  CAS  PubMed  Google Scholar 

  7. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85:2670–7.

    CAS  PubMed  Google Scholar 

  8. Ohara M, Ogawa K, Suda G, et al. Carnitine suppresses loss of skeletal muscle mass in patients with liver cirrhosis. Hepatol Commun. 2018;2:906–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hiramatsu Akira, Aikata Hiroshi, Uchikawa Shinsuke, et al. Levocarnitine use is associated with improvement in sarcopenia in patients with liver cirrhosis. Hepatol Commun. 2019;3:345–55.

    Article  CAS  Google Scholar 

  10. Dasarathy S. Consilience in sarcopenia of cirrhosis. J Cachexia Sarcopenia Muscle. 2012;3:225–37.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sinclair M, Grossmann M, Hoermann R, et al. Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial. J Hepatol. 2016;65:906–13.

    Article  CAS  PubMed  Google Scholar 

  12. Dasarathy S, Merli M. Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol. 2016;65:1232–44.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Qiu J, Thapaliya S, Runkana A, et al. Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB-mediated mechanism. Proc Natl Acad Sci USA. 2013;110:18162–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Qiu J, Tsien C, Thapalaya S, et al. Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab. 2012;303:983–93.

    Article  CAS  Google Scholar 

  15. Allard JP, Chau J, Sandokji K, et al. Effects of ascites resolution after successful TIPS on nutrition in cirrhotic patients with refractory ascites. Am J Gastroenterol. 2001;96:2442–7.

    Article  CAS  PubMed  Google Scholar 

  16. Kaido T, Uemoto S. Direct segmental multi-frequency bioelectrical impedance analysis is useful to evaluate sarcopenia. Am J Transpl. 2013;13:2506–7.

    Article  CAS  Google Scholar 

  17. Fukui H, Saito H, Ueno Y, et al. Evidence-based clinical practice guidelines for liver cirrhosis 2015. J Gastroenterol. 2016;51:629–50.

    Article  CAS  PubMed  Google Scholar 

  18. Yamamura Y, Nakamura S, Itoh S, et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther. 1998;287:860–7.

    CAS  PubMed  Google Scholar 

  19. Mitsiopoulos N, Baumgartner RN, Heymsfield SB, et al. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J Appl Physiol. 1998;85:115–22.

    Article  CAS  PubMed  Google Scholar 

  20. Nishikawa H, Shiraki M, Hiramatsu A, et al. Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): recommendation from the working group for creation of sarcopenia assessment criteria. Hepatol Res. 2016;46:951–63.

    Article  PubMed  Google Scholar 

  21. Hiramine Y, Uojima H, Nakanishi H, et al. Response criteria of tolvaptan for the treatment of hepatic edema. J Gastroenterol. 2018;53:258–68.

    Article  CAS  PubMed  Google Scholar 

  22. Witte MH, Witte CL, Dumont AE. Progress in liver disease: physiological factors involved in the causation of cirrhotic ascites. Gastroenterology. 1971;61:7420750.

    Article  Google Scholar 

  23. Lieberman FL, Ito S, Reynolds TB. Effective plasma volume in cirrhosis with ascites. Evidence that a decreased value dose not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), and a fall in GFR during drug-induced diuretics. J Clin Inverst. 1969;48:975–81.

    Article  CAS  PubMed Central  Google Scholar 

  24. Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8:1151–7.

    Article  CAS  PubMed  Google Scholar 

  25. Sakaida I, Kawasoe S, Kajimura K, et al. Tolvaptan for improvement of hepatic edema: a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Res. 2014;44:73–82.

    Article  CAS  PubMed  Google Scholar 

  26. Sakaida I, Terai S, Kurosaki M, et al. Effectiveness and safety of tolvaptan in liver cirrhosis patients with edema: interim results of post-marketing surveillance of tolvaptan in liver cirrhosis (START study). Hepatol Res. 2017;47:1137–46.

    Article  CAS  PubMed  Google Scholar 

  27. Gassanov N, Semmo N, Semmo M, et al. Vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Eur J Clin Pharmacol. 2011;67:333–46.

    Article  CAS  PubMed  Google Scholar 

  28. Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists; the vaptans. Lancet. 2008;371:1624–32.

    Article  CAS  PubMed  Google Scholar 

  29. Yi JH, Shin HJ, Kim HJ. V2 receptor antagonist: tolvaptan. Electrolyte Blood Press. 2011;9:50–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sakaida I, Nakajima K, Okita K, et al. Can serum albumin level affect the pharmacological action of tolvaptan in patients with liver cirrhosis? A post hoc analysis of previous clinical trials in Japan. J Gastroenterol. 2015;50:1047–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Iwamoto T, Sakaida I, et al. Predictors of the effect of tolvaptan on the prognosis of cirrhosis. Intern Med. 2016;55:2911–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kogiso T, Yamamoto K, Kobayashi M, et al. Response to tolvaptan and its effect on prognosis in cirrhosis. Hepatol Res. 2017;47:835–44.

    Article  CAS  PubMed  Google Scholar 

  33. Atsukawa M, Tsubota A, Kato K, et al. Analysis of factors predicting the response to tolvaptan in patients with liver cirrhosis and hepatic edema. J Gastroenterol Hepatol. 2018;33:1256–63.

    Article  CAS  PubMed  Google Scholar 

  34. Sakaida I, Terai S, Nakajima K, et al. Predictive factors of the pharmacological action of tolvaptan in patients with liver cirrhosis: a post hoc analysis. J Gastroenterol. 2017;52:229–36.

    Article  CAS  PubMed  Google Scholar 

  35. Nakagawa A, Atsukawa M, Tsubota A, et al. Usefulness of portal vein pressure for predicting the effects of tolvaptan in cirrhotic patients. World J Gastroenterol. 2016;22:5104–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Imamura T, Kinugawa K, Fujino T, et al. Increased urine aquaporin-2 relative to plasma arginine vasopressin is a novel marker of response to tolvaptan in patients with decompensated heart failure. Circ J. 2014;78:2240–9.

    Article  CAS  PubMed  Google Scholar 

  37. Nakanishi H, Kurosaki M, Hosokawa T, et al. Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites. J Gastroenterol. 2016;51:620–7.

    Article  CAS  PubMed  Google Scholar 

  38. Hanai T, Shiraki M, Ohnishi S, et al. Rapid skeletal muscle wasting predicts worse survival in patients with liver cirrhosis. Hepatol Res. 2016;46:743–51.

    Article  CAS  PubMed  Google Scholar 

  39. Runyon BA, Committee APG. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;49:2087–107.

    Article  PubMed  Google Scholar 

  40. European Association for the Study of Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53:397–417.

    Article  Google Scholar 

  41. Fede G, D’Amico G, Arvaniti V, et al. Renal failure and cirrhosis: a systematic review of mortality and prognosis. J Hepatol. 2012;56:810–8.

    Article  PubMed  Google Scholar 

  42. Mandai S, Furukawa S, Kodama M, et al. Loop diuretics affect skeletal myoblast differentiation and exercise-induced muscle hypertrophy. Sci Rep. 2017;7:46349.

    Article  CAS  Google Scholar 

  43. Ishikawa, Naito S, Iimori S, et al. Loop diuretics are associated with greater risk of sarcopenia in patients with non-dialysis-dependent chronic kidney disease. PLoS One. 2018;13:e0192990.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Hanai T, Shiraki M, Miwa T, et al. Effect of loop diuretics on skeletal muscle depletion in patients with liver cirrhosis. Heptol Res. 2018. https://doi.org/10.1111/hepr.13244.

    Article  Google Scholar 

  45. Freeman RB Jr, Wiesner RH, Harper A, et al. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl. 2002;8:851–8.

    Article  PubMed  Google Scholar 

  46. Kamath PS, Kim WR. The model for end-stage liver disease. Hepatology. 2007;45:797–805.

    Article  PubMed  Google Scholar 

  47. Tajika M, Kato M, Mohri H, et al. Prognostic value of energy metabolism in patients with viral liver cirrhosis. Nutrition. 2002;18:229–34.

    Article  CAS  PubMed  Google Scholar 

  48. Sam J, Nguyen GC. Protein-calorie malnutrition as a prognostic indicator of mortality among patients hospitalized with cirrhosis and portal hypertension. Liver Int. 2009;29:1396–402.

    Article  PubMed  Google Scholar 

  49. Meza-Junco J, Montano-Loza AJ, Baracos VE, et al. Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma. J Clin Gastroenterol. 2013;47:861–70.

    Article  PubMed  Google Scholar 

  50. Kim WR, Biggins SW, Kremersetal WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359:1018–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nishikawa H, Kita R, Kimura T, et al. Hyponatremia in hepatocellular carcinoma complicating with cirrhosis. J Cancer. 2015;6:482–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ripoll C, Bañares R, Rincón D, et al. Influence of hepatic venous pressure gradient on the prediction of survival of patients with cirrhosis in the MELD era. Hepatology. 2005;42:793–801.

    Article  PubMed  Google Scholar 

  53. Planas R, Montoliu S, Balleste B, et al. Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol. 2006;4:1385–94.

    Article  PubMed  Google Scholar 

  54. Cardenas A, Arroyo V. Management of ascites and hydrothorax. Best Pract Res Clin Gastroenterol. 2007;21:55–75.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research is supported by AMED under Grant number JP19fk0210040.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan

    Maiko Namba, Akira Hiramatsu, Hiroshi Aikata, Kenichiro Kodama, Shinsuke Uchikawa, Kazuki Ohya, Kei Morio, Hatsue Fujino, Takashi Nakahara, Eisuke Murakami, Masami Yamauchi, Tomokazu Kawaoka, Masataka Tsuge, Michio Imamura & Kazuaki Chayama

Authors
  1. Maiko Namba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akira Hiramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroshi Aikata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenichiro Kodama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shinsuke Uchikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuki Ohya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kei Morio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hatsue Fujino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eisuke Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masami Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tomokazu Kawaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masataka Tsuge
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michio Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kazuaki Chayama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Hiramatsu.

Ethics declarations

Conflict of interest

Kazuaki Chayama received honororira from Eizai, AbbVie, Gilead, Dainippon Sumitomo, Bristol-Myers Squibb, Mitsubishi Tanabe and Othuka, and research funding from Dainippon Sumitomo, The Chugoku Electric Power, Toray, EA Pharma, AbbVie, Eizai, Otsuka, MSD, Daiichi Sankyo, Takeda, Roche, Nippon Kayaku, Bristol-Myers Squibb and Mochida Phamaceutical.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Namba, M., Hiramatsu, A., Aikata, H. et al. Management of refractory ascites attenuates muscle mass reduction and improves survival in patients with decompensated cirrhosis. J Gastroenterol 55, 217–226 (2020). https://doi.org/10.1007/s00535-019-01623-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-019-01623-4

Keywords

Search

Navigation