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Reply to: “Gut liver muscle brain axis: A comprehensive viewpoint on prognosis in cirrhosis”

  • Xinxing Tantai
    Affiliations
    Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Peoples Republic of China (PRC)
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  • Yee Hui Yeo
    Affiliations
    Division of General Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
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  • Jinhai Wang
    Affiliations
    Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Peoples Republic of China (PRC)
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  • Fanpu Ji
    Correspondence
    Corresponding author. Address: Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157 Xi Wu Road, Xi'an 710004, Shaanxi Province, PR China; Tel.: +8629-87678223, fax: +8629-87678223.
    Affiliations
    Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PRC

    National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PRC

    Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, PRC
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Published:March 26, 2022DOI:https://doi.org/10.1016/j.jhep.2022.03.013

      Linked Article

      To the Editor:
      We would like to thank Ridola et al.
      • Ridola L.
      • Gioia S.
      • Faccioli J.
      • Riggio O.
      • Nardelli S.
      Gut liver muscle brain axis: a comprehensive viewpoint on prognosis in cirrhosis.
      for their interest in our work
      • Tantai X.
      • Liu Y.
      • Yeo Y.H.
      • Praktiknjo M.
      • Mauro E.
      • Hamaguchi Y.
      • et al.
      Effect of sarcopenia on survival in patients with cirrhosis: a meta-analysis.
      and for validating our conclusion.
      The onset and progression of cirrhosis is accompanied by dysfunction of the gut-liver-brain axis. Gut dysbiosis is often observed in patients with cirrhosis compared to healthy individuals, which causes intestinal barrier dysfunction, increases bacterial translocation, activates circulating immune cells, and ultimately leads to cytokine production and systemic inflammation.
      • Kronsten V.T.
      • Tranah T.H.
      • Pariante C.
      • Shawcross D.L.
      Gut-derived systemic inflammation as a driver of depression in chronic liver disease.
      Systemic inflammation, as a cirrhosis-associated immune dysfunction, is associated with the development of liver decompensation, organ failure, bacterial infection and poor prognosis.
      • Kronsten V.T.
      • Tranah T.H.
      • Pariante C.
      • Shawcross D.L.
      Gut-derived systemic inflammation as a driver of depression in chronic liver disease.
      In addition, intestinal flora are closely related to several aspects of hepatic encephalopathy (HE) pathogenesis, including ammonia toxicity theory, bile acid cycle, gamma-aminobutyric acid hypothesis and neuroinflammation.
      • Chen Z.
      • Ruan J.
      • Li D.
      • Wang M.
      • Han Z.
      • Qiu W.
      • et al.
      The role of intestinal bacteria and gut-brain Axis in hepatic encephalopathy.
      Sarcopenia, as a malnutrition-related complication of cirrhosis, has received increasing attention in recent years. Hyperammonemia and systemic inflammation are the core mechanisms responsible for the development of sarcopenia. Hyperammonemia upregulates myostatin levels, activates autophagy, impairs the mTOR pathway in a manner that increases mitochondrial dysfunction and production of reactive oxygen species.
      • Lai J.C.
      • Tandon P.
      • Bernal W.
      • Tapper E.B.
      • Ekong U.
      • Dasarathy S.
      • et al.
      Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American association for the study of liver diseases.
      Systemic inflammation also promotes sarcopenia by decreasing muscle protein synthesis and increasing protein degradation.
      • Lai J.C.
      • Tandon P.
      • Bernal W.
      • Tapper E.B.
      • Ekong U.
      • Dasarathy S.
      • et al.
      Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American association for the study of liver diseases.
      Thus, muscle can be added as a system to form the gut-liver-brain-muscle axis to better understand the progression and prognosis of cirrhosis.
      The prevalence of sarcopenia in the study by Ridola et al. was 56%,
      • Ridola L.
      • Gioia S.
      • Faccioli J.
      • Riggio O.
      • Nardelli S.
      Gut liver muscle brain axis: a comprehensive viewpoint on prognosis in cirrhosis.
      higher than that of 37.5% in our meta-analysis,
      • Tantai X.
      • Liu Y.
      • Yeo Y.H.
      • Praktiknjo M.
      • Mauro E.
      • Hamaguchi Y.
      • et al.
      Effect of sarcopenia on survival in patients with cirrhosis: a meta-analysis.
      which may be attributed to a higher proportion of males, and patients with Child-Pugh class B/C cirrhosis, and previous HE. Since sarcopenia is associated with the severity of liver dysfunction, their study included patients with cirrhosis and relatively serious liver dysfunction, which can be reflected by higher mortality (39%) during a mean period of 12.7±10.1 months,
      • Ridola L.
      • Gioia S.
      • Faccioli J.
      • Riggio O.
      • Nardelli S.
      Gut liver muscle brain axis: a comprehensive viewpoint on prognosis in cirrhosis.
      compared to the 1-year cumulative probabilities of survival of 76.6% (95% CI 66.4%–85.5%) in patients with sarcopenia in our study.
      • Tantai X.
      • Liu Y.
      • Yeo Y.H.
      • Praktiknjo M.
      • Mauro E.
      • Hamaguchi Y.
      • et al.
      Effect of sarcopenia on survival in patients with cirrhosis: a meta-analysis.
      Our meta-analysis showed that sarcopenia is independently associated with mortality in patients with cirrhosis, and this association was validated by Ridola et al., who considered that the co-presence of previous HE and sarcopenia could improve the prognostic performance of the MELD score alone.
      • Ridola L.
      • Gioia S.
      • Faccioli J.
      • Riggio O.
      • Nardelli S.
      Gut liver muscle brain axis: a comprehensive viewpoint on prognosis in cirrhosis.
      However, there is still controversy about whether sarcopenia can improve the predictive value of existing models. In a model of MELD-sarcopenia established by Montano-Loza et al., they included 669 patients with cirrhosis evaluated for liver transplantation (LT), and found MELD-sarcopenia was not superior to MELD in predicting 3- or 6-month mortality, and MELD-sarcopenia had only a small advantage in predicting overall and 12-month mortality.
      • Montano-Loza A.J.
      • Duarte-Rojo A.
      • Meza-Junco J.
      • Baracos V.E.
      • Sawyer M.B.
      • Pang J.X.
      • et al.
      Inclusion of sarcopenia within MELD (MELD-Sarcopenia) and the prediction of mortality in patients with cirrhosis.
      Subsequently, van Vugt et al. externally validated the MELD-sarcopenia model in 585 European patients, and showed that it was not superior to the MELD score alone in their cohort. Meanwhile, in the same cohort, van Vugt et al., developed a novel score including MELD, sarcopenia, HE and age. However, the discriminative value of the model (c-index 0.851) was very similar to that of MELD alone (c-index 0.839).
      • van Vugt J.L.A.
      • Alferink L.J.M.
      • Buettner S.
      • Gaspersz M.P.
      • Bot D.
      • Darwish Murad S.
      • et al.
      A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: a competing risk analysis in a national cohort.
      In addition, the discriminative value of other combined models such as MELD-psoas score also failed to improve the accuracy of prediction.
      • Durand F.
      • Buyse S.
      • Francoz C.
      • Laouénan C.
      • Bruno O.
      • Belghiti J.
      • et al.
      Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.
      Based on uniform and validated measurement methods and cut-off values, the predictive value of MLED-sarcopenia remains to be externally validated.
      Considering the potential impact of sarcopenia on prognosis, some studies considered that indications for transjugular intraheptic portosystemic shunt (TIPS) and LT could be expanded for patients with cirrhosis and sarcopenia, based on the fact that TIPS can improve sarcopenia and the prognosis of these patients.
      • van Vugt J.L.A.
      • Alferink L.J.M.
      • Buettner S.
      • Gaspersz M.P.
      • Bot D.
      • Darwish Murad S.
      • et al.
      A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: a competing risk analysis in a national cohort.
      ,
      • Artru F.
      • Miquet X.
      • Azahaf M.
      • Labreuche J.
      • Ntandja Wandji L.C.
      • Sergent G.
      • et al.
      Consequences of TIPSS placement on the body composition of patients with cirrhosis and severe portal hypertension: a large retrospective CT-based surveillance.
      However, there is still a lack of high-level evidence to recommend the expansion of these indications. High-quality studies need to be designed to directly demonstrate that the benefits of these operations outweigh the drawbacks, and the economic burden and resource availability should also be taken into account.

      Financial support

      National Natural Science Foundation of China (No.82170626).

      Authors' contributions

      XT, YHY: Drafting of the manuscript. JW, FJ: Study conception and study supervision, critical review of the manuscript. All authors: Approved the manuscript.

      Conflict of interest

      FJ: Speaker: Gilead Sciences, MSD and Ascletis. Consulting or advisory board: Gilead Sciences and MSD. All other authors do not have conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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