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Ammonia - an old friend with a new area of application

  • Simon Johannes Gairing
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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  • Leonard Kaps
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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  • Eva Maria Schleicher
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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  • Peter Robert Galle
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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  • Christian Labenz
    Correspondence
    Corresponding author. Address: Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131 Mainz, Germany. Tel.: +49 (0) 6131 17 2380, fax: +49 (0) 6131 17 477282.
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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Published:August 18, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.007

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      • Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis
        Journal of HepatologyVol. 77Issue 6
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          Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis.
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      • Reply to: "Ammonia - an old friend with a new area of application"
        Journal of Hepatology
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          We are very appreciative of the interest garnered by our recently published article and were pleased to receive further validating data from Gairing et al. in response to our findings.1,2 In our manuscript, we demonstrated that ammonia levels, expressed as a ratio of the local laboratory upper limit of normal (AMM-ULN) is an independent predictor of hospitalisation with liver-related complications and mortality in stable outpatients with cirrhosis and that an AMM-ULN cut-off value of 1.4 defines the risk of liver-related complications and consequent mortality.
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      To the Editor:
      We read with great interest the article by Tranah et al. recently published in the Journal of Hepatology.
      • Tranah T.H.
      • Ballester M.-P.
      • Carbonell-Asins J.A.
      • Ampuero J.
      • Alexandrino G.
      • Caracostea A.
      • et al.
      Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.
      Ammonia is known to play a key role in the pathophysiology of hepatic encephalopathy. Recent evidence has also indicated the pathophysiological role and the value of measuring ammonia even in hospitalized patients with acute decompensation.
      • Shalimar Sheikh M.F.
      • Mookerjee R.P.
      • Agarwal B.
      • Acharya S.K.
      • Jalan R.
      Prognostic role of ammonia in patients with cirrhosis.
      In their current multicenter study, Tranah et al. evaluated the predictive value of ammonia in outpatients with cirrhosis regarding liver-related hospitalizations and mortality. We would like to take the opportunity to congratulate the authors on this important study. However, extensive validation of biomarkers in geographically independent cohorts is required before implementation into clinical routine. Therefore, we decided to analyze and validate the findings by Tranah et al. in our well-defined cohort recruited at the Cirrhosis Center Mainz, Germany. Data from this cohort have previously been published and detailed inclusion and exclusion criteria are described elsewhere.
      • Gairing S.J.
      • Anders J.
      • Kaps L.
      • Nagel M.
      • Michel M.
      • Kremer W.M.
      • et al.
      Evaluation of IL-6 for stepwise diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis.
      ,
      • Labenz C.
      • Nagel M.
      • Kremer W.M.
      • Hilscher M.
      • Schilling C.A.
      • Toenges G.
      • et al.
      Association between diabetes mellitus and hepatic encephalopathy in patients with cirrhosis.
      For the current analysis, we included 147 outpatients with available ammonia levels and follow-up data. Venous ammonia levels were measured according to a standard operating procedure that involved rapid sample transport on ice to the central laboratory within 5 min and the upper limit of normal (ULN) was 72 μmol/L. Patients were followed for liver-related hospitalizations (defined as in the work of Tranah et al.) and mortality (composite of death or need for liver transplantation). Kaplan-Meier curves were used to illustrate incidences of the respective endpoints, attached p values were calculated with a log-rank test. Additionally, receiver-operating characteristic curve analyses were performed. Statistics were performed with IBM SPSS Statistics Version 27 and GraphPad Prism Version 9.4.0. The study was approved by the ethics committee of the Landesärztekammer Rheinland-Pfalz and written informed consent was obtained from all participants.
      Overall, 25 of 147 participants (17%) were hospitalized during a median follow-up of 569 (IQR 371; 745) days and 17 died or needed liver transplantation (12%; n = 13 died; n = 4 liver transplantation). At baseline, most participants were in a compensated cirrhosis stage (Child-Pugh A/B/C: 73%/24%/3%) and the median MELD score was 9 (IQR 7; 12). Only a minority of participants had ammonia levels above the ULN (13%) and the median ammonia level was 46 μmol/L (IQR 36; 57 μmol/L). Baseline characteristics of the cohort are displayed in Table S1. Frequency of liver-related hospitalization was higher in participants with ammonia levels above the ULN (9 of 19, 47.4%) than in those with ammonia levels below the ULN (16 of 128, 12.5%) (Fig. 1). The AUC of ammonia for predicting 6-month and 1-year liver-related hospitalization was 0.74 (95% CI 0.57–0.92) and 0.68 (95% CI 0.52–0.84), respectively. During the total follow-up time, the mortality-rate did not differ between participants with ammonia levels above or below the ULN (log-rank, p = 0.20). The AUC of ammonia for predicting 1-year mortality was 0.73 (95% CI 0.55–0.91). The ammonia cut-off of ≥1.4 x ULN did not prove useful in our German cohort, as only four participants had ammonia levels this high.
      Figure thumbnail gr1
      Fig. 1Validation of ammonia as a predictor for hospitalization.
      Frequency of liver-related hospitalizations stratified by ammonia levels below/equal vs. above the ULN (log-rank p <0.001). ULN, upper limit of normal.
      In summary, our external validation supports the assertion of Tranah et al. that routine measurements of ammonia can identify outpatients with cirrhosis at high-risk of liver-related hospitalization. However, giving the low frequency of events in our cohort, we are unable to validate the independent prognostic value of ammonia due to overfitting in multivariable analyses. Nevertheless, our data extend the study by analyzing a “healthier” cohort than those in the study by Tranah et al. This may explain the fact that the cut-off of >1.4x ULN had no sufficient predictive value, emphasizing the importance of external validation of biomarkers as well as prediction models in diverse cohorts.

      Financial support

      This work was not supported by any grant or funding source.

      Conflict of interest

      The authors disclose no potential financial or non-financial conflict of interests regarding this study.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors' contributions

      SJG: Study concept and design, data acquisition, interpretation of the data, drafting of the manuscript. LK, EMS: Data acquisition, critical revision of the manuscript for important intellectual content. PRG: Resources, Critical revision of the manuscript for important intellectual content. CL: Supervision, study concept and design, data acquisition, analysis, interpretation of the data, drafting the manuscript.

      Supplementary data

      The following are the supplementary data to this article:

      References

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        • Ballester M.-P.
        • Carbonell-Asins J.A.
        • Ampuero J.
        • Alexandrino G.
        • Caracostea A.
        • et al.
        Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.
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        Evaluation of IL-6 for stepwise diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis.
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        • Nagel M.
        • Kremer W.M.
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        Association between diabetes mellitus and hepatic encephalopathy in patients with cirrhosis.
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