Reply to “Mid-regional pro-adrenomedullin (MR-proADM): An even better prognostic biomarker than C reactive protein to predict short-term survival in patients with decompensated cirrhosis at risk of infection?”
Authors: Vincent Di Martino, Jean-Paul Cervoni, Frances Sheppard, Thierry Thévenot
Journal: Journal of Hepatology (2012)

Mid-regional pro-adrenomedullin (MR-proADM): An even better prognostic biomarker than C-reactive protein to predict short-term survival in patients with decompensated cirrhosis at risk of infection?Journal of HepatologyVol. 57Issue 5PreviewWe read with great interest the study by Cervoni et al. [1] investigating C-reactive protein (CRP) as a prognostic marker of short-term mortality in patients with advanced cirrhosis. Although persistently elevated CRP levels discriminated patients with poor prognosis due to presumably ongoing systemic inflammation, in their study, baseline CRP was less accurate discriminating bacterial infection and its hemodynamic and renal complications, which substantially contribute to the increased mortality in patients with cirrhosis and might be discriminated using novel biomarkers. Full-Text PDF Open AccessC-Reactive protein predicts short-term mortality in patients with cirrhosisJournal of HepatologyVol. 56Issue 6PreviewWe aimed at improving prediction of short-term mortality in cirrhotic inpatients by evaluating C-reactive protein (CRP) as a surrogate marker of systemic inflammatory response syndrome (SIRS). Full-Text PDF We thank Reuken et al. for their interest in our study. The prognostic evaluation of cirrhotic patients has improved in the last decade or so, with the consideration of extrahepatic complications common in cirrhosis, and with the dynamic assessment of prognostic scores. The first extrahepatic complication taken into account was hepatorenal syndrome, justifying the incorporation of serum creatinine in the MELD score. More recently, Arvaniti et al. proposed a prognostic classification in which bacterial infection defined the more severe stage of cirrhosis [[1]Arvaniti V. D’Amico G. Fede G. Manousou P. Tsochatzis E. Pleguezuelo M. et al.Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.Gastroenterology. 2010; 139: 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (747) Google Scholar]. However, bacteriological tests that are mandatory for the diagnosis of infection may lack sensitivity in cirrhosis. Moreover, systemic inflammation associated with bacterial infection may persist, even after appropriate antibiotic treatment, thus having an impact on prognosis. Recently, the analysis of a large European cohort has confirmed that the occurrence of an acute-on-chronic liver failure is associated with systemic inflammation even in non-infected patients [[2]Moreau R. Gines P. Jalan R. Pavesi M. Durand F. Angeli P. et al.Diagnosis, prevalence, and prognosis of acute-on-chronic liver failure (ACLF): results of the EASL-chronic liver failure (CLIF) consortium canonic study.J Hepatol. 2012; 56: S552Abstract Full Text PDF Google Scholar]. This is why our study (1) focused on a marker of systemic inflammation (rather than a marker of infection) and (2) considered as relevant only the case of persistent elevation of CRP for 15 days [[3]Cervoni J.P. Thévenot T. Weil D. Muel E. Barbot O. Sheppard F. et al.C-reactive protein predicts short-term mortality in patients with cirrhosis.J Hepatol. 2012; 56: 1299-1304Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar].New prognostic markers are currently under evaluation in cirrhosis. Most of them are influenced by systemic inflammation. For example, our group demonstrated that elevated serum free cortisol is associated with high CRP levels and increased mortality in hemodynamically stable cirrhotic patients [[4]Thévenot T. Dorin R. Monnet E. Qualls C.R. Sapin R. Grandclément E. et al.High serum levels of free cortisol indicate severity of cirrhosis in hemodynamically stable patients.J Gastroenterol Hepatol. 2012; 27: 1440-1746Crossref Scopus (21) Google Scholar]. Copeptin, a surrogate of AVP secretion, also increases in the event of systemic inflammation [[5]Jochberger S. Dörler J. Luckner G. Mayr V.D. Wenzel V. Ulmer H. The vasopressin and copeptin response to infection, severe sepsis, and septic shock.Crit Care Med. 2009; 37: 476-482Crossref PubMed Scopus (87) Google Scholar] and recently appeared as a promising prognostic marker in cirrhotic patients [[6]Coenraad M.J. de Rooij B.J. Verbruggen L. Van Hoek B. Van Der Reijden J.J. Verspaget H.W. Copeptin: an independent prognostic factor in cirrhosis?.J Hepatol. 2012; 56: S245-S246Abstract Full Text PDF Google Scholar]. For all these new markers, it seems important to determine their correlation with CRP levels. In addition, essential information for the clinician is their specific weight for prognosis, independent of MELD and CRP. Indeed, although these new markers appear attractive through their pathophysiological background, they are not routinely available, conversely to CRP.The results presented by Reuken et al. are very interesting but deserve some comments. In their population including a majority of infected patients (52%), the mid regional fragment of pro-adrenomedullin (MR-proADM) appeared to be a reliable marker of spontaneous bacterial peritonitis (SBP). The authors emphasize the relationship between MR-proADM and SBP rather than systemic inflammation. We acknowledge that MR-proADM was a better diagnostic marker of SBP than CRP. However, given the high prevalence of infected patients and the more marked increase of MR-proADM in the event of bacterial infection in the study of Reuken et al. the prognostic value of MR-proADM remains to be demonstrated in non-infected cirrhotic patients. The authors should have provided specific data on this subgroup of patients. Another comment concerns the statistical method used by the authors. Their multivariate model seems questionable since MR-proADM, bacterial infection, SIRS, and MELD were implemented as independent variables, whereas univariate analyses showed that MR-proADM was significantly correlated with INR and creatinine, and was a “poor” but significant predictor of bacterial infection. Hence, the question of the true independent prognostic value of MR-proADM remains unresolved. In our study, CRP and MELD were not collinear, thus allowing us to state that persistently high CRP levels provided greater accuracy than the simple measurement of MELD for evaluating prognosis in cirrhotic patients.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We thank Reuken et al. for their interest in our study. The prognostic evaluation of cirrhotic patients has improved in the last decade or so, with the consideration of extrahepatic complications common in cirrhosis, and with the dynamic assessment of prognostic scores. The first extrahepatic complication taken into account was hepatorenal syndrome, justifying the incorporation of serum creatinine in the MELD score. More recently, Arvaniti et al. proposed a prognostic classification in which bacterial infection defined the more severe stage of cirrhosis [[1]Arvaniti V. D’Amico G. Fede G. Manousou P. Tsochatzis E. Pleguezuelo M. et al.Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.Gastroenterology. 2010; 139: 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (747) Google Scholar]. However, bacteriological tests that are mandatory for the diagnosis of infection may lack sensitivity in cirrhosis. Moreover, systemic inflammation associated with bacterial infection may persist, even after appropriate antibiotic treatment, thus having an impact on prognosis. Recently, the analysis of a large European cohort has confirmed that the occurrence of an acute-on-chronic liver failure is associated with systemic inflammation even in non-infected patients [[2]Moreau R. Gines P. Jalan R. Pavesi M. Durand F. Angeli P. et al.Diagnosis, prevalence, and prognosis of acute-on-chronic liver failure (ACLF): results of the EASL-chronic liver failure (CLIF) consortium canonic study.J Hepatol. 2012; 56: S552Abstract Full Text PDF Google Scholar]. This is why our study (1) focused on a marker of systemic inflammation (rather than a marker of infection) and (2) considered as relevant only the case of persistent elevation of CRP for 15 days [[3]Cervoni J.P. Thévenot T. Weil D. Muel E. Barbot O. Sheppard F. et al.C-reactive protein predicts short-term mortality in patients with cirrhosis.J Hepatol. 2012; 56: 1299-1304Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. New prognostic markers are currently under evaluation in cirrhosis. Most of them are influenced by systemic inflammation. For example, our group demonstrated that elevated serum free cortisol is associated with high CRP levels and increased mortality in hemodynamically stable cirrhotic patients [[4]Thévenot T. Dorin R. Monnet E. Qualls C.R. Sapin R. Grandclément E. et al.High serum levels of free cortisol indicate severity of cirrhosis in hemodynamically stable patients.J Gastroenterol Hepatol. 2012; 27: 1440-1746Crossref Scopus (21) Google Scholar]. Copeptin, a surrogate of AVP secretion, also increases in the event of systemic inflammation [[5]Jochberger S. Dörler J. Luckner G. Mayr V.D. Wenzel V. Ulmer H. The vasopressin and copeptin response to infection, severe sepsis, and septic shock.Crit Care Med. 2009; 37: 476-482Crossref PubMed Scopus (87) Google Scholar] and recently appeared as a promising prognostic marker in cirrhotic patients [[6]Coenraad M.J. de Rooij B.J. Verbruggen L. Van Hoek B. Van Der Reijden J.J. Verspaget H.W. Copeptin: an independent prognostic factor in cirrhosis?.J Hepatol. 2012; 56: S245-S246Abstract Full Text PDF Google Scholar]. For all these new markers, it seems important to determine their correlation with CRP levels. In addition, essential information for the clinician is their specific weight for prognosis, independent of MELD and CRP. Indeed, although these new markers appear attractive through their pathophysiological background, they are not routinely available, conversely to CRP. The results presented by Reuken et al. are very interesting but deserve some comments. In their population including a majority of infected patients (52%), the mid regional fragment of pro-adrenomedullin (MR-proADM) appeared to be a reliable marker of spontaneous bacterial peritonitis (SBP). The authors emphasize the relationship between MR-proADM and SBP rather than systemic inflammation. We acknowledge that MR-proADM was a better diagnostic marker of SBP than CRP. However, given the high prevalence of infected patients and the more marked increase of MR-proADM in the event of bacterial infection in the study of Reuken et al. the prognostic value of MR-proADM remains to be demonstrated in non-infected cirrhotic patients. The authors should have provided specific data on this subgroup of patients. Another comment concerns the statistical method used by the authors. Their multivariate model seems questionable since MR-proADM, bacterial infection, SIRS, and MELD were implemented as independent variables, whereas univariate analyses showed that MR-proADM was significantly correlated with INR and creatinine, and was a “poor” but significant predictor of bacterial infection. Hence, the question of the true independent prognostic value of MR-proADM remains unresolved. In our study, CRP and MELD were not collinear, thus allowing us to state that persistently high CRP levels provided greater accuracy than the simple measurement of MELD for evaluating prognosis in cirrhotic patients. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.