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: Philipp A. Reuken, Michael Kiehntopf, Andreas Stallmach, Tony Bruns
Journal: Journal of Hepatology (2012)

C-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 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?"Journal of HepatologyVol. 57Issue 5PreviewWe 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]. Full-Text PDF Open Access We read with great interest the study by Cervoni et al. [[1]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 (140) Google Scholar] 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. A candidate biomarker is the mid-regional fragment of pro-adrenomedullin (MR-proADM), which has been demonstrated to be an excellent predictor of short-term mortality in patients with sepsis [[2]Christ-Crain M. Morgenthaler N.G. Struck J. Harbarth S. Bergmann A. Müller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study.Crit Care. 2005; 9: R816-824Crossref PubMed Google Scholar], lower respiratory tract infections [[3]Krüger S. Ewig S. Giersdorf S. Hartmann O. Suttorp N. Welte T. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia: results from the German Competence Network, CAPNETZ.Am J Respir Crit Care Med. 2010; 182: 1426-1434Crossref PubMed Scopus (188) Google Scholar] and critically ill patients with new-onset fever [[4]Hoeboer S.H. Alberts E. van den Hul I. Tacx A.N. Debets-Ossenkopp Y.J. Groeneveld A.B.J. Old and new biomarkers for predicting high and low risk microbial infection in critically ill patients with new onset fever: a case for procalcitonin.J Infection. 2012; 64: 484-493Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. MR-proADM is the non-functional, more stable precursor peptide of adrenomedullin, a vasoactive calcitonin peptide family member that is rapidly cleared from circulation [[5]Morgenthaler N.G. Struck J. Alonso C. Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay.Clin Chem. 2005; 51: 1823-1829Crossref PubMed Scopus (314) Google Scholar]. Circulating adrenomedullin mainly originates from endothelial cells and vascular smooth muscle cells and is upregulated under inflammatory stimuli mediated by pro-inflammatory cytokines or bacterial endotoxin, under hypervolemia and during tissue hypoxia [[6]Eto T. Kato J. Kitamura K. Regulation of production and secretion of adrenomedullin in the cardiovascular system.Regul Pept. 2003; 112: 61-69Crossref PubMed Scopus (73) Google Scholar]. It exerts its vasoactive functions via dilatation of resistance and capacitance vessels including mesentery vessels, stimulation of NO synthesis, and increase of cardiac output [[6]Eto T. Kato J. Kitamura K. Regulation of production and secretion of adrenomedullin in the cardiovascular system.Regul Pept. 2003; 112: 61-69Crossref PubMed Scopus (73) Google Scholar]. Studies suggest that adrenomedullin may also have direct antibacterial properties on mucosal surfaces [[7]Hinson J.P. Kapas S. Smith D.M. Adrenomedullin, a multifunctional regulatory peptide.Endocr Rev. 2000; 21: 138-167Crossref PubMed Scopus (695) Google Scholar]. Although adrenomedullin plasma concentrations are increased in end-stage liver disease and correlate with hemodynamic, renal, and neurohumoral impairment in patients with cirrhosis and ascites [8Fábrega E. Casafont F. Crespo J. de la Peña J. San Miguel G. de las Heras G. et al.Plasma adrenomedullin levels in patients with hepatic cirrhosis.Am J Gastroenterol. 1997; 92: 1901-1904PubMed Google Scholar, 9Guevara M. Ginès P. Jiménez W. Sort P. Fernández-Esparrach G. Escorsell A. et al.Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems.Gastroenterology. 1998; 114: 336-343Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 10Kojima H. Tsujimoto T. Uemura M. Takaya A. Okamoto S. Ueda S. et al.Significance of increased plasma adrenomedullin concentration in patients with cirrhosis.J Hepatol. 1998; 28: 840-846Abstract Full Text PDF PubMed Scopus (42) Google Scholar], the prognostic relevance of MR-proADM in patients with advanced cirrhosis and its correlation with bacterial infections and circulating CRP levels have not been evaluated yet. We, therefore, determined MR-proADM and CRP concentrations in serum samples from 213 consecutive hospitalized patients with cirrhosis and ascites that underwent diagnostic paracentesis for suspected bacterial infection using an automated immunofluorescent assay (BRAHMS, Henningsdorf, Germany). Patients (median age 59 years; range: 24–90) were predominantly male (73%) with alcoholic cirrhosis (77%) and had a median MELD score of 17 (range: 6–40) and a median Child–Pugh score of 10 points (range: 7–15). 34 (16%) patients presented with spontaneous bacterial peritonitis (SBP), 76 (36%) with other bacterial infections including pneumonia, bacteremia, cholangitis, urinary tract, and skin infections and 103 (48%) patients had no detectable infectious focus. Systemic inflammatory response syndrome (SIRS) was diagnosed in a total of 96 (45%) patients. MR-proADM positively correlated with CRP (rs = 0.332; p <0.001), interleukin-6 (rs = 0.256; p =0.010), and white blood cell count (rs = 0.181; p =0.008) but also with impaired renal (serum creatinine: rs = 0.507; p <0.001) and liver function (INR: rs = 0.156; p =0.023) in non-parametric correlation. MR-proADM concentrations were higher in patients with SBP irrespective of the presence of SIRS (Fig. 1A), whereas higher CRP levels were found in patients with SBP as well as with other bacterial infections or SIRS (Fig. 1B). While CRP was a good predictor of overt bacterial infection (area under the ROC curve [AUROC] 0.772; 95% CI: 0.711–0.834), MR-proADM was a poor predictor of bacterial infection in general (AUROC 0.579; 95% CI: 0.503–0.656), but an acceptable predictor of SBP in particular (0.719; 95% CI: 0.622–0.816). Within 30 days after paracentesis, 46 (22%) patients died, seven underwent liver transplantation and one was lost to follow-up. MR-proADM concentrations were higher in non-survivors than in survivors independently of the occurrence of SBP at baseline (Fig. 1C), while CRP levels were only higher in patients with SBP-related death but did not statistically significant differ between survivors and non-survivors without SBP at baseline (Fig. 1D). Median MR-proADM levels were identical in the 33 patients with hepatocellular carcinoma (1.7 nmol/L) compared to patients without hepatocellular carcinoma (1.8 nmol/L; p =0.715). The area under the ROC curve for MR-proADM to predict 30-day mortality was higher (0.757; 95% CI: 0.675–0.838) than for CRP (0.712; 95% CI: 0.626–0.797) and for the MELD score (0.703; 95% CI: 0.612–0.795). In multivariate logistic regression, MR-proADM predicted 30-day mortality (OR 1.196 per 1 nmol/L increase; 95% CI: 1.028–1.392; p=0.020) independently of the MELD score (OR 1.071 per 1-point increase; 95% CI: 1.019–1.127; p=0.007), presence of SIRS (OR 2.313; 95% CI: 1.075–4.978; p=0.032) and ongoing bacterial infection (OR 3.190; 95% CI: 1.407–7.234; p=0.005). Our data indicate that, in contrast to CRP, which is frequently elevated in advanced cirrhosis due to ongoing systemic inflammation or bacterial infection, MR-proADM is a promising surrogate marker to identify patients with complicated bacterial infections as well as patients at risk of short-term mortality independently of bacterial infections and SIRS occurrence. The combined interpretation of CRP and MR-proADM may help discriminate patients with persistent sterile systemic inflammation from those with complicated bacterial infections in clinical practice. The authors who have taken part in this study declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.