Improved prediction of mortality by combinations of inflammatory markers and standard clinical scores in patients with acute‐on‐chronic liver failure and acute decompensation

Grønbæk, Henning; Møller, Holger Jon; Saliba, Faouzi; Zeuzem, Stefan; Albillos, Agustı́n; Ariza, Xavier; Graupera, Isabel; Solà, Elsa; Amorós, Àlex; Pavesi, Marco; Bossen, Lars; Jalan, Rajiv; Ginès, Pere; Arroyo, Vicente

doi:10.1111/jgh.15125

Cited by 16 publications

(11 citation statements)

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“…24 This allows one to hypothesise that this cell type, along with macrophages, may be important in ACLF. 45,46 The present study has some important strengths and limitations. This study comprises a very well-defined study cohort of patients with AD and ACLF, derived from the prospectively performed multicentre observational CANONIC trial.…”

Section: Discussionmentioning

confidence: 99%

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Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure

et al. 2021

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Background & Aims Acute-on-chronic liver failure (ACLF) is characterised by organ failure(s), high short-term mortality, and, pathophysiologically, deranged inflammatory responses. The extracellular matrix (ECM) is critically involved in regulating the inflammatory response. This study aimed to determine alterations in biomarkers of ECM turnover in ACLF and their association with inflammation, organ failures, and mortality. Methods We studied 283 patients with cirrhosis admitted for acute decompensation (AD) with or without ACLF, 64 patients with stable cirrhosis, and 30 healthy controls. A validation cohort (25 ACLF, 9 healthy controls) was included. Plasma PRO-C3, PRO-C4, PRO-C5, PRO-C6, and PRO-C8 ( i.e. collagen type III–VI and VIII formation ) and C4M and C6M ( i.e. collagen type IV and VI degradation ) were measured. Immunohistochemistry of PRO-C6 was performed on liver biopsies (AD [n = 7], ACLF [n = 5]). A competing-risk regression analysis was performed to explore the prognostic value of biomarkers of ECM turnover with 28- and 90-day mortality. Results PRO-C3 and PRO-C6 were increased in ACLF compared to AD ( p = 0.089 and p <0.001, respectively), whereas collagen degradation markers C4M and C6M were similar. Both PRO-C3 and PRO-C6 were strongly associated with liver function and inflammatory markers. Only PRO-C6 was associated with extrahepatic organ failures and 28- and 90-day mortality (hazard ratio [HR; on log-scale] 6.168, 95% CI 2.366–16.080, p <0.001, and 3.495, 95% CI 1.509–8.093, p = 0.003, respectively). These findings were consistent in the validation cohort. High PRO-C6 expression was observed in liver biopsies of patients with ACLF. Conclusions This study shows, for the first time, evidence of severe net interstitial collagen deposition in ACLF and makes the novel observation of the association between PRO-C6 and (extrahepatic) organ failures and mortality. Further studies are needed to define the pathogenic significance of these observations. Lay summary This study describes a disrupted turnover of collagen type III and VI in Acute-on-chronic liver failure (ACLF). Plasma biomarkers of these collagens (PRO-C3 and PRO-C6) are associated with the severity of liver dysfunction and inflammation. PRO-C6, also known as the hormone endotrophin, has also been found to be associated with multi-organ failure and prognosis in acute decompensation and ACLF.

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Section: Discussionmentioning

confidence: 99%

“… 24 This allows one to hypothesise that this cell type, along with macrophages, may be important in ACLF. 45 , 46 …”

Section: Discussionmentioning

confidence: 99%

Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure

et al. 2021

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“…Consequently, sMR is not as specific a marker of macrophage activation as sCD163. However, elevated sMR levels have previously been described in patients with liver disease and are shown to be associated to disease severity, portal hypertension and mortality (Gronbaek et al, 2016b;Laursen et al, 2017;Sandahl et al, 2017;Grønbaek et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Divergences in Macrophage Activation Markers Soluble CD163 and Mannose Receptor in Patients With Non-cirrhotic and Cirrhotic Portal Hypertension

et al. 2021

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IntroductionMacrophages are involved in development and progression of chronic liver disease and portal hypertension. The macrophage activation markers soluble (s)CD163 and soluble mannose receptor (sMR), are associated with portal hypertension in patient with liver cirrhosis but never investigated in patients with non-cirrhotic portal hypertension. We hypothesized higher levels in cirrhotic patients with portal hypertension than patients with non-cirrhotic portal hypertension. We investigated sCD163 and sMR levels in patients with portal hypertension due to idiopathic portal hypertension (IPH) and portal vein thrombosis (PVT) in patients with and without cirrhosis.MethodsWe studied plasma sCD163 and sMR levels in patients with IPH (n = 26), non-cirrhotic PVT (n = 20), patients with cirrhosis without PVT (n = 31) and with PVT (n = 17), and healthy controls (n = 15).ResultsMedian sCD163 concentration was 1.51 (95% CI: 1.24–1.83) mg/L in healthy controls, 1.96 (95% CI: 1.49–2.56) in patients with non-cirrhotic PVT and 2.16 (95% CI: 1.75–2.66) in patients with IPH. There was no difference between non-cirrhotic PVT patients and healthy controls, whereas IPH patients had significantly higher levels than controls (P < 0.05). The median sCD163 was significantly higher in the cirrhotic groups compared to the other groups, with a median sCD163 of 6.31 (95% CI: 5.16–7.73) in cirrhotics without PVT and 5.19 (95% CI: 4.18–6.46) with PVT (P < 0.01, all). Similar differences were observed for sMR.ConclusionSoluble CD163 and sMR levels are elevated in patients with IPH and patients with cirrhosis, but normal in patients with non-cirrhotic PVT. This suggests that hepatic macrophage activation is more driven by the underlying liver disease with cirrhosis than portal hypertension.

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“…Lastly, patients suffering from acute liver injury due to acetaminophen overdose, acute cirrhosis decompensation, ACLF, and alcoholic hepatitis have markedly increased plasma levels of sMR with 2.5-to 5fold higher median values compared with healthy individuals (64,68,69). In addition, combining the CLIF-C ACLF score and sCD163 improves the prediction of 90 days mortality, while sMR in addition to the CLIF-C acute decompensation (AD) score improves the prediction of 90 and 180 days mortality (64,70).…”

Section: Macrophage Activation Markers In Liver Diseasesmentioning

confidence: 99%

Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis

et al. 2021

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Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.

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Improved prediction of mortality by combinations of inflammatory markers and standard clinical scores in patients with acute‐on‐chronic liver failure and acute decompensation

Cited by 16 publications

References 45 publications

Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure

Biomarkers of extracellular matrix formation are associated with acute-on-chronic liver failure

Divergences in Macrophage Activation Markers Soluble CD163 and Mannose Receptor in Patients With Non-cirrhotic and Cirrhotic Portal Hypertension

Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis

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