Copeptin in acute decompensation of liver cirrhosis: relationship with acute-on-chronic liver failure and short-term survival

Acute decompensation (AD) of liver cirrhosis is characterized by the occurrence of major complications of the underlying liver disease and is the main cause of hospitalization in cirrhotic patients. Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome that occurs in patients with AD, and is characterized by organ failure and often requires admission to the intensive care unit (ICU) [1, 2]. Several non-evidence-based working definitions have been proposed for ACLF [1, 3, 4]. In order to define clear diagnostic criteria for this syndrome, the European Association for the Study of the Liver—Chronic Liver Failure (EASL-CLIF) consortium has performed the Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study [2]. In that study, a large cohort of patients hospitalized for AD were prospectively followed and ACLF was found to be a distinct entity in patients with AD, as it was characterized by the presence of organ failure and a high short-term mortality rate [2]. The activation of endogenous vasoconstrictor systems as an adaptive response to a decreased effective circulating blood volume in cirrhotic patients with a hyperdynamic circulation is thought to be associated with the development of organ failure in ACLF [5, 6]. Conventional prognostic scoring systems in cirrhosis, such as the Model for End-stage Liver disease (MELD) and Child-Pugh score, do not adequately account for risks associated with hemodynamic derangement and organ failure. The recently developed CLIF-consortium organ failure (CLIF-C OF) score has been shown to be superior to the MELD and Child-Pugh score in predicting prognosis in ACLF patients [7]. However, no marker reflecting the degree of activation of endogenous vasoconstrictor systems has been included in this score. Arginine vasopressin (AVP) is a hypothalamic neurohormone which is secreted into the blood stream by the neurohypophysis upon stimuli, such as hyperosmolarity, arterial hypotension, hypovolemia, and physiological stress. Due to its role in both hemodynamic homeostasis and the endogenous stress response, which is also known to be associated with outcome in acute illness, we hypothesized that the AVP system may be of particular prognostic value in critically ill cirrhotic patients. Circulating AVP concentration as such is not suitable due to its instability in serum and poor reproducibility [8]. Copeptin is a stable cleavage product of the C-terminal part of the AVP precursor and is secreted together with AVP in equimolar amounts [9, 10]. Copeptin is therefore generally considered a surrogate marker for AVP. The present study aimed to assess in a large study population of patients admitted for AD or ACLF: 1) copeptin as a prognostic biomarker of short-term survival and disease progression; and 2) whether copeptin might be of additional prognostic value to conventional prognostic scoring systems in cirrhosis and ACLF.

In this study, we assessed the prognostic ability of copeptin, a surrogate marker of AVP, in patients admitted for AD of cirrhosis or ACLF. The results demonstrate that the presence of ACLF is accompanied by significantly higher serum copeptin levels at admission compared with those with traditional AD. In addition, serum copeptin was found to be independently associated with short-term outcome and was shown to provide additional prognostic information to the MELD and CLIF-C OF scores.

The ideal prognostic biomarker for predicting short-term ACLF development and mortality in patients with AD is one that is elevated at the time of onset of AD, is involved in the pathophysiology of disease progression, and can therefore help in directing and monitoring therapy. Markers reflecting hemodynamic systemic changes in cirrhotic patients, such as the hepatic venous pressure gradient (HVPG) and MAP, are well known to be associated with the presence of organ failure and prognosis in cirrhosis [15‐21]. In clinical practice, a prognostic biomarker reflecting the degree of circulatory derangement may therefore be of importance since it may help to distinguish between patients who are at a higher risk of developing organ failure and short-term mortality. It may also add prognostic information to conventional prognostic scoring systems in cirrhosis, such as the MELD and Child-Pugh score, which take into account indirect, nonspecific, or subjective markers of hemodynamic derangement such as ascites and creatinine concentration. Recent studies have shown an association of high serum copeptin levels with hemodynamics, such as portal hypertension (HVPG > 12 mmHg) [20] and a decreased cardiac output [21]. In this study, the role of copeptin in hemodynamic homeostasis was shown by the finding of a weak, but significant inverse correlation between MAP and DBP with copeptin. The weakness of this association may be explained by the fact that, besides peripheral vasodilation, copeptin levels may also be influenced by a number of other stimuli, such as hyperosmolarity, physiological and psychological stress, and medication (i.e., diuretics, beta blockers and vasopressors) [22].

To date, the prognostic value of copeptin in the setting of liver cirrhosis has been investigated in a few studies [23‐26]. The results of these studies show that serum copeptin levels increase along with the severity of liver disease, as defined by the Child-Pugh class [23, 25]. Moreover, circulating copeptin concentration was found to predict short- and long-term transplant-free mortality in patients with various stages of cirrhosis [23‐26]. In addition, a prospectively conducted study showed the ability of plasma copeptin to predict the development of cirrhosis-related complications and death within 3 months after hospitalization [26]. However, no data have been reported on the prognostic value of serum copeptin in an unselected cohort of patients admitted for AD and ACLF. Currently, several scoring systems are in use for risk stratification in critically ill cirrhotic patients, such as the MELD and Child-Pugh score. The CLIF-C OF score was recently developed as a simplification of the CLIF-SOFA score to diagnose and grade ACLF [7]. Its prognostic accuracy was found to be significantly higher than that of the MELD and Child-Pugh scores in patients with AD or ACLF [7]. In the current study, it was shown that serum copeptin predicts the risk for short-term mortality, independently of the CLIF-C OF (28- and 90-day mortality) and MELD (28-day mortality) scores. Moreover, incorporation of serum copeptin in the MELD and CLIF-C OF scores improved their prognostic ability for 28-day mortality. Serum copeptin measured at days 0–2 and 3–7 after hospital admission was found to be associated with the course of ACLF during short-term follow-up. Finally, serum copeptin at days 0–2 after hospital admission was found to independently predict short-term ACLF development. On the other hand, no association between delta serum copeptin over time and disease course and survival was found. This finding requires further assessment in larger prospectively conducted trials in which serum copeptin can be obtained in all patients at set and well-defined time points.

Deterioration of systemic hemodynamic function is traditionally thought to play a key role in the development of multi-organ failure in ACLF [2, 3, 5]. However, in the light of new knowledge, it is now thought that the presence of systemic inflammation in cirrhosis is the key event in ACLF development [5]. This ‘systemic inflammation hypothesis’ proposes that ACLF develops as a result of aggravation of systemic inflammation and associated systemic circulatory dysfunction which is already present in AD. This hypothesis was tested in a recent study by Clarìa et al. [27]. The authors found that AD is associated with very high plasma levels of cytokines and oxidized albumin and that ACLF develops when there is a further increase in these inflammatory mediators. In addition, Clarìa et al. found that markers of systemic circulatory dysfunction (i.e., copeptin and renin) were significantly more elevated in patients with ACLF compared with those without. Remarkably, in contrast to markers of systemic inflammation, these hemodynamic biomarkers did not consistently increase through ACLF grade I–III, which is consistent with our findings. This finding suggests that hemodynamic dysfunction is present in ACLF, but is not directly associated with the severity of ACLF. This implicates a role for pathophysiological mechanisms other than circulatory dysfunction, such as systemic inflammation, contributing to the severity of ACLF. Nevertheless, in the current study, copeptin was found to be a strong and independent prognostic factor for short-term outcome, especially at 28 days of follow-up. Besides reflecting the activity of the AVP system due to the systemic hemodynamic changes, the prognostic ability of copeptin may also be explained by its non-specificity. As mentioned previously, copeptin may be influenced by various stimuli, such as hyperosmolarity and physiological and psychological stress [22]. In the setting of acute hospitalization for AD or ACLF, this non-specificity may be its strength. As the complexity of the pathogenesis of ACLF is high, single, organ-specific biomarkers may oversimplify the pathology of the disease. Copeptin has been shown to be a reliable novel marker of endogenous stress levels, mirroring moderate stress levels more subtly than cortisol [28]. The prognostic ability of copeptin, as a marker of an acute and generalized hemodynamic stress response, has extensively been studied in general populations of patients admitted to the emergency department and ICU, showing promising results [29, 30]. For future studies, it might be interesting to explore the prognostic ability of copeptin specifically in cirrhotic patients with AD or ACLF admitted to the ICU.

Some limitations concerning the present study have to be considered. Firstly, plasma copeptin levels were markedly higher in patients with ACLF and renal failure than in ACLF patients without renal failure. This may indicate that elevated plasma copeptin levels may not only reflect an increased release of AVP by the neurohypophysis, but also a decreased clearance rate of copeptin in patients with ACLF and renal failure. Although copeptin is thought to be, at least partly, excreted by the kidneys [9, 31], it is currently not entirely clear how copeptin is removed from the body. Future studies should focus on the potential causal relationship between renal function and serum copeptin levels and whether this impacts on the prognostic ability of copeptin in these patients. Secondly, the effect of possible confounding factors such as the use of certain drugs was not (sufficiently) studied due to the lack of information on use (diuretics), moment of blood sampling and drug administration (vasopressors), specification of the indication (vasopressors), and dose (vasopressors and beta blockers). Thirdly, consecutive copeptin measurements were only performed in a limited number of patients. To further explore copeptin as a prognostic marker in AD and ACLF, and the prognostic ability of copeptin in predicting ACLF development, a prospectively conducted and larger cohort study in which copeptin measurements are sequentially performed would be interesting. Finally, another potential confounding factor is the presence of (cirrhotic) cardiomyopathy in this population, especially because of the relatively large proportion of patients with alcoholic liver disease (61.0%). Copeptin has been found to be associated with the presence of both acute and chronic heart failure and is associated with prognosis [32]. Therefore, it would be relevant to take into account cardiac function in future studies.

Serum copeptin levels are significantly more increased in patients with ACLF compared with those with traditional AD. Moreover, serum copeptin is a predictor of mortality in cirrhotic patients admitted for AD, independently of MELD and CLIF-COF scores. Serum copeptin shows the potential to add relevant prognostic information to these prognostic scoring systems. Altogether, these findings suggest that serum copeptin is an interesting potential prognostic marker in hospitalized cirrhotic patients with AD and ACLF.