Looking at the Heart Failure Through the Prism of Liver Dysfunction

Abstract

This article refers to ‘Liver function and prognosis, and influence of sacubitril/valsartan in patients with heart failure with reduced ejection fraction’ by K. Suzuki et al., published in this issue on pages 1662–1671. The understanding of the pathophysiology underlying the syndrome of heart failure (HF) has been evolving during the last decades, from a ‘simple’ haemodynamic problem, through neurohormonally- and inflammatory-driven pathology, to a complex energy depletion syndrome. Recently, much attention has been put on peripheral multi-organ dysfunction/injury in HF, mainly showing its prognostic importance. Still, however, the question remains: does this organ involvement mainly reflect disease severity or is rather an important player in disease progression that can be modified and become target for effective interventions? Dysfunctional cross-talk between the heart and the kidneys with deleterious consequences on the natural history of HF has been well-characterized with subsequent introduction of the term ‘cardio-renal syndrome(s)’.1 Similarly, the interactions between the heart and the liver and HF-related changes in the liver function are well-described, but whether there is enough evidence to support the concept of a distinct ‘cardio-hepatic syndrome in HF’ is not yet clear.2 Liver dysfunction/injury with abnormal liver function tests (LFTs) are frequently present in HF.3-5 Two major haemodynamically-driven mechanisms seem to underlie HF-related hepatopathy: organ hypoperfusion (due to reduced cardiac output, hypotension, vasoconstriction) and/or organ congestion (due to elevated right heart-sided and central venous pressures). Despite dual blood supply (the hepatic artery and the portal vein), the liver is vulnerable to injury/dysfunction and hepatocyte necrosis from both perturbations. Anatomical features predispose the hepatocytes localized in the region near the central vein (relatively poor blood oxygen supply) to damage from hypoxia and venous congestion.2 Additionally, a unique anatomy of hepatic veins (i.e. lack of valves in hepatic veins) favours transfer of inferior caval pressure to the sinusoidal bed.2, 3 Passive congestion in the liver sinusoids ultimately leads to a compression/obstruction of the anatomical structures localized in this area – including bile canaliculi and ductules, with resultant impairment of bile production and flow.6 The former mechanism (impaired perfusion) prevails in the episodes of acute HF decompensation leading to hypoxic hepatitis, injury/necrosis of hepatocytes with subsequent leak of liver enzymes into the blood [reflected by elevated aspartate (AST) and alanine transaminase (ALT) in the blood]. The most typical clinical presentation is acute liver cardiogenic injury developed in patients with severe hypotension and cardiogenic shock.2, 3, 5 The latter mechanism (passive congestion) is a typical feature of acute and chronic HF and can be characterized by the cholestatic pattern of LFTs [i.e. elevated alkaline phosphatase, gamma-glutamyl transferase (GGT) and bilirubin]. However, in the clinical settings, these forward and backward factors often coexist, potentiate each other and may affect the interpretation of LFTs .2, 6, 7 Figure 1 proposes a simplified approach to place different LFT patterns seen in HF into the context of impaired haemodynamics – elevated bilirubin is related to the coincidence of congestion and hypoperfusion, elevated aminotransferases (AST/ALT) to the episode of hypoperfusion/hepatocyte injury irrespective of congestion status, while GGT seems to reflect congestion. Importantly though, interpretation of LTFs in HF needs to take into account some additional, non-haemodynamic factors such as concomitant medications (with potential hepatotoxicity), specific HF aetiologies (e.g. toxic cardiomyopathies, haemochromatosis) and comorbidities.2 The paper by Suzuki et al.8 adds an interesting and novel piece of information to already existing evidence of clinical significance and prognostic relevance of liver dysfunction/injury in HF. In patients with HF and reduced ejection fraction (HFrEF) enrolled in the PARADIGM-HF trial, the authors sought to describe the impact of LFTs on the outcomes but more importantly also the effect of sacubitril/valsartan on the measures of liver function.8 The primary endpoint of the study was a composite of HF hospitalization and cardiovascular death. Among 8232 HFrEF patients with LFTs assessed at screening, around 10% had total bilirubin, ALP, ALT above the upper limit of normal. The authors confirmed that most of abnormal LFTs were associated with an increased risk of the outcomes, and total bilirubin concentration appeared as the strongest independent predictor for the primary endpoint [hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.04–1.15; P < 0.001], HF hospitalization (HR 1.14; 95% CI 1.07–1.22; P < 0.001); cardiovascular death (HR 1.07; 95% CI 1.00–1.14; P = 0.040), and all-cause death (HR 1.08; 95% CI 1.02–1.14; P = 0.009). However, the most interesting and novel finding was statistically significant liver function improvement in the sacubitril/valsartan group compared with the enalapril group after randomization.8 The authors also calculated the MELD-XI score (which comprises bilirubin and creatinine levels, therefore reflecting impaired liver and kidney interaction in HF)9 and found similar improvement after sacubitril/valsartan treatment.8 Despite growing recognition of the clinical relevance of liver dysfunction/injury in HF, the data from large, well-characterized cohorts of patients with chronic HF are still limited.4 Therefore, the results Suzuki et al.8 analysis are important for several reasons. The majority of the studied patients in the PARADIGM -HF trial were in New York Heart Association class II, had preserved blood pressure and did not show overt clinical signs of congestion and/or peripheral hypoperfusion.8 Additionally, those with known history of liver disease and presenting significantly abnormal LFTs at the study entry were excluded. Despite such a favourable profile (which can be referred to as ‘low risk’), nearly 12% of patients had laboratory signs of liver dysfunction/injury, which was associated with poor outcomes. One may extend the interpretation of these findings and propose to look at the HF syndrome as a state characterized by multi-organ dysfunction/injury. It has already been described in acute HF10 and qualitatively, fundamental pathophysiologic mechanisms underlying peripheral organ dysfunction/injury seem not to differ between the chronic and acute settings of HF. The natural history of the disease, even during periods of clinical stability, may comprise episodes of clinically concealed deterioration/imbalance of the equilibrium, which at the end favours predominance of deleterious mechanisms leading to end-organ dysfunction/damage with resultant clinical consequences.11, 12 It is intriguing and promising to see that the use of sacubitril/valsartan was linked with an improvement of LFTs but also of the MELD-XI score. The multifaceted benefits associated with this drug can now be further extended to its potential ‘end-organ protective effect’ as previously documented for the myocardium and the kidneys.13, 14 The responsible mechanisms are not clear, but one can expect correction of deranged haemodynamics and neurohormonal imbalance to play a role. Experimental studies suggest that sacubitril/valsartan significantly reduces portal pressure via hepatic endothelin-1 downregulation – which may lead to perfusion improvement with a further bilirubin decrease in HF.15 Whether an improvement of dysfunctional organs or prevention of organ injury are associated with better outcomes needs further studies. Despite many decades of intensive and fruitful research in the area of HF and numerous important clinical trials, there is still considerable work to be done to comprehend better the complex and still very unclear HF pathophysiology. As this study shows, perhaps for better and broader view (and better treatment) one needs to look at it through the prism of liver (end-organ) dysfunction. And perhaps, in this context the difference between acute and chronic HF is not qualitative but quantitative. Conflict of interest: none declared.

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