Temporal evolution of liver function parameters predicts clinical outcome in chronic heart failure patients (Bio-SHiFT Study)
Authors: Klimczak-Tomaniak D , Baart S , Van Boven N , Akkerhuis K M , Constantinescu A , Kaliskan C , Simsek S , Germans T , Van Ramshorst J , Kuch M , Umans V , Boersma E , Kardys I 
Published: October 2022

Abstract

Background
Liver dysfunction contributes to worse clinical outcome in heart failure (HF) patients, and cholestatic enzymes are associated with mortality in the setting of chronic HF (CHF). However, the temporal evolutions of liver function parameters in stable CHF patients, and their associations with clinical outcome, have not yet been investigated.

Purpose
We aimed to investigate in detail the temporal patterns of alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGTP), total bilirubin (TBIL) and albumin (ALB), and their relation with clinical outcome, in patients with stable CHF with reduced ejection fraction (HFrEF).

Methods
During 2.2 (1.4–2.5) years of follow-up, we collected 1984 tri-monthly plasma samples in 263 patients. We selected 749 samples in the 250 HFrEF patients included in the study - all baseline samples, the last two samples before censoring in event-free patients, and the last two samples preceding the primary endpoint (PEP; composite of cardiac death, heart transplantation, LVAD implantation, and hospitalization for the management of acute or worsened HF). In these samples ALP, GGTP, and ALB were measured using colorimetric assays, TBIL using diazomethod, all by Roche/Hitachi Cobas c analyser. The relationship between repeatedly measured biomarker levels and the PEP was evaluated by joint models.

Results
Mean age was 68±18 years; 74% were men, 25% in NYHA class III or IV. 66 patients (26%) reached the PEP.
Repeatedly measured levels of TBIL, ALP, GGTP and ALB were associated with the PEP in a model adjusted for NT-proBNP and hs-TnT (hazard ratio (HR) [95% confidence interval] per doubling of biomarker level: 1.98 [1.32; 2.95], p=0.002; 1.84 [1.09; 3.05], p=0.018, 1.33 [1.08; 1.63], p=0.006 and 1.14 [1.09; 1.20], p&lt;0.001, respectively). Serially measured ALP and GGTP remained significantly associated with the PEP after adjustment for clinical covariates (HR [95% CI]: 1.13 [1.07; 1.19], p=0.018; 1.03 [1.01; 1.06], p=0.006, respectively).
The levels of ALP and GGTP were higher in patients who experienced the PEP than in event-free patients long before the PEP occurred (&gt;2 years), and as the PEP approached, levels diverged slightly between those with and without the PEP (Figure 1). Conversely, levels of ALB were higher in those with subsequent PEP, &gt;2 years before the PEP, and subsequently fell; while TBIL levels rose less than 1 year before the PEP in those with subsequent PEP. The slopes of the temporal evolution of ALB and TBIL, adjusted for clinical variables, were also significantly associated with the PEP (HR [95% CI] per 20% decrease in the slope for albumin and increase in the slope of TBIL per year: 1.61 [1.43; 1.84], p&lt;0.001 and 1.72 [1.28; 2.55], p&lt;0.001, respectively).

Conclusions
Changes in serum levels of TBIL, ALP, GGTP and ALB precede adverse cardiovascular events in patients with CHF. These routine liver function parameters may provide additional prognostic information in HFrEF patients in clinical practice.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): Jaap Schouten Foundation (Rotterdam, the Netherlands)Noordwest Academie (Alkmaar, the Netherlands)