Clinical course of congestive hepatopathy pre/post heart transplantation

In this single-centre, retrospective study, patients listed for HTX at the Department of Cardiac Surgery of the General Hospital Vienna (AKH), Austria between 01/2015 and 12/2020 were included. We only included adult (≥ 18 years) patients. Patients in whom data was insufficient were excluded from this study. Demographic, clinical, and relevant laboratory parameters were collected at listing, prior to HTX, 4 weeks post HTX, 1 year post HTX and at the last follow-up from available medical records.

The parameters collected within this study included parameters of hepatic injury and hepatic function, blood counts, virus serology, and metabolic parameters/comorbidities/comedications. Radiologic data was evaluated prior to as well as approximately 1 year after HTX. Ascites was graded as none, mild/moderate and severe. The 2016-updated United Network for Organ Sharing Model for end-stage liver disease (MELD) was calculated. It was calculated by incorporating sodium into the original MELD score (MELD[i] = 0.957 × ln[Cr] + 0.378 × ln[bilirubin] + 1.120 × ln[INR] + 0.643; MELD = MELD[i] + 1.32 × [137-Na] − (0.033 × MELD[i] × [137-Na])) [6]. Next to the MELD score, the MELD-excluding INR [7] (MELD-XI = 5.11 × ln[bilirubin] + 11.76 × ln[creatinine] + 9.44) [7] as well as the modified MELD score (Albumin-MELD) [8], replacing INR with albumin levels to substitute impaired production of coagulation factors (as reflected by INR) with albumin (albumin > 41 g/dL: Albumin-MELD[i] = 0.957 × ln[Cr] + 0.378 × ln[bilirubin] + 1.120 × ln[1] + 0.643; albumin ≤ 41 g/dL: Albumin-MELD[i] = 0.957 × ln[Cr] + 0.378 × ln[bilirubin] + 1.120 × ln[41-albumin] + 0.643; Albumin-MELD = Albumin-MELD[i] + 1.32 × [137-Na] − (0.033 × MELD[i] × [137-Na])) were calculated [8]. In addition, the Albumin-Bilirubin (ALBI) score was calculated (ALBI score = −0.085 × [albumin] + 0.66 × ln[bilirubin]) [9], and graded as ALBI-Grade‑1 (≤ −2.6, preserved hepatic function), ALBI-Grade‑2 (> −2.6 to ≤ −1.39, mild hepatic dysfunction), and ALBI-Grade‑3 (> −1.39, severe hepatic dysfunction). To assess the severity of heart insufficiency, N‑terminal pro b‑type natriuretic peptide (NT-proBNP) levels were recorded.

Congestive hepatopathy was defined as a combination of hepatic venous congestion on abdominal imaging and hepatic injury indicated by elevated levels of hepatic transaminase or gamma-glutamyl transferase levels. Evidence of hepatic venous congestion on abdominal imaging was defined by enlarged hepatic veins or reverse flow in hepatic veins. Evidence of hepatic injury was defined by an elevation of alanine aminotransferase > 1.5 of the upper limit of normal (women > 42 U/L, men > 75 U/L), and/or the elevation of gamma-glutamyl transferase > 1.5 of the upper limit of normal (women > 38 U/L, men > 60 U/L).

Statistical analyses were performed using IBM SPSS Statistics 27 (IBM, New York, NY, USA), or GraphPad Prism 8 (GraphPad Software, CA, USA). Categorical variables were reported as absolute (n) and relative frequencies (%), whereas continuous variables as mean ± standard deviation (SD) or median (interquartile range [IQR]), as appropriate. Student’s t‑test was used for group comparisons of normally distributed variables and Mann-Whitney-U-test for non-normally distributed variables. Group comparisons of categorical variables were performed using either Pearson’s Chi-squared or Fisher’s exact test. Median follow-up time was calculated using the reverse Kaplan-Meier method from date of inclusion to death/last follow-up date. Next, variables which were significantly different among baseline characteristics, significantly associated with the outcome of interest in univariable analysis were included into a multivariable Cox regression model as covariables. Primary endpoint was post-HTX survival, with presence of ascites/death 1 year after HTX as secondary combined endpoint. Survival analyses were demonstrated by Kaplan-Meier curves and compared by means of the log-rank test. To evaluate parameters associated with ascites/death at 1 year post HTX, logistic regression analyses were performed. Sankey plots were used for graphical representation of different courses of disease during follow-up. A p-value of < 0.05 was considered statistically significant.

Overall, 267 patients were evaluated for inclusion. After applying in- and exclusion criteria, 205 patients could finally be included into this study (Fig. 1). While data on baseline imaging was available in 193 patients (94%), follow-up imaging was available in 175 (85%).

Mean age of the overall cohort was 54.0 ± 13.5 years (n = 147, 72% males) and mean BMI was 25.4 ± 4.0 kg/m². Dilatative (n = 103, 50%) and ischemic (n = 87, 42%) cardiomyopathies were the main aetiologies of heart failure, while other/unclassified cardiomyopathies (n = 15, 8%) were rare. Almost every fourth patient had diabetes at study inclusion (n = 50, 24%). Significant alcohol consumption was rare (n = 8, 4%). Comedications are summarised in Table 1.

Radiological findings at baseline reveal that one fourth of patients had ascites (n = 39, 20% mild/moderate; n = 11, 6% severe). Liver steatosis was not very common (n = 19, 10%) whereas 22% of patients had splenomegaly (n = 45). Hepatic venous congestion was diagnosed in 104 patients (54%) at imaging, while hepatic injury was present in 97 (47%). Baseline laboratory parameters are provided in Table 1. Mean MELD was 17.2 ± 6.7, while mean MELD-XI was 14.3 ± 5.1, mean Albumin-MELD was 19.9 ± 11.4, and mean ALBI score was −2.7 ± 0.7 points (n = 124, 61% ALBI grade 1; n = 68, 33% ALBI grade 2; n = 13, 6% ALBI grade 3).

Congestive hepatopathy was diagnosed in 60 patients (29%). When comparing patients with vs. without congestive hepatopathy, patients with congestive hepatopathy had significantly lower BMI values (24.5 ± 3.5 vs. 25.7 ± 3.9 kg/m²; p = 0.041). Patients with congestive hepatopathy had more often dilatative and other cardiomyopathies as underlying diseases for HF. Reported alcohol consumption was higher in patients with congestive hepatopathy compared to patients without. Moreover, they had more often ascites (40% vs. 20%; p = 0.010). Interestingly, use of anti-platelet therapy, statins, calcium channel blockers and levothyroxine substitution were significantly different. Patients with congestive hepatopathy also had lower serum sodium levels (136.8 ± 4.7 vs. 138.2 ± 4.4 mmol/L; p = 0.037), higher bilirubin, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase (according to its definition), as well as lower cholinesterase (4.7 ± 1.9 vs. 6.1 ± 2.4 U/L; p < 0.001) but higher C‑reactive protein (1.2 [IQR: 0.5–2.8] vs. 0.4 [IQR: 0.2–1.8] mg/dL; p = 0.004) and NT-proBNP values (5253 [IQR: 2115–9891] vs. 2815 [IQR: 1237–7113] pg/mL; p = 0.014). Considering clinical scores, patients with congestive hepatopathy had significantly higher MELD score (18.9 ± 7.9 vs. 16.4 ± 6.1 points; p = 0.031), MELD-XI (15.6 ± 5.5 vs. 13.6 ± 4.8 points; p = 0.006), Albumin-MELD (23.2 ± 11.5 vs. 18.6 ± 11.3 points; p = 0.009) and ALBI score values (−2.5 ± 0.7 vs. −2.7 ± 0.7 points; p = 0.021).

Table 2 demonstrates measured laboratory parameters across different study time points. Most importantly, alkaline phosphatase as marker for hepatic injury was significantly higher prior to and 4 weeks/1 year after HTX when comparing patients with vs. without congestive hepatopathy. Accordingly, gamma-glutamyl transferase levels were also significantly higher; however, both injury markers decreased after HTX and were below the upper limit of normal at last follow-up (Fig. 2a). This could be demonstrated for each laboratory parameter included in our study, as depicted in Table 2. Furthermore, clinical scores reflecting hepatic function (i.e., MELD and ALBI/MELD-XI and Albumin-MELD scores) were comparable after HTX (Fig. 2b).

Figure 3 demonstrates that not only laboratory markers and hepatic injury/function indicators were normalising after HTX, but also ascites. Interestingly, while ascites was more common in patients with congestive hepatopathy at baseline, ascites regression was comparable in patients with vs. without congestive hepatopathy post-HTX. However, persistence of ascites remained an indicator for poor post-HTX survival, unrelated to congestive hepatopathy status prior to HTX.

Median time on HTX list was 1.7 months and median post-HTX survival was 41.8 months. Five patients had a large-volume paracentesis during follow-up (2%), while 2 of them also had a spontaneous bacterial peritonitis (1%). Variceal bleeding, hepatic encephalopathy as well as hepatocellular carcinoma were not observed. Overall, 26 patients died within the study period (13%).

While MELD and Albumin-MELD scores were associated with post-HTX survival in univariable Cox regression analysis (MELD: hazard ratio [HR]: 1.06 [95% confidence interval [CI]: 1.00–1.12]; p = 0.040; Albumin-MELD: 1.04 [95%CI: 1.00–1.07]; p = 0.029), age, male sex, and severe ascites remained independently associated with post-HTX survival in multivariable analysis (Table 3). This could be demonstrated for different multivariable models. To evaluate factors associated with presence of ascites/death 1 year after HTX, logistic regressions were calculated, demonstrating that severe ascites (HR: 7.20 [95%CI: 1.94–26.68]; p = 0.003), cholinesterase (HR: 0.75 [95%CI: 0.61–0.92]; p = 0.007) as well as MELD (HR: 1.09 [95%CI: 1.02–1.16]; p = 0.007) and MELD-XI scores (HR: 1.10 [95%CI: 1.02–1.18]; p = 0.012) were associated with the combined secondary endpoint of interest. In multivariable analysis, no factor remained independently associated with ascites/death at 1 year after HTX (Table 4). However, MELD/MELD-XI/ALBI scores tended to be associated with the outcome of interest as well as severe ascites.

Figure 4a shows that diagnosis of congestive hepatopathy at HTX did not influence post-HTX survival (log-rank test p = 0.208). Ascites graduation tended to differentiate into distinct clinical courses (log-rank test p = 0.116; Fig. 4b). When stratifying patients according to hepatic function at HTX, graduation with ALBI score (log-rank test p = 0.056) could identify patients at high risk. Both ALBI and MELD scores were robust indicators of post-HTX survival when measured 4 weeks after HTX (ALBI log-rank test p < 0.001; MELD log-rank test p = 0.012; Fig. 4c, d).