Liver involvement during the early toxicity phase after hematopoietic stem cell transplantation (HSCT) is well documented, with reports of mild to moderate elevation in liver enzymes and bilirubin in up to 80% of the patients.1, 2, 3 In contrast, our knowledge regarding liver impairment at long-term follow-up is limited. The primary aim of this study was to describe liver parameters at 1-year follow-up after HSCT and to identify risk factors. The secondary aim was to analyze the impact of liver affection at 1-year follow-up on long-term survival beyond 1 year.
We retrospectively studied alanine aminotransferase (ALT) and bilirubin levels at 1-year follow-up in patients undergoing HSCT at the National Danish HSCT center between 1998 and 2008. Inclusion criteria were (1) first myeloablative allogeneic HSCT, (2) transplantation with either matched sibling donors or matched unrelated donors and (3) available ALT and bilirubin data at 1-year follow-up. Out of 356 patients who were eligible for the study, 219 patients (126 males and 93 females, Table 1) met these criteria and were included in the study; of those 26% were children <16 years of age. The mean of ALT and bilirubin values available between days 330 and 390 post HSCT was used for statistical analysis.
We found that 52% of the patients at follow-up had mean ALT above the normal upper limit of 45 U/L (mean of all 70 U/L (range: 6–670 U/L)), while 4.5% had elevated bilirubin levels (mean of all 11 (range: 2–158 μm/L; normal upper limit 22 μm/L)).
The following set of variables was analyzed for each liver parameter assessed: malignant disease, conditioning regimen, donor type, graft type, age, use of ATG, Karnofsky score, CMV mismatch and acute GvHD (aGvHD). In multivariate analysis of ALT levels, dichotomized at the upper normal limit, we found that age above 16 years (odds ratio (OR)=3.2, 95% confidence interval (CI): 1.6–6.3, P<0.0001), absence of ATG in the conditioning regimen (OR=2.0, 95%CI: 1.1–3.3, P=0.016) and malignant disease (OR=2.6, 95%CI: 1.2–5.9, P=0.013) were associated with increased ALT. In contrast, the level of bilirubin was not associated with baseline clinical variables in multivariate analysis.
Elevated ALT and bilirubin levels at follow-up were both associated with reduced overall survival (OS) in univariate analysis (Figure 1).
Causes of mortality included infection (n=21), liver failure (n=3), cardiopulmonary or multi-organ failure (n=14), aGvHD (n=5), relapse (n=27) and unspecified non-relapse mortality (n=5).
In Cox regression multivariate analysis increased ALT (hazard ratio=1.014 (CI95%: 1.001–1.007), P=0.009) remained significantly associated with inferior OS. Other parameters analyzed in the model but found to be insignificant were age, type of disease, donor type, graft type, ATG, Karnofsky score before HSCT, development of aGvHD and CMV mismatch. Due to the limited number of events, multivariate analysis regarding the impact of bilirubin on survival could not be performed.
Finally, we wanted to evaluate the impact of the early toxic/inflammatory response on liver parameters at follow-up. ALT at 1-year follow-up correlated with ALT and bilirubin levels at day 1–21 (r=0.14, P=0.047; r=0.36, P<0.0001, respectively). Likewise, bilirubin at 1-year follow-up correlated with bilirubin during the early post-HSCT period (r=0.36, P<0.0001).
C-reactive protein (CRP) levels were increased in 44 (13%) patients (mean of all: 25 mg/L (range: 5–240 mg/L)) at day 1–21. CRP at this early stage of the transplant correlated with both ALT and bilirubin at follow-up (r=0.32, P<0.0001 and r=0.36, P<0.0001, respectively).
Our data extends current knowledge by the finding that even moderate elevations in liver parameters in the early post-transplant phase are associated with elevated ALT levels 1 year after the transplant. More importantly, elevated ALT at this stage appears to be predictive of increased mortality beyond 1 year.
The reason for elevated ALT levels at 1-year follow-up is probably multifactorial. A toxic-inflammatory hit during the early post-transplant phase may have a role. Thus increased CRP during the early post-transplant phase was associated with ALT at follow-up. This finding, which is novel, is of importance because it suggests that systemic inflammation during the early phase of HSCT is important for long-term organ toxicity. Previous studies have suggested that the conditioning regimen induces tissue damage primarily involving the gastrointestinal tract,4 resulting in translocation of bacterial products and release of inflammatory cytokines.5, 6, 7, 8 Thus, the liver may be exposed to a high load of pro-inflammatory signals as a direct receiver of the portal blood from the gastrointestinal tract—possibly causing local hepatic inflammation. These signals include IL-6, a main inducer of CRP in hepatocytes.9
Further to this, the association between malignant diagnosis and elevated ALT at follow-up suggests that treatment of the underlying disease before HSCT may dispose to long-term liver toxicity, by rendering the liver more vulnerable to chemotherapy given as part of the pre-transplant conditioning regimen.
Interestingly, absence of ATG was associated with increased levels of ALT at follow-up, as opposed to aGvHD, that was not associated with ALT levels at follow-up. The explanation for this is unclear. However, it may be speculated that absence of ATG in the conditioning may lead to alloreactivity involving the liver, although not recognized clinically as aGvHD.
In summary, the presented data suggest that ALT levels 1 year post HSCT are related to increased ALT and bilirubin levels as well as CRP during the early post-transplant period. Further the study suggests that liver involvement sustained at 1 year post HSCT is prognostic for increased mortality beyond 1 year. This stresses the need for careful assessment of liver test during the transplant and during follow-up, and it emphasizes that patients with elevated ALT 1 year post HSCT should be followed closely to limit long-term mortality.
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This work has been supported by grants from The Danish Cancer Society, Dagmar Marshall Fond,Tømrermester Holm og Hustru Elisa f. Hansens Mindelegat and Juliane Marie Centeret, Rigshospitalet.
The authors declare no conflict of interest.
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Jordan, K., Christensen, I., Jørgensen, M. et al. Prognostic significance of liver parameters at 1-year follow-up in children and adults undergoing myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 50, 876–877 (2015). https://doi.org/10.1038/bmt.2015.54
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