Evolution of non-thyroidal illness syndrome in acute decompensation of liver cirrhosis and acute-on-chronic liver failure.

Background and aims: Non-thyroidal illness syndrome (NTIS) is frequent in critically ill patients and associated with adverse outcomes. We aimed to characterize the evolution of NTIS in patients with acute decompensation (AD) of cirrhosis and acute-on-chronic liver failure (ACLF), since NTIS is not well described in these newly defined syndromes. Methods: Thyroid hormones (TH) were quantified at baseline in consecutive patients with cirrhosis. In addition, 76 inflammatory mediators were quantified by proximity extension analysis assay in a subgroup of patients. Associations between TH, cirrhosis stage, mortality and inflammation were assessed. Results: Overall, 437 patients were included, of whom 165 (37.8%), 211 (48.3%), and 61 (14%) had compensated cirrhosis (CC), AD, and ACLF. FT3 concentrations were lower in AD versus CC, and further decreased in ACLF. Importantly, NTIS was present in 83 (39.3%) patients with AD and in 44 (72.1%) patients with ACLF (P<0.001). Yet, TSH and TSH-based indexes (TSH/FT3-ratio, thyroid index) showed an U-shaped evolution during progression of cirrhosis, suggesting a partially preserved responsiveness of the hypothalamus and pituitary in AD. Infections were associated with lower FT3 concentrations in AD, but not in ACLF. Low FT3 concentrations correlated significantly with 90-day mortality. Both, AD/ACLF and NTIS, were associated with signatures of inflammatory mediators, which were partially non-overlapping. Conclusion: NTIS is frequent already in AD and therefore precedes critically illness in a subgroup of patients with decompensated cirrhosis. This might constitute a new paradigm of TH signaling in cirrhosis, offering opportunities to explore preventive effects of TH in AD.

Pathological neutrophil migration predicts adverse outcomes in hospitalized patients with liver cirrhosis.

BACKGROUND AND AIMS: Given the early response of neutrophil granulocytes to infections, detection of pathological neutrophil migration might help in predicting adverse events in patients with liver cirrhosis. METHODS: Migration of blood neutrophils in hospitalized patients with cirrhosis was characterized by a novel standardized migration assay. Pathological neutrophil migration patterns were associated with a composite endpoint of ACLF, sepsis or death within 7 or 30 days. RESULTS: Overall, 125 patients were included, of whom 11 (8.8%) had compensated cirrhosis, 84 (67.2%) had acute decompensation (AD) and 30 (24%) had acute-on-chronic liver failure (ACLF). The migration response of neutrophils from patients with AD or ACLF to stimulation with the chemotactic formylpeptide f-Met-Leu-Phe (fMLP) was significantly impaired, while the response to chemokine (C-X-C motif)-ligand 8 (CXCL8) was affected less pronouncedly. In contrast, no relevant differences in response to CXCL1 were observed. Of note, neutrophils of a number of patients with AD and ACLF were largely immotile at resting and stimulated conditions. Patients with non-migrating neutrophils at unstimulated conditions were at high risk to develop the composite endpoint of ACLF, sepsis or death. Moreover, expression of chemokine receptors CXCR1 and CXCR2 was significantly decreased in patients with ACLF. Interestingly, the expression of chemokine receptors did not correlate with neutrophil migration patterns, but-based on the increased expression of the cell surface markers CD66b and CD177-neutrophils of patients with AD and ACLF were strongly pre-activated. CONCLUSION: Pathological neutrophil migration in patients with cirrhosis indicates a high risk of developing adverse outcomes.

Dissecting Genetic Control of HLA-DPB1 Expression and Its Relation to Structural Mismatch Models in Hematopoietic Stem Cell Transplantation.

HLA expression levels have been suggested to be genetically controlled by single nucleotide polymorphisms (SNP) in the untranslated regions (UTR), and expression variants have been associated with the outcome of chronic viral infection and hematopoietic stem cell transplantation (HSCT). In particular, the 3'UTR rs9277534-G/A SNP in HLA-DPB1 has been associated with graft-versus-host-disease after HSCT (Expression model); however its relevance in different immune cells and its mode of action have not been systematically addressed. In addition, there is a strong though not complete overlap between the rs9277534-G/A SNP and structural HLA-DPB1 T cell epitope (TCE) groups which have also been associated with HSCT outcome (TCE Structural model). Here we confirm and extend previous findings of significantly higher HLA-DPB1 expression in B cell lines, unstimulated primary B cells, and monocytes homozygous for rs9277534-G compared to those homozygous for rs9277534-A. However, these differences were abrogated by interferon-γ stimulation or differentiation into dendritic cells. We identify at least seven 3'UTR rs9277534-G/A haplotypes differing by a total of 37 SNP, also characterized by linkage to length variants of a short tandem repeat (STR) in intron 2 and TCE group assignment. 3'UTR mapping did not show any significant differences in post-transcriptional regulation assessed by luciferase assays between two representative rs9277534-G/A haplotypes for any of eight overlapping fragments. Moreover, no evidence for alternative splicing associated with the intron 2 STR was obtained by RT-PCR. In an exemplary cohort of 379 HLA-DPB1 mismatched donor-recipient pairs, risk prediction by the Expression model and the Structural TCE model was 36.7% concordant, with the majority of discordances due to non-applicability of the Expression model. HLA-DPB1 from different TCE groups expressed in the absence of the 3'UTR at similar levels by transfected HeLa cells elicited significantly different mean alloreactive CD4+ T-cell responses, as assessed by CD137 upregulation assays in 178 independent cultures. Taken together, our data provide new insights into the cell type-specific and mechanistic basis of the association between the rs9277534-G/A SNP and HLA-DPB1 expression, and show that, despite partial overlap between both models in HSCT risk-prediction, differential alloreactivity determined by the TCE structural model occurs independently from HLA-DPB1 differential expression.