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Lipid Biology Helps Distinguish Hepatitis from Cirrhosis and Identifies 90-Day Mortality
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Untargeted lipidomics identified a glycerophospholipid and sphingolipid signature that differentiated severe alcohol-related hepatitis (sAH) from decompensated cirrhosis (DC).
Untargeted lipidomics helped identify a glycerophospholipid and sphingolipid signature that distinguished severe alcohol-related hepatitis (sAH) from decompensated cirrhosis (DC), according to findings published in the Journal of Hepatology Reports. The study investigators noted that these findings suggest a link between lipid species and their involvement in liver regeneration and immune function.
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sAH is an inflammatory condition that has a high short-term mortality in which hypothesis-driven approaches have previously failed to identify effective treatment options. Because lipids have an established role as inflammatory mediators, the investigators of this study aimed to identify lipidomic changes and species that are associated with the pathogenesis of sAH and its complications.
For this study, the investigators performed untargeted lipidomics on serum samples from 2 cohorts of patients, 1 of which included patients with sAH and the other patients with DC. The authors used a principal component analysis and orthogonal partial least squares discriminant analysis to assess lipidome changes. In addition, correlations were made with lipoproteins, lipid mediators, cytokines, cytokeratin fragments, and histological indices.
In the first part of this study, 78 patients with sAH were matched on bilirubin levels with 23 patients with DC. The lipidomics identified a distinct sAH signature that involved glycerophospholipids, including the phosphocholines PC(34:2) (OR 2.18, 95% CI: 1.45-7.05, p = .01), PC(O-38:5) (OR 3.31, 95% CI: 2.23-7.14, p = .002), PI(38:4) (OR 0.71, 95% CI: 0.46-0.88, p = .02), and LPC(18:1) (OR 0.47, 95% CI: 0.32-0.82, p = .01). These lipids, according to the investigators, demonstrated strong discriminatory power between sAH and DC, with areas under the receiver operating characteristic curves between 0.87 and 0.88.
A second part demonstrated that in 159 sAH patients, specific lipids, including the carnitines CAR(2:0) (OR 2.51, 95% CI: 1.25-4.96, p = .008) and CAR(16:1) (OR 2.21, 95% CI: 1.09-7.48, p = .009), were linked to 90-day mortality. In addition, acylcarnitines were found to correlate with disease severity parameters such as model for end-stage liver disease, pro-inflammatory cytokines levels, and hepatocyte ballooning on pathology.
One main limitation of the study, according to the authors, is the performed lipid analysis’s untargeted design, which lacks the specificity of quantitative techniques targeting 1 or 2 lipid classes, therefore only providing relative differences between the samples. Additionally, although the study shows some strong evidence that LPC-ATX-LPA pathway modulation plays an important role in the phenotype of circulating immune cells in acute-on-chronic liver failure, these findings were not confirmed in the sAH setting in an independent cohort and will require additional research to investigate that correlation further.
The present study highlights the role of several PC/LPC species and sphingolipids to differentiate between sAH and DC. These species were also shown to be associated with the risk of death, incident infection, and acute kidney injury in the population with sAH. Because of the evidence that is accumulating regarding the role of these lipids within the regulation of liver regeneration and immune function, the authors urge that they are explored further for therapeutic potential.
Further, the acylcarnitine accumulation observed in patients with sAH who had a poorer prognosis could reflect the degree of mitochondrial dysfunction as well as gut translocation in this population. Knowing the place of mitochondrial dysfunction in the pathogenesis of the disease, prospective exploration of acylcarnitine pathways as a potential target to modulate this dysfunction is suggested by the investigators.
