Tracking Liver Disease with Top-Down Proteomics

Research has identified specific proteoform signatures in blood plasma that could help monitor the progression of liver cirrhosis and predict its transition to advanced stages. 

Using blood samples from 30 patients across three stages of cirrhosis – compensated, compensated with portal hypertension, and decompensated – the researchers employed top-down mass spectrometry (TDP) to analyze intact proteins, preserving their full structure and post-translational modifications (PTMs). This approach identified over 2,800 proteoforms, with distinct changes in proteins such as fibrinogen, apolipoprotein A-I, and haptoglobin correlating with disease progression.

“Proteoforms are distinct versions of a protein, arising from variations in gene sequence, RNA splicing, and protein processing. Identifying and quantifying these proteoforms is crucial for understanding their roles in liver cirrhosis,” explained Neil L. Kelleher, lead author and Walter and Mary E. Glass Professor of Molecular Biosciences at Northwestern University, in a press release.

The findings reveal that proteoform modifications, such as truncations and phosphorylation, provide a molecular snapshot of how cirrhosis affects liver function over time. For example, fibrinogen proteoforms involved in blood clotting exhibited stage-dependent changes, reflecting worsening liver dysfunction and increased inflammation as the disease advanced.

Unlike traditional liver function tests or imaging, which may miss subtle biochemical changes, proteomic profiling allows for more precise tracking of disease progression. The ability to detect early molecular changes could enable clinicians to intervene sooner, potentially improving patient outcomes.

“By identifying specific proteoform signatures linked to disease progression, we move closer to personalized medicine for liver cirrhosis patients,” said Kelleher.

The study also underscores the power of top-down proteomics in translational research. By analyzing intact proteins, the approach provides deeper insights into the molecular mechanisms driving liver failure, paving the way for the development of targeted therapies.

“This study typifies how CLP enables translational science across Northwestern’s campuses,” Kelleher noted. “We bring best-in-class technology platforms from the basic sciences into collaboration with key, unmet needs seen by our Feinberg clinicians every day.”

Future work will focus on validating these proteoform signatures in larger patient cohorts and exploring their potential for guiding therapeutic strategies.