Tag: Liver

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Liver fibrosis linked to CV events, survival in NAFLD, chronic kidney disease

After a median follow-up of 10 years, NAFLD correlated with an increased risk for: “Variable A” – Cardiovascular events; HR = 1.39 “Variable B” – All-cause mortality; HR = 1.1

Source:

Hydes T, et al. Abstract OS048. Presented at: International Liver Congress; June 22-26, 2022; London (hybrid meeting).


Disclosures:
Hydes reports no relevant financial disclosures.


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LONDON — Elevated noninvasive markers of liver fibrosis correlated with an increased risk for cardiovascular events, end-stage renal disease and worse survival in patients with chronic kidney disease and nonalcoholic fatty liver disease.

“Multimorbidity is increasing, and it is vital to understand the clinical consequences of having more than one medical condition,” Theresa Hydes, MBBS, BSc, PhD, NIHR clinical lecturer in hepatology at the University of Liverpool, told Healio. “Fatty liver disease, in particular, is independently associated with several non-liver conditions, including heart disease and chronic kidney disease.”


After a median follow-up of 10 years, NAFLD correlated with an increased risk for: “Variable A” – Cardiovascular events; HR = 1.39 “Variable B” – All-cause mortality; HR = 1.1



Seeking to assess the effect of NAFLD and NAFLD fibrosis on adverse clinical outcomes and mortality among patients with chronic kidney disease (CKD), Hydes and colleagues analyzed data from 26,074 patients using the UK Biobank. Participants provided information related to medical history, demographics and lifestyle factors, which was supplemented via electronic linkage to hospital records and death records.

Researchers used Cox regression to estimate hazard ratios associated with NAFLD and advanced liver fibrosis on CV events, progression to end-stage renal disease (ESRD) and all-cause mortality.

At baseline, 54,5% of patients with CKD had NAFLD, with evidence of advanced fibrosis among 7% [NAFLD fibrosis score (NFS) 0.676], 3.2% [elevated fibrosis-4 (FIB-4) > 2.67] and 1.1% [AST to platelet ratio index (APRI) 1].

After a median follow-up of 10 years, NAFLD correlated with an increased risk for CV events (HR = 1.39; 95% CI, 1.29-1.51) and all-cause mortality (HR = 1.1; 95% CI, 1.01-1.19) but not ESRD (HR = 1.22; 95% CI, 0.95-1.56) in a univariate analysis. Following multivariate adjustment for demographics, metabolic factors and baseline renal functions, NAFLD did not associate with an increased risk for primary outcomes.

Advanced liver fibrosis using all scores correlated with an increased risk for all-cause mortality (HR = 2.34-2.9), and NFS and FIB-4 associated with an elevated risk for CV events (HR = 2.49; 95% CI, 2.11-2.93 and HR = 1.94; 95% CI, 1.53-2.45) and ESRD (HR = 6.85; 95% CI, 4.29-10.94 and HR = 2.35; 95% CI, 1.19-4.67). After full adjustment, FIB-4 correlated with an increased incidence of CV events (HR = 1.39; 95% CI, 1.06-1.82), notably heart failure (HR = 1.65; 95% CI, 1.16-2.33).

Both FIB-4 and APRI associated with all-cause mortality (HR = 1.55; 95% CI, 1.21-2 and HR = 2.83; 95% CI, 1.95-4.11) and NFS ( –1.455) associated with progression to ESRD (HR = 1.89; 95% CI, 1.13-3.17).

“These results highlight the importance of enhanced recognition of fatty liver disease with fibrosis in people with chronic kidney disease to inform the need for vigorous cardiometabolic risk factor control in this group,” Hydes said. “It also suggests the need for work to understand the mechanisms linking these conditions to help drive new drug discoveries.”


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International Liver Congress

International Liver Congress

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Interactive web portal details the extent of splicing events in noncoding sequences

Interactive web portal details the extent of splicing events in noncoding sequences

An online tool reveals the extent of gene-restructuring events in noncoding sequences.

An interactive web portal developed by scientists at KAUST offers a platform for cancer researchers to interrogate how RNA splicing in noncoding parts of genes fuels the growth of different types of tumors.

The new resource, named SpUR (short for Splicing in Untranslated Regions) and freely available online, details more than 1,000 splicing events found frequently in cancers in noncoding regions of mRNA located just downstream of protein-coding stop signals. The sites and expression levels of these events are catalogued and visualized for nearly 8,000 samples across 10 cancer types and corresponding normal tissues.

With the tool, independent research teams can now further probe the role of individual splice events in cancer development and progression.

These events could become candidates to study RNA dysregulations in cancer for academic researchers. Or they could serve as a primary source for the development of RNA-based anti-cancer drugs.”


Xin Gao, acting associate director of the Computational Bioscience Research Center and deputy director of the Smart Health Initiative at KAUST

Computer scientist Gao, together with postdoc Bin Zhang and research engineer Adil Salhi, created the SpUR database in collaboration with researchers at the Cancer Science Institute of Singapore.

The research showed that splicing in downstream sequences of a gene (known as 3′ untranslated regions, or 3′ UTRs) is pervasive in cancers, especially in genes linked to tumor aggression. Consequently, patients whose cancers harbor more of these gene-restructuring events tend to have poorer survival outcomes.

As a proof of principle, the researchers designed splice-switching agents known as antisense oligonucleotides (ASOs) that could block this splicing process in 3′ UTRs. When administered to liver cancer cells, these drugs helped repress tumor growth. And since the same kinds of splicing events are “ubiquitously expressed across different cancer types,” Gao notes, this type of therapeutic strategy “could be helpful to develop broad-spectrum anti-cancer drugs.”

One potential target:CTNNB1, which is a gene that provides instructions for making a protein called beta-catenin. Drug companies have long tried to target beta-catenin, given its central role in many cancer-signaling pathways, but with only limited success. The study from Gao and his collaborators showed that splicing in the 3′ UTR ofCTNNB1is widespread across cancers of the liver, breast, colon, kidney, lung and other organs, and that a spliced variant is the predominant driver of tumor progression.

In a mouse model of liver cancer, blocking this splicing resulted in complete tumor regression. An ASO therapy directed atCTNNB1splicing could therefore have broad utility in patients, and, as Gao points out, it is not likely to be the only one.

Source:

KAUST – King Abdullah University of Science and Technology

Journal reference:

Chan, J.J., et al. (2022) Pan-cancer, pervasive upregulation of 3’UTR splicing drives tumorigenesis. Nature Cell Biology. doi.org/10.1038/s41556-022-00913-z.