Latest Updates in Liver Disease

Dr. Alexander Miethke, from Cincinnati Children’s Hospital Medical Center, reviewed the direct and indirect action of bile acids on immune responses and inflammation in gut and liver disease. Bile acids are synthesized in the liver, conjugated, and then deconjugated in the intestine, with the resulting pool of bile acid metabolites determined by a combination of genetics, gut microbial commensals, and diet. Binding of bile acids to a diverse array of receptors on immune cells in the gut triggers signaling pathways that regulate the balance of regulatory T cells and inflammatory Th17 T cells. Dysregulation of the Treg/Th17 T cell balance has been associated with a higher risk of inflammatory bowel disease (IBD), autoimmunity, and colorectal cancer, as well as sclerosing cholangitis in the liver. Fecal microbiota transplant for IBD, oral vancomycin treatment of ulcerative colitis, and nor-ursodeoxycholic acid (NorUDCA) treatment for primary sclerosing cholangitis have been associated with changes in bile acid metabolites and reduction in disease activity. Inhibition of bile acid reuptake in intestine with IBAT inhibitors and FXR activation in macrophages are also being investigated as potential therapeutic approaches to restore Treg and reduce Th17 T cell inflammatory responses.

Wissam Ghusn, MD, from Boston University, discussed the potential for expanding GLP-1 therapy to liver disease. MASLD is the most prevalent chronic liver disease, and although obesity and diabetes are strong risk factors for MASLD, there is a subset of individuals with steatosis who are lean. GLP-1 receptor agonists are being investigated as a treatment for MASLD, but individuals with “lean MASLD” would not be eligible based on current indications for these medications. Dr. Ghusn described a cross-sectional analysis of participants of the Framingham Heart Study to quantify the subset with “lean MASLD” who might benefit from an expansion of the current indication for GLP-1 receptor agonists. He found that of slightly over 3000 participants, 49% did not have obesity or diabetes and would not be eligible for GLP-1 receptor agonist treatment. Of these, 14% had MALSD with steatosis, elevated ALT, prediabetes, hypertension, and hyperlipidemia, but 90% did not yet have significant fibrosis. Dr. Ghusn suggested that these patients might benefit from GLD-1 receptor agonist treatment to prevent progression, though more research is needed.

Akshaya Annapragada, from Johns Hopkins University, described the use of the genome-wide cell-free DNA fragmentome for noninvasive detection of liver diseases. A large and growing group of individuals with MASLD are missed by screening but are at high risk of liver cancer. Liquid biopsies have made cancer screening more accessible through detection of gene mutations in tumor DNA fragments in the blood; however, the sensitivity of these tests is low. Dr. Annapragada suggested that the size and distribution of the cell-free tumor DNA fragments and repeat sequences, rather than single gene mutations, could be used as tumor biomarkers. Her group used genome-wide sequencing and machine learning (ARTEMIS-DELFI) to find associations between cell-free tumor DNA fragment patterns and liver cancer and to distinguish liver cancer from viral hepatitis and cirrhosis. The approach was highly sensitive, with an AUC of 0.95 for advanced disease and 0.9 for early disease. This approach can also be used to determine the tissue of origin and methylation patterns to better understand the etiologies of cirrhotic disease.