Katharine H. Cook, DO, Nimish Thakral, MD, Jordan Woodard, MD University of Kentucky, Lexington, KY Introduction: Telomeres are repetitive DNA sequences that cap chromosome ends and preserve genomic stability. They progressively shorten with age, and critically short telomeres can trigger cellular senescence or apoptosis. Mutations in telomere-maintenance genes lead to short telomere syndromes (STS), typically affecting the bone marrow and lungs. Hepatic involvement is less common and rarely occurs in isolation. While RTEL1 mutations are well-established in pulmonary fibrosis, isolated liver disease has not been widely reported. We present a rare case of early-onset cirrhosis in the setting of STS with a confirmed RTEL1 mutation.
Case Description/
Methods: A 29-year-old male with type II diabetes and a history of binge drinking presented with new-onset ascites. He was diagnosed with cirrhosis and experienced rapid decompensation within a year, developing variceal bleeding, hepatic encephalopathy, and recurrent ascites requiring weekly paracentesis. A comprehensive workup—including autoimmune, infectious, and metabolic panels—was unremarkable, except for a mildly elevated smooth muscle antibody (1:20). Due to the unusually rapid progression, genetic testing was pursued. Telomere length resulted below the 10th percentile for age, consistent with STS. Further analysis revealed heterozygous pathogenic variants in RTEL1 and LIG4. The patient is currently receiving medical management for cirrhosis and is undergoing evaluation for liver transplantation. Discussion: RTEL1 mutations are classically associated with early-onset pulmonary fibrosis and bone marrow failure, but isolated cirrhosis has not been well described. Emerging evidence suggests hepatic involvement in STS may be underrecognized, especially when overshadowed by multi-organ disease. Experimental models demonstrate that telomere attrition impairs hepatic regeneration and promotes fibrogenesis. In this case, underlying STS likely amplified the fibrotic response in the setting of metabolic and alcohol-related liver injury. This case underscores the importance of considering STS in patients with cryptogenic or rapidly progressive cirrhosis, particularly at a young age. Early identification through telomere length assessment and genetic testing can guide timely referral for liver transplantation and surveillance for extrahepatic complications.
Disclosures: Katharine Cook indicated no relevant financial relationships. Nimish Thakral indicated no relevant financial relationships. Jordan Woodard indicated no relevant financial relationships.
Katharine H. Cook, DO, Nimish Thakral, MD, Jordan Woodard, MD. P6057 - Short Telomere Length Drives Accelerated Fibrosis in MetALD: A Curious Case of Cirrhosis in a 29-Year-Old, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.
