Sheptulina AF, Golubeva JA, Valeeva DL, Kiselev AR, Drapkina OM. Hyperammonemia as a potential contributor to fatigue in metabolic dysfunction-associated steatotic liver disease: A mechanistic review. World J Hepatol 2026; 18(10): 124519 [DOI: 10.4254/wjh.124519]
Corresponding Author of This Article
Anton R Kiselev, Head, Professor, Coordinating Center for Fundamental Research, National Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, str. 3, Moscow 101990, Moskva, Russia. antonkis@list.ru
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Gastroenterology & Hepatology
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review-article
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Sheptulina AF, Golubeva JA, Valeeva DL, Kiselev AR, Drapkina OM. Hyperammonemia as a potential contributor to fatigue in metabolic dysfunction-associated steatotic liver disease: A mechanistic review. World J Hepatol 2026; 18(10): 124519 [DOI: 10.4254/wjh.124519]
World J Hepatol. Oct 27, 2026; 18(10): 124519 Published online Oct 27, 2026. doi: 10.4254/wjh.124519
Hyperammonemia as a potential contributor to fatigue in metabolic dysfunction-associated steatotic liver disease: A mechanistic review
Anna F Sheptulina, Julia A Golubeva, Diana L Valeeva, Anton R Kiselev, Oksana M Drapkina
Anna F Sheptulina, Julia A Golubeva, Diana L Valeeva, Laboratory of Experimental and Preventive Gastroenterology, National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Moskva, Russia
Anton R Kiselev, Coordinating Center for Fundamental Research, National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Moskva, Russia
Oksana M Drapkina, Department of Fundamental and Applied Aspects of Obesity, National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Moskva, Russia
Author contributions: Sheptulina AF, Golubeva JA, and Valeeva DL drafted the manuscript; Sheptulina AF performed critical revisions related to important intellectual content; Kiselev AR analyzed and interpreted the data; Drapkina OM designed the study; and all authors provided final approval of the version to be published.
AI contribution statement: Portions of this manuscript were edited using AI tools solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Supported by Scientific Work of National Medical Research Center for Therapy and Preventive Medicine According to the State Assignment of the Ministry of Health of the Russian Federation, No. 126020116173-4 (2026-2028).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Anton R Kiselev, Head, Professor, Coordinating Center for Fundamental Research, National Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, str. 3, Moscow 101990, Moskva, Russia. antonkis@list.ru
Received: June 17, 2026 Revised: July 29, 2026 Accepted: September 10, 2026 Published online: October 27, 2026 Processing time: 126 Days and 10.6 Hours
Core Tip
Core Tip: Hyperammonemia may develop in precirrhotic metabolic dysfunction-associated steatotic liver disease (MASLD) as a consequence of impaired ureagenesis associated with reduced expression and activity of urea cycle enzymes, together with alterations in glutamine metabolism. Current evidence suggests that ammonia may contribute to both central and peripheral fatigue through interconnected mechanisms involving neuroinflammation, impaired neurotransmission, mitochondrial dysfunction, oxidative stress, and skeletal muscle impairment. However, most available evidence originates from experimental studies, whereas direct clinical evidence in patients with MASLD remains limited. Although dietary factors, skeletal muscle status, and physical activity may influence ammonia homeostasis, their specific role in hyperammonemia in MASLD remains uncertain and should be regarded as hypothesis-generating. A better understanding of ammonia metabolism may facilitate the development of targeted strategies for fatigue management in MASLD.
