Hyperammonemia as a potential contributor to fatigue in metabolic dysfunction-associated steatotic liver disease: A mechanistic review

Abstract

Non-alcoholic fatty liver disease, now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is a global health problem affecting a substantial proportion of the adult population. Fatigue is among the most common and clinically underrecognized systemic symptoms experienced by patients with MASLD and is associated with reduced physical and cognitive performance, impaired daily activities, decreased work capacity, and poorer adherence to treatment. The pathogenesis of fatigue in MASLD is likely multifactorial and may involve systemic low-grade inflammation, mitochondrial and muscle dysfunction, sleep disorders, psychological factors, changes in the gut microbiota, and hyperammonemia, which has recently received increasing attention in the context of MASLD progression. Although experimental and mechanistic studies suggest that hyperammonemia may contribute to fatigue, direct clinical evidence remains limited. The goal of this narrative review is to systematize current evidence on the potential role of hyperammonemia as a biologically plausible mechanism contributing to fatigue in MASLD, and to critically evaluate current data on the influence of dietary factors, skeletal muscle status, and physical activity on ammonia homeostasis. This review is hypothesis-generating and should not be interpreted as a clinical guideline.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Hyperammonemia; Fatigue; Urea cycle; Sarcopenia; Mediterranean diet; Physical activity

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.