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

Table 2 Current evidence supporting the role of hyperammonemia in fatigue-related mechanisms in metabolic dysfunction-associated steatotic liver disease

Mechanism/finding	Evidence in MASLD patients	Experimental evidence (animal models and non-MASLD human studies)	Strength of evidence
Elevated blood ammonia[15,19,22,33-37,42,79]	Small cohorts, inconsistent	Moderate, human studies	Low to moderate
Urea cycle dysfunction[39,42-45]	Yes	Strong	Moderate to strong
Altered Gln/Glu metabolism, increased glutaminolysis[48,49,53,122]	Yes	Strong	Moderate
Muscle ammonia detoxification[57,60,69,123]	Indirect, stronger in advanced CLD	Extensive	Moderate to strong
Ammonia-induced muscle dysfunction/sarcopenia[54,55,57,111,112]	Limited/indirect	Strong	Moderate
Mitochondrial dysfunction/oxidative stress[39-41,43-45,81]	Indirect	Strong	Moderate
Neuroinflammation/astrocyte dysfunction[81,82]	Indirect	Moderate	Low to moderate
Ammonia-related cognitive impairment[18,36]	Limited	Moderate to strong	Moderate
BCAA involvement in ammonia handling[102-104,118-120]	No MASLD-specific data	Moderate	Low to moderate

BCAA: Branched-chain amino acid; CLD: Chronic liver disease; Gln: Glutamine; Glu: Glutamate; MASLD: Metabolic dysfunction-associated steatotic liver disease.