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

Table 1 Summary of current evidence on ammonia metabolism, hyperammonemia, and fatigue-related mechanisms in metabolic dysfunction-associated steatotic liver disease

Study model/source of evidence	Key findings
Patients with pre-cirrhotic MASLD stages[18,22,33-36,42-45,48]	Impaired ureagenesis; reduced urea cycle enzyme activity (CPS1, OTC); altered glutamine/glutamate metabolism; increased glutaminolysis associated with fibrosis progression; increased biomarkers of mitochondrial dysfunction; cognitive impairment has been described (its association with hyperammonemia remains uncertain)
Patients with MASLD and advanced fibrosis or cirrhosis[57,60,87,88,118,119]	Hyperammonemia is associated with sarcopenia, myosteatosis, minimal/overt HE; skeletal muscle detoxifies ammonia through glutamine synthesis; this mechanism is partly BCAA dependent; induced hyperammonemia worsens sleepiness; BCAAs may improve HE-related outcomes
Animal MASLD/MASH models[39-42,48,49,104,108,110]	Impaired ureagenesis; reduced urea cycle enzyme activity (OTC, CPS1, ASS1); hyperammonemia is linked to fibrosis progression and skeletal muscle alterations; ammonia-lowering strategies attenuate fibrosis and liver-muscle injury; hyperammonemia is associated with dynapenia, sarcopenia, sarcopenic obesity; increased hepatic glutaminolysis and GLS1 activity may trigger MASH progression/fibrosis; BCAAs support muscle ammonia detoxification via glutamine synthesis
Cell cultures and ex vivo mechanistic studies[63,66,67,69,81,102,120]	Ammonia induces mitochondrial dysfunction, oxidative stress; ammonia triggers NF-κB/myostatin activation and autophagy in skeletal muscles; ammonia disturbs protein synthesis in skeletal muscles via GCN2/eIF2α activation and mTORC1 suppression, while BCAAs partially restore protein synthesis ex vivo; ammonia induces astrocyte dysfunction
Exercise physiology and MASLD exercise studies[61,113-117,121]	Acute exercise increases ammonia production through purine nucleotide breakdown and amino-acid metabolism; the magnitude depends on exercise intensity, duration, and training status; in MASLD, exercise improves liver fat and metabolic parameters; direct studies assessing exercise-induced ammonia responses in MASLD are lacking

ASS1: Argininosuccinate synthase 1; BCAA: Branched-chain amino acid; CPS1: Carbamoyl phosphate synthetase 1; eIF2α: Eukaryotic translation initiation factor 2α; GCN2: General control nonderepressible 2; GLS1: Glutaminase 1; HE: Hepatic encephalopathy; MASH: Metabolic dysfunction-associated steatohepatitis; MASLD: Metabolic dysfunction-associated steatotic liver disease; mTORC1: Mechanistic target of rapamycin complex 1; NF-κB: Nuclear factor kappa B; OTC: Ornithine transcarbamylase.

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.