1Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark.
2UCL Institute of Liver and Digestive Health, University College London, United Kingdom.
3European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.
Mechanistically, the symptomatology and disease progression of non-alcoholic fatty liver disease (NAFLD) remain poorly understood, which makes therapeutic progress difficult. In this review, we focus on the potential importance of decreased urea cycle activity as a pathogenic mechanism. Urea synthesis is an exclusive hepatic function and is the body's only on-demand and definitive pathway to remove toxic ammonia. The compromised urea cycle activity in NAFLD is likely caused by epigenetic damage to urea cycle enzyme genes and increased hepatocyte senescence. When the urea cycle is dysfunctional, ammonia accumulates in liver tissue and blood, as has been demonstrated in both animal models and patients with NAFLD. The problem may be augmented by parallel changes in the glutamine/glutamate system. In the liver, the accumulation of ammonia leads to inflammation, stellate cell activation and fibrogenesis, which is partially reversible. This may be an important mechanism for the transition of bland steatosis to steatohepatitis and further to cirrhosis and hepatocellular carcinoma. Systemic hyperammonaemia has widespread negative effects on other organs. Best known are the cerebral consequences that manifest as cognitive disturbances, which are prevalent in patients with NAFLD. Furthermore, high ammonia levels induce a negative muscle protein balance leading to sarcopenia, compromised immune function and increased risk of liver cancer. There is currently no rational way to reverse reduced urea cycle activity but there are promising animal and human reports of ammonia-lowering strategies correcting several of the mentioned untoward aspects of NAFLD. In conclusion, the ability of ammonia-lowering strategies to control the symptoms and prevent the progression of NAFLD should be explored in clinical trials.