Possible pathogenetic role of ammonia in liver cirrhosis without hyperammonemia of venous blood: The so-called latency period of abnormal ammonia metabolism

Ammonia plays a crucial role in the pathogenesis of hepatic encephalopathy. Ammonia is also involved in many other pathological conditions seen in cirrhosis, such as sarcopenia, liver fibrosis, hepatocellular injury, immune dysfunction, and hyperammonemia. Furthermore, the ammonia level of the veins is a useful prognostic factor for cirrhosis. In cirrhosis without hyperammonemia of the vein, however, covert hepatic encephalopathy has been reported. This discrepancy is because of the anatomical features of ammonia metabolism. There are two systems in the body for detoxifying ammonia: one is the urea cycle in the liver, and the other is the glutamine synthesis pathway in skeletal muscle and other tissues. The blood processed in the liver's urea cycle is then transported via arteries to various organs. Further processing occurs in the brain and skeletal muscle's glutamine synthesis pathway before entering the veins. When the urea cycle function decreases in cirrhosis, the ammonia levels in the artery increase. In response, the glutamine synthesis pathway compensates by increasing the capacity to process ammonia. Therefore, the ammonia concentration in the veins downstream of skeletal muscles does not increase immediately. However, the brain and skeletal muscles, which receive arterial blood, might be exposed to high ammonia concentrations. In addition, branched-chain amino acids in venous blood decrease. This period is the transition phase from early- to late-phase cirrhosis, and understanding the pathophysiology during this stage is extremely important for preventing the progression of cirrhosis. In cirrhosis, the detoxification ability of ammonia produced during protein metabolism is reduced, and the arterial blood ammonia concentration is higher than the venous blood ammonia concentration, leading to a decrease in the branched-chain amino acids to tyrosine ratio. Ammonia is thought to have a crucial role in the pathogenesis of various complications of cirrhosis, including hepatic encephalopathy, sarcopenia, liver fibrosis, immunodeficiency, and others. Even during periods when the venous blood ammonia concentration is within the normal range in cirrhosis, abnormal ammonia metabolism within the body is considered if the branched-chain amino acids to tyrosine ratio is low, leading to the concept of the latency period of abnormal ammonia metabolism. image