What causes hyperammonemia (elevated ammonia levels) in the body?

From the Guidelines

Ammonia builds up in the body primarily due to the excessive accumulation from amino acid catabolism, the activity of glutamine dehydrogenase in the liver, kidney, pancreas, and brain, and by the deamination of AMP during exercise in skeletal muscle, which cannot be properly converted into urea for excretion. This occurs when the liver fails to properly process ammonia, often due to liver disease, genetic disorders like urea cycle defects, or other conditions that impair liver function [ 1 ]. The main sources of ammonia include:

• Amino acid catabolism
• The activity of glutamine dehydrogenase in the liver, kidney, pancreas, and brain
• The deamination of AMP during exercise in skeletal muscle When liver function is compromised, ammonia accumulates in the bloodstream, potentially leading to neurological impairment and cerebral edema [ 1 ]. High levels of ammonia can produce toxic effects, and levels >200 µmol/l are associated with poor neurological outcomes [ 1 ]. Certain medications and management strategies, such as stopping protein intake, administering i.v. glucose, lipids, and caloric intake, as well as using ammonia-scavenging agents like sodium benzoate and sodium phenylacetate, can help manage ammonia levels [ 1 ].

From the FDA Drug Label

CLINICAL PHARMACOLOGY Lactulose causes a decrease in blood ammonia concentration and reduces the degree of portal-systemic encephalopathy. These actions are considered to be results of the following: Bacterial degradation of lactulose in the colon acidifies the colonic contents. This acidification of colonic contents results in the retention of ammonia in the colon as the ammonium ion Since the colonic contents are then more acid that the blood, ammonia can be expected to migrate from the blood into the colon to from the ammonium ion. The acid colonic contents converts NH3 to the ammonium ion (NH4)+,trapping it and preventing its absorption. The question asks how ammonia builds up in the body, but the provided text from the drug label 2 explains how lactulose reduces ammonia levels in the body, not how ammonia builds up. No direct information is provided on how ammonia builds up in the body.

From the Research

Ammonia Buildup in the Body

• Ammonia is produced continuously in the body and must be eliminated to maintain a safe blood concentration of around 30 µM 3, 4.
• The body has a complex system to detoxify ammonia, involving the liver, gut, kidney, and muscle, with the liver playing a key role in converting ammonia to non-toxic urea 3, 4.
• The gut and kidney contribute roughly equally to the delivery of ammonia to systemic blood, with the small bowel being a major source of ammonia production 3.
• Ammonia can build up in the body if the urea cycle is unable to control the ammonia load, which can occur due to liver damage, portal blood bypassing the liver, or poor urea cycle function 3, 4.

Causes of Ammonia Buildup

• Liver damage is the most common cause of ammonia buildup, but other causes can include inherited defects of the urea cycle, fatty acid oxidation disorders, and other conditions that affect the body's ability to detoxify ammonia 4, 5.
• In cirrhosis, ammonia can build up even without hyperammonemia of the vein, due to the anatomical features of ammonia metabolism and the compensatory mechanisms of the glutamine synthesis pathway 6.

Consequences of Ammonia Buildup

• High levels of ammonia in the blood can be toxic to the brain and cause hepatic encephalopathy, cerebral edema, and intracranial hypertension 4, 5.
• Ammonia buildup can also contribute to immune dysfunction, sarcopenia, liver fibrosis, hepatocellular injury, and other pathological conditions seen in cirrhosis 5, 6.