The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia

Abstract

The cyclotron-produced radionuclide, 13N, was used to label ammonia and to study its metabolism in a group of 5 normal subjects and 17 patients with liver disease, including 5 with portacaval shunts and 11 with encephalopathy. Arterial ammonia levels were 52-264 μM. The rate of ammonia clearance from the vascular compartment (metabolism) was a linear function of its arterial concentration: μmol/min = 4.71 [NH3]a + 3.76, r = +0.85, P<0.005. Quantitative body scans showed that 7.4 ± 0.3% of the isotope was metabolized by the brain. The brain ammonia utilization rate, calculated from brain and blood activities, was function of the arterial ammonia concentration: μmol/min per whole brain = 0.375 [NH3]a 3.6, r = +0.93, P<0.005. Assuming that cerebral blood flow and brain weights were normal, 47 ± 3% of the ammonia was extracted from arterial blood during a single pass through the normal brains. Ammonia uptake was greatest in gray matter. The ammonia utilization reaction(s) appears to take place in a compartment, perhaps in astrocytes, that includes <20% of all brain ammonia. In the 11 nonencephalopathic subjects the [NH3]a was 100 ± 8 μM and the brain ammonia utilization rate was 32 ± 3 μmol/min per whole brain; in the 11 encephalopathic subjects these were respectively elevated to 149 ± 18 μM (P<0.01), and 53 ± 7 μmol/min per whole brain (P<0.01). In normal subjects ≃ 50% of the arterial ammonia was metabolized by skeletal muscle. In patients with portal-systemic shunting, muscle may become the most important organ for ammonia detoxification. Muscle atrophy may thereby contribute to the development of hyperammonemic encephalopathy with an associated increase in the brain ammonia utilization rate.