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In patients with acute liver failure (ALF), hyperammonemia is related to development of cerebral edema and herniation. The present review discusses the mechanisms for the cerebral uptake of ammonia. A mathematical framework is provided to allow a quantitative examination of whether published studies can be explained by the conventional view that cerebral uptake of ammonia is restricted to diffusion of the unprotonated form (NH3) (the diffusion hypothesis). An increase in cerebral blood flow (CBF) enhanced ammonia uptake more than expected, possibly due to recruitment or heterogeneity of brain capillaries. Reported effects of pH on ammonia uptake were in the direction predicted by the diffusion hypothesis, but often less pronounced than expected. The published effects of mannitol, cooling, and indomethacin in experimental animals and patients were difficult to explain by the diffusion hypothesis alone, unless dramatic changes of capillary surface area or permeability for ammonia were induced. Therefore we considered the possible role of membrane protein mediated transport of NH4+ across the blood–brain barrier (BBB). Early tracer studies in Rhesus monkeys suggested that NH4+ is responsible for 20% or even more of the transport of ammonia from plasma to brain. In other locations, such as in the thick ascending limb of Hendle’s loop and in isolated astrocytes, transport protein mediated translocation of NH4+ is predominant. Many of the ion-transporters involved in renal NH4+ reabsorbtion are also present in brain capillary membranes and could mediate uptake of NH4+. Astrocytic uptake of NH4+ is associated with increased extracellular K+, which is a potent cerebral vasodilator. Such interference between transport of NH4+ and other cations could be clinically important because increased cerebral blood flow often precedes cerebral herniation in acute liver failure. We suggest that protein mediated transport of NH4+ through the brain capillary wall is a realistic possibility that should be more intensely studied.