Abstract Background and Aims: Upper gastrointestinal bleeding (UGI) in patients with cirrhosis of the liver induces hyperammonemia and leads to a catabolic cascade that precipitates life-threatening complications. The haemoglobin molecule is unique because it lacks the essential amino acid isoleucine and contains high amounts of leucine and valine. UGI bleed therefore presents the gut with protein of very low biologic value, which may be the stimulus to induce net catabolism. Results: It has recently been proven that ('simulation') a UGI bleed in patients with cirrhosis leads to impaired protein synthesis that can be restored by intravenous infusion of isoleucine. This may have therapeutic implications for the function of rapidly dividing cells and short half-life proteins such as like clotting factors. Renal and small bowel ammoniagenesis were shown to be the most prominent causes of the hyperammonemia that resulted from a UGI bleed. This provides an explanation for the therapeutic failure of the current clinical therapies that are aimed at large bowel derived ammonia production. Isoleucine infusion did not diminish renal ammoniagenesis. Conclusions: New pharmacological therapies to diminish post-bleeding hyperammonemia should target the altered interorgan ammonia metabolism and promote ammonia excretion and/or increase the excretion of precursors of ammoniagenesis, e.g. l-ornithine-phenylacetatate.