Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS

Abstract

Ammonia is central to the pathogenesis of hepatic encephalopathy. This study was designed to determine the quantitative dynamics of ammonia metabolism in patients with cirrhosis and previous treatment with a transjugular intrahepatic portosystemic stent shunt (TIPSS). We studied 24 patients with cirrhosis who underwent TIPSS portography. Blood was sampled and blood flows were measured across portal drained viscera, leg, kidney, and liver, and arteriovenous differences across the spleen and the inferior and superior mesenteric veins. The highest amount of ammonia was produced by the portal drained viscera. The kidneys also produced ammonia in amounts that equaled total hepatosplanchnic area production. Skeletal muscle removed more ammonia than the cirrhotic liver. The amount of nitrogen that was taken up by muscle in the form of ammonia was less than the glutamine that was released. The portal drained viscera consumed glutamine and produced ammonia, alanine, and citrulline. Urea was released in the splenic and superior mesenteric vein, contributing to whole-body ureagenesis in these cirrhotic patients. In conclusion, hyperammonemia in metabolically stable, overnight-fasted patients with cirrhosis of the liver and a TIPSS results from portosystemic shunting and renal ammonia production. Skeletal muscle removes more ammonia from the circulation than the cirrhotic liver. Muscle releases excessive amounts of the nontoxic nitrogen carrier glutamine, which can lead to ammonia production in the portal drained viscera (PDV) and kidneys. Urinary ammonia excretion and urea synthesis appear to be the only way to remove ammonia from the body.

Actualización en el tratamiento de la encefalopatía hepática

“…El 90% es metabolizado en el hígado dando lugar a la síntesis de urea que sufre posteriormente eliminación renal. En situación de cirrosis hepática, la contribución de otros órganos a la eliminación de amoniaco puede ser muy importante, destacando el papel del músculo esquelético, por su capacidad para la síntesis de glutamina (4). Una vez que el amoniaco atraviesa la barrera hematoencefálica es metabolizado a glutamina en el interior del astrocito, una reacción que consume mucha energía y podría conllevar estrés oxidativo y disfunción celular.…”

“…El metabolismo nitrogenado es complejo y en los últi-mos años se ha identificado un papel importante de diferentes tejidos, como el músculo esquelético y el riñón (4,40). En este sentido es importante señalar que la cirrosis hepática se acompaña de malnutrición energético-proteica.…”

Hepatic encephalopathy: An approach to its multiple pathophysiological features

“…Hepatic and inter-organ traffick�� ing of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. GLN metabolism via glutaminase is located in the intestinal epithelial cells and in the colonic epithelial cells [4] . Removal of hepatic ammonia is a differentiated work that includes the peri�� portal hepatocyte, through the urea cycle and the pe�� rivenous hepatocytes converting ammonia into GLN converting ammonia into GLN via glutamine synthetase.…”

The Rise of Glutaminase in End-Stage Liver Diseases

“…Historically it was thought that the majority of ammonia was produced by gut bacteria, and treatment regimens including non-absorbable antibiotics and enemas have been extensively used. Contrary to popular belief, it has now been shown that at least 50-60% of total gut ammonia is derived from uptake of glutamine, which is metabolized to glutamate and ammonia by the enzyme glutaminase (GA) (Olde Damink, Jalan et al 2002;Romero-Gomez, Ramos-Guerrero et al 2004). Ammonia that would normally be converted to urea by a healthy liver increases to toxic levels.…”

“…In this situation, the enzyme glutamine synthetase (GS) plays a pivotal role in ammonia detoxification, effectively removing ammonia during the conversion of glutamate to glutamine (Rose, Michalak et al 1999). Glutamine deamidation by intestinal GA seems to be the main source of ammonia in patients with cirrhosis (Olde Damink, Jalan et al 2002), and hyperammonaemia and hepatic encephalopathy can appear without the participation of gut bacteria (Weber and Veach 1979).…”