Interorgan ammonia metabolism in liver failure: the basis of current and future therapies

Abstract

Hepatic encephalopathy complicates the course of both acute and chronic liver disease and its treatment remains an unmet clinical need. Ammonia is thought to be central in its pathogenesis and remains an important target of current and future therapeutic approaches. In liver failure, the main detoxification pathway of ammonia metabolism is compromised leading to hyperammonaemia. In this situation, the other ammonia-regulating pathways in multiple organs assume important significance. The present review focuses upon interorgan ammonia metabolism in health and disease describing the role of the key enzymes, glutamine synthase and glutaminase. Better understanding of these alternative pathways are leading to the development of new therapeutic approaches.For over 100 years, ammonia has been thought to be central in the pathogenesis of hepatic encephalopathy (1). Many organs are involved in regulating whole body ammonia homeostasis (2), with the regulation of arterial levels dependent upon 'interorgan ammonia metabolism' in the context of urea cycle disruption and portalsystemic shunting. Previous meta-analysis suggest that current therapeutic strategies aimed at targeting ammonia fall short of the desired impact on clinical HE (3, 4). This review describes interorgan ammonia and amino acid metabolism in health and in patients with liver failure and how these concepts may lead to the development of more targeted therapies. Ammonia metabolism in healthNitrogen is necessary for cellular structure and energy. Humans must therefore assimilate reduced nitrogenous compounds as part of our diet, such as protein, free amino acids and ammonia (derived from the splitting of urea and other amino acids). In the body, ammonia (NH 3 ) is co-existent with its charged form ammonium (NH 4 1 ). Their relative concentrations are dependent on pH (5). At physiological pH, 98% of total ammonia exists as NH 4 1 , with gaseous NH 3 the main diffusible form transported across biological membranes. In this review, we will refer to NH 3 /NH 4 1 as simply, 'ammonia' . Ammonia is hydrophilic and easily transported in plasma. In health, ammonia transport and metabolism are tightly regulated to maintain low plasma concentrations (normal range 10-40 mmol/L), but exists in the mmol/L range in organs such as intestine or kidney. Transport of unionized ammonia into the cell is through diffusion despite low lipid solubility. In metabolic alkalosis, the conversion of NH 4 1 to NH 3 is increased, thus increasing membrane permeability. Conversely within the cell, negatively charged mitochondria show very poor permeability to NH 3 , but high NH 4 1 permeability (6). Transmembrane transport of ammonia can be facilitated by constitutive ion channels and transporters such as the Rhesus proteins (7-9) and Aquaporin (10-12), however, their precise role in whole body ammonia metabolism remains unclear.

Severe hyperammonaemia in adults not explained by liver disease

“…This situation changes dramatically with acute disturbances of acid -base balance: the percentage of ammonia excreted in urine can range from 50% to 70% in acute acidosis to 18% in alkalosis. 3,4 Ammonia is also produced by bacterial degradation of urea and amino acids in the lumen of the large bowel. This accounts for around 50% of ammonia produced in the bowel when fasting, but more after protein feeding or gastrointestinal bleeding.…”

“…This accounts for around 50% of ammonia produced in the bowel when fasting, but more after protein feeding or gastrointestinal bleeding. 3,4 Glutamine Glutamine is a non-toxic/non-essential amino acid which constitutes approximately 50% of the whole-body free amino acid pool and normally is the most abundant amino acid in the plasma and cerebrospinal fluid (CSF). Through metabolism to 2-oxoglutarate, a tricarboxylic acid cycle intermediate, it is an obligatory fuel for rapidly dividing cells, notably of enterocytes in the small intestine and cells of the immune system.…”

“…The proportion of NH 3 is higher in systemic alkalosis. Cell membranes are five times more permeable to NH 3 than NH 4 þ . Since most laboratories analyse total ammonia (NH 3 þ NH 4 þ ), 'ammonia' in the clinical sections of this review includes both.…”

Hepatic encephalopathy: An approach to its multiple pathophysiological features

“…The kidneys are ammonia producers and only 30% of the ammonia produced is excreted with the urine. In liver failure and metabolic acidosis, the kidney has the ability to increase ammonia elimination to 70% of the produced ammonia [21,22] . Aquaporin 2 plays an important role in the regulation of water.…”

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

“…In case of hepatic dysfunction and/or port-systemic shunting systemic ammonia concentration increases up to 10 times, while the main load for its detoxification is shifted to myocytes and astroglia [21]. In patients with liver cirrhosis and metabolic acidosis renal elimination of ammonium ions reaches 70 % of the total formed volume, and renal failure enhances HE in patients with liver cirrhosis [22]. Ammonia is presented in two forms: a weak base -gaseous form (NH 3 [24].…”