The Story of Ammonia in Liver Disease: An Unraveling Continuum

Abstract

Hyperammonemia and liver disease are closely linked. Most of the ammonia in our body is produced by transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, and from the intestine by bacterial splitting of urea. The only way of excretion from the body is by hepatic conversion of ammonia to urea. Hyperammonemia is associated with widespread toxicities such as cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis. Over the past two decades, it has been increasingly utilized for prognostication of cirrhosis, acute liver failure as well as acute on chronic liver failure. The laboratory assessment of hyperammonemia has certain limitations, despite which its value in the assessment of various forms of liver disease cannot be negated. It may soon become an important tool to make therapeutic decisions about the use of prophylactic and definitive treatment in various forms of liver disease.

Keywords: HE (hepatic encephalopathy); MASLD (metabolic dysfunction-associated steatotic liver disease); acute liver failure; ammonia; cACLD (compensated advanced chronic liver disease).

Figure 1

Physiology of ammonia, showing it production, transport, functions and disposal. Major sources of circulating ammonia are deamination and transamination activities in liver and rest of the body. Over two-thirds of it is in form of glutamine (from most sources) and alanine (only from muscles). Glutamate picks mops up ammonia under the influence of glutamine synthase at brain, muscles & liver. Glutamine released ammonia under the influence of glutaminase at intestines, liver and kidneys. Ammonia is disposed off as urea through ornithine cycle (Urea cycle) in liver and urea is excreted mainly in kidneys. aKG, alpha-keto-glutarate; AST, asparate aminotransferase; ALT, alanine aminotransferase.

Figure 2

A cartoon depicting dynamics of ammonia in our body. Left half of the diagram shows normal physiology enclosed in a green line, while right half shows the consequences of cirrhosis and increased circulating ammonia levels. Its untoward consequences are shown with dotted arrows in the red color.

Figure 3

A simplified scheme of urea cycle in the liver. (1) Ammonia combines with carbon di oxide with allosteric activator ORNT-1, N-acetyl- glutamate to form Carbamoyl phosphate in the mitochondria. (2) Carbamoyl phosphate combines with ornithine and is converted to citrulline, which moves to cytosol with the help of ORNT-1. (3) Citrulline combines with aspartate to form arginosuccinate. Steps (1) and (3) are energy consuming processes requiring ATP. (4) Arginosuccinate gives off fumarate to form Arginine. (5) Arginine combines with water to form ornithine and (6) Urea that is transported to kidneys to be excreted. To complete the cycle, Ornithine moves back to mitochondria through ORNT-1 to take part in urea cycle at step (2). Five enzymes that catalyze these five steps of urea cycle are Carbamoyl phosphate synthetase-1, ornithine transcarbamylase, arginosuccinate synthetase, Argino-succinase and Arginase respectively. ORNT-1: ornithine transporter.

Figure 4

Glutamate, a non-essential amino acid is the key molecule in ammonia regulation. It is formed by combining one ammonium radical with a-ketoglutarate under the influence of enzyme Glutamate Dehydrogenase. Ammonia is derived from amino acids under the influence of respective transaminases. Glutamate can accept one more ammonia molecule to form Glutamine (enzyme Glutamine Synthetase). Glutamine can be converted back to Glutamate and to a-ketoglutarate by action of glutaminase and Glutamate oxalacetate transaminase respectively. Muscles do contain some glutamine synthetase but hardly any glutaminase. Enzymes are shown in yellow background. ALT: alanine transaminase, AST: aspartate transaminase, BCAA: branched chain amino acids, BCKA: branched chain keto acids, GOT: Glutamate oxalacetate transaminase, NH3: ammonia.

Figure 5

Prognostic value of plasma ammonia levels in cACLD. Recent studies have shown that ammonia levels >1.4 times ULN can predict liver related complications requiring hospitalization, hepatic encephalopathy and mortality in patients with cACLD. cACLD, compensated aldvanced chronic liver disease; CFF, Critical flickering frequency test; CTP, Child-Pugh-Turcott score; MELD, model for end-stage liver disease; OHE, overt hepatic encephalopathy; PHES, psychometric hepatic encephalopathy score; ULN, upper limit of normal.

Figure 6

Hyperammonemia and acute liver failure. A. Data showing that higher ammonia level is associated with higher risk of progressing to advanced encephalopathy B. Ammonia levels that remain persistently high till day 3 after admission are associated with significantly higher mortality (ref) C. ALFED score 0-1 indicates low risk, 2–3 moderate risk and >4 suggest high risk mortality D. ALFED model is better than othe rprevalent prognostic scores.