Otherwise known as azane, ammonia goes by the chemical formula NH₃. It is an abundant natural gas with a filthy reek. If one were presented with an open tub of raw ammonia gas, one would be forced to conclude that one were in the presence of a large amount of urine. Or the decomposing carcass of a giant squid. The college have made it appear in several LFT interpretation SAQs:

• Question 9.1 from the first paper of 2017 (valproate overdose)
• Question 10.2 from the second paper of 2014 (pan-hepatitis, high ammonia)
• Question 14 from the second paper of 2012 (the utility of serum ammonia)
• Question 29.2 from the second paper of 2011 (pan-hepatitis, high ammonia)
• Question 28.3 from the second paper of 2008 (list four causes of high ammonia)
• Question 28 from the first paper of 2005 (pan-hepatitis, high ammonia)

As far as published sources go, there are several excellent sources:

• Clay et al, 2007
• Weng et al, 2004
• Hawkes et al, 2001

The short-tempered ICU exam candidate will want to avoid having to read through an extensive tract of wank, and will instead demand a short summary of differentials. Here is one such summary, with items linked to relevant articles wherever possible:

Another method of arranging the differentials, according to the physiological mechanism:

Ammonia in the human body is a curious beast. It is one of the few ways we can incorporate atmospheric nitrogen into biological processes (and even that, indirectly). In brief, organisms which are incapable of nitrogen fixation rely on more capable organisms to supply them with ammonium (NH₄). This is vitally important, as the amine NH₂^- group (and all the other nitrogen-contaning organic molecule components, for that matter) cannot come readily from atmospheric nitrogen. Humans imbibe ready-made nitrogen-contanining compounds, and in the course of the metabolism these compounds then release ammonia, which must be dealt with somehow.

Metabolic importance of ammonia

Metabolic origins of ammonia

A 1954 discussion of ammonia declares that ammonia has three main entry points into the human organism. Of these, gastrointestinal absorption of colonic ammonia seems to be the major source. Another source is the deamination of amino acids, which occurs in the course of numerous routine metabolic manipulations. Lastly, the renal tubule generates ammonia from glutamine in order to acidify urine, and this renal ammonia can leak out into the renal vein (but this contribution to systemic ammonia levels is fairly minor)

The bacterial denisens of the bowel create vast amounts of ammonia by action of amino-acid oxidase and urease. The process includes an all-star cast of colonic flora featuring E.coli, Proteus mirabilis, Bacteroides Clostridium Enterococcus and Klebsiella aerogenes. The substrate for these bacterial enzymes (one might guess from names alone) are raw amino acids and urea. The reaction takes place rapidly in an alkaline environment (for instance, when the bicarbonate-rich pancreatic secretions hit the small bowel) and slows as the pH decreases towards acidity. In this fashion, the alkaline environment of the gut in a patient with a gastric bypass tends to favour ammonia prodction. The presence of readily available non-amine metabolic substrate (such as lactulose) creates an environment where there is greater reproductive advantage to be gained from the fermentation of abundant sugars; thus simple sugars decrease intestinal ammonia production, and this is one of the reasons lactulose is beneficial for hepatic encephalopathy.

Metabolic fate of ammonia

An amazingly detailed article from 1977 starts its ode to the urea cycle with a palaeontological digression:

"Urea biosynthesis developed as a survival mechanism when primitive animals made the transition from Devonian seas to a swampy terrestrial existence."

Indeed they did.

Use of ammonia as a biomarker in critical care

Question 14 from the second paper of 2012 asked the candidates to critically evaluate of serum ammonia as a pathology test in the critically ill patient. The following answer was concocted by the author to improve on the (brief and uninformative) college model answer.

The use of ammonia levels in critical care:

• Introduction:
  • Ammonia is a metabolic byproduct of amino acid catabolism; there has been interest in measuring ammonia levels and making attempts to associate them with various forms of pathology.
• Rationale:
  • The most prolific site of production of ammonia ions is in the gut, where amino acids are converted into ammonia by gut microflora. The ammonia is then absorbed into the portal circulation and converted into urea in the hepatic urea cycle.
  • Hepatic damage and the failure of the urea cycle is therefore usually associated with a rise in the serum ammonia levels
  • The normal compensatory responses to raised serum ammonia (eg. conversion into glutamine) can give rise to cerebral oedema and thus is thought to play some role in the pathogenesis of hepatic encephalopathy
  • Other causes of raised ammonia levels include
    • Increased rates of protein catabolism, eg. extreme starvation or hematological malignancy
    • TPN
    • Inherited errors of metabolism
• Evidence:
  • Ammonia levels in the brain and in the venous circulation do not usually correlate in stable liver disease; however there is some degree of correlation in severe hepatic encephalopathy.
  • The severity of encephalopathy does not correlate with the magnitude of ammonia elevation. Severely encephalopathic patients may have normal levels of ammonia, and patients with mild and moderate hyperammonaemia may have reasonably intact sensorium.
• Summary:
  • The use of ammonia to assess the severity of hepatic encephalopathy is still controversial
  • A raised ammonia level may point to an undiagnosed error of metabolism in a patient with an otherwise unexplainable loss of consciousness

Hepatic encephalopathy is discussed in greater detail elsewhere.