List 4 causes of an elevated serum ammonia concentration in critically ill patients

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College Answer

Hepatic failure
Inherited disorders of urea cycle
Drugs: Valproate, glycine, carbamezapine
Porta-systemic shunts
Increased protein load: GI bleed, TPN,
Infection with urease splitting organisms – proteus Gastric bypass, urinary diversion procedures Cancers – myeloma
Chemotherapy.

Discussion

This question closely resembles, though is not identical to, Question 14 from the second paper of 2012. There, one may find a discussion of the usefulness of the serum ammonia levels in critical illness.

Here, one is merely expected to regurgitate a series of differentials.

Using a familiar template, an easily remembered list would look like this:

  • Hepatic vascular insufficiency, eg. hepatic necrosis due to ischaemia
  • Hepatic failure
  • Portosystemic shunts
  • Infection with urea splitting organisms eg. Proteus mirabilis, H.pylori
  • Multiple myeloma
  • Drugs - eg. valproate, carbamazepine
  • Congential disorders of urea cycle
  • Increased protein catabolism, eg. chemotherapy, starvation, GI bleeding, or TPN

More detail, you beg? Impossibly large tables, useless for the purpose of rapid revision?

Causes of Hyperammonaemia, Arranged by Aetiology

Vascular and cardiac causes

  • Ischaemic hepatitis
  • Portal vein thrombosis
  • Portosystemic shunts

Infections

  • Hepatitis (viral)
  • Liver abscess
  • Urease producing bacteria (eg. Proteus, Klebsiella)
  • Herpes virus

Neoplasms

  • Hepatocellular carcinoma
  • Metastatic disease
  • AML
  • Multiple myeloma
  • Post bone marrow transplant

Drugs

  • Ammonium chloride
  • Basically, any drug which causes fulminant hepatotoxicity. Some examples:
    • Halothane and enflurane
    • Paracetamol
  • Also, drugs which affect the urea cycle:
    • Sodium Valproate
    • 5-fluorouracil
    • Asparginase
    • Insulin overdose
    • Glycine (in TURP syndrome)
    • Carbamazepine
    • Salicylates
    • Sulfadiazine
    • Pyrimethamine

Pre-analytical error

  • Prolonged pre-transport time
  • Room temperature storage of sample

Congenital causes

  • Inherited ura cycle defects
  • Organic aciduria
  • Fatty acid oxidation defects

Autoimmune causes

  • Fulminant autoimmune hepatitis

Urinary and renal causes

  • Distal renal tubular acidosis
  • Ureteric diversion
  • Urinary tract infections
  • Vesicoureteric reflux
  • Bladder perforation
  • Glycine (in TURP syndrome)

Endocrine and Metabolic causes

  • Parenteral nutrition
  • Reye's syndrome
  • Primary dietary carnitine deficiency
  • Deficiency of essential amino acids (with resulting increase in protein catabolism
  • Increased protein load
  • Increased protein catabolism, eg. steroids
  • Severe exercise (muscle protein catabolism)
  • Gastric bypass

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

Causes of Hyperammonaemia, Arranged by Physiology

Pre-analytical error

  • Prolonged pre-transport time
  • Room temperature storage of sample

Increased substrate for ammoniagenesis

  • Excess protein catabolism:
    • Essential amino acid deficiency
    • Primary dietary carnitine deficiency
    • Steroids
    • Immobility
    • Severe exercise
    • Increased tissue turnover, eg haematological malignancy
  • Excess protein intake:
    • Weird diet
    • Parenteral nutrition

Bypass of normal metabolism

  • TIPS procedure
  • Portosystemic shunts

Acquired urea cycle defects

  • Fulminant hepatitis of any cause
  • Reye's syndrome
  • Drugs, eg. glycine or valproate

Congenital urea cycle defects

  • Inherited ura cycle defects
  • Organic aciduria
  • Fatty acid oxidation defects

Excess of exogenous ammonia

  • Ammonium chloride therapy
  • Excess generation of ammonia:
    • Gastric bypass
    • Urease-producing organisms
    • UTI

Reabsorption of excreted ammonia

  • Distal renal tubular acidosis
  • Ureteric diversion
  • Urinary tract infections
  • Vesicoureteric reflux
  • Bladder perforation

References

Conway, Edward Joseph, and Robert Cooke. "Blood ammonia." Biochemical Journal 33.4 (1939): 457.

Shambaugh, G. E. "Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle." The American journal of clinical nutrition 30.12 (1977): 2083-2087.

McDermott Jr, William V., Raymond D. Adams, and Athol G. Riddell. "Ammonia metabolism in man." Annals of surgery 140.4 (1954): 539.

Vince, Angela, et al. "Ammonia production by intestinal bacteria." Gut 14.3 (1973): 171-177.

Vince, Angela J., and Sigrid M. Burridge. "Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose." Journal of medical microbiology 13.2 (1980): 177-191.

Dohrenwend, Paul, and Richard D. Shih. "Glycine Induced Hyperammonemia After Bladder Rupture During Transurethral Resection of a Bladder Tumor." Journal of Medical Cases 4.4 (2013): 250-253.

Felipo, Vicente, and Roger F. Butterworth. "Neurobiology of ammonia." Progress in neurobiology 67.4 (2002): 259-279.

Hashim, Ibrahim A., and Jennifer A. Cuthbert. "Elevated ammonia concentrations: Potential for pre-analytical and analytical contributing factors." Clinical biochemistry 47.16 (2014): 233-236.

Clay, Alison S., and Bryan E. Hainline. "Hyperammonemia in the ICU." CHEST Journal 132.4 (2007): 1368-1378.

Weng, Te-I., Frank Fuh-Yuan Shih, and Wen-Jone Chen. "Unusual causes of hyperammonemia in the ED." The American journal of emergency medicine 22.2 (2004): 105-107.

Hawkes, N. D., et al. "Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy." Postgraduate medical journal 77.913 (2001): 717-722.