Hepatic encephalopathy due to liver cirrhosis

The differential diagnosis for hepatic encephalopathy in Ellul et al's review on hepatic encephalopathy due to liver cirrhosis is extensive, but fails to include an important metabolic cause - inherited disorders of the urea cycle. Lists of causes and investigation of encephalopathy in the adult literature are commonplace (1,2). However, with the exception of hepatic encephalopathy, inherited disorders of the urea cycle as a cause do not feature.

Ammonia, when elevated above physiological levels, is a devastating neurotoxin. Even slight elevations above the normal range (10-40 µmol/l in adults) can cause irritability and anorexia whilst five to six fold elevations can cause coma (3). In health, ammonia is maintained at low levels by the formation and excretion of urea via the urea cycle which occurs almost exclusively in the liver. Inherited defects of each of the enzymes of the urea cycle have been described and all are characterized by hyperammonaemia (4). Traditionally disorders of the urea cycle are thought to present in the neonatal period or during childhood and are well known to pediatricians, both trained and in training. However, it is apparent that the initial presentation may be during adulthood. The spectrum of adult presentation is wide with cases unmasked without a clear precipitating cause (5) or as a consequence to triggers such as gastrointestinal bleeding (6) or sodium valproate administration (7). The post-partum period is a time of particular risk and obstetricians need to be aware of the presentation of hyperammonaemia and act accordingly if suspicious (8). Presentation in previously well adults is of great concern as the key to diagnosing hyperammonaemia and defects of the urea cycle is to actually consider and measure blood ammonia. This is unikely to occur unless it is discussed during training and incorporated into standard adult texts as a first-line screening test for encephalopathy. Failure to measure ammonia in this setting may result in death (9).

Hyperammonaemia should be considered as a possible diagnosis in any patient with unexplained neurological symptoms and signs or unusual behaviour, even in adulthood. Unexplained coma should also lead to the measurement of blood ammonia, which is a rapid, simple test commonly available in chemical pathology laboratories serving hospitals with neonatal units, pediatric wards and accident and emergency departments. If there is true hyperammonaemia urgent discussion with a metabolic unit should be undertaken so that appropriate therapy can be instigated in a timely fashion.

1 Bates D. The unconscious patient. In: Warrell D, Cox TM, Firth JD, Benz EJ, eds. Oxford textbook of medicine, 4th ed. Oxford: Oxford University Press,2003.

2 Ropper AH. Acute confusional states and coma. In: Kasper DL, Fauci A, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds. Harrison’s Principles of Internal Medicine, 16th ed. New York NY; McGraw-Hill; 2004:1624-1631.

3 Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatra 2004;43(8):683-9.

4 Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGraw-Hill, 2000.

5 Rohininath T, Costello DJ, Lynch T, Monavari A, Tuchman M, Treacy EP. Fatal presentation of ornithine transcarbamylase deficiency in a 62-year-old man and family studies. J Inherit Metab Dis 2004;27(2):285-8.

6 Trivedi M, Zafar S, Spalding MJ, Jonnalagadda S. Ornithine transcarbamylase deficiency unmasked because of gastrointestinal bleeding. J Clin Gastroenterol 2001;32(4):340-3.

7 Honeycutt D, Callahan K, Rutledge L, Evans B. Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy. Neurology 1992;43(3):666-8.

8 Cordero DR, Baker J, Dorinzi D, Toffle R. Ornithine transcarbamylase deficiency in pregnancy. J Inherit Metab Dis 2005;28(2):237-40.

9 Arn PH, Hauser ER, Thomas GH, Herman G, Hess D, Brusilow SW. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. A cause of postpartum coma. N Engl J Med 1990; 322:1652-55.