Question 9.1

A 51 -year-old female presents with a decreased conscious state, Glasgow Coma Scale (GCS) 12, confusion and myoclonus. She is on treatment for a seizure disorder. Her CT brain scan shows no acute intracranial abnormality.

Her investigations are as follows:

Parameter	Patient Value	Adult Normal Range
Sodium	1 38 mmol/L	135-145
Potassium	4.1 mmollL	3.5 - 5.2
Bicarbonate	18 mmol/l_•	22 - 32
Urea	14.2 mmoVL•	3.0 - 8.0
Creatinine	210 mol/l_•	45 - 90
Bilirubin	54 mol/L*	< 20
Alanine transferase	2710	< 35
Aspartate transferase	1365	< 35
Alkaline phosphatase	103 Ull-	30- 110
Glutam transferase	67 U/L*	< 40
Albumin	37	35-50
Protein	61 IL	60 - 80
Ammonia	156	< 50

List possible causes of the hyper-ammonaemia in this patient. (40% marks)

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College answer

Liver failure
Anti-epileptic drugs – Sodium valproate and Carbamazepine
Other drugs / toxins eg paracetamol, salicylates, mushrooms
Urosepsis with urea-splitting organisms e.g. Klebsiella, Proteus
Urea-cycle disorders (Patients with high ammonia from drugs or urosepsis usually have undiagnosed mild disorders of urea-cycle metabolism)

Discussion

The patient; she is probably on valproate for her seizure disorder. Valproate overdose is a logical explanation for a decreased level of consciousness, myoclonus and high ammonia.

Causes of hyperammonaemia more broadly could be any of the following:

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 urea 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.

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