18 November 2008

Speaker: Dr TSANG Ho Kai, Patrick (ICU Resident, Tuen Mun Hospital)

Chairman: Dr LEE Wai Chuen (Associate Consultant (A&IC), Tuen Mun Hospital)



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Case history

The patient was a 55-year-old housewife who was an ex-smoker and non-drinker. She had been suffering from migraine since 1982 and was given aspirin bought over-the-counter. She had history of gastrointestinal bleeding with partial gastrectomy in 1997 and history of pancreatitis in 2001, which were all managed in the private sector.

She initially presented to our gastroenterologist in 2007 with a 3-month history of diarrhoea in the form of loose stool 3 to 5 times per day.  There was no mucus or per rectal bleeding. She also volunteered subjective weight loss of few pounds and ankle swelling. Physical examination found that the patient was cachexic with bilateral ankle edema. There were no stigmata of chronic liver disease or signs of congestive heart failure.

Blood tests showed normal renal function test and complete blood picture, but severe hypoalbuminaemia with serum albumin 17g/l (NR 35-50) and deranged liver function test with ALP 200 u/l (NR 53-141) and ALT 53 u/l (NR 7-34). The serum bilirubin level was normal. Hepatitis serology, autoimmune markers, antimitochondrial antibody, immunoglobulin level, tumour markers and thyroid function were unremarkable. Twenty-four-hour urine total protein was only 0.3g. Stool for infective investigation, occult blood and fat globulin were all negative.

Colitis from transverse colon and downwards was found by colonoscopy. Lymphocytic infiltration was found on histological examination. Upper GI endoscopy demonstrated previous billroth II gastrectomy with biopsy showing active chronic inflammation and no villous atrophy but the duodenal aspirate yielded heavy growth of both gram positive and negative bacilli. Computer tomography of the abdomen also showed thickened colonic wall suggestive of colitis.

The working diagnoses were stagnant loop syndrome with bacterial overgrowth, aspirin induced lymphocytic colitis and the deranged liver function was secondary to poor nutrition and/or starvation. Primary sclerosing cholangitis caused by inflammatory bowel disease could not be totally excluded. She was given a course of antibiotics and her symptoms improved.

Subsequent follow up found further elevation in ALP and to a lesser extent, ALT. Endoscopic Retrograde Cholangiopancreatography (ERCP) could not be performed because of tight stricture over the afferent loop. Magnetic resonant Cholangiopancreatiography (MRCP) showed small gallstone while the intrahepatic ducts were not dilated. Non-specific bile duct proliferation was demonstrated on liver biopsy which can be secondary to bile duct obstruction or primary sclerosing cholangitis variant.

Follow up colonoscopy and push enteroscopy were performed. Histological examination only revealed mild to moderate villous atrophy and non specific inflammation. Xylose absorption test and stool for alpha antitrypsin clearance were suggestive of protein losing enteropathy. While awaiting further patient investigation including albumin scan and small bowel enema, the patient was admitted to our hospital in April 08 for decreased general condition.

She presented to us with irrelevant speech and confusion for few days, together with cough and sputum. She was afebrile but blood test showed WCC 26 x109/l and right upper zone infiltrate on CXR. She then intubated for respiratory failure and transferred to our unit for further management. Ceftriaxone and azithromycinc was started to treat community acquired pneumonia. Total parenteral nutrition was also commenced on D2 of ICU admission for nutritional support. The patient's condition gradually improved with good oxygenation and ventilation. Sedation was taken off on D3 of ICU admission as extubation was anticipated.

She remained comatose for more than 48 hours after cessation of sedation. CT brain only revealed mild cerebral atrophy and CSF examination was unremarkable. Episodic frontal prominent sharp and slow waves signifying non-specific encephalopathy was seen in EEG.

Blood ammonia level was checked which was elevated to 210 mmol/l (NR 11-51). It was thought that total parenteral nutrition (TPN) was causing the problem. TPN was therefore withheld and oral lactulose and neomycin were given. Serial serum ammonia level decreased and the patient was successfully extubated with full consciousness.

Unfortunately, she succumbed 2 days after extubation because of an acute myocardial infarction and further investigations for underlying causes of her hyperammonaemia were not possible.




Whenever unexplained coma is encountered in ICU, approach as that laid out in Table 1 is sometimes helpful.

Table 1. Causes of coma


C-CO2 narcosis

O-Overdose of medications/Sedations

M-Metabolic: Hypoglycaemia, DKA, hypothyroidism, hypercalcaemia, adrenal failure, uraemia, hepatic coma

A-Apoplexy: HI, CVA, ICH, CNS infection, epilepsy


Hyperammonaemic encephalopathy is not an uncommon cause of coma in ICU, the most common type being hepatic encephalopathy. Ammonia is mainly produced from the gut as a result of the digestion of nitrogenous components of the diet, deamination of glutamine by glutaminase and breakdown of urea by urease present in colonic flora. Kidney is another organ involved in ammonia production and this is important for acid base homeostasis. In case of seizure or intense exercise, small amount of ammonia is produced by muscle. Ammonia is mostly degraded in the liver via the urea cycle (Figure 1). Kidney, liver, brain and muscle may also have some roles in ammonia breakdown.


Figure 1. The urea cycle (urea cycle.jpg)


urea cycle


Thus, causes of hyperammonaemia can be divided into hepatic cause (liver failure) and non-hepatic causes (e.g. drugs, inborn error of metabolism, infection) clinically. Another classification will be increased ammonia production (e.g. Infection by urease producing organism, increased protein load after TPN, gastric bypass surgery) and decreased ammonia breakdown as seen in fulminant liver failure, inborn error of metabolism, and drugs. Initial assessment of hyperammonaemia is summarized in Table2.


 Table 2. Evaluation of hyperammonaemia


Recent drug changes e.g. hepatotoxic drugs, glycine, salicylates, valproate, carbamazepine

Recent surgery e.g. use of glycine in TURP, anaesthetics

Recent addition of TPN

Recent GIB,

Recent UTI in patients with abnormal bladder

Risk factors of hepatitis

Family history of inborn error of metabolism


Diagnostic evaluation

Hepatitis serology

Toxicology screening

Sepsis workup including CMV and EBV titres

USG abdomen

Liver Biopsy

Urine and blood amino acids analysis







For our patient, USG of abdomen did not show any evidence of cirrhosis or abnormal venous flow and the urine and blood amino acids analysis was inconclusive of inborn error of metabolism. When the past medical history together with the information obtained in ICU admission were taken into consideration, Madam Choi was likely suffering from hyperammonaemic encephalopathy secondary to

1.      TPN (High protein content)

2.      Bacterial overgrowth ( Hx of Billroth II gastrectomy+ stagnant bowel loop syndrome)


Other possibilities include

1.      Drugs such as aspirin intake for migraine

2.      Underlying liver disease/Inborn error of metabolism which could not be totally excluded by previous liver biopsy and urine/blood amino acid analysis

3.      Deficiency of Zinc, a cofactor of enzymes in urea cycle, which was found to be associated with hyperammonaemic encephalopathy in several case reports after gastric bypass surgery for morbid obesity

4.      Coeliac disease. For patients with hyperammonaemic encephalopathy complicated with intracranial hypertension, apart from elevation of head of bed, hyperventilation, osmotherapy such as mannitol and use of barbiturates, mild hypothermia and use of N-acetylcystine may be helpful.



Despite the lack of high quality evidence, administration of osmotic cathartic agent like lactulose and poorly absorbed antibiotics like neomycin remained the cornerstone of treatment of hyperammonaemic encephalopathy. Other agents like sodium phenylacetate, sodium benzoate, oral L-ornithine L-aspartate, L-carnitine, Zinc supplementation, renal replacement therapy, artificial liver support and liver transplantation have also been used with some success. Enough calorie by dextrose and lipids and minimal daily protein (0.8-1g/kg) must be provided to prevent protein catabolism.

To conclude, whenever dealing with patients with unexplained coma, especially after introduction of TPN, it is worthwhile to have blood ammonia taken as one of the investigations despite a seemingly normal LFT or unremarkable family history of inborn error of metabolism. Fulminant liver failure and non-hepatic causes like TPN, drugs remain the commonest causes of hyperammonaemic encephalopathy in the adult ICU.



1.      Andrew Fenves, C. Richard Boland, Rita Lepe, Paulino Rivera-Torres, Stuart Jon Spechle. Fatal Hyperammonemic Encephalopathy After Gastric Bypass Surgery. The American Journal of Medicine Vol 121, No 1, January 2008

2.      Juan Co´ rdoba, Beatriz Mı´nguez. Hepatic Encephalopathy. Semin Liver Dis 2008;28:70–80.

3.      Alison S. Clay, Bryan E. Hainline. Hyperammonemia in the ICU. CHEST 2007; 132:1368–1378

4.      David M. Felig, Saul W. Brusilow, James L. Boyer. Hyperammonemic Coma Due to Parenteral Nutrition in a Woman With Heterozygous Ornithine Transcarbamylase Deficiency. Gastroenterology 1995;109:282-284

5.      Gregory M. Enns, Susan A. Berry, Gerard T. Berry, William J. Rhead, Saul W. Brusilow, Ada Hamosh. Survival after Treatment with Phenylacetate and Benzoate for Urea-Cycle Disorders. N Engl J Med 2007;356:2282-92

6.      Gustavo Justo Schulz, Antoˆnio Carlos Ligocki Campos and Julio Cezar Uili Coelho. The role of nutrition in hepatic encephalopathy. Current Opinion in Clinical Nutrition and Metabolic Care 2008, 11:275–280