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Non-Hepatic Hyperammonaemia: An Important, Potentially Reversible Cause of Encephalopathy
Non-Hepatic Hyperammonaemia: An Important, Potentially Reversible Cause of Encephalopathy
com
CASE REPORTS
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Figure 1 The early phase of the mesenteric angiogram (A) shows dense contrast filling the splenic artery (SA) and a
normal sized spleen. Exiting the spleen contrast flows via the splenic vein (SV) into a grossly enlarged inferior mesenteric
vein (IMV). The portal vein is not seen and there is no evidence of cavernous transformation of the portal vein or collateral
vessels. The filling of the inferior vena cava (IVC) on the later phase of the angiogram (B) confirms that the IMV forms a
lower mesorectal shunt with the rectal veins and systemic circulation.
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episode of headache, vomiting, confusion, and µmol/l, respectively (normal <750 for both),
drowsiness associated with mild hyponatraemia serum ornithine level 15 µmol/l (normal >25),
and non-specific, excess slow wave activity on and a large urinary orotic acid peak.
his EEG. He had been treated with acyclovir for A diagnosis of late onset ornithine transcarb-
suspected herpes simplex encephalitis and after amylase deficiency was made. After a peak of
a quick recovery was discharged. 170 µmol/l venous blood ammonia returned to
On examination he was apyrexial with a GCS normal. He improved without requiring so-
of 15/15. He was disorientated in time and place, dium benzoate treatment. Dietary protein was
but not in person. He was slightly confused with gradually increased without a significant rise in
slurred speech. Neurological examination re- ammonia levels and he was discharged home.
vealed the longstanding sixth nerve palsy, Allopurinol loading tests and genetic analysis
increased tone in the lower limbs with hyper- confirmed both brothers and his mother
reflexia and bilateral extensor plantar responses. carried the same aVected allele in exon 2 of the
General examination was otherwise normal. ornithine transcarbamylase gene (located on
Full blood count, urea and electrolytes,
the X chromosome). His family received coun-
serum glucose, and clotting screen were
selling and advice on emergency management.
normal. Arterial blood gases showed a pH of
He has remained well but one sibling has
7.40 and serum bicarbonate level of 15.6
mmol/l (normal 22–27). Serum alkaline phos- required hospital admission.
phatase was 307 IU/l (normal 30–115) but liver In this case the precipitating event was not
function was otherwise normal. CSF examina- clear. This is not unusual in urea cycle enzyme
tion and computed tomography head were deficiencies, though an increased dietary nitro-
normal. Electroencephalography showed non- gen load or intercurrent infection may proceed
specific changes identical to those of his previ- clinical deterioration. A gradual onset of symp-
ous admission. Urinalysis registered “+++” toms is common to these disorders—a more
ketones. Serum ammonium and lactate levels abrupt presentation should lead to consideration
were raised at 156 µmol/l and 2.3 mmol/l (nor- of other causes of raised intracranial pressure.
mal 0.8–1.2) respectively.
Initial treatment with acyclovir, cefotaxime, Discussion
and dexamethasone did not result in clinical Amino acids, the products of endogenous and
improvement. He was transferred to our hospi- exogenous protein digestion, are degraded by
tal and started on a 10% glucose infusion (6 hepatic transamination and oxidative deamina-
mg/kg/min), to render him anabolic. Dietary tion to produce ammonia, which is then
protein was excluded. converted to urea and excreted by the kidneys.
A metabolic screen showed raised glutamine Any disruption to this cycle of nitrogen
levels in serum and CSF, 1345 µmol/l and 2103 excretion (fig 2) has the potential to cause
Systemic accumulation of
ammonia escaping liver
metabolism
Pathological sources
Hepatic Additional nitrogen in
metabolism: gut lumen
via the urea cycle Amino acids and
ammonia absorbed
into portal circulation GI bleed
Urea
Urinary
diversion
Portosystemic shunt:
for example haemorrhoidal veins, iliac Gut
veins, IMV, iatrogenic shunts
Figure 2 Schematic representation of the major sources of ammonia production and its excretory pathway
(GI = gastrointestinal, IMV = inferior mesenteric vein).
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*Need to exclude inborn errors of metabolism as possible cause—for example, medium chain acyl-CoA deficiency.
†With normal liver function, as distinct from portosystemic shunts occurring in the context of chronic liver disease where resultant hyperammonaemia may be termed
hepatic hyperammonaemia.
hyperammonaemia and the clinical syndrome the cause of this vascular abnormality. The
of encephalopathy. most common cause of an absent portal vein is
Firstly, the cycle may not be able to handle a portal vein thrombosis at birth, secondary to
normal nitrogen load (for example, specific infection.7 Usually, if recanalisation has not
enzyme defect or liver cell failure resulting in occurred, this results in the formation of
poor hepatic function); secondly, though liver collateral vessels in the region of the portal vein
function is normal, excess nitrogen (for exam- which were not present in this case. Congenital
ple, from a gastrointestinal bleed or urinary absence of the portal vein8 or congenital
diversion) may oversaturate the liver’s excre- pancreatitis may also account for some of the
tory capacity; or thirdly, the nitrogen load may radiological findings. The formation of such a
bypass the liver, entering directly into the large inferior mesenteric vein may favour a pri-
systemic circulation via a portosystemic shunt. mary vascular malformation, although the
Encephalopathy is most commonly seen in presence of other congenital anomalies might
patients with liver cirrhosis where the problem be expected if this were the case.8 This situation
is due to a combination of decreased capacity is distinct from the extrahepatic shunting that
due to liver cell damage and portosystemic occurs, usually via multiple collateral vessels, in
shunting of the increased nitrogen load.1 2 chronic liver disease associated with portal
While hyperammonaemia is present in the hypertension, or from iatrogenic portosystemic
majority of patients with hepatic encephalopa- shunts, though hyperammonaemia results from
thy,3 this is not always the case and the under- the same mechanism of hepatic bypass.
lying neuropathophysiology remains the sub- Hyperammonaemia arising as a metabolic
ject of further research and debate.2 4–6 The complication of surgery to create a urinary
production of false transmitters, activation of diversion is well recognised.9–11 The longer seg-
central (ã-aminobutyric acid-benzodiazepine ment of bowel exposed to urine may explain
receptors by endogenous ligands, altered cer- why this arises more commonly after uretero-
ebral metabolism, disturbed activity of the sigmoidostomy than ileal conduits.12 Ammonia
Na+/K+ ATPase, and zinc deficiency with is formed in the colonic lumen, through the
deposition of manganese in the basal ganglia bacterial degradation of the large quantities of
have all been proposed as possible contributory nitrogenous componds excreted in the urine.
factors in the development of encephalopathy Production is enhanced by the presence of
in cirrhotic patients.2 urease-producing, Gram negative bacilli.13 14 As
Non-hepatic causes of hyperammonaemia the diversion retains its venous drainage,
may present with an identical clinical syn- ammonia crosses the colonic wall and is
drome (table 1). Though rare, the underlying absorbed into the portal circulation. In the
cause may be reversible, and potentially majority of patients, with normal liver function,
curable, or specific therapy in addition to the excess ammonia is excreted by hepatic
general measures to reduce hyperammonaemia metabolism—via the urea cycle (fig 3). How-
may be indicated—therefore prompt recogni- ever, hyperammonaemia suYcient to result in
tion may be lifesaving. encephalopathy may still occur even in the set-
The first case had a very unusual vascular ting of a patient with normal liver function.15
anomaly which behaved diVerently to classic Increased production of ammonia, sufficient to
portal vein thrombosis, both radiologically and over-saturate hepatic excretory pathways—for
clinically. No flow through the portal vein was example, after the action of urea-splitting bac-
seen on mesenteric angiography, the contrast teria or delayed colonic transit; direct diVusion
instead passing through a greatly enlarged of ammonia into the inferior vena cava bypass-
inferior mesenteric vein to form a large lower ing the liver (via the haemorrhoidal veins after
mesorectal shunt with the rectal veins and sys- urinary diversion or internal iliac veins in the
temic circulation—therefore despite normal case of a neurogenic bladder); and decreased
liver function, the significant protein load metabolic activity in asymptomatic females
absorbed into the mesenteric blood supply heterozygous for ornithine transcarbamylase
after gastrointestinal haemorrhage, was deficiency16 have all been proposed as possible
shunted directly into the systemic circulation, mechanisms to explain this observation in
via the inferior vena cava, resulting in hyperam- patients who have undergone diversion proce-
monaemia. It is a matter for speculation as to dures.
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Notes