Absence of neuropsychological impairment in hyperammonaemia in healthy young adults; possible synergism in development of hepatic encephalopathy (HE) symptoms?

Abstract

The aetiology of minimal hepatic encephalopathy (mHE) remains unclear. It is generally accepted that hyperammonaemia plays a major role, however there are a multitude of metabolic perturbations present. To determine the contribution of hyperammonaemia to mHE symptom development, ten healthy males (Age:25 ± 5 yrs, BM:76.3 ± 7.1 kg, Height:178.6 ± 4.5 cm, mean ± SD) received two 4 h intravenous infusions of either a 2% ammonium chloride solution (AMM) or a placebo (PLA;0.9% sodium chloride) using a double blind cross-over design. Sensations of fatigue were measured at baseline, 2 and 4 h using the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) questionnaire. Learning& memory, motor control and cognition were assessed using Rey's Auditory Verbal Learning Test (AVL), Continuous Compensatory Tracking (COMPTRACK) Task and Inhibitory Control Test (ICT) respectively. Arterialised venous blood samples were collected every hour, and analysed for ammonia concentration. There was a significantly higher plasma ammonia concentration in the AMM trial than the PLA trial at every time point during the infusion, peaking at 2 h (57 ± 4 μmol/L PLA, 225 ± 14 μmol/L AMM; p < 0.05). At 2 h there were significantly higher sensations of general fatigue (Z = -2.527, p = 0.008, 2 tailed) and physical fatigue (Z = -2.156, p = 0.027, 2 tailed), and lower sensations of vigour (Z = -2.456, p = 0.012, 2 tailed) for the AMM trial. There were no significant effects on the performance of the psychological tasks. These results demonstrate that hyperammonaemia in the absence of other complications induces significant sensations of fatigue but does not cause the typically observed performance impairment in individuals with mHE. Supporting the hypothesis for synergism between ammonia and other co-factors in mHE.

Hyperammonemia and Systemic Inflammatory Response Syndrome Predicts Presence of Hepatic Encephalopathy in Dogs with Congenital Portosystemic Shunts

“…This result is also consistent with the observation that dogs with urea cycle enzyme deficiency have increased plasma ammonia concentrations but do not typically developing clinical signs of HE [34]. It is also supported by the finding that humans, when administered ammonium chloride, do not develop classical signs of HE [35]. …”

Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure

“…Nevertheless, whether a correlation exists between hyperammonemia and HE severity in CLF still remains controversial [11], [12], [13], [14] and [15]. A recent study demonstrated that ammonia administered intravenously to healthy volunteers did not cause any significant neuropsychological impairment [16], supporting the premise that pathogenic factors other than ammonia are involved in the pathogenesis of brain edema and HE in CLF.…”

Histamine‐induced plasticity and gene expression in corticostriatal pathway under hyperammonemia

“…Further clinical studies are on their way testing the possible benefit of H3R antagonists in other neurodegenerative diseases characterized by fatigue and day‐time sleepiness. Although not accompanied by neurodegeneration, hyperammonemic conditions are associated with fatigue especially during extreme exercise or liver pathology . Thus, patients suffering from hyperammonemia may benefit from symptomatic treatment with H3R antagonists/inverse agonists.…”

“…Although not accompanied by neurodegeneration, hyperammonemic conditions are associated with fatigue especially during extreme exercise or liver pathology. 4,5 Thus, patients suffering from hyperammonemia may benefit from symptomatic treatment with H3R antagonists/inverse agonists.…”