Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure

Abstract

High circulating ammonia concentrations are common in patients with acute liver failure (ALF) and are associated with hepatic encephalopathy (HE) and intracranial hypertension (ICH). Other risk factors are poorly characterized. We evaluated the relation of the admission arterial ammonia concentration and other clinical variables with the development of HE and ICH. Arterial ammonia was measured on admission to the intensive care unit in 257 patients; 165 had ALF and severe HE, and there were 3 control groups: acute hepatic dysfunction without severe HE (n ‫؍‬ 50), chronic liver disease (n ‫؍‬ 33), and elective surgery (n ‫؍‬ 9). Variables associated with ICH and HE were investigated with regression analysis. Ammonia was higher in ALF patients than controls. An independent risk factor for the development of severe HE and ICH, a level greater than 100 mol/L predicted the onset of severe HE with 70% accuracy. The model for end-stage liver disease (MELD) score was also independently predictive of HE, and its combination with ammonia increased specificity and accuracy. ICH developed in 55% of ALF patients with a level greater than 200 mol/L, although this threshold failed to identify most cases. After admission, ammonia levels remained high in those developing ICH and fell in those who did not. Youth, a requirement for vasopressors, and renal replacement therapy were additional independent risk factors. Conclusion: Ammonia is an independent risk factor for the development of both HE and ICH. Additional MELD scoring improved the prediction of HE. T here is now strong evidence of a central role for ammonia in the pathogenesis of hepatic encephalopathy (HE) that defines acute liver failure (ALF) and the cerebral edema (CE) and intracranial hypertension (ICH) that contribute to the high mortality seen in this condition. Elevations in the circulating ammonia concentration are a frequent finding in experimental and human ALF and appear to be closely related to these complications. 1-3 Experimental studies have demonstrated ammonia-induced changes in neurotransmitter synthesis and release, neuronal oxidative stress, impaired mitochondrial function, and osmotic disturbances resulting from astrocytic metabolism of ammonia to glutamine. [4][5][6] The net result of these changes is a marked alteration in cerebral function and astrocytic swelling. [5][6][7] Recent studies reporting circulating ammonia concentrations in patients with ALF have found levels higher than those seen in patients with HE accompanying chronic liver disease (CLD). 2,3,8,9 The magnitude of the elevation of ammonia, particularly if it is above 150 mol/L, has been reported to be related to an increased risk of major cerebral complications, including reduced consciousness level, seizures, cerebral herniation (CH), and death. 2,3,8,10,11 If confirmed, these findings have the potential to alter clinical practice; patients identified as being at high risk for HE and ICH in this way could be targeted with specific therapies to reduce the circulating ammonia concen-

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

“…In ALF, arterial ammonia concentrations have been demonstrated to correlate with ICP, severity of clinical presentation, and death by brain herniation (Bernal et al, 2007, Clemmesen et al, 1999and Tofteng et al, 2006. This suggests a direct link between hyperammonemia, brain ammonia and ICP (possibly brain edema).…”

Management in Acute Liver Failure

“…Some amount of ammonia is also generated by the urease activity of gut flora and renal production (kidney also contains glutaminase and glutamine synthase). 9 The circulating ammonia to some extent is excreted by the kidney, used by the muscles to re-synthesise glutamine (muscle also has glutamine synthase and glutaminase), but predominantly is converted to urea (Kreb's urea cycle present in periportal hepatocytes) as well as glutamine (by glutamine synthase present in perivenous hepatocytes) in the liver. Brain also contains glutamine synthase as well as glutaminase.…”

“…8 Recent data suggest that cerebral edema is less frequent now than in former years, but this may reflect earlier admission to hospital and better intensive care unit care. 9 Infection is a common complication in ALF that has been documented across the globe. 10 An incidence of infection has been reported as high as 90% has been reported in the initial series from UK; the causative organisms being bacteria in 80% of cases and fungal infections in 32%.…”

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

“…1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death.…”