Role of ammonia, inflammation, and cerebral oxygenation in brain dysfunction of acute‐on‐chronic liver failure patients

Abstract

Hepatic encephalopathy (HE) is a common feature of acute-on-chronic liver failure (ACLF). Although ammonia, inflammation, and cerebral oxygenation are associated with HE in acute liver failure, their roles in ACLF are unknown. The aim of this prospective, longitudinal study was to determine the role of these pathophysiological variables in ACLF patients with and without HE. We studied 101 patients with ACLF admitted to the intensive care unit. Severity of ACLF and HE, arterial ammonia, jugular venous oxygen saturation (JVO 2 ), white blood cell count (WCC), and Creactive protein were measured at days 0, 1, 3, and 7. Patients were followed until death or hospital discharge. Mortality was high (51 patients, 50.5%), especially in patients with HE of whom 35 of 53 (66.0%) died regardless of ACLF severity. At baseline, increased WCC and abnormal JVO 2 (high or low) were independent predictors of death. Further deterioration in inflammation, JVO 2 , and ammonia were also predictive of mortality. JVO 2 deviation and hyperammonemia were associated with the presence and severity of HE; improvement in these parameters was associated with a reduction in HE grade. No direct interaction was observed between these variables in regards to mortality or HE. In conclusion, this study describes potential mechanisms of HE in ACLF indicating that ammonia and abnormal cerebral oxygenation are important. The results suggest that ammonia, JVO 2 , and WCC are important prognostic biomarkers and therapeutic targets. The relative roles of these pathophysiological factors in the pathogenesis of HE in ACLF or guiding therapy to improve survival requires future study. Liver Transplantation 22 732-742 2016 AASLD.Received November 21, 2015; accepted February 20, 2016. Acute-on-chronic liver failure (ACLF) is characterized by acute deterioration of cirrhosis resulting in organ failures in association with systemic inflammation and high mortality.(1-3) Hepatic encephalopathy (HE) in patients with cirrhosis often requires hospitalization, particularly the clinically manifest or "overt" form.(4) In hospitalized patients with cirrhosis with HE, Cordoba et al. (4) showed the presence of ACLF defined their in-hospital and 1-year mortality and that HE in ACLF was associated with a marked systemic inflammatory response. Because ACLF itself is associated with high mortality rates, systemic inflammation, and organ failures, it is not clear which pathophysiological factors associated with HE are relevant to patients with ACLF and superimposed HE.Data from experimental models of ACLF suggest hyperammonemia, inflammation, astrocyte swelling, altered cerebral blood flow (CBF), and cerebral edema are potential contributory mechanisms for HE development. (5,6)

Prognostic Role of Ammonia in Patients With Cirrhosis

“…It was interesting to note that the patients in whom ammonia levels were reduced at day 5 had significantly better survival compared to the patients in whom this was unchanged or increased. These data are in keeping with previous studies in patients with ACLF and acute liver failure . From this study, it is not possible to ascertain whether the relationship between the change in ammonia and survival is a cause or an effect.…”

“…This population was a nested cohort of 101 patients within a previously reported larger prospective cohort study of patients with cirrhosis with AD admitted to University College London (UCL) Hospital, London, between 2000 and 2006 . Those requiring admission to the intensive care unit were included.…”

“…However, in cirrhosis ammonia levels can predict risk and frequency of HE episodes and HE‐related admissions, and in ACLF patients higher levels are observed in those with HE compared to those without. A failure in the reduction of ammonia levels in ACLF over time increases the probability for death . Even in ACLF survivors without HE, a serial decrease in ammonia levels over 7 days has been observed, possibly suggesting an additional role of ammonia in outcomes of ACLF other than HE .…”

“…A failure in the reduction of ammonia levels in ACLF over time increases the probability for death . Even in ACLF survivors without HE, a serial decrease in ammonia levels over 7 days has been observed, possibly suggesting an additional role of ammonia in outcomes of ACLF other than HE . Admission ammonia levels have also been shown to be predictive of in‐hospital survival in patients with alcoholic hepatitis and of transplant‐free survival of AD patients with cirrhosis and are lower in ACLF patients who survive compared to those who die …”

Ammonia Mediates Cortical Hemichannel Dysfunction in Rodent Models of Chronic Liver Disease

“…(46) Evidence for critical reduction in cerebral oxygenation was obtained in the majority of patients with acute-on-chronic liver failure who had poor neurologic outcome, supporting the hypothesis that the brain energy metabolism is critically compromised in cirrhosis and that further perturbations as demonstrated in the present study may be clinically deleterious. (47) Our data indicating an impaired hemichannel-mediated lactate release during tissue hypoxia, in combination with these observations, could help explain the severe neurological manifestations in patients with HE. Because ammonia is central in causing this dysfunction, the potential clinical implications involve the use of ammonia-lowering treatments as a main therapeutic strategy, as well as attempts to increase cerebral oxygenation to preserve neuronal function.…”