Research ArticleInfection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis
Introduction
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome which is associated with liver dysfunction and remains a major clinical problem in patients with cirrhosis. Furthermore, HE is an important component of prognostic models for acute liver failure [1], [2], [3] where 25% of patients with acute and hyperacute aetiologies may succumb from brain oedema and intracranial hypertension resulting from astrocyte swelling [4]. In cirrhosis, HE occurs more insidiously causing a range of neuropsychiatric abnormalities including psychomotor retardation, impaired memory, increased reaction time, sensory abnormalities, and poor concentration. Cirrhosis patients with severe HE may develop varying degrees of confusion, marked reduction in conscious level, and even coma [5]. HE can be extremely challenging to manage in a ward environment and such patients may benefit from augmented levels of care in High Dependency (HDU) and Intensive Care Unit (ICU) environments.
Although the evidence supporting a pivotal role of ammonia is robust [6], [7], [8], a consistent correlation between the concentration of ammonia in the blood and the manifest symptoms of HE in cirrhosis is not always observed in clinical practice. Indeed, numerous studies have shown that a single test for blood ammonia concentration is a poor method to assess HE [9]. Ong et al. studied blood ammonia levels in patients with cirrhosis and compared these levels to the patients’ mental states. In patients considered not to have any signs of HE, 60% had ammonia levels higher than normal, whereas there was a high proportion of those with Grade 3 or Grade 4 HE with normal or only mildly elevated blood ammonia levels [7]. While there is no denying that ammonia is involved in the pathogenesis of HE, it seems that there may be other factors involved which may be as, if not more, important.
The synergistic role of inflammation and infection in modulating the cerebral manifestation of elevated ammonia has been shown to be important. The presence and severity of neuropsychological dysfunction in minimal HE in cirrhosis have been shown to be independent of the severity of liver disease and plasma ammonia concentration, but markers of inflammation were significantly higher in those patients with minimal HE compared to those without [10]. A further study demonstrated significant deterioration of neuropsychological test scores in patients with cirrhosis following induced hyperammonemia during an infective state, but not after its resolution. This observation reinforces the role of infection in determining cerebral manifestations of ammonia in liver disease therefore supporting an ‘inflammatory hypothesis’ [11]. Potential synergy between ammonia and inflammation in cirrhosis has been explored in animal models and found to be important [12], [13]. Furthermore, hyponatremia is synergistic in the evolution of HE and frequently occurs in the cirrhotic population [14], [15].
Patients with cirrhosis are functionally immuno-suppressed [16], [17] and prone to infection [18], which is a frequent precipitant for the development of HE and organ dysfunction, including renal failure and circulatory dysfunction [19], [20]; this constellation of features is frequently referred to as ‘acute-on-chronic’ liver failure [21]. Sepsis and/or the Systemic Inflammatory Response Syndrome (SIRS) occur in approximately 40% of hospitalised patients with cirrhosis and the resultant organ failures lead to significant mortality [22], [23].
To date, clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and in patients with cirrhosis and minimal or low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis, although this has not been examined to date. In this observational cohort study, our aim was to report the precipitants, physiological disturbance, organ support, and outcomes of patients with cirrhosis admitted to a specialist ICU where the primary determinant for admission was Grade 3/4 HE. The hypothesis was that, in this cohort, infection and/or SIRS was associated with the development of severe HE in the majority of cases and conferred a poor prognosis.
Section snippets
Data collection
Data were collected prospectively by an independent team of research audit nurses on 100 consecutive emergency admission episodes of patients with cirrhosis, whose severe HE (Grade 3/4) was the primary indication for admission to the Liver ICU at King’s College Hospital. Data were collected between 1st January, 2000 and March 2008. These data were collected anonymously as part of an ongoing prospective audit within the department. Data on patients with <Grade 3 HE, managed in a ward
Patient demographics
Seventy-two percent of patients in this study cohort were male. The median (IQR) age was 49 years (39–59) and the median length of stay in the ICU was 11 days (4–19 days). Alcohol was the most common etiology of cirrhosis (46%). Among those cirrhosis patients, 13/46 (28%) had a clinical diagnosis of alcoholic hepatitis (5/13 biopsy proven) and had last drunk alcohol between 10–28 days prior to the admission; the remaining 27/46 (72%), who had alcohol-related cirrhosis, had been abstinent from
Discussion
In this prospective audit study of 100 consecutive patients with cirrhosis, presenting with Grade 3/4 HE as the primary indication for ICU admission, our data support an association between infection/SIRS but not ammonia, in patients with cirrhosis who develop severe HE. SIRS score was significantly higher in patients with Grade 4 HE than Grade 3, while HE grade/GCS did not correlate with arterial ammonia, serum sodium or serum creatinine. Patients with Grade 3 HE were more likely to survive
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this paper.
Author contributions
Shawcross – Principal Investigator of this study; led in data collection, analysis, and writing of this paper.
Sharifi – Data collection and analysis. Co-author of this paper.
Canavan – Data and statistical analysis and gave input into revision of the paper.
Yeoman – Data collection and gave input into revision of this paper.
Abeles – Data collection and gave input into revision of this paper.
Taylor – Data collection.
Auzinger – Liver intensivist involved in patient care and prospective data
Acknowledgements
We thank the following people for their invaluable help and assistance with data collection and collation: Tony Chang, Managing Director, Medical Associated Software House Limited (ICARE Program). The Liver ICU Audit Nurses: Sarah Hughes, Maggie Gomba, and Vimbai Mutendereki. Dr. Shawcross holds a Clinical Senior Lectureship funded by the Higher Education Funding Council for England. Drs. Canavan and Abeles hold NIHR Clinical Research Fellowships funded by the Department of Health and the NIHR
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2022, Annals of HepatologyCitation Excerpt :It has been found that hyperammonaemia is associated with significant neuropsychological deterioration during the inflammatory state, secondary to infection in patients with cirrhosis [12]. Another prospective study found that the Systemic Inflammatory Response Syndrome score was higher in patients admitted for grade 4 HE, suggesting an association between inflammation and HE [13]. Microbiota also play a critical role since the function and composition of microbiota may alter the disease's course [4].
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These authors contributed equally to this paper.