Infection, inflammation and hepatic encephalopathy, synergism redefined.

Every housestaff officer in charge of overnight admissions to a Hepatology service is aware of the need to rule out infection in patients with cirrhosis who present with hepatic encephalopathy (HE). During the day, he/she had been repeatedly taught that spontaneous bacterial peritonitis could exhibit changes in mental state as its sole clinical manifestation. In fact, the instructor should also highlight the entire spectrum of hepatic encephalopathy being influenced by the presence of infection and the concomitant systemic inflammatory response syndrome (SIRS), defined as a temperature greater than 38 8C or less than 36 8C; heart rate greater than 90 beats per minute; tachypnea greater than 20 breaths per minute or PaCO2 less than 4.3 kPa; white cell count greater than 12 £ 10/l or less than 4 £ 10/l or the presence of greater than 10% immature neutrophils [1]. In acute liver failure, large clinical series have documented the higher prevalence of infection and SIRS among individuals with severe HE [2]. In a recent study of the US Acute Liver Failure group, progression of HE from mild to deeper stages was temporarily associated with the development of infection, especially in those with acetaminopheninduced ALF [3]. The development of acute-on-chronic liver failure, where HE and renal failure dominate the clinical picture [4], is often triggered by the presence of infection and its serious systemic consequences. It is important to note that other inflammatory conditions associated with the development of SIRS result in changes in mental state. Some are not related to liver disease, such as pancreatitis and burns. In the case of liver disease, a subset of patients with severe alcoholic hepatitis may present with ‘spontaneous’ HE without an identified precipitant [5], with patients exhibiting features of the SIRS. Infection and concomitant inflammation are most noticeable in patients with cirrhosis and overt HE. In this issue of the Journal, Jalan and co-workers present data [6] to suggest that the subtlest manifestation of HE, minimal encephalopathy in subjects with cirrhosis, can also be added to this list. The investigators studied patients with cirrhosis who presented with a diverse group of infections and who did not exhibit overt signs of HE. At baseline, within 24–36 h of starting antibiotics, neuropsychological testing was performed after the administration of an oral amino acid solution that results in a transient increase in blood ammonia levels without causing overt changes in mental state. Results of neuropsychological testing were abnormal but improved 1 week later, once the infection had been contained. Plasma levels of inflammatory cytokines were decreased. After resolution of the infection, the same amino acid challenge resulted in a similar rise in ammonia but without affecting neuropsychological reactions. The authors conclude that the SIRS to infection modulates the effects of ammonia on the brain. Studies of the pathogenesis of hepatic encephalopathy have focused on the deleterious role of toxins on the brain. Zieve had postulated several decades ago a synergistic role of ammonia with products of bacterial metabolism in the gut, such as short chain fatty acids, mercaptans and phenols [7]. The clinical evidence reviewed above supports a different paradigm, where the question is reformulated: how does infection and subsequent inflammation affect mental state in liver disease? A role for ammonia need not be challenged, as the importance of ammonia is based on substantial experimental and clinical evidence [8]. Rather, the challenge is to determine how inflammation and infection exert synergistic effects with toxins such as ammonia. There is surprisingly scant information in the hepatological literature to answer this question and it is useful to explore the experience of other groups. Patients with all forms of sepsis may develop changes in mental state. Up to 70% of patients with bacteremia exhibit neurological symptoms ranging from lethargy to coma, encompassing a range of symptoms and findings that has been termed sepsisassociated encephalopathy [9]. As often the case in