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INTRODUCTION AND OBJECTIVES: Spontaneous bacterial peritonitis (SBP) is a frequent complication to cirrhosis with an unclear long-term prognosis. We aimed to examine its effect on mortality in two independent patient cohorts. PATIENTS AND METHODS: We used Danish healthcare data on cirrhosis patients with a first-time paracentesis in 2000-2014 and data from three randomized controlled trials on satavaptan treatment of ascites conducted in 2006-2008. We used the Kaplan-Meier method to estimate cumulative mortality, and Cox regression to compare the confounder-adjusted mortality hazard for patients with vs. without SBP. RESULTS: In the Danish Healthcare Cohort, we included 1.282 patients of whom 133 (10.4%) had SBP. The SBP patients' cumulative 4-month mortality was 51.2% (95% CI: 43.0-59.9%) vs. 34.7% (95% CI: 32.0-37.6) in those without SBP. The SBP patients' confounder-adjusted mortality hazard was 1.54-fold higher (95% CI: 1.18-2.00) in the four months after paracentesis, but was not increased thereafter (confounder-adjusted mortality hazard 1.02, 95% 0.72-1.46). In the satavaptan trial data of 1,198 cirrhosis patients with ascites, the 93 patients with SBP had a cumulative 4-month mortality of 38.6% (95% CI: 29.3-49.7) compared with 11.4% (95% CI: 8.5-15.2) in those without. The SBP patients' confounder-adjusted mortality hazard ratio was 3.86 (95% CI: 2.44-6.12) during the first four months, and was 1.23 (95% CI: 0.54-2.83) thereafter. CONCLUSIONS: In both cohorts of patients with cirrhosis, an SBP episode had a high short-term mortality compared to patients without SBP, and had no lasting effect on the long-term mortality.

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AIM: To investigate the plasma amino acid response and tolerance to normal or high protein meals in patients with cirrhosis. METHODS: The plasma amino acid response to a 20 g mixed protein meal was compared in 8 biopsy-proven compensated cirrhotic patients and 6 healthy subjects. In addition the response to a high protein meal (1 g/kg body weight) was studied in 6 decompensated biopsy-proven cirrhotics in order to evaluate their protein tolerance and the likelihood of developing hepatic encephalopathy (HE) following a porto-caval shunt procedure. To test for covert HE, the "number connection test" (NCT) was done on all patients, and an electroencephalogram was recorded in patients considered to be at Child-Pugh C stage. RESULTS: The changes in plasma amino acids after a 20 g protein meal were similar in healthy subjects and in cirrhotics except for a significantly greater increase (P < 0.05) in isoleucine, leucine and tyrosine concentrations in the cirrhotics. The baseline branched chain amino acids/aromatic amino acids (BCAA/AAA) ratio was higher in the healthy persons and remained stable-but it decreased significantly after the meal in the cirrhotic group. After the high protein meal there was a marked increase in the levels of most amino acids, but only small changes occurred in the levels of taurine, citrulline, cysteine and histidine.The BCAA/AAA ratio was significantly higher 180 and 240 min after the meal. Slightly elevated basal plasma ammonia levels showed no particular pattern. Overt HE was not observed in any patients. CONCLUSION: Patients with stable liver disease tolerate natural mixed meals with a standard protein content. The response to a high protein meal in decompensated cirrhotics suggests accumulation of some amino acids but it did not precipitate HE. These results support current nutritional guidelines that recommend a protein intake of 1.2-1.5 g/kg body weight/day for patients with cirrhosis.

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Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme. Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways in a mouse neuronal-astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure enhanced the synthesis and release of alanine. Collectively, our results demonstrate that (1) formation of glutamine is seminal for detoxification of ammonia; (2) neuronal oxidative metabolism is increased in the presence of ammonia; and (3) synthesis and release of alanine is likely to be important for ammonia detoxification as a supplement to formation of glutamine.

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