BACKGROUND. We have recently demonstrated that in humans, circulating levels of tumor necrosis factor‐α (TNF) correlate positively with severity of hepatic encephalopathy (HE) due to chronic liver failure. AIM. The main aim of this larger population study is to determine the relationship between TNF and ammonia in patients with HE and chronic liver failure due to liver cirrhosis. METHODS. Circulating levels of TNF and ammonia were measured in 108 patients with liver cirrhosis due to various etiologies in various clinical grades of HE (grades 0–4). TNF concentrations were measured in venous serum using commercially available solid‐phase high sensitivity enzyme‐linked immunosorbent assay. Ammonia levels were determined in venous plasma by the enzymatic method, using the glutamate dehydrogenase reaction. RESULTS. The mean±SEM values of circulating levels of TNF and ammonia at presentation in patients with grade 0 of HE (n = 30) were 3.89±0.2 pg/mL and 49.8±2.8 µg/mL respectively, in patients with grade 1 of HE (n = 26) were 8.56±0.34 pg/mL and 101.6±6.5 µg/mL respectively, in patients with grade 2 of HE (n = 22) were 11.59±0.48 pg/mL and 160.3±10.7 µg/mL respectively, in patients with grade 3 of HE (n = 20) were 19.98±0.94 pg/mL and 228.8±16.1 µg/mL respectively, and in patients with grade 4 of HE (n = 10) were 51.53±8.59 pg/mL and 284.2±20.3 µg/mL respectively. A significant positive correlation was found between circulating levels of TNF and those of ammonia (r = 0.62, P<0.0001), and also between circulating levels of both substances and severity of HE in these patients (r = 0.95, P<0.0001, and r = 0.9, P<0.0001 respectively). TNF and ammonia were both significant independent predictors of severity of HE (P<0.0001 for both variables). CONCLUSION. The results of this study demonstrate a significant relationship between TNF and ammonia in patients with chronic liver failure and HE, and so strengthen the suggestion that TNF could be strongly involved in the pathogenesis of HE in these patients. Hence, we suggest a new theory in the pathogenesis of HE, the ‘TNF theory’.

Background: Several previous studies have shown that circulating levels of tumor necrosis factor-α (TNF) are elevated in patients with advanced congestive heart failure. However, the relationship between circulating levels of TNF and severity of peripheral oedema in these patients has not been previously evaluated. Aims: To investigate the relationship between circulating levels of TNF, and severity of peripheral oedema in patients with right-sided heart failure (RHF). Methods and results: Circulating levels of TNF were measured in 15 healthy volunteers, and in 83 patients with RHF with various levels of peripheral oedema. At presentation, 13 patients had no peripheral oedema (grade 0), 22 patients had mild peripheral oedema (grade 1), 23 patients had moderate peripheral oedema (grade 2), and 25 patients had severe peripheral oedema (grade 3). The values of circulating TNF levels (mean±S.E.M.) at presentation in the control group and in the RHF patients (oedema grades 0—3) were 2.98±0.21, 4.22±0.55, 4.67±0.29, 7.66±0.44, and 10.94±0.67 pg/mL respectively. There was a significant difference between the groups (p<0.0001, ANOVA), and a significant positive correlation was found between circulating TNF levels and severity of peripheral oedema (r=0.77, p<0.0001). Conclusion: A significant relationship is present between circulating levels of TNF and severity of peripheral oedema in patients with RHF.

H2-receptor antagonists may cause various types of central nervous system reactions, particularly in patients with advanced age and/or impaired renal or liver function. These reactions have rarely been reported in association with famotidine. In five elderly patients, four of them with renal failure, central nervous system reactions developed shortly after initiation with famotidine therapy. These adverse reactions completely resolved after famotidine withdrawal. The authors' five cases and the other seven previously reported emphasize the need for dosage adjustment of famotidine in elderly patients and in those with renal failure, and that these patients should be carefully monitored for development of central nervous system reactions, which sometimes could be very serious.