I. Camacho

Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy.

Oral glutamine challenge (OGC) has been found to be safe, and an altered response predicts elevated risk of overt hepatic encephalopathy (HE) in patients with minimal hepatic encephalopathy (MHE). We assessed the survival prognosis of patients with cirrhosis, but without current overt HE, who have an altered OGC and MHE. MHE was inferred using 3 neuropsychological tests. Venous ammonia concentrations were measured pre‐ and post‐60 minutes of a 10 g oral glutamine load. The median follow‐up was 25.2 months, by which time 22 patients had had bouts of overt HE and 18 had died from liver‐related causes. The results in 126 patients with cirrhosis, indicated 25 with MHE and abnormal OGC response. Survival among patients who developed overt HE was 59% at 1 year and 38% at 3 years. In patients without HE, survival was 96% and 86% at 1 and 3 years, respectively (log‐rank 50.9, P < .0001). The presence of MHE was not related to survival (log‐rank 2.21, P = .23). Patients with MHE and abnormal OGC test had elevated mortality risk (log‐rank 13.1, P = .0003). Multivariate analyses indicated Child‐Pugh score (hazard ratio [HR] 1.46; 95% CI, 1.46‐2.08), and MHE plus altered OGC response (HR 5.5; 95% CI, 1.81‐16.6) were predictors of mortality, whether from liver‐related or non–liver‐related causes. In conclusion, a pathological OGC response in patients with MHE appears to be associated with lower survival rate and may prove useful in the selection of candidates for liver transplantation. (HEPATOLOGY 2004;39:939–943.)

Altered response to oral glutamine challenge as prognostic factor for overt episodes in patients with minimal hepatic encephalopathy

BACKGROUND/AIMS We assessed the usefulness of oral glutamine challenge (OGC) and minimal hepatic encephalopathy in evaluating risk of overt hepatic encephalopathy in cirrhotic patients. METHODS Minimal hepatic encephalopathy (MHE) was inferred using neuro-psychological tests. Venous ammonia concentrations were measured pre- and post-60 min (NH(3)-60m) of a 10 g oral glutamine load. Receiver-operating-characteristic curve analysis indicated a pathological glutamine tolerance cut-off value of NH(3)-60m >128 microg/dl. RESULTS In healthy control subjects (n=10) ammonia concentrations remained unchanged but increased significantly in cirrhotic patients (from 70.41+/-45.2 to 127.43+/-78.6; P<0.001). In multiple logistic regression analysis, altered OGC was related to Child-Pugh (odds ratio, OR=7.69; 95% confidence interval, CI=1.72-33.3; P<0.01) and MHE (OR=5.45; 95% CI=1.17-25.4; P<0.05). In the follow-up 11 patients (15%) developed overt hepatic encephalopathy (HE). In multivariate analysis OGC (OR=14.5; 95% CI=1.26-126.3) and MHE (OR=1.56; 95% CI=1.02-21.9) were independently related with HE in the follow-up. Patients with MHE and altered OGC showed significantly higher risk of overt HE in the follow-up (60%) than patients without MHE and normal OGC (2.8%) (Log rank test=21.60; P<0.0001). CONCLUSIONS A pathological OGC in patients with MHE appears to be a prognostic factor for the development of overt hepatic encephalopathy, whereas a normal OGC in patients without MHE could exclude risk of overt HE.

Metformin Inhibits Glutaminase Activity and Protects against Hepatic Encephalopathy

Aim To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro. Methods Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizers experienced (metformin) and 41 as controls (cirrhotic patients with type 2 diabetes mellitus without metformin treatment). Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutations in glutaminase gene. We performed an experimental study in vitro including an enzymatic activity assay where glutaminase inhibition was measured according to different metformin concentrations. In Caco2 cells, glutaminase activity inhibition was evaluated by ammonia production at 24, 48 and 72 hours after metformina treatment. Results Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82): 4.9% (2/41) in patients receiving metformin and 41.5% (17/41) in patients without metformin treatment (logRank 9.81; p = 0.002). In multivariate analysis, metformin use [H.R.11.4 (95% CI: 1.2–108.8); p = 0.034], age at diagnosis [H.R.1.12 (95% CI: 1.04–1.2); p = 0.002], female sex [H.R.10.4 (95% CI: 1.5–71.6); p = 0.017] and HE risk [H.R.21.3 (95% CI: 2.8–163.4); p = 0.003] were found independently associated with hepatic encephalopathy. In the enzymatic assay, glutaminase activity inhibition reached 68% with metformin 100 mM. In Caco2 cells, metformin (20 mM) decreased glutaminase activity up to 24% at 72 hours post-treatment (p<0.05). Conclusions Metformin was found independently related to overt hepatic encephalopathy in patients with type 2 diabetes mellitus and high risk of hepatic encephalopathy. Metformin inhibits glutaminase activity in vitro. Therefore, metformin use seems to be protective against hepatic encephalopathy in diabetic cirrhotic patients.

606 METFORMIN PREVENTS OVERT HEPATIC ENCEPHALOPATHY (HE) IN CIRRHOTICS: A RETROSPECTIVE OBSERVATIONAL STUDY

605 METFORMIN TREATMENT REDUCES HEPATOCELLULAR CARCINOMA (HCC) RISK IN PATIENTS WITH CIRRHOSIS C: A RETROSPECTIVE OBSERVATIONAL STUDY OF TWO INDEPENDENT COHORTS J. Ampuero, M. Fernandez-Gil, D. Nunez, S. Alonso, M. Maraver, M.L. Gutierrez, C. Cano, A. Rojas, J.L. Lledo, M. Millan, R. Gallego-Duran, I. Camacho, B. Figueruela, E. Suarez, C. Fernandez-Rodriguez, M. Romero-Gomez. UCM Digestive Diseases and CIBERehd, Valme University Hospital, Sevilla, Digestive Diseases Unit, Alcorcon University Hospital, Madrid, Spain E-mail: javi.ampuero@gmail.com