M. Guevara

Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis

BACKGROUND & AIMS Tolvaptan is a vasopressin V2-receptor antagonist that improves serum sodium concentration by increasing renal solute-free water excretion. Specific data on the safety and efficacy of tolvaptan in patients with cirrhosis and hyponatremia has not been exclusively evaluated. METHODS This sub-analysis of the Study of Ascending Levels of Tolvaptan trials examined cirrhotic patients with hyponatremia who received 15 mg oral tolvaptan (n=63; increased to 30 or 60 mg if needed) or placebo (n=57) once-daily for 30 days. At baseline, 44% had mild hyponatremia (serum sodium 130-134 mmol/L), 56% had marked hyponatremia (serum sodium <130 mmol/L), 85% had cirrhosis due to alcohol and/or hepatitis B/C, and 80% were Child-Pugh class B/C. RESULTS Tolvaptan was effective in raising serum sodium. Average daily area under the curve for serum sodium was significantly greater in the tolvaptan group from baseline to day 4 (p<0.0001) and day 30 (p<0.0001). This superiority was maintained after stratification by baseline hyponatremia (mild and marked), estimated glomerular filtration rate (≤ 60 ml/min and >60 ml/min), or serum creatinine levels (<1.5mg/dl and ≥ 1.5mg/dl). Hyponatremia recurred 7 days after discontinuation of tolvaptan. Mean mental component summary scores of the SF-12 health survey improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, p=0.02). Major side effects due to tolvaptan were dry mouth and thirst. Gastrointestinal bleeding occurred in 10% and 2% of patients in the tolvaptan and placebo group, respectively (p=0.11). Adverse event rates, withdrawals, and deaths were similar in both groups. CONCLUSIONS One month of tolvaptan therapy improved serum sodium levels and patient-reported health status in cirrhotic patients with hyponatremia. Hyponatremia recurred in tolvaptan-treated patients after discontinuation.

Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy

BACKGROUND & AIMS We applied advanced magnetic resonance imaging and Voxed based Morphometry analysis to assess brain tissue density in patients with cirrhosis. METHODS Forty eight patients with cirrhosis without overt hepatic encephalopathy (17 Child A, 13 Child B, and 18 Child C) and 51 healthy subjects were matched for age and sex. Seventeen patients had history of overt hepatic encephalopathy, eight of them had minimal hepatic encephalopathy at inclusion, 10 other patients had minimal hepatic encephalopathy at inclusion but without history of previous overt hepatic encephalopathy, and 21 patients had none of these features. RESULTS Patients with cirrhosis presented decreased brain density in many areas of the grey and white matter. The extension and size of the affected areas were greater in patients with alcoholic cirrhosis than in those with post-hepatitic cirrhosis and correlated directly with the degree of liver failure and cerebral dysfunction (as estimated by neuropsychological tests and the antecedent of overt hepatic encephalopathy). Twelve additional patients with cirrhosis who underwent liver transplantation were explored after a median time of 11months (7-50months) after liver transplant. At the time of liver transplantation, three patients belonged to class A of the Child-Pugh classification, five to class B and four to class C. Compared to healthy subjects, liver transplant patients showed areas of reduced brain density in both grey and white matter. CONCLUSIONS These results indicate that loss of brain tissue density is common in cirrhosis, progresses during the course of the disease, is greater in patients with history of hepatic encephalopathy, and persists after liver transplantation. The significance, physiopathology, and clinical relevance of this abnormality cannot be ascertained from the current study.

844 COMPARISON OF AKIN CRITERIA AND CONVENTIONAL CRITERIA FOR DEFINITION OF RENAL IMPAIRMENT IN CIRRHOSIS. PRELIMINARY RESULTS OF A PROSPECTIVE STUDY

25 patients (33.8%) in group I and 39 (55.7%) patients in group II, and in 25 patients (33.8%) versus 31 patients (44.3%) after the second session. 24 patients (32.4%) in group I achieved variceal eradication after the third session. Fever, chest pain and dysphagia were observed more frequently in group II than in group I, fatal bleeding from post sclerotherapy ulcer was seen in three patients in group II which never occurred in group I. Conclusion: Band ligation is a good alternative to cyanoacrylate injection in treatment of actively bleeding junctional varices.

952 MELD-SODIUM PREDICTS SURVIVAL AND DEVELOPMENT OF TYPE-1 HEPATORENAL SYNDROME IN PATIENTS WITH TYPE-2 HEPATORENAL SYNDROME

Patients with type 2 hepatorenal syndrome (HRS) may develop type-1 HRS; however, the frequency and risk factors associated with the occurrence of this complication are currently unknown. With the aim of studying the risk factors associated with the development of type-1 HRS, 164 consecutive patients with cirrhosis and type-2 HRS were evaluated. The mean age was 62±10 years, 70% were male and 47% had alcoholic cirrhosis. At diagnosis, serum creatinine value was 1.77±0.25mg/dL, 57% patients had refractory ascites and 40% hyponatremia (serum sodium 131±5 mEq/L). Patients showed a marked deterioration in systemic hemodynamics and liver function, as evidenced by low mean arterial pressure (78±11mmHg), an increase in endogenous vasoactive systems activity (plasma renin activity 10.7±9ng/ml*h) and high values for MELD and MELD-sodium (18±5 and 23±5, respectively). At one year, only 34 patients were still alive, 29 had been transplanted and 92 had died. Thirty-nine patients (24%) developed type-1 HRS within a median of 65 days (95%CI 15– 117). Mean serum creatinine value at the time of diagnosis was 3.77±1.17mg/dL, which corresponded to mean an increase of 117% respect to baseline (95%CI 100–137%). No precipitating event was identified in 22 patients (56%). Bacterial infections were the most common precipitating factor of type-1 HRS (observed in 14 patients (37%). On multivariate analysis, MELD-Sodium was the only factor independently associated with survival and development of type-1 HRS, and the best cut-off point was 22. At 6 months, the incidence of type 1 HRS was significantly higher in patients with MELD-Sodium greater than or equal to 22, when compared to patients with MELD-Sodium lower than 22 (29 vs. 9%, p = 0.002). In conclusion, development of type-1 HRS is a frequent event in patients with type-2 HRS and occurs in absence of any precipitating event in almost half of cases. MELD-Sodium is a useful tool to predict both survival and development of type-1 HRS in this population. These results should be accounted not only on prediction of prognosis of these patients, but also for design of possible future therapeutic strategies.

189 CIRRHOTIC CARDIOMYOPATHY: ABNORMAL VENTRICULAR FILLING OR ACTUAL MYOCARDIAL DYSFUNCTION?

189 CIRRHOTIC CARDIOMYOPATHY: ABNORMAL VENTRICULAR FILLING OR ACTUAL MYOCARDIAL DYSFUNCTION? E. Sola, A. Nazar, M. Sitges, M. Guevara, C. Guigou, S. Poyatos, G.H. Pereira, C. Fagundes, V. Arroyo, P. Gines. Liver Unit, Hospital Clinic. University of Barcelona. Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS). CIBER ehd (CIBER de Enfermedades Hepaticas y Digestivas), Cardiology, Hospital Cĺinic. University of Barcelona, Barcelona, Spain E-mail: esola@clinic.ub.es