Joan Manuel Salmerón

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure

Objective:The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. Summary Background Data:In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. Methods:A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. Results:For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). Conclusions:This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.

Prognostic value of early measurements of portal pressure in acute variceal bleeding

BACKGROUND & AIMS Variceal bleeding is the most important complication of portal hypertension. However, the relationship between the increase in portal pressure and the outcome of variceal bleeding has not been well defined. METHODS We measured the hepatic venous pressure gradient (HVPG) of 65 cirrhotic patients with acute variceal hemorrhage, early after admission (20.6 +/- 15.6 hours). RESULTS Twenty-three patients had a poor evolution (failure to control bleeding or early variceal rebleeding), and 42 had an uneventful evolution. The only variable associated with outcome was the HVPG, which was higher in patients with a poor evolution (23.7 +/- 6.1 vs. 19.2 +/- 3.3 mm Hg; P < 0.0004). This was confirmed by multivariate analysis. HVPG was >/=20 mm Hg in 19 of 23 patients with poor evolution vs. 12 of 42 patients with uneventful evolution (P < 0.0001). An initial HVPG of >/=20 mm Hg was associated with a significantly longer intensive care unit stay (7 +/- 5 vs. 4 +/- 2 days; P < 0.02), longer hospital stay (19 +/- 10 vs. 14 +/- 6 days; P < 0.02), greater transfusion requirements (9.0 +/- 7.7 vs. 4.7 +/- 3.2 UU; P < 0.007), and a worse actuarial probability of survival (1-year mortality, 64% vs. 20%; P < 0.002). CONCLUSIONS Early measurement of HVPG in cirrhotic patients during acute variceal bleeding provides useful prognostic information on the evolution of the bleeding episode and long-term survival.

Paracentesis with Intravenous Infusion of Albumin as Compared with Peritoneovenous Shunting in Cirrhosis with Refractory Ascites

BACKGROUND There is no satisfactory treatment for refractory ascites in patients with cirrhosis. Both peritoneovenous shunts and paracentesis have been used, but there is uncertainty about their relative merits. METHODS We studied 89 patients with cirrhosis and refractory ascites who were randomly assigned to receive either repeated large-volume paracentesis plus intravenous albumin or a LeVeen peritoneovenous shunt. Patients in the paracentesis group in whom recurrent tense ascites developed during follow-up were treated with paracentesis, and those in the peritoneovenous-shunt group with diuretic agents or by the insertion of a new shunt if there was shunt obstruction. RESULTS During the first hospitalization, ascites was removed in all 41 patients in the paracentesis group and in 44 of the 48 patients in the peritoneovenous-shunt group. The mean (+/- SD) duration of hospitalization in the two groups was 11 +/- 5 and 19 +/- 9 days, respectively (P less than 0.01). There were no significant differences in the number of patients who had complications or died. During follow-up, 37 patients in each group were hospitalized again. In the paracentesis group, the number of rehospitalizations for any reason (174 vs. 97 in the peritoneovenous-shunt group) or for ascites (125 vs. 38) was significantly higher, and the median time to a first readmission for any reason (1 +/- 1 vs. 2 +/- 2 months) or for ascites (2 +/- 2 vs. 8 +/- 17 months) was significantly shorter than in the peritoneovenous-shunt group. The total times in the hospital during follow-up, however, were similar in the two groups (48 +/- 49 and 44 +/- 39 days, respectively). Three patients had obstructions of their peritoneovenous shunts during their first hospitalizations, and 15 patients had a total of 20 obstructions during follow-up. Survival was similar in both groups. CONCLUSIONS The LeVeen shunt and paracentesis are equally effective in relieving refractory ascites. The former may provide better long-term control of ascites, but shunt occlusion is common and survival is not improved.

Ecstasy: A common cause of severe acute hepatotoxicity

BACKGROUND/AIMS Ecstasy is a synthetic amphetamine recently identified as a possible cause of acute liver injury. This drug is consumed by young people and has a marked effect on improving sociability. The extent of ecstasy-associated severe hepatic damage is unknown to date. METHODS The clinical histories of 62 patients with acute liver failure admitted to the Intensive Care Liver Unit between January 1994 and December 1996 were reviewed to assess the frequency, the epidemiological, clinical and histological characteristics and the outcome of ecstasy-induced severe hepatitis. RESULTS Over this period of time, five patients (8%) were admitted because of ecstasy-induced acute liver failure, representing 31% of the cases with drug hepatotoxicity. Ecstasy was the second most common cause of liver injury in patients under the age of 25 years, being 20% in this subset of patients and 36% after ruling out the cases of viral etiology. All the patients had severe liver disease of acute onset, with jaundice, high peak of serum transaminases activity, hypoglycemia and low prothrombin activity, but no hepatic encephalopathy. Full recovery was observed in all cases from 3 to 12 months. CONCLUSIONS Ecstasy is responsible for a relatively high number of cases of acute liver failure in young people. Therefore, the use of this drug should be investigated in all patients with severe hepatitis of unclear origin. Efforts must be made to advise young people of the risks of ecstasy consumption.

Extracorporeal albumin dialysis: a procedure for prolonged relief of intractable pruritus in patients with primary biliary cirrhosis.

BACKGROUND AND AIMS:Pruritus is a distressing symptom in patients with primary biliary cirrhosis, and when uncontrollable it is an indication for liver transplantation. Since pruritus can result from unknown substances that accumulate systemically as a consequence of impaired biliary secretion, we have assessed whether a new extracorporeal albumin dialysis (ECAD) procedure, the molecular-adsorbing recirculating system—MARS™, has any effect on pruritus of cholestasis.METHODS:Four patients with primary biliary cirrhosis and resistant pruritus were treated with two 7-h ECAD sessions 1 day apart. Pruritus was recorded from 15 days before the first session, before and after each session, and during the follow-up using a visual analogue scale (VAS). Standard liver tests as well as serum bile acid levels were also measured.RESULTS:There was a clear association between ECAD treatment and relief of itching, which promptly disappeared in two patients, or decreased markedly in the other two. One patient was free of pruritus for 18 months except for short periods with mild pruritus. The second patient experienced amelioration of itching, which almost disappeared completely and recurred mildly 4 months later. In the other two patients pruritus was alleviated markedly after ECAD but gradually recurred. These two patients were treated again 9 and 7 months later with favorable effects on pruritus. The scratching skin lesions improved or disappeared in parallel with the alleviation of itching. The albumin dialysis procedure did not result in liver test changes, except for circulating bile acids, which decreased in all the patients. No significant adverse effects were observed.CONCLUSIONS:The ECAD procedure seems to be an effective alternative for the treatment of patients with pruritus of cholestasis who do not respond to other therapeutic methods.

Liver transplantation for acute liver failure: analysis of applicability.

BACKGROUND Liver transplantation has emerged as the most important advance in the therapy of acute liver failure. To assess the applicability of liver transplantation in this setting, the outcome of 62 patients with acute liver failure consecutively admitted to hospital was analyzed. METHODS Criteria for indicating liver transplantation were grade III-IV hepatic encephalopathy or progression of encephalopathy following a transient improvement. In subfulminant cases, liver transplantation was also indicated when no improvement was observed after a 3-day period of conservative treatment. RESULTS Thirteen (21%) of the 62 patients never met criteria for transplant indication; all of them were discharged after receiving conventional therapy. Twenty-one (34%) patients with criteria for indicating liver transplantation could not receive the transplant because of either contraindications (17 patients; only 1 being discharged from hospital) or death before donor organ availability (4 patients). Finally, 28 (45%) patients received a liver transplant and 22 were discharged from hospital. CONCLUSIONS The applicability of liver transplantation in acute liver failure is relatively low. Considering the high survival rate (79%) obtained in the patients with transplantations and the poor survival rate (6%) observed in those who could not be transplanted, efforts should be made to increase liver transplant applicability to improve the prognosis in acute liver failure.

Selective intestinal decontamination in the prevention of bacterial infection in patients with acute liver failure

To investigate whether selective intestinal decontamination from oral administration of poorly absorbable antibiotics is effective in preventing bacterial infection in patients with acute liver failure, the incidence of nosocomial infection in 34 patients consecutively admitted to hospital between 1985-1990 and treated with either neomycin + colistin + nystatin or norfloxacin + nystatin (group I) was compared to the incidence of infection in 57 patients who did not receive oral, poorly absorbable antibiotics and who were consecutively admitted between 1972-1984 (group II). Patients from groups I and II had similar clinical and laboratory data at hospital admission. Twelve patients from group I and 33 from group II developed bacterial infection during the study period. The probability of infection was significantly different (p = 0.0083) in the two groups: 19% vs. 39% at the 3rd day of admission, 33% vs. 74% at the 7th day, and 48% vs. 78% at the 14th day, respectively. This difference was due to a different rate of infection from enterobacteria. Enterobacteria caused one infectious episode in group I and 24 in group II (p less than 0.001). The incidence of infections caused by other organisms, however, was similar in both groups (15 and 19 episodes, respectively). These results suggest that selective intestinal decontamination is useful in reducing the risk of infection from enterobacteria in patients with acute liver failure.

Effects of somatostatin on renal function in cirrhosis

To investigate the renal effects of somatostatin in cirrhosis, renal function and plasma and urinary levels of endogenous neurohumoral vasoactive substances were measured in conditions of intravenous water overload (20 mL/kg body wt with 5% glucose) before and during the intravenous infusion of somatostatin (250-500 micrograms/h) in 6 cirrhotic patients without ascites and 17 nonazotemic cirrhotic patients with ascites. Somatostatin induced a significant reduction of renal plasma flow, glomerular filtration rate, and free water clearance in both groups of patients. In patients with ascites, somatostatin also reduced urinary sodium excretion. Changes in renal function were significantly more marked in patients with ascites than in those without ascites and occurred in the absence of changes in mean arterial pressure and plasma levels of renin, aldosterone, norepinephrine, antidiuretic hormone, and atrial natriuretic peptide. Somatostatin induced a significant reduction in the plasma concentration of glucagon and urinary excretion of prostaglandin E2 that was not related to changes in renal function. These findings indicate that somatostatin administration induces renal vasoconstriction and impairs glomerular filtration rate, free water clearance, and sodium excretion in cirrhosis by a mechanism unrelated to systemic hemodynamics and endogenous neurohumoral vasoactive systems.

Disulfiram-induced hepatitis. Report of four cases and review of the literature

Liver test abnormalities following disulfiram therapy are common. However, overt disulfiram-induced hepatitis is rare but has a high mortality rate, specially when the etiologic role of disulfiram is not suspected and treatment is not discontinued. We report four cases of disulfiram-induced acute hepatitis with different degrees of severity and review the cases reported in the literature. The clinical spectrum of disulfiram hepatotoxicity ranges from minor elevation of serum aminotransferases to fulminant hepatitis. Although some patients with disulfiram-induced hepatitis have manifestations of hypersensitivity, recent clinical and experimental data suggest that disulfiram hepatotoxicity is produced by the accumulation of toxic metabolites.

Induction doses of interferon‐α‐2a in combination with ribavirin and/or amantadine for the treatment of chronic hepatitis C in non‐responders to interferon monotherapy: a randomized trial

Summary.  The benefit of the triple therapy (interferon + amantadine + ribavirim) is still unknown. The efficacy of induction doses of interferon‐α‐2a monotherapy or in combination with ribavirin and/or amantadine was evaluated in interferon non‐responders with chronic hepatitis C. A total of 378 patients were randomized. All the groups received the same doses and duration of interferon‐α‐2a: (i) interferon 9 MUI/day for 4 weeks and then 3 MUI/3 t.i.w. for 44 weeks (n = 53); (ii) interferon in combination with amantadine 100 mg twice daily for 48 weeks (n = 111); (iii) interferon in combination with ribavirin 1000–1200 mg (n = 106); (iv) interferon in combination with amantadine and ribavirin (n = 108). Baseline parameters were similar in the four groups. Sustained virological and biochemical responses were 13%, 6%, 18% and 22% respectively. No significant differences were found between double ribavirin arm vs triple therapy, but the difference was significant between interferon–amantadine (P = 0.008) and triple therapy (P = 0.0005). Hence, the induction doses of interferon in combination with ribavirin or ribavirin plus amantadine showed encouraging results in patients with chronic hepatitis C who were resistant to interferon. However, triple therapy is not superior to double.