Toxicidad hepática recurrente secundaria a metilprednisolona intravenosa / No disponible

Las reacciones adversas hepáticas relacionadas con la administraciónde fármacos (hepatotoxicidad) son cuadros relativamentefrecuentes que presentan una amplia variabilidad clínica e histológica.La identificación precoz de estos cuadros es fundamental enla práctica clínica debido a su potencial gravedad. En la mayoríade los casos la suspensión del fármaco desencadenante es suficientepara la resolución del cuadro clínico.A pesar de que los esteroides son utilizados en una amplia variedadde situaciones clínicas, la notificación de cuadros de hepatotoxicidadsecundaria a esteroides intravenosos es excepcional.Presentamos el caso clínico de una mujer diagnosticada de esclerosismúltiple, que recibió metilprednisolona a altas dosis enforma de “pulsos” intravenosos como tratamiento de las reagudizacionesde su enfermedad y presentó 3 brotes recurrentes de hepatitisde predominio hepatocelular con un patrón clínico, analíticoe histológico compatible con toxicidad hepática agudasecundaria a metilprednisolona intravenosa. En el tercer episodiose realizó una biopsia hepática que demostró un patrón de hepatitisaguda con necrosis líticas confluentes, histología no descritapreviamente en pacientes tratados con esteroides intravenosos

Adverse drug reactions (hepatotoxicity) are a frequent cause ofacute liver injury with a wide clinical and histological spectrum. Anearly recognition of drug-related liver disease has been consideredessential in clinical practice due to potential risks. In most casesexposure discontinuation improves the clinical picture.Steroids are used in a variety of clinical settings. However, intravenoussteroids have rarely been associated with hepatotoxicity.We report the case of a middle-aged woman with multiple sclerosiswho received a bolus of methylprednisolone on threeoccasions for the management of relapsing disease, with the developmentof repeated episodes of elevated liver enzymes aftercorticoid administration. In the third episode a liver biopsy wasperformed, which showed acute hepatitis with bridging necrosis;such histological picture has not been described before in patientstreated with intravenous steroids

[Recurrent acute liver toxicity from intravenous methylprednisolone]. / Toxicidad hepática recurrente secundaria a metilprednisolona intravenosa.

Adverse drug reactions (hepatotoxicity) are a frequent cause of acute liver injury with a wide clinical and histological spectrum. An early recognition of drug-related liver disease has been considered essential in clinical practice due to potential risks. In most cases exposure discontinuation improves the clinical picture.Steroids are used in a variety of clinical settings. However, intravenous steroids have rarely been associated with hepatotoxicity. We report the case of a middle-aged woman with multiple sclerosis who received a bolus of methylprednisolone on three occasions for the management of relapsing disease, with the development of repeated episodes of elevated liver enzymes after corticoid administration. In the third episode a liver biopsy was performed, which showed acute hepatitis with bridging necrosis; such histological picture has not been described before in patients treated with intravenous steroids.

Multicenter randomized controlled trial comparing different schedules of somatostatin in the treatment of acute variceal bleeding.

BACKGROUND/AIMS: The dose of somatostatin used for variceal bleeding (250 microg/h) is lower than that proven to effectively decrease portal pressure and azygos blood flow (500 microg/h). Moreover, i.v. somatostatin boluses have greater effects than continuous infusions. The aim of this study was to investigate whether higher doses of somatostatin and repeated boluses may increase its efficacy in controlling variceal bleeding. METHODS: A total of 174 patients with acute variceal bleeding were randomized to receive for 48 h: (A) one 250 microg bolus +250 microg/h infusion; (B) three 250 microg boluses +250 microg/h infusion; (C) three 250 microg boluses +500 microg/h infusion. RESULTS: The three schedules of somatostatin were equally effective in controlling variceal bleeding (73, 75 and 81%, respectively, NS). Multivariate analysis showed active bleeding at endoscopy (n=75) as the only predictor of failure to control bleeding. In these patients, the 500 microg/h infusion dose achieved a higher rate of control of bleeding (82 vs. 60%, P<0.05), less transfusions (3.7 +/- 2.7 vs. 2.5 +/- 2.3 UU, P=0.07) and better survival (93 vs. 70%, P<0.05) than schedules A/B. CONCLUSIONS: Somatostatin is highly effective in controlling variceal bleeding. Patients with active bleeding at emergency endoscopy may benefit from higher doses of somatostatin infusion.

Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers.

BACKGROUND & AIMS: Nonselective beta-blockers (beta-blockers) are very effective in preventing first variceal bleeding (FVB) in patients with cirrhosis. However, 15%-25% of patients have contraindications or develop severe side effects precluding its use. The present study evaluates whether isosorbide-5-mononitrate (Is-MN) effectively prevents variceal bleeding in patients with contraindications or who could not tolerate beta-blockers. METHODS: One hundred thirty-three consecutive cirrhotic patients with gastro-esophageal varices and contraindications or intolerance to beta-blockers were included in a multicenter, prospective, double-blind randomized controlled trial. Sixty-seven were randomized to receive Is-MN, and 66 to receive placebo. RESULTS: There were no significant differences in the 1- and 2-year actuarial probability of experiencing a FVB between the 2 treatment groups. Presence of variceal red signs at endoscopy was the only variable independently associated with an increased risk of variceal bleeding on follow-up (relative risk 3.4; P < 0.01). Survival and adverse events were similar in the 2 groups. There were no significant differences in the incidence of ascites or changes in renal function. CONCLUSIONS: Is-MN does not reduce the incidence of FVB in patients with cirrhosis and esophageal varices who cannot be treated with beta-blockers because contraindications or intolerance to these drugs, suggesting that Is-MN has no place in the primary prophylaxis of variceal bleeding.

Increased production of vascular endothelial growth factor in peritoneal macrophages of cirrhotic patients with spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis (SBP) is a common complication of cirrhotic patients with ascites that usually results in renal failure and death despite the efficacy of the current antibiotic therapy. The pathogenesis of these phenomena is poorly known but it has been related to the production of vasoactive cell mediators locally acting on the splanchnic vasculature. Because previous studies showed that peritoneal macrophages of cirrhotic patients may produce high quantities of vascular endothelial growth factor (VEGF), a powerful vessel permeabilizing agent, when stimulated by cytokines and bacterial lipopolysaccharide, the present study was aimed to seek whether peritoneal macrophages of SBP patients are induced to produce increased amounts of VEGF. Our results indicate that the production rate and the messenger RNA (mRNA) and protein expression of this substance are increased in macrophages of patients with SBP in comparison with those of noninfected cirrhotic patients. This characteristic feature is absent in circulating monocytes of these patients. Moreover, enhanced endothelial cell proliferation induced by conditioned medium of macrophages isolated from the ascites of patients with SBP is abolished by anti-VEGF antibody, and peritoneal tissue of cirrhotic patients expresses both VEGF receptors, Flt-1 and KDR. These results, therefore, are consistent with the concept that locally released macrophage-derived VEGF may result in increased vascular permeability and plasma leakage in the peritoneal vessels of cirrhotic patients with SBP.

Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study.

Failure to control bleeding and early rebleeding account for the high mortality associated with variceal hemorrhage in cirrhosis. We compared endoscopic sclerotherapy to terlipressin, a drug that effectively controls acute bleeding while reducing in-hospital mortality. This multicenter randomized controlled trial included 219 cirrhotic patients admitted for endoscopy-proven acute variceal bleeding and randomized to receive repeated injections of terlipressin during 6 days (n = 105) or emergency sclerotherapy (n = 114). Success was defined as obtaining control of bleeding (24-hour bleeding-free period during the first 48 hours) and lack of early rebleeding (any further bleeding from initial control to 5 days later) and survival during the study. Both groups were similar at inclusion. Failure rate for terlipressin was 33% and 32% for sclerotherapy (not significant [NS]). Early rebleeding was responsible for 43% and 44% of failures, respectively. This high efficacy was observed in both Child-Pugh class A + B and Child-Pugh class C patients. Both treatments were similar regarding transfusion requirements, in-hospital stay, and 6-week mortality (26 vs. 19 patients). Side effects appeared in 20% of patients receiving terlipressin and in 30% of those on sclerotherapy (P =.06); being serious in 4% and 7%, respectively (NS). In conclusion, terlipressin and sclerotherapy are equally highly effective therapies achieving the initial control of variceal bleeding and preventing early rebleeding. Both treatments are safe, but terlipressin is better tolerated. Therefore, terlipressin may represent a first-line treatment in acute variceal bleeding until the administration of elective therapy, especially in hospitals where a skilled endoscopist is not available 24 hours a day.

Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.

BACKGROUND: In patients with cirrhosis and spontaneous bacterial peritonitis, renal function frequently becomes impaired. This impairment is probably related to a reduction in effective arterial blood volume and is associated with a high mortality rate. We conducted a study to determine whether plasma volume expansion with intravenous albumin prevents renal impairment and reduces mortality in these patients. METHODS: We randomly assigned 126 patients with cirrhosis and spontaneous bacterial peritonitis to treatment with intravenous cefotaxime (63 patients) or cefotaxime and intravenous albumin (63 patients). Cefotaxime was given daily in dosages that varied according to the serum creatinine level, and albumin was given at a dose of 1.5 g per kilogram of body weight at the time of diagnosis, followed by 1 g per kilogram on day 3. Renal impairment was defined as nonreversible deterioration of renal function during hospitalization. RESULTS: The infection resolved in 59 patients in the cefotaxime group (94 percent) and 62 in the cefotaxime-plus-albumin group (98 percent) (P=0.36). Renal impairment developed in 21 patients in the cefotaxime group (33 percent) and 6 in the cefotaxime-plus-albumin group (10 percent) (P=0.002). Eighteen patients (29 percent) in the cefotaxime group died in the hospital, as compared with 6 (10 percent) in the cefotaxime-plus-albumin group (P=0.01); at three months, the mortality rates were 41 percent (a total of 26 deaths) and 22 percent (a total of 14 deaths), respectively (P=0.03). Patients treated with cefotaxime had higher levels of plasma renin activity than those treated with cefotaxime and albumin; patients with renal impairment had the highest values. CONCLUSIONS: In patients with cirrhosis and spontaneous bacterial peritonitis, treatment with intravenous albumin in addition to an antibiotic reduces the incidence of renal impairment and death in comparison with treatment with an antibiotic alone.

Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharide.

Vascular endothelial growth factor (VEGF) is an angiogenic peptide with vascular permeability and relaxing properties. This study assessed whether peritoneal macrophages of cirrhotic patients can be up-regulated to produce VEGF under proper stimulatory conditions. Macrophages were isolated from ascites. VEGF protein secretion and mRNA expression were measured in basal conditions and after stimulation with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), and interleukin-1 (IL-1). These substances induced a time- and dose-dependent increase in both VEGF production and transcript expression. Assays with actinomycin D showed that VEGF mRNA induction is secondary to both higher VEGF gene transcription and mRNA stability. Ascites and plasma concentration of VEGF was also measured in cirrhotic patients with (n = 15) and without (n = 10) spontaneous bacterial peritonitis (SBP). Plasma values did not differ between both groups of patients. However, ascites VEGF levels were higher in SBP patients than in noninfected cirrhotic patients (710 +/- 183 vs. 94 +/- 15 pg/mL; P <.025). These results indicate that cytokines and LPS markedly increase VEGF protein secretion and mRNA expression in macrophages of cirrhotic patients, and suggest that this substance could be an important mediator of the pronounced arterial vasodilation frequently occurring in SBP patients.

Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis.

BACKGROUND & AIMS: Therapeutic paracentesis may be associated with a circulatory dysfunction, manifested by a marked increase of the plasma renin activity and plasma norepinephrine. The aim of the study was to characterize the systemic and hepatic hemodynamic changes associated with paracentesis-induced circulatory dysfunction. METHODS: Changes in plasma renin, aldosterone, and norepinephrine, and in systemic and hepatic hemodynamics were assessed 1 hour and 6 days after complete mobilization of ascites in 37 patients treated by total paracentesis plus intravenous dextran-70 infusion. RESULTS: Paracentesis-induced circulatory dysfunction occurred in 10 patients (renin and norepinephrine increased from 9.0 +/- 10.5 to 28.8 +/- 19.0 ng.mL-1.h-1 and from 752.0 +/- 364.0 to 1223.0 +/- 294.0 pg/mL, respectively) and was associated with significant reduction in systemic vascular resistance (-13.0% +/- 2.6%; P < 0.05) and increase in hepatic venous pressure gradient (from 19.5 +/- 1.5 to 22.5 +/- 2.4 mm Hg; P < 0.01). In the remaining 27 patients, mobilization of ascites also induced a significant but smaller reduction in systemic vascular resistance (-5.0% +/- 1.6%; P < 0.05) without significant changes in renin, norepinephrine, and hepatic venous pressure gradient. CONCLUSIONS: Paracentesis-induced circulatory dysfunction is predominantly caused by an accentuation of the arteriolar vasodilation already present in untreated cirrhotic patients with ascites. The homeostatic activation of endogenous vasoactive systems may account for the increased intrahepatic vascular resistance associated with this condition.

Double-blind randomized controlled trial comparing terlipressin and somatostatin for acute variceal hemorrhage. Variceal Bleeding Study Group.

BACKGROUND & AIMS: Terlipressin and somatostatin decrease portal pressure and have been used to treat variceal hemorrhage, but they have not been adequately compared. The aim of this study was to compare the efficacy and safety of these drugs in the treatment of variceal bleeding in cirrhotic patients. METHODS: Of 161 patients with variceal bleeding. 80 were randomized to receive (double-blind) intravenous terlipressin (2 mg/4 h) and 81 to receive somatostatin (continuous infusion of 250 micrograms/h after an intravenous injection of 250 micrograms). Success of therapy was defined as a 24-hour bleeding-free period within 48 hours from randomization. RESULTS: Success of therapy was similar with terlipressin (80%) and somatostatin (84%). In patients with Child's class A and B disease, terlipressin was effective in 52 of 60 (87%) and somatostatin in 48 of 55 (87%). Success rates in class C were 60% and 77% (P = 0.33). No differences were observed in rebleeding rates (30% vs. 28.4%) and 6-week mortality rates (13 vs. 13 patients). Incidence of side effects was significantly higher in the terlipressin group (38.8% vs. 23.5%; P = 0.042). Severe side effects requiring intervention occurred in 5 of 80 and 4 of 81 patients, respectively. CONCLUSIONS: Terlipressin and somatostatin are highly effective as first-line treatment of variceal hemorrhage in cirrhotic patients. The low incidence of severe side effects suggests that drug therapy may be maintained for longer periods to prevent early rebleeding.

Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.

BACKGROUND & AIMS: Paracentesis associated with plasma expanders is widely used for the treatment of ascites in cirrhosis. This study investigated the clinical importance of paracentesis-induced-circulatory dysfunction and compared the efficacy of albumin, dextran 70, and polygeline in preventing this complication. METHODS: A total of 289 cirrhotic patients with ascites were randomized to treatment by total paracentesis plus intravenous albumin (97 patients), dextran 70 (93 patients), or polygeline (99 patients). Postparacentesis circulatory dysfunction was defined as an increase in plasma renin activity on the sixth day after paracentesis of more than 50% of the pretreatment value to a level > 4 ng.mL-1.h-1. RESULTS: Postparacentesis circulatory dysfunction occurred more frequently in patients treated with dextran 70 (34.4%; P = 0.018) or polygeline (37.8%; P = 0.004) than in those receiving albumin (18.5%). The plasma expander used and the volume of ascites removed were independent predictors of this complication. Postparacentesis circulatory dysfunction persisted during follow-up and was associated with a shorter time to first readmission (1.3 +/- 0.5 vs. 3.5 +/- 0.8 months, median +/- SEM; P = 0.03) and shorter survival (9.3 +/- 4.2 vs. 16.9 +/- 4.3 months; P = 0.01). Creatinine and sodium levels in serum, and Child-Pugh score at inclusion, and postparacentesis circulatory dysfunction were independent predictors of survival. CONCLUSIONS: Postparacentesis circulatory dysfunction is not spontaneously reversible and is associated with a shorter time to first readmission and shorter survival. Albumin is the best plasma expander to prevent this complication.