The evolution of knowledge on the pathophysiology of portal hypertension.
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Epoprostenol↗
Biomedical subjects
J Rodés
Publications and source records attributed to J Rodés.
[Severe hepatotoxicity of tuberculostatic agents. Increase in the incidence].
Hepatotoxicity by antituberculous drugs is well known. Nonetheless, severe liver involvement is infrequent. Several series of fulminant hepatitis by antituberculous drugs have recently been reported with a much greater frequency than previously reported. The present study describes the authors' experience which, similar to other groups, has shown a marked increase with respect to previous experience. During 1994 5 patients with acute severe hepatitis associated to antituberculous drugs were admitted to the authors' unit. The mean age of the patients was 43 years (range: 25-62). Two patients were healthy HBsAg carriers, one undergoing enzymatic inducer treatment and was anti-HIV positive. Another patient presented compensated liver cirrhosis by HCV. The 5 cases received combined isoniazid and rifampicin and four had also received pyrazinamide. Four patients presented hepatic encephalopathy. Of these cases, three could not undergo emergency liver transplantation because of contraindications and died due to complications of acute severe liver failure. Another patient evolved favorably following emergency liver transplantation. The only patient who presented good evolution with conservative treatment and who did not present hepatic encephalopathy had discontinued isoniazid because of the finding of slight hypertransaminasemia during a routine analytical control. Several risk factors have been reported for the appearance of hepatotoxicity by antituberculous drugs. The factor of greatest clinical importance for the development of severe hepatotoxicity is probably continuation of the treatment once hepatic dysfunction has initiated. The important increase in cases of severe toxicity urges the need for strict analytical monitoring following initiation of treatment.
Acute Disease↗
[Treatment of chronic hepatitis C. Many interrogatives and some answers].
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Antiviral Agents↗
[Prolonged administration of hepatitis B hyperimmune gamma globulin in patients with liver transplantation in liver diseases caused by hepatitis B virus].
To prevent reinfection by the hepatitis B virus (HBV) in liver transplant patients, the administration of anti-HBV hyperimmune gammaglobulin (HBIg) was proposed. This study compares the efficacy of HBIg administration alone during the anhepatic phase of liver transplantation (group 1, 19 transplantations) with that obtained with prolonged and permanent HBIg administration (group II, 18 transplantations) in patients transplanted because of liver disease by HBV. HBIg was administered intravenously in the intrahospital phase, followed by intramuscular administration in the undefined follow up period. Thirteen patients (68%) of group 1 and 5 (28%) of group II developed post transplantation reinfection by HBV (p = 0.015). Survival of the grafts with reinfection by HBV was lower than that in grafts without reinfection (6/18, 33%, and 16/19, 84%; p = 0.002). Most grafts with reinfection by HBV were lost due to patient death as a consequence of this complication. No adverse secondary effects were found to be related with HBIg administration. In conclusion, the prolonged use of HBIg in patients undergoing liver transplantation because of liver disease by HBV reduces the risk of post transplant reinfection by HBV and is well tolerated.
Graft Survival↗
Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.
In patients with variceal bleeding as a complication of hepatic cirrhosis, propranolol therapy reduces the risk of recurrent variceal haemorrhage. However, the relation between portal pressure response to pharmacological treatment and clinical events has not been well defined. This relation was prospectively investigated in 69 cirrhotic patients receiving continued propranolol therapy after an episode of variceal bleeding. Hepatic venous pressure gradient (HVPG) was measured before and at 3 months of continued drug therapy. At 3 months HVPG had fallen by 20% or more in 25 patients. During follow-up of 28 (SD 17) months rebleeding occurred in 2 of these 25 patients compared with 23 of 44 who had lesser reductions in HVPG. Cumulative probability of rebleeding at 1, 2, and 3 years was 4%, 9%, and 9% in patients with a decrease in HVPG > or = 20%, and 28%, 39%, and 66% in patients with a decrease in HVPG < 20% (p < 0.001, log-rank test). On multivariate analysis, a decrease in HVPG > or = 20% was the only independent predictor of rebleeding (relative risk 0.09, 95% CI 0.02-0.41. Of the 8 patients in whom the HVPG fell to 12 mm Hg or less, none rebled. This study suggests that measurement of the HVPG response to pharmacotherapy will provide useful prognostic information on the long-term risk of variceal rebleeding.
Administration, Oral↗
Evidence that the rat hepatic mitochondrial carrier is distinct from the sinusoidal and canalicular transporters for reduced glutathione. Expression studies in Xenopus laevis oocytes.
Mitochondrial GSH derives from a mitochondrial transport system (RmGshT), which translocates cytosol GSH into the mitochondrial matrix. Mitochondria of oocytes, isolated 3-4 days after microinjection of total liver mRNA, expressed a RmGshT compared with water-injected oocytes. The expressed RmGshT exhibited similar functional features as reported in isolated mitochondria of rat liver such as ATP stimulation, inhibition by glutamate, and insensitivity to inhibition by sulfobromophthalein-glutathione (BSP-GSH) and S-(2,4-dinitrophenyl)glutathione (DNP-GSH). The expressed RmGshT is localized in the inner mitochondrial membrane since expression is still observed in mitoplasts prepared from total liver mRNA-injected oocytes. Fractionation of poly(A)+ RNA identified a single mRNA species of approximately 3-3.5 kilobases encoding for the RmGshT, which was stimulated by ATP and inhibited by glutamate but not by BSP-GSH or DNP-GSH. Microinjection of this fraction did not lead to expression of plasma membrane GSH transport in intact oocytes, and conversely, oocytes microinjected with cRNA for rat liver sinusoidal GSH transporter (RsGshT) or rat liver canalicular GSH transporter (RcGshT) did not express mitochondrial GSH transport activity. Thus, our results show the successful expression of the rat hepatic mitochondrial GSH carrier, which is different from RsGshT and RcGshT, and provide the strategic basis for the cloning of this important carrier.
Animals↗
[Assessment of the performance of sabbatical leave: Hospital Clínic i Provincial of Barcelona (1990-1991). Research Committee of the Hospital Clínic i Provincial of Barcelona].
BACKGROUND: The development of an evaluation protocol for assessing the scientific contribution and the impact on medical care of the sabbatical leaves granted in a large Spanish teaching hospital. METHODS: The sabbatical leaves for all faculty staff of the Hospital Clínic i Provincial of Barcelona (HCPB) were analyzed since 1980 trough 1991. The scientific production analysis was done according to the impact factor (IF) score of the Science Citation Index. Descriptive statistical techniques as well as parametric and non-parametric tests were used for comparisons. RESULTS: A total of 52 sabbatical leaves was analyzed of all 60 leaves granted (87%). Mean duration of the leave was 7.94 +/- 3.86 months. The scientific production includes 89 original articles published in peer-reviewed medical journals, with a total score of 300.82 IF points (mean score: 5.78 +/- 7.12 IF points by leave). There were significant differences in the mean duration, number of papers published and IF points score by sabbatical leave between the Medicine, Surgery and Other Departments. In 16 cases (31%) there was a professional promotion following the sabbatical leave and in 20 cases (39%) an academic promotion. In 27 cases (60%) there was no promotion after the leave. Most of the faculty staff physicians (96%) are still employed in the same institution, and believe that the sabbatical leave has significantly contributed to their promotion (67%). A high percentage (94%) has also been able to develop afterwards the methods and techniques learned during the sabbatical leave. CONCLUSIONS: The experience of the Hospital Clinic of Barcelona in granting sabbatical leaves has been highly positive. The scientific performance of the individuals on leave is high. Our institution has been able to add and develop most of the techniques and methods learned overseas. The future of the sabbatical leaves in other Spanish Universities and Hospitals should be regarded as a high priority target. The performance of these leaves is supported by its scientific results, that could be quantified.
Education, Medical, Continuing↗
Dilemmas of organ transplantation from anti-HCV-positive donors.
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Hepacivirus↗
Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes.
Mitochondrial glutathione plays an important role in maintaining a functionally competent organelle. Previous studies have shown that ethanol feeding selectively depletes the mitochondrial glutathione pool, more predominantly in mitochondria from perivenous hepatocytes. Because S-adenosyl-L-methionine (SAM) is a glutathione precursor and maintains the structure and function of biological membranes, the purpose of the present study was to determine the effects of SAM on glutathione and function of perivenous (PV) and periportal (PP) mitochondria from chronic ethanol-fed rats. SAM administration resulted in a significant increase in the basal cytosol and mitochondrial glutathione in both PP and PV cells from both pair-fed or ethanol-fed groups. When hepatocytes from ethanol-fed rats supplemented with SAM were incubated with methionine plus serine or N-acetylcysteine, mitochondrial glutathione increased in parallel with cytosol, an effect not observed in cells from ethanol-fed rats without SAM. Feeding equimolar N-acetylcysteine raised cytosol glutathione but did not prevent the mitochondrial glutathione defect. In addition, SAM feeding resulted in significant preservation of cellular adenosine triphosphate (ATP) levels (23% to 43%), mitochondrial membrane potential (17% to 25%), and the uncoupler control ratio (UCR) of respiration (from 5.1 +/- 0.7 to 7.3 +/- 0.6 and 2.1 +/- 0.3 to 6.1 +/- 0.7) for PP and PV mitochondria, respectively. Thus, these effects of SAM suggest that it may be a useful agent to preserve the disturbed mitochondrial integrity in liver disease caused by alcoholism through maintenance of mitochondrial glutathione transport.
Administration, Oral↗
Effect of upright posture and physical exercise on endogenous neurohormonal systems in cirrhotic patients with sodium retention and normal supine plasma renin, aldosterone, and norepinephrine levels.
It is well known that sodium retention occurs in a significant proportion of patients with cirrhosis despite normal supine plasma levels of renin, aldosterone (ALDO), and norepinephrine (NE). The current study was performed to assess whether this subset of patients also present normal activity of the renin-aldosterone and sympathetic nervous systems during upright posture in sitting position and moderate physical exercise. Nine healthy controls, 14 patients with compensated cirrhosis and 10 patients with cirrhosis, ascites, sodium retention, and normal supine plasma renin activity (PRA) and ALDO and NE concentration were sequentially studied after 60 minutes in supine rest, 30 minutes in sitting position, and 30 minutes of cycloergometric exercise (3-METs). Sitting position and exercise were associated with similar stimulation of the renin-aldosterone and sympathetic nervous systems in the three groups of subjects. Consequently, cirrhotic patients with ascites showed values of PRA and plasma concentration of ALDO and NE similar to healthy subjects and patients with compensated cirrhosis during supine rest (renin: 1.4 +/- 0.3, 0.8 +/- 0.2, and 0.8 +/- 0.3 ng/mL; aldosterone: 24.3 +/- 4.7, 20.2 +/- 3.9 and 21.4 +/- 3.4 ng/dL; norepinephrine: 252 +/- 23, 250 +/- 16, and 255 +/- 23 pg/mL), sitting position (renin: 2.1 +/- 0.5, 1.1 +/- 0.3, and 1.6 +/- 0.4; aldosterone: 32.2 +/- 7.3, 23.7 +/- 5.3, and 26.2 +/- 4.5; norepinephrine: 356 +/- 38, 401 +/- 63, and 420 +/- 35), and exercise (renin: 2.9 +/- 0.8, 1.6 +/- 0.4, and 2.2 +/- 0.5; aldosterone: 43 +/- 6.4, 34.9 +/- 8.5, and 38.2 +/- 5.3; norepinephrine: 481 +/- 35, 499 +/- 54, and 534 +/- 48).(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗
Vertebral fractures and osteopenia in chronic alcoholic patients.
To assess whether vertebral fractures are associated with osteopenia in chronic alcoholic patients, a transversal study was carried out in 76 chronic alcoholic males and 62 age-matched healthy males. Lumbar bone mineral density (BMD) by dual photon absorptiometry and spinal chest X-ray films were done in all patients. Twenty-seven patients (36%) had vertebral fractures, but only 5 of them had a BMD below the fracture threshold. Twenty-two patients (29%) had osteoporosis by densitometric criteria. There were no significant differences in lumbar BMD between alcoholic patients with and without vertebral fractures (1.11 +/- 0.2 versus 1.13 +/- 0.2, P = ns). Previous trauma was recorded in 24 of the 27 patients with vertebral fractures and in 28 of the 49 patients without vertebral fractures (P < 0.001). Moreover, patients with vertebral fractures had more peripheral fractures than patients without vertebral fractures (81% versus 49%, P = 0.01). Only one patient was aware of a previous episode of traumatic vertebral fracture. In conclusion, chronic alcoholics frequently have traumas and vertebral fractures, the latter despite having a lumbar BMD above the fracture threshold, suggesting a frequent but unrecognized association between both processes. These results suggest that both spine films and BMD measurements should be obtained for diagnosis of osteoporosis in alcoholic patients.
Absorptiometry, Photon↗
Endothelin 1 does not play a major role in the homeostasis of arterial pressure in cirrhotic rats with ascites.
BACKGROUND/AIMS: Patients with cirrhosis and ascites have increased plasma levels of endothelin, a powerful vasoconstrictor peptide. This study assessed the mechanisms underlying this phenomenon. METHODS: Plasma endothelin was measured in control rats and cirrhotic rats with and without ascites. In addition, the tissue concentration of endothelin and endothelin 1 messenger RNA (mRNA) and the effect of an endothelin A receptor antagonist on arterial and portal pressure were assessed in cirrhotic rats with ascites and control rats. RESULTS: Plasma endothelin levels were significantly higher in cirrhotic rats with ascites (24.5 +/- 2.8 pg/mL; P < 0.001) than in cirrhotic rats without ascites and control rats (7.9 +/- 2.0 and 5.8 +/- 0.9 pg/mL, respectively). In animals with ascites, endothelin and endothelin 1 mRNA content in the lung, kidney, and aorta was similar to that of the controls. In contrast, higher endothelin content (0.567 +/- 0.217 vs. 0.045 +/- 0.002 pg/mg protein; P < 0.05) and endothelin 1 mRNA was observed in hepatic tissue of rats with cirrhosis and ascites. Endothelin A receptor blockade was not associated with significant changes in arterial and portal pressure in any group of animals. CONCLUSIONS: Increased endothelin 1 mRNA and endothelin production occurs in the livers of cirrhotic rats with ascites. In addition, our findings suggest that endothelin is not involved with the homeostasis of arterial or portal pressure in cirrhosis with ascites.
Animals↗
Aquaretic effect of the kappa-opioid agonist RU 51599 in cirrhotic rats with ascites and water retention.
BACKGROUND & AIMS: It has recently been described that kappa-opioid receptor agonists inhibit antidiuretic hormone secretion and promote water excretion in humans and experimental animals. The aim of this study was to evaluate the aquaretic efficacy of the kappa-opioid receptor agonist RU 51599 in conscious cirrhotic rats with ascites and water retention. METHODS: In protocol 1, arterial pressure, heart rate, and renal water metabolism were measured in basal conditions and then were measured for 120 minutes after the administration of Ringer's solution (n = 8; 0.4 mL) or RU 51599 (n = 7; 1 mg/kg). In protocol 2, plasma antidiuretic hormone concentration was measured (n = 6) before and 60 minutes after administration of RU 51599 (1 mg/kg). In protocol 3, the effect of RU 51599 (n = 9; 1 mg/kg) was compared with that of the V2-receptor antagonist SKF 100398 (n = 9; 30 micrograms/kg). RESULTS: RU 51599 administration induced a profound diuretic and aquaretic effect without altering arterial pressure and heart rate. In protocol 2, the kappa-opioid agonist reduced by about 50% plasma antidiuretic hormone levels (from 6.6 +/- 0.9 to 3.4 +/- 0.6 pg/mL; P < 0.05). Finally, the improvement in renal water metabolism induced by RU 51599 was similar to that produced by the V2-receptor antagonist. CONCLUSIONS: RU 51599 has a potent aquaretic effect in cirrhotic rats with water retention, suggesting that kappa-opioid receptor agonists may be useful for the treatment of water retention and dilutional hyponatremia in cirrhosis.
Analysis of Variance↗
Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients.
BACKGROUND & AIMS: The progression of hepatocellular carcinoma may be influenced by estrogens. This has offered the rationale for evaluating the therapeutic usefulness of estrogen-receptor blockers; it is being debated whether long-term tamoxifen administration improves survival in patients with this neoplasm. The aim of this study was to assess the efficacy of tamoxifen administration in the treatment of hepatocellular carcinoma. METHODS: One hundred twenty patients with this neoplasm who were not suitable for surgery, ethanol injection, or transarterial embolization were included in a placebo-controlled trial and randomized to tamoxifen, 20 mg/day per os, (group A, n = 58) or placebo (group B, n = 62). Patients with terminal diseases were excluded. RESULTS: Both groups were similar with regard to sex, age, liver function (Child-Pugh's score, 6.5 +/- 1.4 vs. 6.4 +/- 1.4), baseline performance status, and tumor stage. Tamoxifen had no antitumoral effect with no differences in the survival between groups (1- and 2-year actuarial rate: group A, 51% and 27%; and group B, 43% and 29%; P = 0.75), even when stratifying patients according to baseline status. Furthermore, there were no differences in the probability of disease progression (P = 0.46) and baseline performance status maintenance (P = 0.93) during follow-up. CONCLUSIONS: Tamoxifen has no efficacy in the treatment of patients with advanced hepatocellular carcinoma.
Aged↗
Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats.
BACKGROUND/AIMS: Excessive nitric oxide biosynthesis caused by expression of inducible NO synthase has been implicated in the hyperdynamic circulation of portal hypertension. The aim of the study was to investigate whether inducible NO synthase is expressed in portal hypertension an accounts for the hyperdynamic circulation. METHODS: In study 1, NO synthase activities were measured by the conversion of L-arginine to citrulline in tissues from portal-hypertensive, cirrhotic, and sham-operated rats and from normal rats pretreated with endotoxin and after long-term administration of dexamethasone, which inhibits the expression of inducible NO synthase. In study 2, systemic and splanchnic hemodynamics (radiolabeled microspheres) and gastric blood flow (hydrogen gas clearance and reflectance spectrophotometry) were measured in portal-hypertensive rats after long-term administration of dexamethasone (0.25 mg.kg-1.day-1) or vehicle. RESULTS: In study 1, constitutive and inducible NO synthase activities in portal-hypertensive or cirrhotic rats were similar to those observed in sham-operated rats. The significant increase in the inducible activity observed after endotoxin injection was prevented when rats received long-term treatment with dexamethasone. In study 2, cardiac index, portal-pressure, portal venous inflow, and gastric blood flow were similar in dexamethasone-or vehicle-treated portal-hypertensive rats. CONCLUSIONS: These results to not support a role for an increased expression of the inducible NO synthase in the hyperdynamic circulation of portal hypertension.
Amino Acid Oxidoreductases↗
Increased plasma endothelin in cirrhosis. Relationship with systemic endotoxemia and response to changes in effective blood volume.
BACKGROUND/AIMS: Patients with cirrhosis and ascites show high plasma concentrations of endothelin. The aim of the current study was to investigate whether this feature is a compensatory response to effective hypovolemia or a consequence of systemic endotoxemia. METHODS: Protocols 1 and 2 assess the effect of acute changes in effective blood volume on plasma endothelin, and protocol 3 investigates the relationship between plasma endotoxin and endothelin in patients with cirrhosis and ascites. Protocol 1 included nine healthy subjects and 26 patients with cirrhosis studied during supine rest, upright tilt (which decreases effective blood volume) and cycloergometric exercise (which activates vasoactive systems by a baroreceptor independent mechanism). Protocol 2 included six patients studied before and 1 and 3 h after the intravenous administration of a plasma expander. In protocol 3, the plasma levels of endothelin and endotoxin were measured in 17 non-infected patients with cirrhosis and also in four patients with spontaneous bacterial peritonitis at diagnosis and following resolution of infection. RESULTS: Plasma endothelin was 3-5 times higher in patients with cirrhosis than in healthy volunteers. In healthy subjects, upright tilt and exercise were associated with a significant activation of the renin-aldosterone and sympathetic nervous systems and an increase in plasma endothelin. In patients with cirrhosis, upright tilt and exercise were associated with a significant increase and plasma volume expansion with a marked suppression of the renin-aldosterone and sympathetic nervous systems. However, in these patients none of these maneuvers affected plasma endothelin levels. In the patients with cirrhosis in protocol 3, there was no correlation between plasma endotoxin and endothelin. Resolution of peritonitis was associated with a marked fall in plasma endotoxin and no changes in plasma endothelin. CONCLUSIONS: These findings suggest that mechanisms other than effective hypovolemia or systemic endotoxemia are involved in the increased plasma endothelin of cirrhosis with ascites.
Blood Volume↗
Androgen receptors in hepatocellular carcinoma and surrounding liver: relationship with tumor size and recurrence rate after surgical resection.
BACKGROUND/AIMS: This study aimed to evaluate the parameters associated with the presence of androgen receptors in hepatocellular carcinoma and surrounding non-tumoral liver. Furthermore, we have assessed whether androgen receptor positivity influences disease recurrence after surgical resection. METHODS: Androgen receptor concentration was calculated by receptor binding assay in tumoral and non-tumoral liver in 43 patients (40 of them with cirrhosis) with hepatocellular carcinoma who underwent surgical resection. RESULTS: Androgen receptors were found in 28 of the tumoral and in 30 of the non-tumoral samples, at concentrations ranging between 5 and 211 fmol/mg protein. The presence of androgen receptors within the tumor was significantly related to a smaller tumor size. Thereby, 22 of the 29 nodules < or = 3 cm contained androgen receptors, while this occurred in only six of the 14 tumors larger than 3 cm (p < 0.05). In contrast, the only parameter associated with the presence of androgen receptors in the non-tumoral liver was a lower gamma-glutamyltranspeptidase concentration. Disease recurrence after surgical resection was not only related to some tumor characteristics (increased alfa-fetoprotein concentration, presence of satellites, differentiation degree), but also to the presence of androgen receptors in the surrounding liver. Thus, the probability of recurrence after 1- and 2-year follow up in patients with androgen-positive livers was 33% and 50%, respectively, while it was 0% and 20% in those with androgen-negative livers (p < 0.05). In contrast, the presence of androgen receptors within the tumor was not associated with a higher recurrence rate. CONCLUSIONS: These results show that only two thirds of hepatocellular carcinomas contained androgen receptors and that this feature was more frequent in small tumors. In addition, our data indicate that the presence of androgen receptors within the tumor does not imply a different outcome after surgical resection. In contrast, the presence of these receptors in the surrounding non-tumoral liver may be considered a risk factor for a higher incidence of disease recurrence.
Carcinoma, Hepatocellular↗
Microwave treatment of serum facilitates detection of hepatitis B virus DNA by the polymerase chain reaction. Results of a study in anti-HBe positive chronic hepatitis B.
Investigation by polymerase chain reaction of HBV-DNA in serum from chronic hepatitis B virus carriers is not widely used for routine diagnosis because polymerase chain reaction assays are complex and may be too sensitive. We investigated the sensitivity, the specificity and the possible value for clinical use of a simplified polymerase chain reaction method in which a single, 30 cycles round of polymerase chain reaction is performed using only 10 microliters of serum treated with microwaves. The efficiency of the polymerase chain reaction in amplifying HBV-DNA was greater after microwave irradiation of serum than after alkaline extraction, but lower than after protein digestion and phenol chloroform precipitation. Despite its simplicity and high sensitivity, the assay was very specific. Studies in anti-HBe positive chronic hepatitis B virus carriers demonstrated HBV-DNA sequences in 1/15 (7%) healthy carriers, in 4/20 (20%) patients with slight alanine aminotransferase elevation, in 16/18 (89%) with marked alanine aminotransferase elevation and in all 20 with fluctuating alanine aminotransferase levels. In the latter, HBV-DNA was detected either at exacerbation (two cases), during remission (one case) or both (17 cases). HBV-DNA was detected by classical dot-blot hybridization in only 24/58 (41%) samples that were positive by the simplified polymerase chain reaction method. Although extremely high sensitivity is not achieved, microwave irradiation of serum simplifies considerably the detection of small amounts of HBV-DNA and makes polymerase chain reaction suitable for monitoring patients in whom weak hepatitis B virus replication is associated with ongoing liver disease.
Adult↗