The treatment of viral hepatitis, present and future.
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Amantadine↗
Biomedical subjects
Juan Rodés
Publications and source records attributed to Juan Rodés.
Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis.
Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.
Animals↗
Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II.
BACKGROUND & AIMS: The renin-angiotensin system plays an important role in hepatic fibrogenesis. In other organs, myofibroblasts accumulated in damaged tissues generate angiotensin II, which promotes inflammation and extracellular matrix synthesis. It is unknown whether myofibroblastic hepatic stellate cells, the main hepatic fibrogenic cell type, express the renin-angiotensin system and synthesize angiotensin II. The aim of this study was to investigate whether quiescent and activated human hepatic stellate cells contain the components of the renin-angiotensin system and synthesize angiotensin II. METHODS: Hepatic stellate cells were freshly isolated from normal human livers (quiescent hepatic stellate cells) and from human cirrhotic livers (in vivo activated hepatic stellate cells). Culture-activated hepatic stellate cells were used after a second passage of quiescent hepatic stellate cells. Angiotensinogen, renin, and angiotensin-converting enzyme were assessed by quantitative polymerase chain reaction. Angiotensin II production was assessed by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Quiescent hepatic stellate cells barely express the renin-angiotensin system components--angiotensinogen, renin, and angiotensin-converting enzyme--and do not secrete angiotensin II. In contrast, both in vivo activated hepatic stellate cells and culture-activated hepatic stellate cells highly express active renin and angiotensin-converting enzyme and secrete angiotensin II to the culture media. Mature angiotensin II protein is also detected in the cytoplasm of in vivo activated and culture-activated hepatic stellate cells. Growth factors (platelet-derived growth factor and epidermal growth factor) and vasoconstrictor substances (endothelin-1 and thrombin) stimulate angiotensin II synthesis, whereas transforming growth factor-beta and proinflammatory cytokines have no effect. Vasodilator substances markedly attenuate the effect of endothelin-1. CONCLUSIONS: After activation, human hepatic stellate cells express the components of the renin-angiotensin system and synthesize angiotensin II. These results suggest that locally generated angiotensin II could participate in tissue remodeling in the human liver.
Angiotensin II↗
Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats.
BACKGROUND & AIMS: Portal hypertension in cirrhosis is secondary to an increase in hepatic resistance that occurs mainly through collagen deposition. However, recent evidence points to a major contribution by other factors, such as an intrahepatic reduction in nitric oxide production. Akt is a major activator of the endothelial nitric oxide synthase (eNOS) enzyme, but its potential role in intrahepatic resistance in cirrhosis is unknown. For this reason the aims of the present study were to determine whether there is an impaired Akt activation in cirrhotic livers and how this phenomenon relates to the decrease in NO production associated with portal hypertension. METHODS: Cirrhosis was induced in rats by carbon tetrachloride inhalation. Protein abundance and phosphorylation status of Akt and eNOS were examined by Western blotting. The role of Akt in the liver of cirrhotic rats was investigated through infection with adenoviruses encoding either beta-galactosidase (beta-gal) or constitutively active Akt (myr-Akt). RESULTS: The liver of cirrhotic animals showed a significant reduction in Akt and eNOS phosphorylation. Adenoviral delivery of myr-Akt restored eNOS phosphorylation and increased the intrahepatic concentration of guanosine 3',5'-cyclic monophosphate. These events were associated with normalization in portal pressure and a significant increase in mean arterial pressure after 3 days of adenoviral infection. In contrast, transduction of livers with beta-gal did not produce any change in these hemodynamic parameters. CONCLUSIONS: myr-Akt gene therapy restored Akt activation and NO production in the cirrhotic liver, suggesting that this therapy may be useful for the treatment of portal hypertension.
Adenoviridae↗
Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial.
BACKGROUND/AIMS: The efficacy and safety of rifaximin in comparison with lactitol in the treatment of acute hepatic encephalopathy was assessed in a prospective randomized, double-blind, double-dummy, controlled trial. METHODS: A total of 103 patients with grade I-III acute hepatic encephalopathy were randomized to receive rifaximin (50 patients, 1200 mg/day) or lactitol (53 patients, 60 g/day) for 5-10 days. Changes in the portal-systemic encephalopathy (PSE) index on entry and at the end of the study were used to evaluate the efficacy of the two therapies. RESULTS: Both groups were comparable before treatment with regard to demographic data and characteristics of the hepatic encephalopathy episode. The global efficacy of both therapies was similar: 81.6% in the rifaximin group and 80.4% in the lactitol group showed improvement or total regression of the episode. A significantly better evolution of the PSE index was observed in the rifaximin group, due to a greater effect of rifaximin in two components of the index: EEG abnormalities and ammonia levels. No serious adverse events related to either treatment were found during the study. CONCLUSIONS: Rifaximin may be considered a useful and safe alternative therapy to lactitol in the treatment of acute hepatic encephalopathy in cirrhosis.
Acute Disease↗
p27(Kip1) is an independent predictor of recurrence after surgical resection in patients with small hepatocellular carcinoma.
BACKGROUND/AIMS: Alterations in p27(Kip1) (p27) and cyclin E (cycE) expression are found in tumors and are related to poor prognosis. This study assesses the role of these cell cycle regulators in the development of recurrence after surgical resection in 46 cirrhotic patients (age: 61.3+/-7 years, 30 males, 44 Child-Pugh's A, 30 HCV-positive) with small hepatocellular carcinoma (HCC, size: 3.1+/-1.5cm, 40 solitary at pathological examination). METHODS: p27 and cycE expression in tumoral and non-tumoral liver were analyzed by Western blot (WB). p27 was also assessed by immunohistochemistry (IHC). RESULTS: Tumor p27 underexpression (50% decreased vs. non-tumoral liver) occurred in 12 cases. Throughout follow-up, 26 patients developed recurrence, which was significantly higher in patients with p27 underexpression than in those without (3-year recurrence: 80 vs. 44%, respectively, P=0.026). IHC showed concordant inverse findings: 13 tumors showed high p27 staining that was related to lower recurrence rate (P=0.019). Multivariate analysis identified p27 measured by WB as an improved predictor of recurrence (OR: 3.09, 95% CI: 1.26-7.08, P=0.016). By contrast, cycE, increased in 66% of the tumors, had no impact on recurrence but was associated to poor differentiation (P=0.015) and microvascular invasion (P=0.016). CONCLUSIONS: p27 underexpression is frequent in relatively early stages of HCC and constitutes an independent predictor of recurrence after surgical resection.
Aged↗
Effect of the V1a/V2-AVP receptor antagonist, Conivaptan, on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites.
BACKGROUND: Selective V(2)-AVP receptor antagonists are effective in inducing aquaresis in humans and rats with cirrhosis, hyponatremia and water retention. However, it is unknown whether dual V(1a)/V(2)-AVP antagonists are also efficacious as aquaretic agents under these conditions. This is important, particularly considering that blockade of V(1a)-AVP receptors could aggravate cardiocirculatory function in decompensated cirrhosis. AIMS: To evaluate the renal, hormonal and hemodynamic effects induced by the chronic oral administration of the V(1a)/V(2)-AVP antagonist, Conivaptan, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention. METHODS: We assessed the aquaretic efficacy of 10-day chronic oral administration of Conivaptan (0.5mg/kg body weight (bw)) in cirrhotic rats with hyponatremia and water retention. Urine volume (UV), osmolality (UOsm), and sodium excretion (U(Na)V) were measured daily. At the end of the study arterial pressure was also measured. RESULTS: Conivaptan produced an acute increase in UV, a reduction in UOsm and, at the end of the investigation, cirrhotic rats receiving the V(1a)/V(2)-AVP receptor antagonist did not show hyponatremia or hypoosmolality. Conivaptan also normalized U(Na)V without affecting creatinine clearance and arterial pressure. CONCLUSIONS: Dual V(1a)/V(2)-receptor antagonists may be therapeutically useful for the treatment of water retention and dilutional hyponatremia in human cirrhosis.
Administration, Oral↗
Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation.
BACKGROUND/AIMS: After liver transplantation (LT) infection of the graft with the hepatitis C virus (HCV) is almost universal and chronic hepatitis and cirrhosis develop in a significant proportion of patients. One of the possible strategies to prevent HCV infection recurrence is to eradicate HCV before LT. METHODS: We evaluated the efficacy and safety of antiviral therapy to prevent HCV recurrence in 30 HCV-cirrhotic patients awaiting LT. At the time of inclusion 15 patients were Child-Pugh A and 15 Child-Pugh B/C. The infecting genotype was 1b in 25 patients. Treatment with interferon alpha-2b 3 MU/day and ribavirin 800 mg/day was initiated when the expected time for LT was less than 4 months and continued until LT. The median duration of treatment was 12 weeks. RESULTS: Nine patients (30%) achieved a virological response and 21 did not respond to therapy. In nine (43%) of the 21 non-responders viral load decreased > or =2 log10 during treatment. A viral load decrease > or = 2 log10 at week 4 of treatment was the strongest predictor of virological response. All nine virological responders have already undergone LT; six patients remain free of infection after a median follow-up of 46 weeks and HCV infection recurred in three patients after LT. In one of these patients HCV-RNA was still detectable in the explanted liver. Side effects were frequent and dose reduction was necessary in 19 (63%) of the 30 patients; no patient died while on therapy. CONCLUSIONS: Our data support the utilization of antiviral therapy in HCV-infected patients awaiting LT as one of the strategies to prevent hepatitis C recurrence after transplantation.
Adult↗
Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.
BACKGROUND/AIMS: Cirrhotic livers exhibit endothelial dysfunction that contributes to the increased hepatic vascular resistance. The present study evaluates the role of cyclooxygenase (COX)-derived prostanoids, implicated in the pathogenesis of endothelial dysfunction in other settings, in the pathogenesis of endothelial dysfunction in cirrhotic livers. METHODS: Endothelial dysfunction was evaluated by performing concentration-effect curves to acetylcholine after precontracting the liver with methoxamine in groups of control and CCl(4)-cirrhotic rat livers preincubated either with vehicle, indomethacin, the COX-1 selective inhibitor, SC-560, the COX-2 selective inhibitor, SC-236, the thromboxane A(2) receptor antagonist, SQ 29,548 or the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine. Thromboxane A(2) (TXA(2)) production was determined in samples of the perfusate. RESULTS: Cirrhotic livers exhibited endothelial dysfunction, as shown by the significantly lower relaxation to acetylcholine than control livers, that was totally corrected by indomethacin. COX-1 inhibition and TXA(2) blockade, but not COX-2 inhibition, also corrected endothelial dysfunction. Acetylcholine significantly increased TXA(2) production in cirrhotic but not in control livers. Indomethacin and COX-1 inhibition, but not COX-2 or NO inhibition, prevented the increased production of TXA(2). CONCLUSIONS: An increased production of TXA(2) is involved in the pathogenesis of endothelial dysfunction in cirrhotic rat livers. This is mainly mediated by COX-1, but not by COX-2.
Animals↗
Natural history of primary biliary cirrhosis.
The natural history of PBC is characterized by slowly progressive cholestasis with liver damage, development of cirrhosis and its complications, and death, unless the patient undergoes liver transplantation. The disease has at least three clinical presentations, each with a different course and prognosis: the silent and usually less aggressive form, the asymptomatic form, and the symptomatic form. There are no identifiable features that distinguish the asymptomatic population who will remain symptom-free from those patients who will develop symptoms. As expected, the survival is longer in asymptomatic than in symptomatic patients. Overall survival of asymptomatic PBC is shorter than for an age- and gender-matched control population, but the patients remaining asymptomatic had a survival equal to that of the general population. Natural history studies have identified several variables associated with survival, particularly age, bilirubin, albumin, prothrombin time, ascites, encephalopathy, and advanced histological stage. Development of esophageal varices and hepatocellular carcinoma can also affect survival. Serum bilirubin level is, however, the most heavily weighted prognostic variable and can be used as a simplistic prognostic index for patients with PBC. In the last two decades, natural history models have been developed that include clinical, biochemical, and histological variables, the most popular being the Mayo model. It has the advantage ofavoiding histological variables, and therefore can be applicable to a broad spectrum of patients with PBC. The models may also be used to evaluate the efficacy of different new treatments. Prognostic models based on serial measurements of the independent predictors of poor prognosis would lead to a more accurate prediction of survival; however, they probably will not replace clinical outlook.
Cholagogues and Choleretics↗
Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers.
In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the alpha(1)-adrenergic vasoconstrictor methoxamine and the mechanisms involved in its regulation. A portal perfusion pressure dose-response curve to methoxamine was performed in control and cirrhotic rat livers preincubated with vehicle, the nitric oxide synthase blocker N(G)-nitro-L-arginine (L-NNA), indomethacin cyclooxygenase (COX) inhibitor, L-NNA + indomethacin, or the thromboxane (TX) A(2) receptor blocker SQ 29,548. TXA(2) production, COX-1 and COX-2 mRNA expression, and immunostaining for TXA(2) synthase were evaluated. Cirrhotic livers exhibited a hyperresponse to methoxamine associated with overexpression of COX-2 and TXA(2) synthase as well as with increased production of TXA(2). The hyperresponse to methoxamine of cirrhotic livers disappeared by COX inhibition with indomethacin but not after NO inhibition. SQ 29,548 also corrected the hyperresponse of cirrhotic livers to methoxamine. In conclusion, COX-derived prostanoids, mainly TXA(2), play a major role in regulating the response of cirrhotic livers to methoxamine.
6-Ketoprostaglandin F1 alpha↗
Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis.
Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 +/- 1.4 mm Hg vs. 5.2 +/- 2.1 mm Hg, P =.002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (-7.5% +/-.5%; P <.01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension.
Aged↗
Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.
In cirrhotic patients under pharmacologic treatment for portal hypertension, a reduction in hepatic venous pressure gradient (HVPG) of >or=20% of baseline or to or=20% of baseline or to or=20% or to <or=12 mm Hg is associated with a marked reduction in the long-term risk of developing complications of portal hypertension and with improved survival.
Antihypertensive Agents↗
Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis.
Carbon monoxide, a product of the heme-oxygenase (HO) pathway, is an important endogenous vasoactive substance. Production of CO has not been assessed in human cirrhosis. The aim of this study was to assess production of CO in patients with cirrhosis with and without spontaneous bacterial peritonitis (SBP). CO concentration in the exhaled air and blood carboxyhemoglobin (COHb) levels, as estimates of total HO activity, were determined in 16 healthy subjects, 32 noninfected cirrhotic patients (20 with ascites), and 19 patients with SBP, all nonsmokers. Noninfected cirrhotic patients had a CO concentration in the exhaled air and COHb levels significantly higher compared with values of healthy subjects (2.3 +/- 0.2 ppm vs. 0.7 +/- 0.1 ppm and 1.0% +/- 0.1% vs. 0.6% +/- 0.1%, respectively; P <.05 for both). Patients with ascites had the highest values. Both CO concentration in the exhaled air and COHb levels were very high in patients with SBP (5.6 +/- 0.6 ppm and 1.9% +/- 0.2%; P <.01 vs. the other 2 groups) and decreased slowly after resolution of the infection, reaching values similar to those of noninfected patients 1 month after SBP. In patients with SBP, there was a significantly direct correlation between CO and plasma renin activity (PRA) (r = 0.71, P <.001). In conclusion, these results support the existence of increased CO production in human cirrhosis, which further increases in the setting of SBP. Increased CO production may participate in the disturbance of circulatory function that occurs during severe bacterial infections in cirrhosis.
Bacterial Infections↗
Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation.
Following cell activation, hepatic stellate cells (HSCs) acquire proinflammatory and profibrogenic properties. We investigated whether activated HSCs also display immune properties. Here we show that cultured human HSCs express membrane proteins involved in antigen presentation, including members of the HLA family (HLA-I and HLA-II), lipid-presenting molecules (CD1b and CD1c), and factors involved in T-cell activation (CD40 and CD80). Exposure of HSCs to proinflammatory cytokines markedly up-regulates these molecules. Importantly, cells freshly isolated from human cirrhotic livers (in vivo activated HSCs) highly express HLA-II and CD40, suggesting that HSCs can act as antigen-presenting cells (APCs) in human fibrogenesis. We also explored whether human HSCs can efficiently process exogenous antigens. Activated HSCs internalize low- and high-molecular-weight dextran and transferrin, indicating that they can perform fluid-phase and receptor-mediated endocytosis. Moreover, HSCs can perform phagocytosis of macromolecules because they internalize latex particles as well as bacteria. Interestingly, both culture-activated and in vivo activated HSCs express high levels of CD68, a protein involved in antigen trafficking. Finally, we studied whether HSCs modulate T-lymphocyte proliferation. In basal conditions, coculture of irradiated HSCs barely induces allogeneic T-lymphocyte proliferation. However, cytokine-stimulated HSCs stimulate the allogeneic T-lymphocyte response in an HLA-II-dependent manner. In conclusion, human activated HSCs express molecules for antigen presentation, internalize macromolecules, and modulate T-lymphocyte proliferation. These results suggest that HSCs may play a role in the immune function of the liver.
Antigen Presentation↗
Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.
OBJECTIVES: Osteopenia increases the morbidity of primary biliary cirrhosis (PBC). In this study, we have compared two bisphosphonates, alendronate and cyclical etidronate, that inhibit osteoclast-mediated bone resorption and have examined their effects on bone mass in patients with this disease. METHODS: A total of 32 women with PBC were randomly assigned to receive alendronate (10 mg/day) or etidronate (400 mg/day) for 14 days every 3 months. Bone mineral density of the lumbar spine and proximal femur were measured initially and every 6 months. Bone fractures and markers of bone mineral metabolism were also evaluated. RESULTS: Sixteen patients were allocated to each group, which were comparable with respect to the severity of PBC and osteopenia. Thirteen patients in each group completed the 2-yr trial. Both treatments increased bone mineral density after 2 yr, although the increase at the lumbar spine and at the proximal femur was significantly higher in patients receiving alendronate than in patients on etidronate. This higher effect of alendronate paralleled with changes in the biochemical markers of bone turnover. No patient developed new vertebral fractures, but new peripheral fractures were detected in two patients on alendronate and in one on etidronate. There were no serious adverse effects. Neither treatment impaired liver function or cholestasis. CONCLUSIONS: Alendronate effectively increases bone mass and has greater antiresorptive power than etidronate in patients with primary biliary cirrhosis, and is associated with minor or no side effects.
Adult↗
EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version).
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Hepatitis B↗
Increased plasma levels of neuropeptide Y in hepatorenal syndrome.
BACKGROUND/AIMS: To investigate the relationship between neuropeptide Y (NPY), a potent renal vasoconstrictor peptide released upon marked stimulations of sympathetic nervous system (SNS), and renal and circulatory function in cirrhosis. METHODS: Plasma levels of NPY (radioimmunoassay) and norepinephrine and renal function parameters were determined in 17 healthy controls, nine patients with cirrhosis without ascites, and 37 patients with cirrhosis and ascites, of whom 12 had hepatorenal syndrome (HRS). RESULTS: Patients with ascites showed circulating levels of NPY similar to those of patients without ascites and controls (73+/-4, +/-4 and 68+/-4 pmol/l, respectively; NS). However, patients with HRS had significantly increased levels of NPY with respect to the other groups (110+/-6 pmol/l; P<0.001). NPY levels correlated inversely with renal plasma flow and glomerular filtration rate and directly with norepinephrine. In patients with HRS (n=6) treatment with terlipressin and albumin was associated with a marked improvement in circulatory and renal function and marked suppression of NPY and norepinephrine levels. CONCLUSIONS: Patients with HRS have increased levels of NPY which are related to circulatory dysfunction and SNS activation and may contribute to renal vasoconstriction.
Ascites↗