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Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect, defined by an increased alveolar-arterial oxygen gradient, induced by pulmonary vascular dilatations in the context of liver disease. The pathogenesis of HPS is poorly understood. Morphologic changes associated with HPS are unknown. This study aimed at describing imaging and pathology changes associated with HPS.

Autophagy is a regulated process that can be involved in the elimination of intracellular microorganisms and in antigen presentation. Some in vitrostudies have shown an altered autophagic response in hepatitis C virus infected hepatocytes. The present study aimed at evaluating the autophagic process in the liver of chronic hepatitis C (CHC) patients. Fifty-six CHC patients and 47 control patients (8 with nonalcoholic steatohepatitis or alcoholic liver disease, 18 with chronic heptatitis B virus infection, and 21 with no or mild liver abnormalities at histological examination) were included. Autophagy was assessed by means of electron microscopy and microtubule-associated protein light chain 3 immunoblotting. Using light chain 3 immunoblotting, the form present on autophagic vesicle (light chain 3-II) was significantly higher in CHC patients than in controls (P< 0.05). Using quantitative electron microscopy analysis, the median number of autophagic vesicles observed in hepatocytes from CHC patients was sixfold higher than in overall controls (P< 0.001). In contrast, there was no difference between CHC patients and controls in the number of mature lysosomes with electron-dense contents arguing in favor of a lack of fusion between autophagosome and lysosome. Neither genotype nor viral load influenced the autophagy level. In conclusion, autophagy is altered in hepatocytes from CHC patients, likely due to a blockade of the last step of the autophagic process.

Background & Aims:In rats with portal vein stenosis, the initial cause of aortic nitric oxide (NO) overproduction might be overactivation of endothelial NO synthase (eNOS) related to increased shear stress. Cardiac output is higher in cirrhosis than in extrahepatic portal hypertension. The aims of this study were to evaluate the role of shear stress, vascular endothelial growth factor (VEGF), and cytokines in aortic eNOS up-regulation in rats with biliary cirrhosis and to compare these results with those in rats with portal vein stenosis. Methods:NOS activities, NOS protein, heat shock protein (Hsp) 90, and VEGF expressions were studied in rat aortas. Propranolol was administered to rats with cirrhosis to reduce cardiac output and thus shear stress. Results:In cirrhotic rats, the aortic eNOS protein was 3.0 and 1.7 times higher than in control and portal vein–stenosed rats, respectively. In cirrhotic rats, the Hsp90 content was 3.2 and 2.2 times higher than in control and portal vein–stenosed rats, respectively. Propranolol decreased NOS activity by 47% and eNOS and Hsp90 expression by 75% and 72%, respectively. Aortic VEGF expression was decreased in cirrhotic rats. VEGF-induced stimulation of NOS activity was greater in aortas from control rats than in aortas from portal vein–stenosed or cirrhotic rat aortas. eNOS expression was up-regulated after VEGF incubation. After lipopolysaccharide administration, eNOS expression did not change in portal vein–stenosed or cirrhotic rats. Conclusions:This study shows that in aortas from rats with biliary cirrhosis, systemic vasodilation depends mainly on eNOS up-regulation related to shear stress.

In patients with cirrhosis, discrepant findings have been reported on the evolution of pulmonary hemodynamics and gas exchange after liver transplantation. The aim of this study was to evaluate the effects of liver transplantation on pulmonary and systemic hemodynamics and gas exchange in patients transplanted for cirrhosis. Forty-three patients with cirrhosis underwent hemodynamic investigations before and one year after liver transplantation. Mean pulmonary arterial pressures did not significantly change after transplantation (from 17 ± 4 to 17 ± 3 mm Hg) whereas pulmonary vascular resistance significantly increased by 62%. Cardiac index significantly decreased by 20%. Pao2did not change significantly after transplantation (from 88.8 ± 13.9 to 88.5 ± 12.1 mm Hg) and PaCo2significantly increased by 16%. In conclusion, liver transplantation has no effect on pulmonary pressures but normalizes pulmonary vascular resistance in patients with cirrhosis without pulmonary hypertension. Moreover, it has no major effect on gas exchange in patients with cirrhosis without hypoxemia.

In splanchnic arteries, vasodilators decrease the cytosolic free calcium concentration ([Ca2+]i) by inducing Ca2+sequestration and extrusion, by limiting the entry of extracellular Ca2+via L-type Ca2+channels and by decreasing the agonist-induced mobilization of intracellular Ca2+. Cyclic GMP kinase and membrane hyperpolarization are important mediators of the decrease in [Ca2+]i. Vasoconstrictors increase [Ca2+]i by mobilizing intracellular Ca2+from the sarcoplasmic reticulum and by stimulating extracellular Ca2+entry via L-type Ca2+channels. Activation of G proteins, inositol trisphosphate, diacylglycerol and membrane depolarization are important mediators of the increase in [Ca2+]i.

Background & Aims:Although protein kinase C (PKC) alterations may play a role in the abnormal reactivity of cirrhotic rat aortas, its isoforms and cellular distribution are unknown. We therefore studied the protein expression and cellular distribution of PKC isoforms and their activation in cirrhotic rat aortas. Methods:Endothelium-denuded aortas from control and cirrhotic rats were examined. Immunoblots were performed with PKC isoform–specific antibodies. Aortic reactivity was determined for phorbol myristate acetate and phenylephrine after PKC down-regulation. Results:PKC-α expression was reduced in both the cytosolic and membrane fractions in cirrhotic aortas. Trace amounts of PKC-β were detected in cirrhotic aortas. PKC-δ was detected in the cytosolic fraction of control and cirrhotic aortas. PKC-ζ was detected in the membrane fraction in control aortas and in the cytosolic fraction in cirrhotic aortas. Phorbol myristate acetate and phenylephrine triggered translocation of PKC-α and PKC-δ isoforms from the cytosol to the membrane in control aortas; in cirrhotic aortas, only PKC-α was translocated. Aortic reactivities were reduced after PKC down-regulation. PKC-α and -δ activities were reduced in cirrhotic aortas. Conclusions:These results suggest that a change in PKC isoforms may be responsible in part for the abnormal reactivity and intracellular transduction through the PKC pathway in cirrhotic rat aortas.

Background & Aims:In portal hypertension, the mechanisms responsible for nitric oxide (NO) overproduction and vasodilation have not yet been clearly identified. One hypothesis is that NO synthase (NOS) 3 is overactivated because of shear stress in endothelial cells caused by hyperkinetic circulation. The aim of this study was to evaluate aortic NOS3 after a reduction of blood flow by long-time β-adrenoceptor antagonist administration. Methods:Propranolol or atenolol was administered by gavage in portal vein–stenosed and sham-operated rats. The vascular reactivity of thoracic aortic rings to phenylephrine, total aortic NOS activity, and aortic NOS3 messenger RNA and protein expressions were studied. Results:After propranolol or atenolol administration, the aortic hyporesponse returned to normal in portal vein–stenosed rats. Total aortic NOS activity was higher in portal vein–stenosed aortas and significantly decreased after β-blocker administration. Aortic NOS3 expressions were more marked in portal vein–stenosed aortas than in controls, but NOS3 expressions were reduced after propranolol administration. Conclusions:In portal hypertension, aortic NOS3 activity and expressions are enhanced but return to normal after β-blocker administration. These results suggest that in portal hypertension, increased shear stress, related to high blood flow, induces enhanced aortic NOS3.

AbstractThe technical factors which could influence regeneration of the native liver (NL) in auxiliary liver transplantation (ALT) for fulminant hepatic failure (FHF) are not well known. We studied NL regeneration according to the location of graft anastomosis in the recipient's portal system (superior mesenteric vein versus portal vein), and graft weight (50 % reduced‐size versus full‐size graft) in a rat model of ALT with 80% reduction of the NL, and graft arterialization. NL regeneration was significantly more obvious when the graft was anastomosed on the recipient's superior mesenteric vein, thus establishing venous flow to the NL from the pancreas, the spleen, and the stomach, and when a full‐size graft was used. The influence of portal venous flow on NL regeneration, assessed by [3H]‐thymidine incorporation, was measurable as early as day 2. Both technical variables in combination resulted in significantly greater regeneration (ratio weight of NL/body weight at day 30: 2.32 ± 0.68% versus 1.21 ± 0.63 % respectively, P= 0.02). Early preservation of portal flow to the NL is advisable to maximize NL regeneration in ALT. In any case, this regeneration is not impeded by the use of large auxiliary grafts.

Abstract: The technical factors which could influence regeneration of the native liver (NL) in auxiliary liver transplantation (ALT) for fulminant hepatic failure (FHF) are not well known. We studied NL regeneration according to the location of graft anastomosis in the recipient's portal system (superior mesenteric vein versus portal vein), and graft weight (50 % reduced-size versus full-size graft) in a rat model of ALT with 80 % reduction of the NL, and graft arterialization. NL regeneration was significantly more obvious when the graft was anastomosed on the recipient's superior mesenteric vein, thus establishing venous flow to the NL from the pancreas, the spleen, and the stomach, and when a full-size graft was used. The influence of portal venous flow on NL regeneration, assessed by [3H]-thymidine incorporation, was measurable as early as day 2. Both technical variables in combination resulted in significantly greater regeneration (ratio weight of NL/body weight at day 30: 2.32 0.68 % versus 1.21 0.63 % respectively, P = 0.02). Early preservation of portal flow to the NL is advisable to maximize NL regeneration in ALT. In any case, this regeneration is not impeded by the use of large auxiliary grafts.

In cirrhosis there is a hyperdynamic circulation, which occurs mainly in the systemic and splanchnic regions. Using isolated-vessel models, previous studies have shown reduced aortic reactivity to vasoconstrictors in rats with cirrhosis. The aim of the present study was to evaluate and compare the vascular responsiveness to phenylephrine in arterial rings and the blood flows from different regions in rats with cirrhosis and controls. Reactivity was studied in isolated thoracic aortic, superior mesenteric arterial and carotid arterial rings from sham-operated and bile-duct-ligated rats by measuring the cumulative concentration-dependent tension induced by phenylephrine (10-9–10-4 M). Blood flows were measured by the radioactive microsphere method. In rats with cirrhosis, a significant hyporeactivity to phenylephrine was observed in both the aorta and the superior mesenteric artery compared with the corresponding arteries of normal rats. This hyporesponsiveness was corrected by Nω-nitro-l-arginine (0.1 mM). In contrast, carotid artery reactivity and the responses to Nω-nitro-l-arginine were similar in the cirrhotic and control groups. In each case, cardiac output and mesenteric arterial blood flow were significantly higher in cirrhotic than in normal rats. Cerebral blood flows were not significantly different between the two groups. In cirrhotic rats, arterial hyporeactivity may be a consequence of increased regional blood flow and increased production of nitric oxide.

The prevalence of pulmonary hypertension in 507 patients hospitalized with portal hypertension but without known pulmonary hypertension who underwent cardiac catheterization was prospectively studied. Ten (2%) of these patients, 6 of whom were clinically asymptomatic, had primary pulmonary hypertension. Second, 26 patients with symptomatic pulmonary hypertension complicating portal hypertension were reviewed. Pulmonary hypertension occurred later after diagnosis of portal hypertension in patients with a surgical shunt (10 patients) than in those without a shunt (147 ± 49 vs. 44 ± 27 months; P< 0.0001). Cardiac index correlated inversely with pulmonary arterial pressure (r= −0.45; P< 0.01) and was lower in the 5 patients who died of pulmonary hypertension than in the 5 who died of liver failure (1.52 ± 0.14 vs. 3.69 ± 1.88 L/min · m2; P< 0.05). Third, systemic and splanchnic hemodynamics were compared in 285 patients with alcoholic cirrhosis and 29 controls. No significant relation was found between elevated pulmonary vascular resistance and increased portal pressure, azygos blood flow, or cardiac index. Pulmonary hypertension is considerably more frequent than was previously estimated in patients with portal hypertension. The risk of developing pulmonary hypertension could increase with the duration of portal hypertension without any clear relation to the degree of portal hypertension, hepatic failure, or amount of blood shunted.

Background/Aims:The effects of C-type and brain natriuretic peptides (CNP and BNP, respectively) on renal excretion of sodium and hemodynamics have not yet been studied in cirrhosis.

We report a 33-year-old woman who took oral contraceptives for 8 years, and who developed gastrointestinal bleeding from esophageal varices. Celiac and mesenteric angiography demonstrated a portal vein thrombosis. Because of several episodes of dyspnea, a pulmonary angiogram was also performed, and showed partial or complete obstruction of both inferior pulmonary arteries with “pruning” of lower lobes. Despite immediate anticoagulant therapy, the patient died suddenly some days later. We believe that oral contraceptive treatment could have induced thromboembolic disease both in portal and pulmonary circulations in this patient.

Membranous obstruction of the inferior vena cava has been reported mainly in South Africa, Japan, and India; in 20–40 of patients the disease is complicated by hepatocellular carcinoma. We report a case of membranous obstruction of the inferior vena cava with hepatocellular carcinoma in a 43-year-old Caribbean man of Indian origin. The Caribbean islands may constitute another geographical area where the population is at risk for the development of membranous obstruction of the inferior vena cava and subsequent hepatocellular carcinoma.

We carried out hepatic vein catheterization in 73 patients with liver cancer, 52 with primary and 21 with metastatic cancer. A heterogeneous hepatic venous pressure gradient, defined as a difference of >4 mmHg between the highest and lowest values of the pressure gradient in any patient, was found in 46 of the hepatocellular carcinoma cases and 43 of the metastatic cancers. Comparing the diagnostic efficacy of this phenomenon with an elevated a-fetoprotein, based on 500 randomly selected catheterizations, showed that the heterogeneous gradient was 46 sensitive and 99 specific for the diagnosis of hepatocellular carcinoma, while the α-fetoprotein was 67 sensitive and 99 specific. Positive and negative predictive values were 86 and 95, respectively, for the heterogeneous gradient, and 83 and 97 for the a-fetoprotein. Its expense and relative invasiveness make hepatic vein catheterization an unacceptable routine in patients suspected of having hepatic malignancy. However, we suggest that the unexpected finding of a heterogeneous pressure gradient should trigger a search for hepatic cancer.

1. Although pentoxifylline has been shown to reduce portal hypertension, the mechanism for this is unclear. Since pentoxifylline decreases tumour necrosis factor-α production and since this cytokine may induce vasodilatation per se, a pentoxifylline-induced decrease in tumour necrosis factor-α production may limit arterial vasodilatation and decrease portal pressure. The aim of the present study was to examine the effects of pentoxifylline administration on plasma tumour necrosis factor-α concentrations and haemodynamics in normal and cirrhotic rats. 2. In both groups, systemic and splanchnic haemodynamics and plasma tumour necrosis factor-α concentrations were measured before and 120 min after the administration of saline or pentoxifylline (20 mg/kg intravenous bolus). 3. In cirrhotic rats, pentoxifylline significantly decreased portal pressure (24 ± 13%) and tributary blood flow (33 ± 30%). On the other hand, pentoxifylline significantly increased vascular resistance in portal and hepatic arterial territories. Systemic haemodynamics were not altered. In normal rats, pentoxifylline significantly decreased portal pressure but induced no other significant changes in splanchnic or systemic haemodynamics. In cirrhotic rats, plasma tumour necrosis factor-α concentrations were significantly reduced after pentoxifylline administration but not after saline administration. No significant correlations were found between pentoxifylline-induced changes in tumour necrosis factor-α levels and changes in splanchnic haemodynamics. In normal rats, plasma tumour necrosis factor-α concentrations significantly decreased after pentoxifylline or saline administration. 4. This study shows that in rats with cirrhosis, pentoxifylline induces a decrease in both portal pressure and plasma tumour necrosis factor-α concentrations. These reductions were not correlated however.

A somatostatin analogue, a long-acting octapeptide (SMS 201-995), has been reported to decrease portal pressure, but the mechanism is unclear. To elucidate the effects of this drug on both systemic and splanchnic hemodynamics, it was administered in two conscious rat models of portal hypertension. The dose-response curves showed that the somatostatin analogue significantly decreased portal pressure at a lower dose in rats with cirrhosis than in portal vein-stenosed rats. Calculated ED50values were significantly different among all groups. Intravenous infusion of 8 μg/kg body wt · h of somatostatin analogue significantly decreased cardiac output by ~20% in both groups of portal hypertensive rats and increased mean arterial pressure by 7%. Accordingly, systemic vascular resistance markedly increased, indicating vasoconstrictor effects of this drug. The somatostatin analogue also significantly decreased portal tributary blood flow by 18% in portal vein-stenosed rats and 27% in cirrhotic rats. In sham-operated rats, somatostatin analogue had no effect on the systemic or splanchnic circulation. This study shows that somatostatin analogue decreases portal pressure principally by reducing portal tributary blood flow. This reduction may be due to either a direct vasoconstrictive effect or diminution in vasoactive hormone release.

The relationship between the degree of portal hypertension and histologic liver lesions was studied in a group of 84 patients with histologically proven alcoholic cirrhosis. The degree of portal hypertension was evaluated by the gradient between wedged and free hepatic venous pressures. Five histologic lesions were quantified: liver cell necrosis, Mallory bodies, neutrophilic infiltrate, fibrosis, and fatty infiltration. The gradient between wedged and free hepatic venous pressures was significantly correlated with the degree of liver cell necrosis and the degree of neutrophilic infiltrate. The stepwise regression analysis showed that only liver cell necrosis has a significant and independent correlation for the degree of portal hypertension. The value for the gradient between wedged and free hepatic venous pressures was significantly higher in patients with (N=48) than in those without (N=36) acute alcoholic hepatitis (19.4±0.8 and 16.5±0.7 mmHg, respectively). Thus, histologic liver lesions observed in acute alcoholic hepatitis may play a role in the risk of complications of portal hypertension in patients with alcoholic cirrhosis.

Terlipressin (Glypressin), a vasopressin analog, may be administered to patients with cirrhosis receiving aβ-adrenergic antagonist. Since terlipressin alone andβ-blockers alone both decrease portal pressure, a combination of these substances may have additional portal hypotensive effects. However, the negative side effects of terlipressin may be accentuated by long-termβ-blockade. Thus, the present study examined hemodynamic and metabolic responses to terlipressin in 12 patients receiving nonselectiveβ-blockers (propranolol or nadolol). Hemodynamics and oxygen (O2) -derived variables were measured prior to and 30 min after the administration (intravenous bolus) of terlipressin (1 to 2 mg, according to body weight). The hepatic venous pressure gradient and azygos blood flow significantly decreased (from 15.3±1.1 to 12.5±1.1 mm Hg, and from 0.6±0.1 to 0.5±0.1 liters/min, respectively). Arterial and pulmonary wedged pressures significantly increased. Heart rate, cardiac index, and O2 consumption were not significantly affected by terlipressin. In conclusion, in patients with cirrhosis being treated with a nonselectiveβ-blocker, terlipressin administration decreased portal pressure. Moreover, terlipressin induced only mild systemic hemodynamic effects in these patients. These results suggest that terlipressin can be administered in patients receiving aβ-adrenergic blocker.

Liver involvement is common in acute and chronic Q fever and consists of nonspecific hepatitis and granulomas without fibrosis. We report the case of a patient suffering from chronic Q fever with nonspecific hepatitis and granulomas, in whom progressive development of extensive liver fibrosis was documented by repeated biopsies.

Portal hypertension is treated by reducing portal pressure in order to prevent esophageal variceal bleeding or recurrent bleeding. Because portal hypertension depends on both elevated portal tributary blood flow and intrahepatic vascular resistance, the pharmacologic therapy of this sydrome consists in reducing portal blood flow or vascular resistance, or both. The pharmacologic prevention of first bleeding or recurrent bleeding has been performed with nonselective ß-adrenergic antagonists (propranolol or nadolol). Certain controlled studies have shown that this type of drug signifcantly reduces the risk of first bleeding by approximately 40% in patients with esophageal varices. A meta-analysis showed that death due to bleeding was also significantly lower in the ß-blocker group than in the placebo group. Moreover, ß-blockers are effective in patients in both good and poor condition and with all types of cirrhosis. The efficacy of ß-blockers on the risk of recurrent bleeding is less clear, but these substances significantly decrease the risk of rebleeding, by approximately 30%. Recurrent bleeding in patients treated with ß-blockers is associated with the occurrence of hepatocellular carcinoma or lack of compliance. In conclusion, it is clear that different substances have portal hypotensive effects and can be used to treat or prevent complications of portal hypertension. However, other drugs should be tested, and other clinical studies are needed to identify good responders.

1. In order to study the acute effects of blood volume changes on the vascular resistance of portal-systemic collaterals (collateral vascular resistance), a model of total portal vein occlusion with 100% portal-systemic shunts was developed in the rat. In this model, we determined the haemodynamic effects of haemorrhage (1.8 ml/100 g body weight) or intravenous infusion of a volume expander (1.8 ml/100 g body weight). Cardiac output and regional blood flows were measured by the radioactive microsphere method. 2. Haemorrhage significantly reduced arterial pressure from 108 ± 4 to 92 ± 4 mmHg (mean ± sem), cardiac output from 56 ± 4 to 24 ± 2 ml min−1 100 g−1 body weight, portal pressure from 15.1 ± 1.5 to 10.0 ± 1.4 mmHg and portal tributary blood flow from 19.9 ± 2.3 to 8.3 ± 1.4 ml/min. Consequently, collateral vascular resistance significantly increased from 6.6 ± 0.9 × 103 to 11.1 ± 2.0 × 103 kPal−1 s. 3. Volume expansion reduced arterial pressure from 98 ± 3 to 90 ± 3 mmHg, and significantly increased cardiac output from 43 ± 3 to 55 ± 3 ml min−1 100 g−1 body weight, portal pressure from 13.9 ± 0.7 to 16.5 ± 0.8 mmHg and portal tributary blood flow from 16.4 ± 1.3 to 28.2 ± 3.2 ml/min. Consequently, collateral vascular resistance significantly decreased from 7.0 ± 0. 5 × 103 to 4.9 ± 0.4 × 103 kPa l−1 s. 4. This study shows that in rats with portal hypertension, portal-systemic collateral vascular resistance is modified by alterations in blood volume.

The effect of propranolol on systemic and hepatic hemodynamics was studied in patients with cirrhosis. One hour after 40 mg propranolol by mouth as well as during continuous oral dosing at doses that reduced heart rate 25%, cardiac output and the hepatic venous pressure gradient fell significantly, whereas arterial pressure and hepatic blood flow did not change significantly. In six patients with cirrhosis and surgical end-to-side portacaval shunts, cardiac output and the hepatic venous pressure gradient also decreased 15 minutes after intravenous propranolol (5 mg), whereas hepatic blood flow did not change significantly. In the patients with surgical shunts, systemic vascular resistance rose significantly but hepatic arterial vascular resistance fell. Our data show that in patients with cirrhosis, propranolol induces an increase in the fraction of cardiac output reaching the liver.Clinical Pharmacology and Therapeutics (1985) 37, 376–380; doi:10.1038/clpt.1985.54

Patients with suspected portal hypertension must first be evaluated by physical examination, upper digestive endoscopy and ultrasonography with Doppler. Moreover, the evaluation of patients with portal hypertension depends on the cause of portal hypertension, the presence of complications and the specific treatment considered. Haemodynamic assessment with measurement of the hepatic venous pressure gradient is useful in confirming the origin of portal hypertension. This technique is the ‘gold-standard’ for evaluating haemodynamic treatments. Splanchnic and systemic circulation must also be measured. Quantitative evaluation of the splanchnic territory by Doppler sonography and other non-invasive investigations, may be performed. Further clinical studies are, however, needed to determine their interest in portal hypertension.

The degree of portal hypertension and its haemodynamic complications can be easily determined. However, the interpretation of these values is not entirely clear and further clinical and experimental studies are needed to explain why some patients with portal hypertension bleed from oesophageal varices while others do not.

Catecholamines, which are elevated during alcohol withdrawal, can alter hepatic blood flow and increase hepatic oxygen consumption. We hypothesized that, in the withdrawal state, hepatic oxygen consumption and delivery could be altered in relation to an increased sympathetic activity. Thirteen chronic alcoholics were studied 34–72 h after withdrawal and 10 days later (control period) using conventional hemodynamic methods. As compared with the control period, splanchnic oxygen uptake was elevated at withdrawal (74.5 ± 27.1 vs. 59.2 ± 16.8 ml/min, p < 0.025) and its variation was correlated with that of plasma epinephrine (r = 0.70, p < 0.01). The hepatic venous oxygen content was reduced at withdrawal (113 ± 22 vs. 126 ± 21 ml/L, p < 0.025) and correlated inversely with plasma norepinephrine levels (r = 0.56, p < 0.01). We conclude that, during alcohol withdrawal in humans, hepatic energy expenditure may be elevated in relation to epinephrine secretion and that sympathetic overactivity may hinder the adaptive response in hepatic blood flow. The wide range in sympathetic nervous response to alcohol withdrawal could explain some differences in individual susceptibility to liver damage caused by alcohol.

Background/Aims:Because the vasodilator nitric oxide is overproduced in cirrhosis, this substance may decrease pressor responses to the vasoconstrictor endothelin 1. This study aimed to examine the effects of a NO synthesis inhibitor (Ng-nitro-l-arginine methyl ester; l-NAME) on vascular responsiveness to endothelin 1 in normal and cirrhotic rats. Methods:Pressor doseresponse curves to endothelin 1 (0.5, 1, 3, 6, and 10 μg/kg intravenously) were obtained in animals with or without pretreatment with l-NAME. Results:Pressor responses to endothelin 1 alone were significantly lower in cirrhotic than in normal rats. In cirrhotic animals, pressor responses to 3, 6, and 10 μg/kg of endothelin 1 were significantly higher in the presence than in the absence of l-NAME. The responses to the other doses of endothelin 1 were not affected by l-NAME. In normal rats, pressor responses to all doses of endothelin 1 were significantly higher in the presence than in the absence of l-NAME. In animals pretreated with l-NAME, pressor responses to 6 and 10 μg/kg of endothelin 1 did not differ between cirrhotic and normal rats, whereas responses to other doses remained lower in cirrhotic than in normal rats. Conclusions:In rats with cirrhosis, NO seems to contribute to vascular hyporeactivity to high doses but not to low doses of endothelin 1.

To elucidate a possible role for reduction of intrahepatic vascular space in the pathogenesis of portal hypertension, we studied a partially hepatectomized rat model in vitro and in vivo. The in vitro study used livers from normal, ⅓-hepatectomized, and 2/3-hepatectomized rats, and rats with cirrhosis caused by chronic bile duct ligation, for isolated, perfused flow-pressure plotting. Resistance to perfusion increased such that significant differences were found between all groups except the last two, which showed similar resistances. The in vivo study measured splanchnic blood flow by radioactive microspheres and portal pressure in anesthetized shamoperated and ⅓- and 2/3-hepatectomized rats. Although absolute portal tributary blood flows did not change, portal flow per gram of remnant liver showed significant increases: 1.57 ± 0.32 ml/min · g liver, 2.52 ± 0.60 ml/min · g liver, p < 0.01; 3.48 ± 1.04 ml/min · g liver, p < 0.01, respectively. Although intrahepatic resistance increased significantly only in the 2/3-hepatectomized group, portal pressures increased significantly in both groups of hepatectomized rats: normal, 7.5 ± 1.1 mmHg; ⅓-hepatectomized, 9.4 ± 1.1 mmHg; and 2/3-hepatectomized, 11.1 ± 1.2 mmHg. Thus, decreased intrahepatic vascular space caused by resection and hepatocellular hypertrophy leads to portal hypertension, thereby suggesting that this reduction in space may be the pathogenic factor common to a number of different theories of portal hypertension.

The aim of the present study was to examine the short- and long-term effects of the α2-agonist clonidine on sympathetic overactivity, systemic, splanchnic, and renal circulation changes, and abnormal renal sodium excretion in cirrhotic patients with ascites. Of 17 patients, 8 received clonidine and 9 a placebo. Measurements were taken before and after either a single dose of clonidine (150 μg) and placebo or a 1-week treatment with clonidine (150 μg/day) and placebo. Clonidine but not placebo induced significant short- and long-term decreases in plasma norepinephrine concentrations in the pulmonary artery and the right renal vein. Acute clonidine administration induced a significant reduction in cardiac output, heart rate, arterial pressure, and hepatic venous pressure gradient but had no effect on renal hemodynamics. Long-term clonidine administration induced a significant decrease in the hepatic venous pressure gradient from 20.1 ±1.9 to 17.6 ± 2.0 mm Hg (mean ± SEM) but had no significant effects on systemic or renal hemodynamics or renal excretion of sodium. It is concluded that long-term clonidine administration in cirrhotic patients induced a sustained decrease in sympathetic nervous activity and portal pressure. In contrast, clonidine had no prolonged effect on systemic hemodynamics. In addition, short- and longterm clonidine administration did not modify renal hemodynamics or induce a natriuretic response in patients with ascites.

To determine the reproducibility of splanchnic blood flow measurements by the microsphere method in rats with portal hypertension and the effects of laparotomy with portal vein cannulation, eight groups of 10 rats were studied. Cardiac output and regional blood flows were measured twice, 10 min apart, in pentobarbital anesthetized or awake, sham-operated or portal vein-ligated rats, with or without portal cannulation. Variability between the two successive measurements was not affected by portal hypertension or portal cannulation, and was not different in the splanchnic territory and in other organs. Laparotomy with portal cannulation had no significant effect in sham-operated rats. In awake portal hypertensive rats, cardiac output (53.9 ± 3.0 vs 45.8 ±2.9 ml · min-1· 100 g body wt-l, P< 0.01) and splanchnic blood flow (12.31 ± 0.72 vs 9.34 ± 0.85 ml · min-1· 100 g body wt-1, P< 0.01) were lower in portal vein cannulated rats compared with those of non-cannulated animals. In anesthetized portal hypertensive rats blood flows were unaffected by portal cannulation, but arterial pressure (100.2 ± 4.3 vs 119.9 ± 3.4 mm Hg, P< 0.01) and heart rate (366.5 ± 10.0 vs 405.5 ± 7.4 beats · min-1, P< 0.01) were elevated. Anesthesia also decreased portal pressure (14.8 ± 0.5 vs 12.0 ± 0.4 mm Hg, P< 0.05) in portal hypertensive rats. We conclude that the microsphere method remains reproducible in portal hypertensive rat models. Laparotomy with portal cannulation can alter systemic and splanchnic hemodynamics in portal hypertensive rats; these effects can also be changed during pentobarbital anesthesia. Regional blood flow measurements in portal hypertensive rats should be performed in animals without portal cannulation and preferably in the awake state.

Summary The authors report the case of a patient suffering from ulcerative colitis, who had several episodes of digestive hemorrhage due to portal hypertension. Portal hypertension was secondary to chronic portal vein thrombosis. This diagnosis was made on the venous phase of celiac and mesenteric angiography. The authors review the published cases of ulcerative colitis with portal vein thrombosis and discuss the possible etiologic factors: hypercoagulability, thrombocytosis, and intraabdominal sepsis.

Portal hypertension is treated by reducing portal pressure in order to prevent esophageal variceal bleeding or recurrent bleeding. Because portal hypertension depends on both elevated portal tributary blood flow and intrahepatic vascular resistance, the pharmacologic therapy of this sydrome consists in reducing portal blood flow or vascular resistance, or both. The pharmacologic prevention of first bleeding or recurrent bleeding has been performed with nonselective ß-adrenergic antagonists (propranolol or nadolol). Certain controlled studies have shown that this type of drug signifcantly reduces the risk of first bleeding by approximately 40% in patients with esophageal varices. A meta-analysis showed that death due to bleeding was also significantly lower in the ß-blocker group than in the placebo group. Moreover, ß-blockers are effective in patients in both good and poor condition and with all types of cirrhosis. The efficacy of ß-blockers on the risk of recurrent bleeding is less clear, but these substances significantly decrease the risk of rebleeding, by approximately 30%. Recurrent bleeding in patients treated with ß-blockers is associated with the occurrence of hepatocellular carcinoma or lack of compliance. In conclusion, it is clear that different substances have portal hypotensive effects and can be used to treat or prevent complications of portal hypertension. However, other drugs should be tested, and other clinical studies are needed to identify good responders. Le traitement de l'hypertension portale repose sur la réduction de la pression sanguine dans le système porte de façon à prévenir le saignement par rupture de varices oesophagiennes ou la récidive. Puisque l'hypertension portale dépend à la fois d'une élévation de la pression dans les collatérales du système porte et de la résistance intrahépatique, la pharmacothérapie de ce syndrome vise donc à réduire le débit porte ou à réduire la résistance intrahépatique voire les deux. La prévention pharmacologique de la première hémorragie ou de la récidive relèvent des antagonistes béta-adrénergiques non sélectifs (propranalol ou nadolol). Certaines études contrôlées ont montré que ce type de médicament réduit significativement le risque d'une première hémorragie de 40% chez le patient ayant les varices oesophagienes. Par méta-analyse, il a été démontré que la mortalité en rapport avec une hémorragie était significativement plus basse chez le patient traité par bêta bloqueurs par rapport à un groupe placebo. Les bêta-bloqueurs sont également (mais de façon moins nette) plus efficace dans la prévention de récidives. La récidive hémorragique chez le patient traité par des bêta-bloqueurs est associé à une frénence plus élevée de carcinome hépatocellulaire ou un manque de coopération. En conclusion, il est clair que de nombreuses substances ont une efficacité dans le traitement ou la prévention de complications de l'hypertension portale. D'autres médicaments, cependant, méritent d'être essayés et des études cliniques sont nécessaires pour identifier les répondeurs. La hipertensión portal es tratada mediante la reducción de la presión portal, con el propósito de prevenir el sangrado de las várices esofágicas o hemorragia recurrente. Puesto que la hipertensión portal depende tanto del flujo tributario en el territorio portal como de la resistencia vascular intrahepática, la farmacoterapia en este síndrome persigue la reducción del flujo portal o de la resistencia vascular, o de ambos. La prevención farmacológica del primer sangrado o del sangrado recurrente ha sido lograda por medio de los antagonistas B-adrenérgicos (propanol o nadolol): algunos estudios clínicos controlados han demostrado que este tipo de fármacos reduce en forma significativa el riesgo de hemorragia primaria en aproximadamente un 40% de los pacientes con várices esofágicas. Un meta-análisis demostró que la mortalidad debida a hemorragia varicosa era significativamente más baja en el grupo que recibió B-bloqueadores que an el grupo placebo. Además, los B-bloqueadores son efectivos en pacientes tanto en buena como en mala condición y con todo tipo de cirrosis. Aparece menos clara la eficacia de los B-bloqueadores sobre el sangrado recurrente, aunque estos fármacos disminuyen el riesgo de hemorragia recurrente aproximadamente en un 30%. Cuando se presenta sangrado recurrente, éste se ve asociado con la aparición de carcinoma hepatocelular, con pobr cumplimiento por parte del paciente en cuanto al tratamiento, con falla en la reducción de la frecuencia cardiaca o con falla en la abstinencia del alcohol. En conclusión, es claro que diversas sustancias exhiben efecto hipotensor sobre el sistema portal y que pueden ser utilizadas en la prevención de las complicaciones de la hipertensión portal. Sin embargo, deben ensayarse otras drogas vasoactivas y se requieren estudios clínicos adicionales para identificar diversas modalidades terapéuticas para la hipertensión portal.

Orthotopic liver isotransplantation was performed in one group of Lewis rats using cuffs for the portal vein and the infrahepatic vena cava, stents for the hepatic artery and the bile duct. Three other groups were also investigated: group A, normal rats; group B, sham-transplanted rats (clamping of the vessels, washing of the liver, placing cuffs around the portal vein); and group C, sham-transplanted rats with ligature section of the hepatic artery. Blood-flow measurements were performed, 1 week after the surgical procedure, with the radioactive microsphere method in conscious animals. Transplanted rats exhibited significant (ANOVA, P< 0.05) increase in cardiac index and decrease in mean arterial pressure and systemic vascular resistance. Blood flows of the portal territory and to the kidneys were not significantly modified. Arterial liver blood flow and arterial liver vascular resistance in rats with liver transplantation were not significantly different between normal and sham-transplanted rats but were significantly different from rats with ligature of the hepatic artery. These results confirm the validity of the method used for vascular anastomoses. Hypotensive hemorrhage (2 ml/100 g bw) induced marked hemodynamic changes, but rats with liver transplantation when compared with normal and sham-transplanted rats exhibited the following: (a) significantly lower percentage of decrease in cardiac index and in mean arterial pressure; and (b) significantly higher renal and portal tributary blood flows. Plasma catecholamine concentrations and plasma volume were higher in rats with liver transplantation than in normal rats but were not significantly different from sham-operated rats. Histologic examination of the liver revealed slight portal edema in sham-operated rats and small necrotic areas in the liver, probably corresponding to the reperfusion injury, in rats with liver transplantation.

74 cirrhotic patients with a history of variceal or gastric bleeding were randomly assigned to treatment with propranolol (40 to 360 mg/day) or placebo. The patients were all in good condition and doses of propranolol were titrated until a 25% reduction in heart rate was achieved. After 2 years, the cumulative percentage of patients free from rebleeding was significantly greater among the patients receiving propranolol (79%) than in the placebo group (32%; p<0.0001). Similarly, the percentage of surviving patients was significantly greater with propranolol (90%) than with placebo (57%; p<0.02) after 2 years. It was concluded that in cirrhotic patients in good condition, propranolol reduced both the risk of recurrent gastrointestinal haemorrhage and the mortality rate during a 2-year period of continuous administration of the drug.

Chronic administration of ursodeoxycholic acid (UDCA) has recently been suggested as a potential treatment for cholestatic liver disease. The purpose of this study was to examine the effects of chronic oral administration of UDCA on the histological, biochemical, and hemodynamic abnormalities induced by bile duct ligation in the rat. Fifty-one rats with ligation-section of the common bile duct were randomly and blindly assigned to receive UDCA (25 mg/kg each day) or placebo by gavage for 4 weeks. At the end of the treatment period, morphometric analysis showed that in rats treated with UDCA, hepatocyte and sinusoidal volume fractions were significantly higher than in rats receiving placebo [41.9 ± 3.2% vs. 28.1 ± 1.8%, (mean ± SE) and 7.4 ± 0.1% vs. 4.3 ± 0.3%, respectively], whereas bile duct volume fraction (reflecting bile ductular proliferation) and connective tissue fraction were significantly lower in rats treated with UDCA than in rats receiving placebo (14,2 ± 1.5% vs. 20.0 ± 1.0% and 35.4 ± 2.4% vs. 47.6 ± 1.7%, respectively). Serum aminotransferase and alkaline phosphatase activities, and total serum bile acids and individual bile acid concentrations were not significantly different between the two groups. Portal pressure (12.7 ± 0.5 mm Hg vs. 17.1 ± 0.5 mm Hg), portal tributary blood flow (5.7 ± 0.4 vs. 9.3 ± 0.4 mL · min−1· 100 g−1body weight), and cardiac index (41.1 ± 1.8 vs. 50.6 ± 1.4 mL · min−1· 100 g−1body weight) were significantly lower in UDCA-treated rats than in placebo-treated animals. In portal vein stenosed rats, chronic administration of UDCA had no hemodynamic effects, a finding that suggests UDCA has no direct vasoactive effect on splanchnic circulation. It is concluded that in rats with bile duct ligation UDCA limits the severity of liver disease and consequently of portal hypertension and hyperkinetic circulation.

Little is known about the plasma concentrations of cyclic 3′,5′‐guanosine monophosphate (cGMP) in patients with cirrhosis. However, plasma cGMP concentrations provide information on cellular cGMP production by particulate guanylyl cyclases (which are stimulated by natriuretic peptides, such as atrial natriuretic peptide; ANP). In contrast, because intracellular cGMP elicits vasorelaxant mechanisms, plasma cGMP concentrations may be related to haemodynamic alterations in patients with cirrhosis. The aim of the present study was to measure plasma cGMP concentrations in patients with cirrhosis and controls and to examine the relationship between cGMP levels and plasma ANP concentrations and haemodynamic values. Plasma concentrations of cGMP and ANP and splanchnic and systemic haemodynamics were measured in 23 subjects; 13 subjects had cirrhosis and 10 were controls. All subjects had normal glomerular filtration. Plasma cGMP concentrations were significantly higher in patients (6.5±0.8 pmol/mL) than in controls (2.7±0.4 pmol/mL), while plasma ANP concentrations did not significantly differ between the two groups (127±22 and 123±27 pg/mL, respectively). In patients with cirrhosis, no significant correlation was found between plasma cGMP concentrations and plasma ANP concentrations, hepatic venous pressure gradient, cardiac output or systemic vascular resistance. In conclusion, in patients with cirrhosis, increased plasma cGMP concentrations may be due to an activation of particulate guanylyl cyclases by natriuretic peptides other than ANP. The present study suggests that plasma cGMP concentrations are not related to cirrhosis‐induced haemodynamic alterations.

The effects of dobutamine infusion on cardiac output, hepatic blood flow, and the gradient between wedged and free hepatic venous pressures were studied in 14 patients with alcoholic cirrhosis. Cardiac output rose from 5.8 ± 1.2 l/min (mean ± SD) to 7.1 ±7.5 l/min. Hepatic blood flow and the gradient between wedged and free hepatic venous pressures did not change significantly during the dobutamine infusion (1.360 ± 0.510 l/min to 1.446 ± 0.502 l/min and 17.7 ± 4.9 mm H g to 17.9 ± 3.7 mm Hg). We conclude that in alcoholic cirrhotic patients, dobutamine increased cardiac output as a result of increased heart rate and that there were no significant changes in percentage of cardiac output distributed to the liver.Clinical Pharmacology and Therapeutics (1983) 34, 56–59; doi:10.1038/clpt.1983.129

Since catecholamines can alter splanchnic oxygen transport and extraction, the suppression of sympathetic overactivity during alcohol withdrawal might improve hepatic oxygen extraction. Therefore, this study investigated the effects of clonidine, a centrally-acting α2-agonist which reduces sympathetic nervous outflow, on splanchnic oxygen transport and extraction in 13 patients with chronic alcoholism during alcohol withdrawal. All patients had elevated transaminases and steatosis at liver biopsy and were withdrawn from alcohol 51±15 h (mean±SD) before the study. Hepatic blood flow, cardiac output and the oxygen contents were measured in the radial and pulmonary arteries and in the hepatic veins before and 45 min after intravenous administration of clonidine, 150 μg. Basal hepatic blood flow was inversely correlated with norepinephrine plasma concentrations (r=−0.63, p<0.025). After clonidine administration, the decrease in plasma norepinephrine correlated with the norepinephrine basal value (r=0.889, p<0.001), and splanchnic oxygen extraction increased (from 40±15 to 49±17%, p<0.025). After clonidine administration, splanchnic oxygen extraction was correlated with the decrease in plasma norepinephrine (r=0.72, p<0.01). Arterial lactate concentration decreased (from 0.74±0.20 to 0.64±0.23 mmol/l, p<0.01). These results suggest that defective liver oxygen extraction might occur during alcohol withdrawal as a result of sympathetic nervous hyperactivity. Alterations in the hepatic microcirculation during withdrawal might be related to catecholamine secretion and be controlled by pharmacological manipulation.