Hepatic venous pressure gradient determination in patients with hepatitis C virus-related and alcoholic cirrhosis

OBJECTIVES: Few data exist regarding the degree of portal hypertension in hepatitis C virus (HCV)-related cirrhosis, as the majority of studies have included mainly patients with alcoholic cirrhosis. This study was aimed at comparing the severity of portal hypertension in patients with HCV-related or alcoholic cirrhosis. METHODS: In total, 59 cirrhotic patients with portal hypertension (HCV-related in 34 cases and alcoholic in 25) underwent main right hepatic vein catheterization, with determination of the wedged and free hepatic venous pressures, and of hepatic venous pressure gradient (HVPG). RESULTS: HVPG values did not differ between the two groups of patients (19.4 +/- 6.0 mmHg vs 18.5 +/- 3.5 mmHg; P = 0.51). The prevalence and degree of oesophageal and gastric varices and portal hypertensive gastropathy did not correlate with the aetiology. Patients with viral cirrhosis had a lower prevalence of previous bleeding than those with alcoholic cirrhosis, despite a similar proportion of large varices in the two groups and similar HVPG levels. In both groups of patients, HVPG did not differ between patients with previous bleeds and those without. CONCLUSIONS: The degree of portal hypertension in cirrhotic patients does not correlate with the cause of the disease. Thus, current statements on the management of portal hypertension, although based upon studies including mainly patients with alcoholic cirrhosis, can be applied also to patients with viral-related cirrhosis.     

Comparison between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related cirrhosis

Portal vein pressure and wedged hepatic vein pressure were measured simultaneously in 21 patients with hepatitis B-related cirrhosis of the liver and were compared to pressure measured in six patients with idiopathic portal hypertension. No significant difference in the portal venous pressure gradient was found between patients with cirrhosis and those with idiopathic portal hypertension (17.3 +/- 4.3 mmHg (mean +/- S.D.) vs. 19.7 +/- 3.1 mmHg, P greater than 0.05). However, the difference between the portal and the hepatic venous pressure gradient was significantly smaller in patients with cirrhosis than in idiopathic portal hypertension patients (1.3 +/- 1.7 vs. 10.8 +/- 2.1 mmHg, P less than 0.001). An excellent correlation was found between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related cirrhosis (r = 0.94, P less than 0.001). There was no linear relationship between the portal venous pressure gradient and varix size or bleeding episodes. We concluded that a close agreement existed between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related liver cirrhosis. Therefore, measurement of wedged hepatic vein pressure reliably reflects portal vein pressure in these patients.     

Portal hypertension in fulminant viral hepatitis.

The gradient between wedged and free hepatic venous pressures were measured in 10 unselected adult patients suffering from fulminant viral hepatitis. The gradient was increased in all the studied patients, ranging from 0.9 to 2.1 kPa; this finding indicates that portal hypertension was present in all these cases. Ascites was present in all the five patients having a gradient about 1.5 kPa and affected only two of the five patients having a gradient below 1.5 kPa; this observation suggests that portal hypertension plays a role in the mechanism of ascites in fulminant viral hepatitis. Portal hypertension in fulminant viral hepatitis is likely to be the consequence of an intrahepatic block due to massive necrosis of the liver cells.     

Wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis

Hepatic venous catheterization is widely used to assess portal pressure. However, it remains unclear whether wedged hepatic venous pressure is a close indicator of portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis. To address this issue, we analyzed the data from our previous published studies. Forty patients with nonalcoholic cirrhosis (HBV infection in five, HCV infection in 28, and cryptogenic in seven) were available in this analysis. A vasoconstrictor (N=14), vasodilator (N=10), or combination (N=16) was administered. The agreement of the changes between portal and wedged hepatic venous pressures during pharmacological manipulation was assessed by an intraclass correlation coefficient. The intraclass correlation coefficient in each subgroup was more than 0.60 (0.62 in vasoconstrictor group, 0.87 in vasodilator group, and 0.73 in combination group). When the analysis was performed according to the cause of liver disease, the values were 0.67 in HBV infection, 0.73 in HCV infection, and 0.74 in cryptogenic cirrhosis. These results suggest that wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in patients with nonalcoholic cirrhosis.     

Relation between plasma catecholamines, the severity of the liver disease and hemodynamics in patients with cirrhosis

Plasma noradrenaline and adrenaline concentrations were measured in 75 patients with cirrhosis in order to attempt to correlate these concentrations and liver failure and hemodynamic changes. The increased noradrenaline concentration was not correlated with the degree of liver failure estimated by Pugh's classification, with the cause of cirrhosis, with the presence of acute alcoholic hepatitis or with the presence of ascites. Adrenaline concentration was higher in cirrhotic patients with acute alcoholic hepatitis than in those without these lesions. Noradrenaline concentration was significantly correlated with heart rate, wedged hepatic venous pressure and renal blood flow. Noradrenaline concentration was also negatively correlated with stroke volume and adrenaline concentration was negatively correlated with cardiac output and stroke volume. These findings confirm the relationships between portal hypertension, sympathetic hyperactivity and renal function in patients with cirrhosis.     

Haemodynamic effects of enalaprilat on portal hypertension in patients with HBsAg-positive cirrhosis

Abstract It has been suggested that enalaprilat inhibits the renin-angiotensin-aldosterone system in plasma and tissue; it may therefore reduce portal vascular pressure owing to secondary hyperaldosteronism in patients with liver cirrhosis. In order to evaluate this concept, 20 patients with hepatitis B surface antigen (HBsAg)-positive liver cirrhosis and portal hypertension received an intravenous infusion of 2.5 mg of enalaprilat. Wedged hepatic venous pressure, free hepatic venous pressure and cardiac index were measured before, immediately after, and then 15 min, 30 min and 1 h after intravenous enalaprilat infusion. The mean pressure gradient between wedged hepatic venous pressure and free hepatic venous pressure was significantly decreased, by 13% immediately after, 18% at 15 min, 23% at 30 min and 13% at 1 h after infusion of enalaprilat. Thirteen patients experienced a decrease of hepatic venous pressure gradient (HVPG) greater than 5 mmHg, another three 3-5 mmHg and the remaining four patients exhibited no significant change in HVPG. Systemic haemodynamic indices, including pulmonary arterial pressure, pulmonary capillary wedge pressure and central venous pressure, decreased significantly at 15 and 30 min after enalaprilat infusion ( P < 0.01). Liver function, renal function and blood routine before and after enalaprilat infusion showed no significant changes. There were no adverse effects during or after enalaprilat infusion. We conclude that enalaprilat infusion can quickly and safely reduce the hepatic venous pressure gradient in patients with HBsAg-positive cirrhosis.     

Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients

BACKGROUND: Measuring wedged hepatic venous pressure and hepatic venous pressure gradient as indices of portal pressure is being increasingly used in assessing the prognosis and response to pharmacological treatment for portal hypertension in cirrhotic patients. AIM: To re-evaluate the agreement and correlation between wedged hepatic pressures and directly measured portal pressures. METHODS: Medline search for studies comparing direct portal with wedged hepatic pressure measurement and assessment of correlation and agreement of the pooled data. RESULTS: Eleven suitable studies included 320 patients. Coefficient of determination (r2) was 0.87 in all patients, 0.87 in 102 patients with alcoholic liver disease, 0.83 in 88 patients with non-alcoholic liver disease and 0.75 in 53 patients with hepatitis C-related liver disease. Coefficient of determination was 0.85 in the 194 patients in whom a wedge catheter and 0.90 in the 113 patients in whom a balloon catheter was used. Agreement according to the method of Bland and Altman was also found to be good, with only 4-8% of the measurements outside 2 standard deviations. CONCLUSIONS: Wedged hepatic pressure measurement correlates well with direct portal pressure measurement and the agreement is sufficiently good to use this as a surrogate measurement.     

Discrepancy between wedged hepatic venous pressure and portal venous pressure after acute propranolol administration in patients with alcoholic cirrhosis

In patients with alcoholic cirrhosis, wedged hepatic venous pressure closely reflects portal venous pressure. This study was carried out to determine if propranolol-induced reductions in portal venous pressure are accurately evaluated by the measurement of wedged hepatic venous pressure. Hepatic venous cannulation and percutaneous transhepatic catheterization of the portal vein were simultaneously performed in 7 patients with alcoholic cirrhosis. One hour after oral administration of 40 mg of propranolol, wedged hepatic and portal venous pressures significantly decreased from 24.3 +/- 3.5 (mean +/- SD) to 19.0 +/- 3.0 mmHg, and from 24.7 +/- 3.9 to 22.4 +/- 3.6 mmHg, respectively. Although no significant difference was found between baseline wedged hepatic and portal venous pressures, a significant difference was found between these pressures after propranolol administration. We concluded that during acute administration of a drug acting on the splanchnic circulation, the measurement of wedged hepatic venous pressure may not provide a reliable estimation of the magnitude of the changes in portal venous pressure. There is, however, no evidence that the direction of the changes might not be adequately assessed by wedged hepatic venous pressure measurement.     

Hepatic venous pressure gradient measurement: Time to learn!

Portal hypertension is a clinical syndrome defined by a pathological increase in portal pressure. The development of cirrhosis of the liver is characterized by clinical manifestations related to portal hypertension like esophageal varices, ascites, bleeding, and encephalopathy. Direct measurement of portal pressure is invasive, inconvenient, and clinically impractical. Currently, the most commonly used parameter is the Hepatic Venous Pressure Gradient (HVPG), i.e., the difference between the wedged (WHVP) and the free hepatic venous pressures. HVPG represents the gradient between pressures in the portal vein and the intra-abdominal portion of inferior vena cava. When blood flow in a hepatic vein is stopped by a wedged catheter, the proximal static column of blood transmits the pressure from the preceding communicated vascular territory (hepatic sinusoids) to the catheter. Thus, WHVP reflects hepatic sinusoidal pressure and not the portal pressure itself. In the normal liver, due to pressure equilibration through interconnected sinusoids, wedged pressure is slightly lower than portal pressure, though this difference is clinically insignificant. In liver cirrhosis, the static column created by balloon inflation cannot be decompressed at the sinusoidal level due to disruption of the normal intersinusoidal communications; therefore, WHVP gives an accurate estimation of portal pressure in cirrhosis. The normal HVPG value is between 1 to 5 mmHg. Pressure higher than this defines the presence of portal hypertension, regardless of clinical evidence. HVPG >/= 10 mmHg (termed clinically significant portal hypertension) is predictive of the development of complications of cirrhosis, including death. HVPG above 12 mmHg is the threshold pressure for variceal rupture. The main advantages of HVPG are its simplicity, reproducibility, and safety. This review summarizes the technique of the HVPG measurement.     

CO(2) wedged hepatic venography in the evaluation of portal hypertension

BACKGROUND/AIMS/METHODS: During hepatic vein catheterisation, in addition to measurement of hepatic venous pressure gradient (HVPG), iodine wedged retrograde portography can be easily obtained. However, it rarely allows correct visualisation of the portal vein. Recently, CO(2) has been suggested to allow better angiographic demonstration of the portal vein than iodine. In this study we investigated the efficacy of CO(2) compared with iodinated contrast medium for portal vein imaging and its role in the evaluation of portal hypertension in a series of 100 patients undergoing hepatic vein catheterisation, 71 of whom had liver cirrhosis. RESULTS: In the overall series, CO(2) venography was markedly superior to iodine, allowing correct visualisation of the different segments of the portal venous system. In addition, CO(2), but not iodine, visualised portal-systemic collaterals in 34 patients. In cirrhosis, non-visualisation of the portal vein on CO(2) venography occurred in 11 cases; four had portal vein thrombosis and five had communications between different hepatic veins. Among non-cirrhotics, lack of portal vein visualisation had a 90% sensitivity, 88% specificity, 94% negative predictive value, and 83% positive predictive value in the diagnosis of pre-sinusoidal portal hypertension. CONCLUSIONS: Visualisation of the venous portal system by CO(2) venography is markedly superior to iodine. The use of CO(2) wedged portography is a useful and safe complementary procedure during hepatic vein catheterisation which may help to detect portal thrombosis. Also, lack of demonstration of the portal vein in non-cirrhotic patients strongly suggests the presence of pre-sinusoidal portal hypertension.     

Hemodynamic changes in patients with portal venous obstruction

Splanchnic and systemic hemodynamics were evaluated in five adult patients with portal hypertension due to portal venous obstruction and were compared with those of patients with cirrhosis and those of a control group. In patients with portal venous obstruction, the gradient between wedged and free hepatic venous pressures ranged from 2 to 3 mm Hg, as in the control group, and was significantly lower than in patients with cirrhosis. Hepatic blood flow averaged 0.521 +/- 0.127 liter per min per m2 (mean +/- S.D.) and was significantly lower than that measured in cirrhotic and normal patients. Cardiac index averaged 3.788 +/- 0.629 liters per min per m2; this high value for cardiac index was not significantly different from that measured in cirrhotic patients, but was significantly higher than in patients of the control group. It is suggested that a hyperkinetic circulatory state may result from the development of portal-systemic venous collateral circulation in patients with portal venous obstruction having normal liver and hepatic venous pressures.     

Combination of ketanserin and verapamil or propranolol in patients with alcoholic cirrhosis: search for an additive effect

Drugs reported to reduce portal pressure through different mechanisms were combined in the hope of either additive portal hypotensive effects in "responders," or inducing a portal hypotensive effect in "nonresponders" to the initial drug. Seven patients with alcoholic cirrhosis received verapamil, 10 mg i.v., and, 60 min later, ketanserin, 5 mg i.v. Verapamil decreased heart rate and increased free hepatic venous pressure but had no effect on hepatic venous pressure gradient or azygos blood flow. When combined with verapamil, ketanserin significantly diminished wedged hepatic venous pressure and hepatic venous pressure gradient. Ten other patients with alcoholic cirrhosis received propranolol, 15 mg i.v., and 45 min later, ketanserin, 5 mg i.v. In all patients, heart rate, cardiac index and azygos blood flow significantly decreased after propranolol. After propranolol alone, however, wedged hepatic venous pressure decreased in only five patients, responders. In five other patients, defined as nonresponders, propranolol did not decrease this pressure. The addition of ketanserin to propranolol induced further significant reduction in wedged hepatic venous pressure, hepatic venous pressure gradient and azygos blood flow. Among the five nonresponders, three had a reduced wedged hepatic venous pressure after ketanserin was combined. We conclude that verapamil does not reduce portal pressure or collateral blood flow in patients with alcoholic cirrhosis. The splanchnic hemodynamic effects of propranolol and ketanserin appear to be independent and additive, without significant systemic alteration.     

Sinusoidal portal hypertension in hepatic amyloidosis.

Hepatic venous catheterisation and transvenous liver biopsy were performed in five patients with hepatic amyloidosis. In three patients, hepatic venous pressures were normal and histological examination of the liver biopsy specimen showed discrete and sparse perisinusoidal amyloid deposits. In the other two, however, the gradient between wedged and free hepatic venous pressures was increased (12 and 16 mmHg; normal 1-4 mmHg) and amyloid deposits were abundant and diffuse in the Disse's space. This study shows that portal hypertension in patients with hepatic amyloidosis is of the sinusoidal type and is related to the reduction of vascular space of hepatic sinusoids by massive perisinusoidal amyloid deposits. Furthermore, portal hypertension is associated with a poor prognosis in patients with hepatic amyloidosis.     

Portal hypertension in chronic hepatitis: relationship to morphological changes.

Various anatomical factors were examined which might provide passive resistance to portal venous flow and so cause portal hypertension. Methods included the measurement of portal pressure (WHVPG) in cirrhotic and non-cirrhotic patients, morphological assessment by semiquantitative grading of severity of disease, calculation of hepatocyte size indices, and assessment of volume density of hepatocytes, sinusoids, Disse's space and Disse's space collagen by electron microscopy. The wedged hepatic venous pressure gradient increased with progression of disease and portal hypertension was present before histologically detectable cirrhosis had developed. With increasing progression of disease towards cirrhosis, the relationship between individual and aggregated features and the WHVPG diminished and lost statistical significance. Hepatocyte size increased with progression of histological changes and correlated significantly with increase of WHVPG, both in non-alcoholic and alcoholic patients. Disse's space collagen was increased significantly in non-alcoholic chronic active hepatitis compared with patients with near-normal liver. No significant decrease of sinusoidal space was found. Multiple factors rather than any single feature influence the development of portal hypertension.     

Percutaneous transhepatic measurement of the pressure gradient between the portal and hepatic veins

Abstract Background: Knowledge of the portal pressure may be of value in the assessment of patients with chronic liver disease but its measurement is problematic. Aims: To evaluate the ease and safety of percutaneous transhepatic measurement of the pressure gradient between the portal and hepatic veins and to determine directly the need for an internal zero. Methods: Sixty-one patients undergoing liver biopsy for suspected liver disease had pressures in branches of portal and hepatic veins measured using a flexible 22G (Chiba) needle. Results: The procedure was successful in all patients, took less than ten minutes in most, and was associated with minimal discomfort. Post-procedure morbidity was similar to that of liver biopsy. Portal pressure using an external zero (either puncture site or sternal angle) was inaccurate compared with pressures obtained using the generally accepted gold standard internal zero, hepatic venous pressure, and led to incorrect classification of the presence or absence of portal hypertension in at least 10% of patients. Variations in hepatic venous pressure were not predictable on clinical grounds. The only histopathological feature predictive of portal hypertension was cirrhosis, 20 of 25 patients with and four of 36 patients without cirrhosis having portal hypertension. Of routine biochemical and haematological tests, only plasma albumin and platelet count jointly (and negatively) predicted hepatic venous pressure gradient on multiple regression analysis (R²= 0.40). Conclusions: The use of an internal zero is essential for accurate measurement of portal pressure and this can be achieved safely using the percutaneous, transhepatic route in patients with well compensated liver disease.     

Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. CONCLUSION: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.     

Portal hypertension and hemorrhoids. Cause effect relationship?

The aim of this study was to compare the prevalence and the size of hemorrhoids with the degree of portal hypertension; 101 patients with intrahepatic portal hypertension documented by measuring wedged and free hepatic venous pressures before performing transjugular liver biopsy and 67 patients free of liver disease were investigated by proctoscopy. Portal hypertension was associated with a higher prevalence of hemorrhoids (93 p. 100 vs 76 p. 100); there was no relation between portal pressure and the size of haemorrhoids; no relation was found between the size of hemorrhoids and the grade of esophageal varices.     

Serum laminin and portal pressure in alcoholic cirrhosis. A study of 39 patients

A correlation between serum laminin, a glycoprotein found in basement membranes, and hepatic wedge pressure has previously been reported in a small number of patients with various liver diseases. To study this relationship in patients with alcoholic cirrhosis, we measured the wedge hepatic pressure and venous gradient, in comparison with serum concentrations of laminin and collagen metabolism products: N-terminal peptide of type III procollagen, collagen type I, and collagen type III in 39 patients. A statistically significant correlation was observed between serum laminin and wedged hepatic pressure (r = 0.529; p less than 10(-3] or hepatic venous gradient (r = 0.482; p = 0.002). By contrast, no statistically significant correlation was found between hemodynamic parameters and serum concentrations of N-terminal peptide of type III procollagen, collagen type I or collagen type III. These results suggest that, in patients with alcoholic cirrhosis, portal pressure may be estimated by serum concentration of laminin, and that perisinusoidal fibrosis, especially basement membrane thickening, may play an important role in the pathogenesis of portal hypertension in these patients.     

An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats

ABSTRACT— Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its receptors increase in human and carbon tetrachloride (CCl₄)-induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET-1 receptors ameliorates CCl₄-induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl₄ (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl₄ treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its receptors, and portal venous pressures were determined. Increases in ET-1 and its receptors occurred within 24 h of CCl₄ administration, and progressively thereafter during the development of cirrhosis. The acute CCl₄-induced hepatic injury was characterized by significant increases in portal pressure (from 8.7 ± 1.8 to 17.6 ± 3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62±8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 reduced portal pressure to 13.6±2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.     

Invasive diagnosis of portal hypertension in cirrhosis: a critical evaluation of the hepatic venous pressure gradient measurement

Portal hypertension is defined by an increased pressure gradient between the portal vein and the inferior vena cava (N < 5 mmHg). The most commonly used technique to assess the severity of portal hypertension is the catheterization of one hepatic vein with measurement of pressures in a free position and in a wedged position using preferably a balloon catheter. The hepatic venous pressure gradient is calculated by the difference between both pressures. In most cirrhotic processes, venous pressure gradient gives a good evaluation of portal hypertension however, portal vein pressure can be higher than wedged hepatic venous pressure, particularly in presence of an increased pre-sinusoidal resistance. In such cases, a direct access to portal vein might be needed to assess the severity of portal hypertension. For an accurate interpretation of the hepatic venous pressure gradient, several strict criteria must be followed; otherwise the validity of measurements might be seriously questioned. Hepatic venous pressure gradient has been used as a prognostic marker of portal hypertension, particularly for the occurrence of bleeding from gastrophageal varices which almost never occur below a threshold value of 12 mmHg. However, the prognostic value of the hepatic venous pressure gradient for survival is still a controversial matter On the other hand, the use of hepatic venous pressure gradient has been proposed to monitor the pharmacological treatment of portal hypertension and it is generally accepted that reaching a same threshold value of 12 mmHg should almost completely abolish the risk of first or recurrent variceal bleeding. A large number of studies have also reported that a 20% hepatic venous pressure gradient decrease should be considered as a significant response to therapy, the risk of the first or recurrent bleeding being significantly reduced in responders. But again there are conflicting results.