Medical Treatment Of Portal Hypertension Research Articles

Expanding Role of US in Diagnosis of Portal Hypertension and Cirrhotic Complications

Color Doppler Ultrasonography (CD-US) has an advantage of being non-invasiveness, so many attempts to investigate the hemodynamic alterations in cirrhosis and the response to medical treatment of portal hypertension as well as morphologic change of liver have been made. In particular, any CD-US parameter that could be a suitable substitute for the invasive current gold standard for assessing portal hypertension by measuring hepatic venous pressure gradient (HVPG) and hepatic fibrosis evaluated by liver biopsy, would be highly desirable. The presence of intrahepatic shunts resulting from portal hypertension can be helpful to diagnosis of portal hypertension and cirrhosis through novel characteristic CD-US index. It has been recently suggested that the extent of abnormality in Doppler hepatic vein (HV) waveform is associated with degree of HVPG as well as severity of hepatic fibrosis, and a change in HV waveform is closely correlated with that in HVPG. Abnormal flattened HV wave form is thought to be due to hemodynamically blunting the effect of variations in central venous pressure during the cardiac cycle, which is arising from increased HV inflow via intrahepatic shunts secondary to portal hypertension. Moreover, under microbubble contrast enhancement, CD-US detection of decreased hepatic vein transit time due to presence of intrahepatic shunts can be useful to assess the severity of portal hypertension and grade of fibrosis. However, for being reproducible and accurate, a cooperative training program of operators with strict examination protocol would be helpful to reduce the rate of intra-and inter-observer variation. Consequently, developments of novel CD-US indices and techniques are ongoing to overcome the limitations of conventional CD-US methods in diagnosis of portal hypertension and cirrhosis, and some of them are enough to potentially allow widespread clinical use.

High-dose propranolol attenuates pressor responses to norepinephrine in mesenteric arterial beds of rats

Propranolol is used for medical treatment of portal hypertension as it is believed to act as an indirect splanchnic vasoconstrictor via blockade of vasodilatory β2-receptors. However, a high proportion of nonresponders have been demonstrated in hemodynamic studies of the portal hypotensive effect of propranolol. The aim of the present study was to investigate the effect of various concentrations of propranolol on norepinephrine-induced pressor responses in isolated perfused mesenteric arteries of rats. Mesenteric arterial beds of six rats were perfused at a constant rate of 2 ml/minute with Krebs-Ringer solution at 37°C, and perfusion pressure was continuously recorded. Pressor responses to bolus injections of norepinephrine tended to increase in the presence of 10−6 M propranolol but were significantly attenuated in the presence of 10−5 M propranolol. In conclusion, a high concentration of propranolol paradoxically attenuates the pressor responses to norepinephrine in mesenteric arterial beds of rats. This is most likely explained by a nonspecific local anesthetic effect of propranolol.

Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review

Doppler ultrasonography (US) has an advantage of being non-invasive; therefore, several attempts have been made to investigate the haemodynamic alterations in cirrhosis and the response to medical treatment of portal hypertension. Doppler indices, which have been commonly used for the evaluation of portal hypertension, include the measurement of portal and splenic venous blood velocity and flows, and the resistive and pulsatility index at hepatic, splenic, renal, superior mesenteric artery. Although many positive evidences have been suggested, its clinical usefulness in portal hypertension remains unsettled because of being plagued by lack of reproducibility and accuracy characterized by intra- and interobserver variation. However, recently, Doppler's usefulness in assessment of severity of portal hypertension in terms of reproducibility, technical ease and accuracy and response to drugs that reduce the portal pressure has been proposed. In addition, because most of the patients with cirrhosis and portal hypertension have intrahepatic shunts, they show a decrease in intrahepatic circulatory time (IHCT). Doppler US using microbubble contrast agents allows measurement of IHCT. Therefore, application of contrast-enhanced Doppler US can be prospective for the assessment of the severity of portal hypertension. Several reports have demonstrated that colour Doppler endoscopic US enable haemodynamic study to assess the portal hypertension and has a role of guidance to measure the imaging-based variceal pressure. We have reviewed briefly the clinical usefulness of Doppler US in assessing the severity of portal hypertension and its response to treatment.

Clinical significance of worsening portal hypertension during long-term medical treatment in patients with cirrhosis who had been classified as early good-responders on haemodynamic criteria

It is established that cirrhotic patients who respond to beta-blockers by lowering their hepatic venous pressure gradient (HVPG) to < or =12 mmHg or by > or =20% of the baseline values are protected from bleeding. However, it is not known whether the effect remains unchanged over the treatment period. A group of 24 patients with cirrhosis and oesophageal varices, treated with beta-blockers+/-nitrates, good-responders on haemodynamic criteria, were followed for up to 76 months with sequential HVPG measurements. Another group of 16 patients was used for validation. HVPG worsened in 10 of the 24 patients during follow-up. Changes in HVPG correlated to concomitant changes in liver function parameters. Variceal bleeding occurred in four of the 10 patients whose HVPG had worsened (bleed; 3-21 months after the measured increase in HVPG) and in none of those with stable HVPG (p=0.02). Patients with increased HVPG also had shorter survival (p=0.05). Worsening of HVPG was an independent predictor of death, additive to Child-Pugh or MELD scores, in a time-dependent Cox's regression analysis. This relationship was confirmed in the validation group. Worsening HVPG during follow-up in patients who had initially been good-responders to medical treatment is related to worsening in hepatic function. The maintenance of a good haemodynamic response to medical treatment of portal hypertension is an excellent predictor of outcome in these patients.

Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis

Extrahepatic vasodilation and increased intrahepatic vascular resistance represent attractive targets for the medical treatment of portal hypertension in liver cirrhosis. In both dysfunctions, dysregulation of the contraction-mediating Rho kinase plays an important role as it contributes to altered vasoconstrictor responsiveness. However, the mechanisms of vascular Rho kinase dysregulation in cirrhosis are insufficiently understood. They possibly involve mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-dependent mechanisms in extrahepatic vessels. As the multikinase inhibitor sorafenib inhibits ERK, we tested the effect of sorafenib on haemodynamics and dysregulated vascular Rho kinase in rats with secondary biliary cirrhosis. Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Sorafenib was given orally for 1 week (60 mg.kg(-1).d(-1)). Messenger RNA levels were determined by quantitative real time polymerase chain reaction, protein expressions and protein phosphorylation by Western blot analysis. Aortic contractility was studied by myographic measurements, and intrahepatic vasoregulation by using livers perfused in situ. In vivo, haemodynamic parameters were assessed invasively in combination with coloured microspheres. In BDL rats, treatment with sorafenib decreased portal pressure, paralleled by decreases in hepatic Rho kinase expression and Rho kinase-mediated intrahepatic vascular resistance. In aortas from BDL rats, sorafenib caused up-regulation of Rho kinase and an improvement of aortic contractility. By contrast, mesenteric Rho kinase remained unaffected by sorafenib. Intrahepatic dysregulation of vascular Rho kinase expression is controlled by sorafenib-sensitive mechanisms in rats with secondary biliary cirrhosis. Thus, sorafenib reduced portal pressure without affecting systemic blood pressure.

Medical treatment of portal hypertension

In this chapter we give a quick review of the rationale for treatment of portal hypertension. The different scenarios for treatment of variceal bleeding will be discussed—that is, primary and secondary prophylaxis of variceal bleeding as well as the treatment of the acute bleeding episode. The role of the pharmacological, endoscopic and derivative treatments in each one of these scenarios will be discussed. Particular attention will be devoted to the potential role of the combination therapy of beta-blockers with isosorbide-5-mononitrate for preventing re-bleeding and to the best approach to patients with intolerance or contraindications to beta-blockers. We also give a rational review of the data comparing sclerotherapy against ligation as well as the potential role of the latter on primary prophylaxis.

The Hemodynamic Response to Medical Treatment of Portal Hypertension as a Predictor of Clinical Effectiveness in the Primary Prophylaxis of Variceal Bleeding in Cirrhosis

In the prevention of variceal rebleeding, it is already established that hemodynamic response to drug treatment (decrease in hepatic venous pressure gradient [HVPG] to 12 mm Hg or by >20%) is predictive of clinical effectiveness. In primary prophylaxis very few clinical data are available. We assessed the role of the hemodynamic response to beta-blockers or beta-blockers plus nitrates in predicting clinical efficacy of prophylaxis. A total of 49 cirrhotic patients with varices at risk of bleeding, without prior variceal bleeding, were investigated by hepatic vein catheterization before and after 1 to 3 months of chronic treatment with nadolol or nadolol plus isosorbide mononitrate, and were followed during treatment for up to 5 years. A total of 30 patients (61%) were good hemodynamic responders, and among them in 12 (24%) HVPG was ≤12 mm Hg during treatment. During treatment 9 patients had variceal bleeding: 7 were poor responders and 2 were good responders. The probability of bleeding at 3 years of follow-up was significantly higher in poor responders (41%) than in good responders (7%; P = .0008). No patient reaching an HVPG of 12 mm Hg or less during treatment had variceal bleeding during follow-up. Cox's regression analysis showed that poor hemodynamic response was the main factor predicting bleeding (β = 1.91; SE(β) = 0.80; P = .01). During follow-up 11 patients died of hepatic causes. Survival was related to Child-Pugh class and to initial value of HVPG, according to Cox's analysis. In conclusion, the assessment of hemodynamic response to drugs in terms of HVPG is the best predictor of efficacy of prophylaxis of variceal bleeding in patients treated with beta-blockers or beta-blockers plus nitrates. (Hepatology 2000;32:930-934.)

Medical treatment of portal hypertension and oesophageal varices.

Medical treatment of portal hypertension and oesophageal varices.

Medical treatment of portal hypertension and oesophageal varices.

Medical treatment of portal hypertension and oesophageal varices.

Medical Treatment of Portal Hypertension

The focus here is on portal hypertension in patients with alcoholic cirrhosis. The major aim of medical therapy is to restore the ability of the liver to function normally, and to deal with specific complications such as hypersplenism, ascites, hepatic encephalopathy, and variceal hemorrhage.