These authors contributed equally to this work.
Hemodynamic response to propranolol in patients with recurrent hepatitis C virus–related cirrhosis after liver transplantation: A case-control study
Article first published online: 19 MAR 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 19, Issue 4, pages 450–456, April 2013
How to Cite
Schepis, F., Vukotic, R., Berzigotti, A., Carrión, J. A., Forns, X., Abraldes, J. G., García-Valdecasas, J.-C., Navasa, M., García-Pagán, J.-C. and Bosch, J. (2013), Hemodynamic response to propranolol in patients with recurrent hepatitis C virus–related cirrhosis after liver transplantation: A case-control study. Liver Transpl, 19: 450–456. doi: 10.1002/lt.23614
This work was supported in part by grants from the Carlos III Institute of Health (Health Research Fund grants 06/0623 and 09/1261). The Network Center for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd) is funded by the Carlos III Institute of Health.
- Issue published online: 27 MAR 2013
- Article first published online: 19 MAR 2013
- Accepted manuscript online: 13 FEB 2013 12:51PM EST
- Manuscript Accepted: 13 JAN 2013
- Manuscript Received: 23 NOV 2012
Cirrhosis recurrence is frequent after orthotopic liver transplantation for hepatitis C virus (HCV). Because transplantation causes liver denervation, we hypothesized that the response to propranolol might differ in transplant patients versus nontransplant patients with cirrhosis and portal hypertension. Twenty-one patients with cirrhosis recurrence after orthotopic liver transplantation with portal hypertension were compared to 20 nontransplant patients with cirrhosis, HCV, and portal hypertension, and they were matched by sex, age, presence of varices, and Child-Pugh score. The patients underwent systemic and hepatic hemodynamic measurements at the baseline and 20 minutes after intravenous propranolol (0.15 mg/kg). At the baseline, the transplant patients with cirrhosis had a lower hepatic venous pressure gradient (HVPG) than the nontransplant patients with cirrhosis (14.8 ± 2.9 versus 17.3 ± 4.4 mm Hg, P = 0.03) but a higher mean arterial pressure (MAP; 100.3 ± 12.3 versus 91.8 ± 11.6 mm Hg, P = 0.04) and higher systemic vascular resistance (2253 ± 573 versus 1883 ± 525 dyn/second/cm−5, P = 0.03). There were no differences in the cardiac index (CI). Propranolol significantly decreased HVPG to similar extents in transplant patients and nontransplant patients with cirrhosis (−14.1% ± 8.0% versus −16.9% ± 9.5%, P > 0.99). MAP tended to increase in transplant patients with cirrhosis, whereas it slightly decreased in nontransplant patients (5.1% ± 14.2% versus −4.8% ± 6.4%, P = 0.007); however, the reduction in CI was less marked in transplant patients with cirrhosis (−18.6% ± 7.6% versus −26.9% ± 9.0%, P = 0.005). In conclusion, patients with HCV-related cirrhosis and portal hypertension after orthotopic liver transplantation have lower baseline HVPG values but similar HVPG responses to propranolol infusions in comparison with nontransplant patients with cirrhosis. In contrast to nontransplant patients, propranolol increases the systemic vascular resistance and arterial pressure in transplant patients with cirrhosis and attenuates the fall in CI. Liver Transpl 19:450–456, 2013. © 2013 AASLD.
free hepatic venous pressure
hepatic blood flow
hepatitis C virus
hepatic sinusoidal resistance
hepatic venous pressure gradient
indexed systemic vascular resistance
mean arterial pressure
Model for End-Stage Liver Disease
wedged hepatic venous pressure.
In patients with cirrhosis, the elevation of the hepatic venous pressure gradient (HVPG) is the major factor leading to the development of clinical complications such as gastrointestinal bleeding and ascites.[1-3] Furthermore, HVPG measurements in these patients have proven useful in assessing the efficacy of nonselective beta-blockers for both primary and secondary prevention of variceal bleeding and other complications of cirrhosis. In particular, patients achieving an HVPG reduction ≥ 20% versus pretreatment values or an HVPG value < 12 mm Hg are considered to be at very low risk of bleeding or rebleeding. Recently, it has been demonstrated that patients exhibiting an HVPG reduction ≥ 10% after acute intravenous propranolol administration are also at low risk of rebleeding and death.
Beta-blockers reduce HVPG by decreasing the portal inflow. This is achieved by 2 mechanisms: a reduction of the cardiac index (CI) by beta1-adrenoreceptor blockade and splanchnic vasoconstriction due to unopposed alpha-adrenergic vasoconstriction in the setting of beta2-adrenoreceptor blockade.[3, 7, 8] In the intrahepatic circulation, however, unopposed alpha-adrenergic tone may also result in the unwanted effect of increased hepatic vascular resistance, which would attenuate the decrease in the portal pressure.
Cirrhosis due to hepatitis C virus (HCV) infection is the main indication for liver transplantation in Western countries. Unfortunately, the recurrence of HCV infection is universal after transplantation and may lead to cirrhosis in as many as 30% of individuals after 5 years.[11-13] These patients are at risk of portal hypertension–related complications, but very few data are available to demonstrate that treatments developed for patients with cirrhosis would be equally useful for cirrhosis developing on a grafted liver. There are several reasons to suspect that the response would indeed be different. First, autonomic denervation, which persists up to 3 years after liver transplantation, may enhance the fall in HVPG by abrogating the increase in intrahepatic resistance associated with beta2-adrenoreceptor blockade. Second, chronic exposure to immunosuppressant agents may result in enhanced sympathetic activity, endothelial dysfunction, and arterial hypertension,[15, 16] and it can be hypothesized that this might attenuate the hemodynamic response to beta2-adrenoreceptor blockade and result in a lower reduction in HVPG.
The present study was designed to clarify these issues by comparing the effects of acute intravenous propranolol administration in patients with cirrhosis recurrence after liver transplantation to the effects achieved in nontransplant patients with cirrhosis.
PATIENTS AND METHODS
This was a case-control study comparing HCV-infected patients with posttransplant recurrent cirrhosis (cases) to HCV-infected patients with pretransplant cirrhosis (controls). The study was performed in patients with cirrhosis referred to our unit for HVPG measurement and/or transjugular liver biopsy. Except for 9 controls who were retrospectively selected from a database of patients observed at our laboratory in order to provide adequate matching with cases, the cases and the controls were prospectively recruited over the same period.
The inclusion criteria were as follows: HCV-related cirrhosis demonstrated by clinical, biochemical, imaging and/or histological data and baseline HVPG values ≥ 12 mm Hg. The exclusion criteria were an age < 18 years or > 80 years; the presence of hepatocellular carcinoma or portal vein thrombosis; contraindications to beta-blockers; recent bleeding, infection, or another condition causing hemodynamic instability; the presence of acute or chronic graft rejection; the administration of antihypertensive drugs (if these had been given, their administration should had been stopped 24 hours before the study); a serum creatinine level > 2.5 mg/dL; pregnancy; and a refusal to participate in the study.
The cases and the controls were matched by sex, age, presence of varices, and Child-Pugh score.
After informed consent was signed, the entry and exclusion criteria were assessed. Patients volunteering for the study with an HVPG ≥ 12 mm Hg were included. The study was conducted according to the principles of the Declaration of Helsinki (2000 Edinburgh revision) and was approved by the ethics committee of the Hospital Clinic. All patients gave written informed consent after a complete explanation of the purpose of the study.
Hemodynamic measurements (discussed later) were performed at the baseline and 20 minutes after the intravenous administration of propranolol (0.15 mg/kg in 10 minutes). Hemodynamic studies were performed after overnight fasting under light sedation with intravenous midazolam (0.02 mg/kg). Under local anesthesia, a venous introducer was placed in the right internal jugular vein with the Seldinger technique. Under fluoroscopy, a 7-Fr balloon-tipped catheter (Boston Scientific, Cork, Ireland) was guided into the main right hepatic vein for measurements of the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP). The adequacy of occlusion was checked by the hand injection of a small amount of a radiological contrast medium.
The portal pressure gradient was measured as HVPG (the difference between WHVP and FHVP). All measurements were performed in triplicate, and permanent tracings were obtained on a multichannel recorder (Marquette Electronics, Milwaukee, WI) and read by an experienced investigator unaware of the clinical conditions of the patients.
The hepatic blood flow (HBF) was measured according to Fick's principle during a continuous infusion of indocyanine green (0.2 mg/minute) as previously described. The hepatic sinusoidal resistance (HSR; dyn/second/cm5) was estimated as HVPG (mm Hg) × 80/HBF (L/minute−1).
Cardiopulmonary pressures and cardiac output (CO) were measured via thermal dilution with a Swan-Ganz catheter (Edwards Laboratory, Los Angeles, CA) advanced into the pulmonary artery. The mean arterial pressure (MAP; mm Hg) was measured every 5 minutes with an automatic sphygmomanometer (Marquette Electronics). The heart rate was derived from continuous electrocardiogram monitoring. CI (L/minute/m2) was calculated as CO divided by the body mass surface. The systemic vascular resistance index (dyn/second/cm−5/m2) was calculated as [MAP (mm Hg) − right atrium pressure (mm Hg)] × 80/CI (L/minute/m2).
Because there were no data available on the hemodynamic response to propranolol in patients with cirrhosis after liver transplantation, we a priori hypothesized that the fall in HVPG after propranolol administration would be 10% greater in these patients versus nontransplant patients with cirrhosis. If we assumed a 15% HVPG reduction in nontransplant patients and a standard deviation of 6 and used a 2-tailed test with α = 0.05 and β = 0.20, a sample size of 40 patients (20 in each group) was supposed to be required to demonstrate such a difference.
Continuous data are reported as means and standard deviations, whereas categorical data are reported as frequencies and percentages. Comparisons of continuous variables were performed with the Student t test for paired samples (within-group analysis) and independent samples (intergroup analysis). Categorical data were compared with Fisher's exact test. Significance was established at a P level of 0.05. Statistical analyses were performed with the SPSS 15.0-16.0 statistical package (SPSS, Inc., Chicago, IL) for Windows XP (Microsoft Corp.).
Baseline Characteristics of the Patients
The average time from liver transplantation was 6 ± 4 years. Nineteen of the 21 transplant patients were receiving either tacrolimus (n = 14) or cyclosporine (n = 5), whereas the remaining patients (n = 2) were treated with mycophenolate and prednisone. The cases and the controls were well matched by Child-Pugh and Model for End-Stage Liver Disease (MELD) scores, prevalence and size of esophageal varices, previous variceal bleeding, presence of ascites, and previous hepatic encephalopathy (Table 1). Previous episodes of ascites were more frequent in transplant patients. Transplant patients had higher creatinine levels, but these were within normal limits. Plasma norepinephrine levels were similar in the 2 groups of patients.
|Cases (n = 21)||Controls (n = 20)||P Value|
|Sex: male/female [n/n (%/%)]||13/8 (62/38)||12/8 (60/40)||0.90|
|Age (years)||61.4 ± 9.5||59.5 ± 21.9||0.71|
|Body mass index (kg/m2)||27.8 ± 5.5||27.3 ± 3.3||0.73|
|Child-Pugh score||6.6 ± 1.8||6.1 ± 1.6||0.34|
|MELD score||11.5 ± 3.5||11 ± 3.9||0.66|
|Creatinine (mg/dL)||1.1 ± 0.3||0.9 ± 0.2||0.01|
|Total bilirubin (mg/dL)||1.8 ± 1.4||2.2 ± 2.7||0.62|
|Albumin (g/L)||35.7 ± 7.2||37.7 ± 4.4||0.27|
|International normalized ratio||1.2 ± 0.3||1.3 ± 0.3||0.46|
|Platelets (/mm3)||133 ± 68||97 ± 48||0.07|
|Circulating norepinephrine (pg/mL)||215.8 ± 120.1||236.1 ± 203.9||0.75|
|Esophageal varices [n (%)]||12 (57.1)||12 (60)||0.42|
|Medium/large varices [n (%)]||3 (14.3)||6 (30)||0.28|
|Previous bleeding [n (%)]||1 (5)||3 (15)||0.34|
|Ascites [n (%)]||8 (38.1)||4 (20)||0.20|
|Previous ascites [n (%)]||13 (62)||3 (15)||0.004|
|Previous encephalopathy ≥ grade 2 [n (%)]||3 (14.3)||3 (15)||0.65|
|Arterial hypertension [n (%)]||9 (42.9)||3 (15)||0.09|
|Diuretic treatment [n (%)]||4 (19)||5 (25)||0.65|
|Heart rate (bpm)||72.2 ± 12.3||77.9 ± 13.2||0.16|
|MAP (mm Hg)||100.3 ± 12.3||91.8 ± 11.6||0.03|
|ISVR (dyn/second/cm−5/m2)||2252.6 ± 572.9||1882.4 ± 525.3||0.04|
|CI (L/minute/m2)||3.5 ± 0.6||3.9 ± 0.9||0.15|
|FHVP (mmHg)||9.2 ± 3.6||8 ± 2.6||0.25|
|WHVP (mmHg)||23.9 ± 4.5||25.3 ± 4.5||0.34|
|HVPG (mmHg)||14.8 ± 2.8||17.3 ± 4.4||0.03|
|HBF (L/minute)||1.1 ± 0.5||1.3 ± 0.7||0.27|
|HSR (dyn/second/cm−5)||1284.3 ± 651.7||1497 ± 1205.9||0.48|
None of the studied cases or controls showed intrahepatic venovenous communicating vessels, so HVPG could be properly calculated for the entire included population.
There were differences in the baseline hemodynamics between the 2 groups (Table 1): the basal HVPG values were significantly lower in transplant patients versus controls, whereas the MAP and indexed systemic vascular resistance (ISVR) values were significantly higher. When we considered only patients with esophageal varices, the difference in baseline HVPG values disappeared (16.5 ± 2.6 mm Hg for transplant patients versus 16.7 ± 3.2 mm Hg for nontransplant patients). However, the differences in the systemic hemodynamics were more evident when the analysis was restricted to patients with varices (data not shown). Previous decompensation due to episodes of ascites was also more frequent in transplant patients with esophageal varices versus nontransplant controls (9 versus 2, P < 0.01).
Response to Acute Propranolol Administration
HVPG decreased significantly after propranolol (Table 2). In contrast to what was hypothesized, the magnitude of the HVPG reduction was similar in transplant patients and nontransplant patients (−14.1% ± 8.0% versus −16.9% ± 9.5%, P = 0.31; Table 3). Moreover, the proportions of patients whose HVPG decreased to <12 mm Hg (47.6% versus 25%, P = 0.13) or by ≥15% of the baseline (48% versus 51%, P = 0.62) or ≥20% of the baseline (23.8% versus 35%, P = 0.43) were similar in the 2 groups. Likewise, HBF decreased significantly and to similar extents in both transplant patients and nontransplant patients. The calculated HSR values were not modified by propranolol in either group (Table 2).
|Cases (n = 21)||P Value||Controls (n = 20)||P Value|
|Baseline||After Propranolol||Baseline||After Propranolol|
|Heart rate (bpm)||72.2 ± 12.3||61.4 ± 9.9||<0.001||77.9 ± 13.2||62 ± 10.1||<0.001|
|MAP (mm Hg)||100.3 ± 12.3||105.2 ± 17.4||0.11||91.8 ± 11.6||87.2 ± 10.3||0.003|
|ISVR (dyn/second/cm−5/m2)||2225.7 ± 559.3||2829.4 ± 767.2||<0.001||1847.6 ± 548.4||2304.1 ± 587.2||<0.001|
|CI (L/minute/m2)||3.5 ± 0.7||2.9 ± 0.5||<0.001||3.9 ± 1||2.8 ± 0.5||<0.001|
|FHVP (mm Hg)||9.2 ± 3.6||9.8 ± 3.4||0.01||8 ± 2.6||9.2 ± 2.6||0.001|
|WHVP (mm Hg)||23.9 ± 4.5||22.5 ± 3.9||<0.001||25.3 ± 4.6||23.6 ± 4.4||<0.001|
|HVPG (mm Hg)||14.8 ± 2.8||12.7 ± 2.8||<0.001||17.3 ± 4.4||14.5 ± 4.1||<0.001|
|HBF (L/minute)||1.1 ± 0.5||0.9 ± 0.4||0.03||1.3 ± 0.7||1.1 ± 0.6||<0.001|
|HSR (dyn/second/cm−5)||1284.4 ± 651.7||1296.2 ± 607.4||0.88||1497 ± 1205.9||1550.3 ± 1278.3||0.33|
|Cases (n = 21)||Controls (n = 20)||P Value|
|Heart rate (bpm)||−14.7 ± 6.0||−19.5 ± 12.4||0.12|
|MAP (mm Hg)||5.1 ± 14.2||−4.7 ± 6.4||0.007|
|ISVR (dyn/second/cm−5/m2)||28.2 ± 26.7||27.1 ± 18.6||0.89|
|CI (L/minute/m2)||−18.6 ± 7.7||−26.9 ± 8.9||0.005|
|FHVP (mm Hg)||9.4 ± 13.9||17.3 ± 17.8||0.12|
|WHVP (mm Hg)||−5.9 ± 4.3||−6.9 ± 6.9||0.60|
|HVPG (mm Hg)||−14.1 ± 8||−16.9 ± 9.5||0.31|
|HBF (L/minute)||−12.7 ± 24.5||−19 ± 11.8||0.30|
|HSR (dyn/second/cm−5)||4 ± 22.7||4.1 ± 15.2||>0.99|
In contrast, there were significant differences in the changes in the systemic hemodynamics induced by propranolol between the 2 groups (Table 3 and Fig. 1); the main difference was that CI decreased significantly less in the transplant patients versus the nontransplant patients with cirrhosis. Furthermore, there were significant differences in the behavior of MAP, which slightly decreased in nontransplant patients but increased in transplant patients with cirrhosis (Tables 2 and 3). This was accompanied by a trend of a smaller reduction in the heart rate in transplant patients (Table 3). Overall, these data indicate a reduced systemic sensitivity to propranolol in transplant patients.
To our knowledge, this is the first study addressing hepatic and systemic hemodynamic responses to the acute intravenous administration of beta-blockers in patients with the recurrence of cirrhosis after liver transplantation for HCV-related liver disease.
Our findings indicate that patients with clinically significant portal hypertension due to the recurrence of HCV-related cirrhosis after liver transplantation have a splanchnic hemodynamic response to propranolol similar to that of nontransplant patients with respect to the magnitude of the decrease in HVPG. This finding goes against our working hypothesis, in the sense that we expected a greater fall in HVPG in transplant patients because transplanted livers are denervated and, as such, are free from the effects of unopposed alpha-adrenergic vasoconstriction on the hepatic vasculature after propranolol administration,[21, 22] which would attenuate the decrease in HVPG.
The explanation for this finding probably can be found in our observation that propranolol administration caused a smaller effect on the systemic hemodynamics of transplant patients versus nontransplant patients with cirrhosis. In particular, the decreases in CO and, therefore, the splanchnic blood inflow were much less in the transplant patients. The fact that despite this smaller decrease in the splanchnic inflow the transplant patients exhibited a reduction in HVPG equal to that exhibited by nontransplant patients with cirrhosis indicates that our working hypothesis was not that far from reality. The question that emerges is the reason for the diminished systemic hemodynamic response to propranolol after liver transplantation. Notably, transplant patients have differences in their baseline systemic hemodynamics in comparison with nontransplant patients: they have significantly higher arterial pressure and systemic vascular resistance and a lower CI, and this leads to a hemodynamic pattern different from the canonical hyperkinetic circulatory syndrome of patients with cirrhosis and portal hypertension. It is likely that the reduced systemic effects of propranolol are related to the factors that determine the lack of hyperkinetic circulation in transplant patients with cirrhosis. Specifically, it could be that the immunosuppressive agents used after liver transplantation, which are known to cause arterial hypertension through sympathetic activation,[15, 16] stimulation of renal sensory nerve endings that contain synapsin-positive microvesicles, and endothelial dysfunction,[15, 16] are involved in the reduced responsiveness to nonselective beta-blockade. This issue has been insufficiently studied in patients with cirrhosis. However, our data are consistent with our observation that patients with cirrhosis and cardiovascular conditions leading to systemic endothelial dysfunction have a less pronounced response to propranolol than patients with unimpaired or enhanced endothelial function, as assessed by measurements of the postischemic flow-mediated dilatation of the brachial artery. Actually, it is intuitive that patients who already have lower CI values would exhibit a less marked reduction after beta-blockade. Indeed, several studies have suggested that patients or experimental animals with a less pronounced hyperkinetic circulation show a less marked HVPG response to propranolol.[26, 27]
Alternatively, it may be speculated that the lack of differences in the hepatic hemodynamic response between nontransplanted cirrhotic livers (ie, innervated) and transplanted cirrhotic livers (ie, not innervated) lies in the microanatomy of regenerative nodules in humans. Although nerve endings in normal livers reach hepatocytes, sinusoidal endothelial cells, and stellate cells, nerve endings in cirrhotic livers seem to poorly penetrate the nodules. Because stellate cells express both alpha-adrenoceptors and beta-adrenoceptors, contraction and/or relaxation of the sinusoidal walls in cirrhotic nodules can occur in an innervation-independent way. This would explain the susceptibility of sinusoidal blood flow to the effects of adrenergic antagonists in cirrhosis despite a lack of direct innervation.[31, 32] However, increased nerve fiber density in fibrous septa and around portal veins has been described in cirrhosis,[33, 34] but its role in controlling liver circulation has not been fully elucidated. Clearly, more studies are required on the importance of neurocontrol of the hepatic circulation in cirrhosis.
Our findings may have clinical implications for the use of beta-blockers in the treatment of portal hypertension in patients with recurrent cirrhosis after liver transplantation. It is possible that although in nontransplant patients the effects of propranolol are enhanced by the addition of a nitric oxide donor (eg, isosorbide mononitrate) or by the use of beta-blockers with intrinsic vasodilatory action (eg, carvedilol), this may not occur in transplant patients with cirrhosis, and this emphasizes the importance of repeat measurements of HVPG during pharmacological therapy in these patients. On the other hand, simvastatin might enhance the effects of beta-blockers because simvastatin has been shown to correct the abnormal vascular function induced by cyclosporine A[37, 38] and improves liver microcirculation and decreases HVPG in patients with cirrhosis[39-41]; this effect is additive to that of propranolol.
The main limitation of our study is that it is restricted to the assessment of the acute effects of propranolol administration on splanchnic and systemic hemodynamics. Thus, we cannot exclude the idea that increasing the dosage of propranolol during therapy might enhance the fall in HVPG. Also, longitudinal studies would be required to verify that the hemodynamic target defining a good response in nontransplant patients also applies to patients after liver transplantation. In this respect, it is worth noting that ascites, the more common complication of portal hypertension in transplant patients with cirrhosis, may be favored by factors such as impaired renal function from immune suppression and abnormal drainage of hepatic lymph caused by transplant surgery. In addition, it can be speculated that these patients might be at increased risk for developing varices. Most patients have large varices before transplantation, and this is likely to facilitate their reappearance when the portal pressure increases because of the recurrence of cirrhosis; this is analogous to what occurs in patients treated with a transjugular intrahepatic portosystemic shunt when a shunt obstruction develops. Obviously, it is likely that such longitudinal studies will require the joint effort of several centers in a cooperative initiative. We do hope that our study stimulates the constitution of such a consortium.
The authors thank Ms. M. A. Baringo, L. Rocabert, and R. Saez for their expert nursing assistance. The authors also express their gratitude to Ms. Clara Esteva for her secretarial support.
- 25Systemic endothelial dysfunction in patients with cirrhosis and portal hypertension: relationship with cardiovascular risk factors, systemic and hepatic hemodynamics and with the HVPG response to propranolol [abstract]. Hepatology 2009;50(suppl 4):438A., , , , , , .
- 26Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 2006;290:G980-G987., , , , , .
- 27Lack of effect of non-selective beta-blockers on the hepatic venous pressure gradient (HVPG) in patients with mild portal hypertension: a tale of two studies [abstract]. Hepatology 2010;52(suppl 1):1020A., , , , , .
- 34Stromal mast cells and nerve fibers in various chronic liver diseases: relevance to hepatic fibrosis. Am J Gastroenterol 1999;94: 1923-1932., , .Direct Link: