Ascites in Cirrhosis With Severe Portal Hypertension
Ascites in Cirrhosis With Severe Portal Hypertension
This study shows that in compensated cirrhosis with severe PHT and large esophageal varices a reduction in HVPG >10% from the baseline (considered hemodynamic response) lowers the risk of decompensation. In addition to a reduced risk of first variceal bleeding, hemodynamic responders had lower probability of first ascitic decompensation. Complications of ascites, such as refractory ascites and hepatorenal syndrome, were also less frequent in responders. Previous studies have shown that development of ascites is mainly dependent on the progression of PHT. An increase in HVPG above 10 mm Hg dramatically increases the risk of transition from a compensated to a decompensated stage. However, beyond this threshold the contribution of changes in HVPG to the risk of ascites has not been clearly established. Previous studies focused on the prevention of variceal hemorrhage have shown that a reduction in HVPG to <12 mm Hg or ≥ 20% from baseline, in addition to lower risk of bleeding, is also associated with a decreased risk of ascites. However, controversial results have been reported. This may be due to methodological differences among studies. None of them was specifically designed to evaluate the relationship between changes in HVPG and ascites development. Heterogeneous stages of cirrhosis, with different prognosis, were included in these studies, meaning patients with compensated and decompensated disease, with previous history of ascites in many cases. Another important limitation of these studies was the subjective definition used for ascites development, even including worsening of preexisting ascites. To deal with these limitations the current study specifically select an homogeneous group of patients with compensated cirrhosis and without any previous decompensation, but at high risk of decompensation indicated by the presence of HVPG ≥ 12 mm Hg and large varices, who were treated with nonselective β-blockers for primary prophylaxis of bleeding. Our results provide additional evidence on the contribution of PHT to the progression of cirrhosis, showing that once clinically significant PHT is reached, it is still possible to reduce the probability of developing ascites by achieving a decrease in HVPG ≥ 10% from baseline. Otherwise ascites will develop in the majority of patients (up to 90%) without such a reduction in HVPG. In agreement with previous observations, the current study shows that hemodynamic response also decreases the risk of refractory ascites and hepatorenal syndrome. However, SLR analysis showed that only ascites, and neither hepatorenal syndrome nor refractory ascites, was independently associated with hemodynamic response. This suggests that, in compensated cirrhosis, hemodynamic response reduces the risk of complications related with ascites by decreasing the probability of developing ascites.
Predictors of ascites development have not been clearly established. Previous studies have shown that several parameters reflecting liver and circulatory dysfunction, such as bilirubin, MELD, arterial hypotension, urinary sodium excretion, or plasma renin activity, provide prognostic information on development of ascites. This is clinically sound because both, liver and circulatory dysfunction, are involved in the development of ascites as well as PHT. In keeping with this, the current study clearly demonstrates that lack of hemodynamic response is a strong predictor of ascites. We also found that patients who developed ascites had worse liver function, as indicated by a higher MELD score, and had changes related to the circulatory dysfunction that accompanies the progression of cirrhosis, such as a greater arterial vasodilatation indicated by a lower systemic vascular resistance. However, classification-and-regression-tree analysis showed that hemodynamic nonresponse provides the strongest prognostic information on the risk of developing ascites, whereas MELD score may be helpful to identify patients at risk despite achieving a hemodynamic response.
The definition of response in this study differs from the traditional criteria of an HVPG decrease >20%. However, this criterion was established in decompensated cirrhosis with previous variceal bleeding and frequently also with ascites. In keeping with our results, several studies have shown that in earlier stages of cirrhosis, with less severe PHT, a lower threshold reduction in HVPG may be enough to prevent decompensation. In compensated cirrhosis with moderate PHT (HVPG >6 mm Hg) and absence of varices, a 10% threshold reduction in HVPG was independently associated with a reduced risk of developing either varices or variceal bleeding and also lower risk of cirrhotic decompensation. In a recent study from our unit, this threshold reduction was the best cutoff to predict first bleeding in patients with large varices under primary prophylaxis. In that study, we also observed that hemodynamic responders had a lower risk of development or worsening of ascites. However, more than 50% of the patients included had previous history of ascites precluding an appropriate evaluation of the relationship between changes in HVPG and progression into decompensation.
Another relevant finding in this study was the prognostic value of acute response to β-blockers on long-term risk of ascites. Although the prognostic ability was inferior than that of chronic response, as indicated by a lower area under ROC curve, the predictive value of acute response, in a single hemodynamic study, on long-term risk of decompensation was accurate as shown in previous studies. Both endoscopic variceal ligation and β-blockers are currently recommended as first-line option in primary prophylaxis of bleeding. Our findings show that a single hemodynamic study with an acute test is able to predict patients in whom β-blockers may provide relevant additional benefit. This in turn suggests that restricting EVL, a therapy with potential for severe side-effects, to acute nonresponders may improve the efficacy of prophylactic treatment in compensated cirrhosis, but requires further investigation.
In compensated cirrhosis mortality largely depends on the progression of liver disease to decompensation. Accordingly, in the current study the majority of deaths occurred after either ascites or bleeding and as expected we found that development of decompensation had a robust predictive value of mortality. Both development of ascites and bleeding had independent predictive value of death. In keeping with previous studies, we also found that hemodynamic response was the strongest predictor of decompensation of cirrhosis, which will ultimately determine survival.
A possible limitation of this study is related to the population investigated. We included patients in compensated phase of cirrhosis and in the stage with large esophageal varices. Whether the results can be applied to patients without varices or with decompensated cirrhosis remains to be determined. However, it has been shown that an HVPG decrease ≥10% is an independent predictor of decompensation in compensated cirrhosis without varices and with mild PHT (with HVPG ≥ 6 mm Hg). In decompensated cirrhosis, it has been shown that an HVPG decrease ≥ 20% may avoid complications such as ascites. Whether a lesser decrease in HVPG may be enough to prevent ascites in these patients remains to be determinate. Another potential limitation is related to the fact that the study was not blinded and this may have introduced a bias. It is unlikely, however, as the hemodynamic response was not predefined and all consecutive patients referred primary prevention of bleeding were included and prospectively followed for development of decompensation. The absence of a control group, without treatment with β-blockers, does not allow to ascertaining whether other cofactors may have induce an improvement of PHT or may have account for development of ascites. However, it has been shown that hemodynamic response, either induced by therapy or spontaneous, is an independent predictor of decompensation in compensated cirrhosis without varices. Whether treatment of PHT, with β-blockers or other drugs, can prevent the development of ascites as suggested by our study should be confirmed in future randomized control trial.
In conclusion, the results of this study indicate that in patients with compensated cirrhosis and severe PHT with large varices, achieving an HVPG decrease >10% from baseline with β-blockers provides a significant reduction on the risk of first ascitic decompensation. Hemodynamic responders also have lower risk of other decompensations related with ascites, such as refractory ascites and hepatorenal syndrome, in addition to lower risk of variceal bleeding.
Discussion
This study shows that in compensated cirrhosis with severe PHT and large esophageal varices a reduction in HVPG >10% from the baseline (considered hemodynamic response) lowers the risk of decompensation. In addition to a reduced risk of first variceal bleeding, hemodynamic responders had lower probability of first ascitic decompensation. Complications of ascites, such as refractory ascites and hepatorenal syndrome, were also less frequent in responders. Previous studies have shown that development of ascites is mainly dependent on the progression of PHT. An increase in HVPG above 10 mm Hg dramatically increases the risk of transition from a compensated to a decompensated stage. However, beyond this threshold the contribution of changes in HVPG to the risk of ascites has not been clearly established. Previous studies focused on the prevention of variceal hemorrhage have shown that a reduction in HVPG to <12 mm Hg or ≥ 20% from baseline, in addition to lower risk of bleeding, is also associated with a decreased risk of ascites. However, controversial results have been reported. This may be due to methodological differences among studies. None of them was specifically designed to evaluate the relationship between changes in HVPG and ascites development. Heterogeneous stages of cirrhosis, with different prognosis, were included in these studies, meaning patients with compensated and decompensated disease, with previous history of ascites in many cases. Another important limitation of these studies was the subjective definition used for ascites development, even including worsening of preexisting ascites. To deal with these limitations the current study specifically select an homogeneous group of patients with compensated cirrhosis and without any previous decompensation, but at high risk of decompensation indicated by the presence of HVPG ≥ 12 mm Hg and large varices, who were treated with nonselective β-blockers for primary prophylaxis of bleeding. Our results provide additional evidence on the contribution of PHT to the progression of cirrhosis, showing that once clinically significant PHT is reached, it is still possible to reduce the probability of developing ascites by achieving a decrease in HVPG ≥ 10% from baseline. Otherwise ascites will develop in the majority of patients (up to 90%) without such a reduction in HVPG. In agreement with previous observations, the current study shows that hemodynamic response also decreases the risk of refractory ascites and hepatorenal syndrome. However, SLR analysis showed that only ascites, and neither hepatorenal syndrome nor refractory ascites, was independently associated with hemodynamic response. This suggests that, in compensated cirrhosis, hemodynamic response reduces the risk of complications related with ascites by decreasing the probability of developing ascites.
Predictors of ascites development have not been clearly established. Previous studies have shown that several parameters reflecting liver and circulatory dysfunction, such as bilirubin, MELD, arterial hypotension, urinary sodium excretion, or plasma renin activity, provide prognostic information on development of ascites. This is clinically sound because both, liver and circulatory dysfunction, are involved in the development of ascites as well as PHT. In keeping with this, the current study clearly demonstrates that lack of hemodynamic response is a strong predictor of ascites. We also found that patients who developed ascites had worse liver function, as indicated by a higher MELD score, and had changes related to the circulatory dysfunction that accompanies the progression of cirrhosis, such as a greater arterial vasodilatation indicated by a lower systemic vascular resistance. However, classification-and-regression-tree analysis showed that hemodynamic nonresponse provides the strongest prognostic information on the risk of developing ascites, whereas MELD score may be helpful to identify patients at risk despite achieving a hemodynamic response.
The definition of response in this study differs from the traditional criteria of an HVPG decrease >20%. However, this criterion was established in decompensated cirrhosis with previous variceal bleeding and frequently also with ascites. In keeping with our results, several studies have shown that in earlier stages of cirrhosis, with less severe PHT, a lower threshold reduction in HVPG may be enough to prevent decompensation. In compensated cirrhosis with moderate PHT (HVPG >6 mm Hg) and absence of varices, a 10% threshold reduction in HVPG was independently associated with a reduced risk of developing either varices or variceal bleeding and also lower risk of cirrhotic decompensation. In a recent study from our unit, this threshold reduction was the best cutoff to predict first bleeding in patients with large varices under primary prophylaxis. In that study, we also observed that hemodynamic responders had a lower risk of development or worsening of ascites. However, more than 50% of the patients included had previous history of ascites precluding an appropriate evaluation of the relationship between changes in HVPG and progression into decompensation.
Another relevant finding in this study was the prognostic value of acute response to β-blockers on long-term risk of ascites. Although the prognostic ability was inferior than that of chronic response, as indicated by a lower area under ROC curve, the predictive value of acute response, in a single hemodynamic study, on long-term risk of decompensation was accurate as shown in previous studies. Both endoscopic variceal ligation and β-blockers are currently recommended as first-line option in primary prophylaxis of bleeding. Our findings show that a single hemodynamic study with an acute test is able to predict patients in whom β-blockers may provide relevant additional benefit. This in turn suggests that restricting EVL, a therapy with potential for severe side-effects, to acute nonresponders may improve the efficacy of prophylactic treatment in compensated cirrhosis, but requires further investigation.
In compensated cirrhosis mortality largely depends on the progression of liver disease to decompensation. Accordingly, in the current study the majority of deaths occurred after either ascites or bleeding and as expected we found that development of decompensation had a robust predictive value of mortality. Both development of ascites and bleeding had independent predictive value of death. In keeping with previous studies, we also found that hemodynamic response was the strongest predictor of decompensation of cirrhosis, which will ultimately determine survival.
A possible limitation of this study is related to the population investigated. We included patients in compensated phase of cirrhosis and in the stage with large esophageal varices. Whether the results can be applied to patients without varices or with decompensated cirrhosis remains to be determined. However, it has been shown that an HVPG decrease ≥10% is an independent predictor of decompensation in compensated cirrhosis without varices and with mild PHT (with HVPG ≥ 6 mm Hg). In decompensated cirrhosis, it has been shown that an HVPG decrease ≥ 20% may avoid complications such as ascites. Whether a lesser decrease in HVPG may be enough to prevent ascites in these patients remains to be determinate. Another potential limitation is related to the fact that the study was not blinded and this may have introduced a bias. It is unlikely, however, as the hemodynamic response was not predefined and all consecutive patients referred primary prevention of bleeding were included and prospectively followed for development of decompensation. The absence of a control group, without treatment with β-blockers, does not allow to ascertaining whether other cofactors may have induce an improvement of PHT or may have account for development of ascites. However, it has been shown that hemodynamic response, either induced by therapy or spontaneous, is an independent predictor of decompensation in compensated cirrhosis without varices. Whether treatment of PHT, with β-blockers or other drugs, can prevent the development of ascites as suggested by our study should be confirmed in future randomized control trial.
In conclusion, the results of this study indicate that in patients with compensated cirrhosis and severe PHT with large varices, achieving an HVPG decrease >10% from baseline with β-blockers provides a significant reduction on the risk of first ascitic decompensation. Hemodynamic responders also have lower risk of other decompensations related with ascites, such as refractory ascites and hepatorenal syndrome, in addition to lower risk of variceal bleeding.
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