Hepatic arterial buffer response (HABR) is an intrinsic regulatory

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1 Hepatic Arterial Buffer Response in Patients With Advanced Cirrhosis Veit Gülberg, 1 Klaus Haag, 2 Martin Rössle, 2 and Alexander L. Gerbes 1 Hepatic arterial buffer response (HABR) is considered an important compensatory mechanism to maintain perfusion of the liver by hepatic arterial vasodilation on reduction of portal venous perfusion. HABR has been suggested to be impaired in patients with advanced cirrhosis. In patients with hepatopetal portal flow, placement of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal venous liver perfusion. Accordingly, patients with severe cirrhosis should have impaired HABR after TIPS implantation. Therefore, the aim of this study was to investigate the effect of TIPS on HABR as reflected by changes in resistance index (RI) of the hepatic artery. A total of 366 patients with cirrhosis (Child-Pugh class A, 106; class B, 168; class C, 92) underwent duplex Doppler ultrasonographic examination with determination of RI and maximal flow velocity in the portal vein before and 1 month after TIPS placement. Portosystemic pressure gradient was determined before and after TIPS placement. In 29 patients with hepatofugal portal blood flow, RI was significantly lower than in 337 patients with hepatopetal flow ( vs ; P <.001). TIPS induced a significant decrease of the RI in patients with hepatopetal flow (RI, before vs after TIPS; P.001) but not in patients with hepatofugal flow (RI, before vs after TIPS; NS). This response was not dependent on the Child-Pugh class. In conclusion, our results suggest that some degree of HABR is preserved even in patients with advanced cirrhosis with significant portal hypertension. (HEPATOLOGY 2002;35: ) Hepatic arterial buffer response (HABR) is an intrinsic regulatory mechanism of the liver to maintain total hepatic blood flow when portal perfusion decreases. Increased hepatic arterial blood flow mediated by adenosine washout in the portal triad 1-3 and independent of hepatic oxygen supply or demand compensates for the reduced portal tributary blood flow (for review, see Lautt 4,5 ). This phenomenon has been shown under various experimental conditions such as endotoxinemia 6 or portal vein ligation 7 and in the clinical setting after liver transplantation. 8 Just recently, maintenance of HABR has been shown in an animal model of cirrhosis (namely, CCl 4 -induced cirrhosis in the rat). 9,10 Thus far, it is not clear whether HABR is preserved in patients with cirrhosis and whether it is dependent on the stage of liver disease. Several studies have shown an increased hepatic arterial resistance in patients with cirrhosis. This was related to the degree of portal hypertension, 11,12 portal resistance, 12,13 and Child-Pugh score, 12 respectively. In contrast to these observations, Kleber et al. 14 recently reported an increased hepatic arterial flow volume Abbreviations: HABR, hepatic arterial buffer response; TIPS, transjugular intrahepatic portosystemic shunt; RI, resistance index. From the 1 Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany; and 2 Department of Medicine II, Albrecht-Ludwigs-University, Freiburg, Germany. Received March 7, 2001; accepted December 12, Address reprint requests to: Veit Gülberg, M.D., Department of Medicine II, Klinikum Grosshadern, Marchioninistra e 15, Munich, Germany. Veit.Guelberg@med2.med.uni-muenchen.de; fax: (49) Copyright 2002 by the American Association for the Study of Liver Diseases /02/ $35.00/0 doi: /jhep and decreased pulsatility index of the hepatic artery in Child-Pugh class C patients. In this study, intra-arterial infusion of adenosine induced an increase in hepatic arterial blood flow that was independent of Child-Pugh class, suggesting that HABR may be independent of the stage of liver disease. Hepatofugal portal venous blood flow has been reported in 2% to 15% of patients with cirrhosis According to the HABR hypothesis, this condition should be a strong stimulus for hepatic arterial vasodilation. Similarly, the transjugular intrahepatic portosystemic shunt (TIPS) procedure results in a decreased portal perfusion fraction of total liver blood flow. 18 Therefore, assuming an impaired HABR in patients with advanced cirrhosis, hepatic arterial blood flow should increase less and the decrease in resistance of the hepatic artery should be lower after the TIPS procedure than in patients with compensated cirrhosis. To test this hypothesis, we compared the hepatic arterial resistance index (RI) in cirrhotic patients with hepatopetal and hepatofugal portal venous blood flow. Furthermore, the effects of TIPS on RI were examined in both groups of patients using duplex Doppler ultrasonography. Patients and Methods Patients. A total of 454 patients were evaluated before placement of TIPS. Thirty-seven of these patients could not be evaluated 1 month after placement of TIPS, leaving 417 patients. In 51 of these 417 patients, a good quality RI signal could not be obtained on at least 1 of the 2 visits before and 1 month after placement of TIPS. Thus, 366 patients were analyzed in the present study (244 men and 122 women; age, 52 1 years). The cause of 630

2 HEPATOLOGY, Vol. 35, No. 3, 2002 GÜLBERG ET AL. 631 cirrhosis was alcohol induced in 253 patients, viral hepatitis in 47 patients, autoimmune liver disease in 6 patients, cholestatic liver disease in 13 patients, and other in 47 patients. Child-Pugh class was A in 106 patients, B in 168 patients, and C in 92 patients. Indication for TIPS insertion was massive ascites in 82 patients, prevention of variceal rebleeding in 275 patients, and both ascites and rebleeding prophylaxis in 9 patients. The present study only included elective TIPS procedures. Therefore, patients with active bleeding and/or clinical or laboratory signs of infection were excluded from this investigation. Written and informed consent to participate in the study was obtained from all patients. Duplex Doppler Ultrasonographic Examination. Duplex Doppler ultrasonographic examination with determination of RI and maximal flow velocity in the portal vein before and 1 month after placement of TIPS were performed by the same investigators as described earlier. 19 The systolic and diastolic flow velocity of the main right intrahepatic branch of the hepatic artery was determined, and the RI was calculated as the difference between the systolic and diastolic flow velocity divided by the systolic flow velocity. The examination was performed with Ultramark 9 equipment (Advanced Technology Laboratories, Solingen, Germany) using a phased array transducer (3.5 MHz) and a wall filter of 50 Hz. The sampling size was equal to the vessel diameter, and the angle between the Doppler beam and the longitudinal axis of the vessel was 30 to 60. Measurements of flow velocities were performed in triplicate in the morning between 8 and 10 AM by the same investigators with an intraobserver variation of less than 10%. Patients were investigated after a fasting period of 12 to 16 hours before the examination. TIPS Procedure. The TIPS procedure was performed as described earlier in detail. 20,21 Briefly, a puncture needle was advanced transjugularly into a hepatic vein. After successful puncture of the right intrahepatic branch of the portal vein, a metallic stent was implanted. The portosystemic pressure gradient was determined before and immediately after the shunt was inserted. Statistical Analysis. Data are presented as mean and SE. Mean values were compared by 1-way ANOVA and paired or unpaired t test where appropriate. Correlation coefficients were calculated by the least squares method (Pearson s r). Multiple regression analysis was performed by the stepwise inclusion of independent variables at a P value less than.05 (SPSS Inc.). A P value less than.05 was considered statistically significant. Table 1. Portal Hemodynamics in the Study Population Child-Pugh A (n 106) Child-Pugh B (n 168) Child-Pugh C (n 92) V max PV (cm/s) Hepatopetal flow (n 337) Hepatofugal flow (n 29) PSPG (cm H 2 O) Hepatopetal flow (n 337) Hepatofugal flow (n 29) NOTE. Values expressed as mean SEM; no significant differences were observed for the parameters between the 3 groups. Abbreviations: V max PV, maximal flow velocity in the portal vein; PSPG, portosystemic pressure gradient. Table 2. TIPS-Induced Changes of Serum Albumin, Bilirubin, and Prothrombin Index in Patients With Cirrhosis Results Portohepatic Hemodynamics at Baseline. Maximal flow velocities in the portal vein are shown in Table 1. Hepatofugal portal venous blood flow was observed in 29 of 366 patients (7.9%). The portosystemic pressure gradient did not differ between patients with hepatofugal or hepatopetal blood flow or between Child- Pugh classes (Table 1). RI of the hepatic artery did not differ between Child-Pugh classes (Table 2). However, RI was significantly lower in patients with hepatofugal portal blood flow ( ) than in patients with hepatopetal flow direction ( ; P.001). A significant correlation between RI and portosystemic pressure gradient or maximal flow velocity in the portal vein was not observed in patients with hepatofugal or hepatopetal portal blood flow. TIPS-Induced Hemodynamic Changes. Insertion of TIPS resulted in a similar reduction in the portosystemic pressure gradient by 56% 1% in patients with hepatopetal flow and by 63% 1% in patients with hepatofugal flow. TIPS induced a significant decrease of the RI in patients with hepatopetal but not with hepatofugal flow (Table 3). This response was not dependent on the Child-Pugh class (Fig. 1). TIPS-induced changes in portal venous peak flow velocity were not correlated to the changes in RI (r 0.069; P.195). Multiple regression analysis including Child- Pugh score, portal pressure gradient, peak flow velocity in the portal vein, and change in portal pressure gradients as independent variables and change in RI as the dependent parameter showed a poor relation between the change in RI and the change in portal pressure gradients (r 0.122; r ; P.025) and no relation between Child-Pugh score or portal pressure gradient at baseline and the changes in RI. Discussion Before TIPS 1 Month After TIPS All patients Serum albumin (g/dl) Serum bilirubin (mg/dl) Prothrombin index (%) NS Hepatopetal flow Serum albumin (g/dl) Serum bilirubin (mg/dl) Prothrombin index (%) NS Hepatofugal flow Serum albumin (g/dl) NS Serum bilirubin (mg/dl) NS Prothrombin index (%) NS NOTE. Values expressed as mean SEM. This study argues against impairment of HABR in patients with advanced cirrhosis and significant portal hypertension. This is based on the following main findings obtained in a large series of patients with cirrhosis. (1) RI of the hepatic artery is similar in patients with Child-Pugh class A, B, or C with hepatopetal portal P

3 632 GÜLBERG ET AL. HEPATOLOGY, March 2002 Fig. 1. Changes in RI after TIPS placement. Percent changes of baseline values are shown with SE. ( ) Hepatopetal; ( ) hepatofugal. blood flow. (2) RI is significantly decreased in cirrhotic patients with hepatofugal blood flow. (3) After TIPS insertion, RI of the hepatic artery decreases in patients with hepatopetal blood flow irrespective of Child-Pugh class. It has been suggested that HABR is impaired in cirrhotic patients. 13 This assumption was derived from the observation that cirrhotic patients with portal vein thrombosis have higher hepatic arterial RI than patients without portal vein thrombosis. 13 Data on the influence of portal vein thrombosis are controversial; another study reported decreased hepatic arterial RI in patients with portal vein thrombosis compared with patients with liver disease without portal vein thrombosis or healthy controls. 22 However, it is difficult to draw conclusions about HABR in liver disease from these studies because no data were provided on intraindividual changes in hepatic arterial RI. Recently, Kleber et al. 14 showed that intraarterial adenosine infusion is able to increase hepatic arterial blood flow even in advanced cirrhosis. However, this pharmacologic intervention does not provide direct evidence for persistence of HABR in cirrhosis because the primary target vessel for manipulation of blood flow in this study was not the portal vein. TIPS insertion results in a decreased portal perfusion fraction of total liver blood flow in cirrhotic patients. 18 In the present study, we therefore determined intraindividual changes in RI before and after TIPS placement in cirrhotic patients with both hepatopetal or hepatofugal blood flow. Interestingly, we observed similar baseline RI before TIPS placement in all Child-Pugh classes of the study population with hepatopetal portal blood flow before TIPS placement and an equal decrease in RI after intervention. These findings are in accordance with the results of direct transarterial flow determination of hepatic arterial perfusion in a small number of patients undergoing the TIPS procedure. 18 Therefore, duplex Doppler ultrasonography seems suitable for estimation of hepatic arterial perfusion. Moreover, this indicates that HABR in our patients was not dependent on the severity of liver disease. Hepatic arterial RI does not exclusively reflect vascular resistance but also may be influenced by cardiac output and stroke volume. 23 It might therefore be argued that changes in RI in the present study reflect TIPS-induced changes in cardiac output rather than HABR. Indeed, both cardiac output and stroke volume increase acutely after TIPS placement. 24 However, 9 hours after the intervention, all hemodynamic parameters almost returned to baseline values. This is in line with our previous observations 25 showing no changes in systemic hemodynamic parameters 7 days after TIPS placement as well from another study showing significant increases in heart rate and mean arterial blood pressure only 30 minutes after TIPS placement, with return to baseline values after 1 week, 3 months, and 1 year of follow-up. 26 In contrast, other investigators have shown an increased cardiac output and reduced peripheral resistance, demonstrating a worsening of hyperdynamic circulatory state at least 1 month after TIPS placement. 27 However, based on our own observations, 24,25 it was anticipated that there were no significant changes in systemic hemodynamic parameters in cirrhotic patients when RI of the hepatic artery was reevaluated 1 month after TIPS placement. One might argue that the observed changes in RI after TIPS placement were only moderate. This could raise doubt about the biological relevance of our finding. However, the magnitude of change in RI after TIPS placement corresponds to what has been observed in cirrhotic patients after a meal ingestion, 28 and a decrease in RI in cirrhotic patients from 0.70 to 0.63 has been reported after orthotopic liver transplantation. 29 Furthermore, a recent investigation of arterial blood flow by selective catheterization of the hepatic artery before and after TIPS placement showed an increase in hepatic arterial blood flow of 35%. 18 These patients had a similar decrease in the portosystemic pressure gradient as the patients included in the present study. Therefore, the mean decrease in RI of approximately 6% in our study reflects a significant increase in hepatic arterial blood flow. The question remains if the observed decrease in RI may compensate for the reduction of portal tributary blood flow to the sinusoids after TIPS placement in our patients. Determination of total hepatic blood flow before and after TIPS placement has been performed and reported by others. Lotterer et al. 26 observed a significant (20%-25%) decrease in sorbitol clearance in 21 cirrhotic patients at 1 week, 3 months, and 1 year after TIPS placement. In line with this observation were the findings of Rodríguez-Laiz et al., 30 who reported a significant (50%) decrease in hepatic blood flow in 15 cirrhotic patients as evaluated by indo- Table 3. TIPS-Induced Changes of Hepatic Arterial RI in Patients With Cirrhosis Before TIPS After TIPS P All patients (n 366) Child-Pugh A (n 106) Child-Pugh B (n 169) Child-Pugh C (n 92) Hepatopetal flow All patients (n 337) Child-Pugh A (n 105) Child-Pugh B (n 160) Child-Pugh C (n 73) Hepatofugal flow All patients (n 29) * NS Child-Pugh A (n 1) Child-Pugh B (n 9) NS Child-Pugh C (n 19) NS NOTE. Values expressed as mean SEM. *P.001 vs. all patients with hepatopetal flow.

4 HEPATOLOGY, Vol. 35, No. 3, 2002 GÜLBERG ET AL. 633 cyanine green clearance before and about 1 month after TIPS placement. At first glance, it therefore seems that HABR in cirrhosis may not fully compensate for the TIPS-induced reduction in portal blood flow. Furthermore, experimental data from the cirrhotic rat clearly show that the maximum buffer capacity of the hepatic artery is limited to 50% to 60% in both cirrhotic and control animals. 10 Thus, it seems quite reasonable that HABR cannot fully compensate for TIPS-induced reduction of portal blood supply to the sinusoids in cirrhotic patients. Interestingly, despite reduction of total liver blood flow to 71% to 76% of baseline values in the animal model, 9 portal vein occlusion did not cause a deterioration in hepatic tissue po 2 in the presence of HABR. Cirrhotic patients with hepatofugal blood flow showed significantly lower RI before TIPS placement than patients with antegrade portal flow direction. In these patients, the portal perfusion fraction tends toward 0, which should be a maximum stimulus for HABR. Because TIPS placement in these patients will result in portal venous decompression without further reduction of the hepatic portal perfusion fraction, additional hepatic arterial vasodilation would not be expected. This assumption is supported by our observation of unchanged RI after TIPS placement in patients with retrograde portal venous blood flow before TIPS placement. In summary, our results show that there is some degree of HABR even in patients with advanced cirrhosis with significant portal hypertension. Acknowledgment: technical assistance. References The authors thank E. Berger for skillful 1. Lautt WW, Legare DJ, d Almeida MS. Adenosine as putative regulator of hepatic arterial flow (the buffer response). Am J Physiol 1985; 248:H331-H Ezzat WR, Lautt WW. Hepatic arterial pressure-flow autoregulation is adenosine mediated. 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