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Effects of Prostaglandin E₁ Injection Through the Superior Mesenteric Artery on the Hemodynamics of Hepatocellular Carcinoma

¹ All authors: Department of Radiology, Kyoto Prefectural University of Medicine, 465 Kajii-chyo, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan.

Received May 4, 2001; accepted after revision August 9, 2001.

 
Address correspondence to T. Yamagami.

Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBJECTIVE. The purpose of our study was to assess the effects of portal blood flow on contrast enhancement in hepatocellular carcinoma lesions on CT hepatic arteriography.

SUBJECTS AND METHODS. We examined 43 tumors in 39 patients who simultaneously underwent CT during arterial portography and CT hepatic arteriography for examination of liver tumors and then CT hepatic arteriography with prostaglandin E₁ injection via the superior mesenteric artery. All lesions pathologically confirmed to be hepatocellular carcinomas exhibited portal perfusion defects on CT during arterial portography. Changes in CT attenuation, size, and shape of liver tumors visualized on CT hepatic arteriography after intraarterial injection of prostaglandin E₁ were studied. In addition, changes in CT attenuation of the liver parenchyma surrounding the tumor were measured.

RESULTS. The CT attenuation increased significantly after injection of prostaglandin E₁ in 91% (39/43) of the lesions (mean increase from 176.4 to 206.6 H; p = 0.0006, paired t test). The size and shape of the enhanced area generally did not change. The CT attenuation of the liver parenchyma surrounding each liver tumor significantly decreased in 58% (25/43) of the hepatocellular carcinoma lesions (mean decrease from 94.8 to 92.0 H; p = 0.0166, paired t test) and lesion conspicuity increased in 91% (39/43) of the tumors.

CONCLUSION. Lesion conspicuity on CT hepatic arteriography between hepatocellular carcinoma and the surrounding liver parenchyma increased because of greater portal perfusion after the prostaglandin E₁ injection.

Introduction

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In recent years, noninvasive imaging, such as dynamic CT or MR imaging [1,2,3], has altered the role of angiographically assisted CT imaging, such as helical CT during arterial portography and CT hepatic arteriography [4]. However, these latter methods, which use the difference in hemodynamic features between normal liver parenchyma and liver tumors, continue to be among the most sensitive techniques for detecting focal hepatic lesions [2, 3]. Moreover, angiographically assisted CT is the most useful imaging modality available to precisely evaluate the perfusion phenomenon in the liver without resorting to surgical laparotomy [4,5,6,7]. We believe that the information gained from such CT imaging is also of importance in correctly interpreting various hepatobiliary images using intrahepatic hemodynamics, such as Doppler sonography, dynamic CT, and dynamic MR imaging.

Recently, we developed a method to distinguish solitary pseudolesions revealed by angiographically assisted CT imaging from tumors by adding an intraarterial injection of prostaglandin E₁, a vasodilator, during CT hepatic arteriography [8]. Increased portal blood flow [9] and pressure [10] after injection of prostaglandin E₁ via the superior mesenteric artery influence blood perfusion in pseudolesions caused by direct venous inflow to the liver parenchyma from the splanchnic organs independent of portal venous flow [11,12,13,14]. As a result, findings of most such pseudolesions change after the prostaglandin E₁ injection [8].

We hypothesized that such hemodynamic changes also influence findings of liver tumor and normal liver parenchyma. The main purpose of our study was to clarify the standard hemodynamic changes in hepatocellular carcinoma and surrounding normal liver parenchyma after an increase in portal blood flow. In addition, we determined whether the quality of angiographically assisted CT imaging can be improved by adding an intraarterial infusion of prostaglandin E₁ via the mesenteric artery to CT hepatic arteriography.

Subjects and Methods

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Patients
To investigate the effect of increased portal blood flow on hepatocellular carcinoma lesions, we selected 39 patients with suspected hepatocellular carcinoma to undergo both CT during arterial portography and CT hepatic arteriography during the same procedure followed by CT hepatic arteriography with prostaglandin E₁ injection via the superior mesenteric artery. In all patients, the combination of CT during arterial portography and CT hepatic arteriography was performed for the diagnosis and evaluation of hepatocellular carcinoma suspected on the basis of the findings of previous sonography, CT, or MR imaging.

Criteria for enrollment in the study were no stenosis or obstruction of the portal or hepatic vein; a single or a few nondiffuse tumorous lesions; no stenosis of the superior mesenteric or celiac artery; a clinically based determination of no severe cirrhosis (i.e., not belonging to type C of the Child-Pugh classification); no developed hepatofugal portosystemic venous collaterals or severely atrophic liver on diagnostic imaging; and no pathologic circulation in the liver, such as large arterioportal venous shunting. All patients underwent CT during arterial portography and CT hepatic arteriography to establish an angiographically based diagnosis before undergoing surgical laparotomy or treatment using interventional techniques (such as transcatheter arterial chemoembolization). In five patients, divergence of the right hepatic artery from the hepatic artery was replaced by its divergence from the superior mesenteric artery. Informed consent from each patient and approval by the institutional ethics committee were obtained before the study.

Imaging Methods
While the patient was in the angiography room, we used the Seldinger technique to insert two 4- or 5- French angiographic catheters into the right inguinal region, with both catheters being inserted at the same puncture site. After confirmation by test injection of contrast medium that one catheter tip was located in the superior mesenteric artery and the other in the hepatic artery, the patient was transferred to the CT room.

CT during arterial portography, CT hepatic arteriography, and CT hepatic arteriography with prostaglandin E₁ injection were sequentially performed in that order, with an interval of approximately 10 min between each of the three studies. CT imaging during arterial portography was started 25-30 sec after the injection of 50-60 mL of 150 mgI/mL of iopamidol (Iopamiron; Schering, Berlin, Germany) at a rate of 2 mL/sec via the catheter with its tip in the superior mesenteric artery. No vasodilators were used while CT during arterial portography was performed. CT hepatic arteriography imaging was started 7 sec after the injection of 20-25 mL of iopamidol (150 mgI/mL) at a rate of 1 mL/sec via the catheter with its tip in the hepatic artery (common hepatic artery, n = 34; right hepatic artery, n = 5). For the CT hepatic arteriography with intraarterial prostaglandin E₁ injection, 20 µg of prostaglandin E₁ diluted with 10 mL of physiologic saline was injected into the superior mesenteric artery via the catheter. After 15-20 sec, iopamidol (150 mgI/mL) in the same amount and at the same rate as we used for CT hepatic arteriography was injected in the hepatic artery via the catheter. CT scanning was started 7 sec after the injection of iopamidol. The CT unit used in this study was X Vigor Laudator (Toshiba Medical System, Tokyo, Japan). Images from CT during arterial portography, CT hepatic arteriography, and CT hepatic arteriography with prostaglandin E₁ injection were obtained during a single breath-hold, with the entire liver imaged using a helical CT system (120 kV, 190 mAs). The beam width was 7 mm, table feeding speed was 7 mm/sec, and image reconstruction was performed with a width of 7 mm.

Investigated Parameters
Among the 39 patients, 43 tumors were confirmed pathologically as hepatocellular carcinomas. Twentysix lesions in 24 patients were examined by laparotomy. The remaining 17 lesions in 15 patients were confirmed pathologically as hepatocellular carcinomas by percutaneous needle biopsy. Image analysis was performed by three radiologists experienced in abdominal diagnostic imaging with discussion until a consensus was reached.

First, we determined the enhancement of the 43 pathologically confirmed hepatocellular carcinoma lesions on CT hepatic arteriography within the decreased area of portal perfusion on CT during arterial portography. We then retrospectively investigated changes in the size, shape, and CT attenuation of the enhancement of the tumors on CT hepatic arteriography after the intraarterial prostaglandin E₁ injection via the superior mesenteric artery. We also examined changes in CT attenuation on CT hepatic arteriography of liver parenchyma surrounding the tumor and lesion conspicuity (i.e., the difference in CT attenuation between the tumor and adjacent parenchyma). The changes in the CT attenuation of tumor and liver parenchyma and in lesion conspicuity were analyzed using a paired t test.

To quantify the CT attenuation of the hepatocellular carcinoma lesions and the surrounding liver parenchyma, CT attenuation values (expressed in Hounsfield units, H) were measured on CT hepatic arteriography. CT attenuation of the tumors was measured in the region of interest corresponding to the enhanced area of the tumors on CT hepatic arteriography. CT attenuation of the liver parenchyma around the tumor was measured using between one and five (mean, 3.4) circular region-of-interest cursors with 10-mm diameters that were placed on the images of the hepatic parenchyma near the tumor. The average CT attenuation of all regions of interest was then calculated. We tried to avoid measuring the regions of hepatic arteries, veins, and portal branches. CT attenuation of tumor and liver parenchyma on CT hepatic arteriography after the prostaglandin E₁ injection was measured using the same region-of-interest sizes and locations as used with CT hepatic arteriography performed before the prostaglandin E₁ injection.

Results

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In two of 43 hepatocellular carcinoma lesions, enhancement of the tumor was isodense compared with the normal liver parenchyma and was not detected on CT hepatic arteriography. However, after the prostaglandin E₁ injection, the tumor could be clearly distinguished from the surrounding liver (Fig. 1A,1B,1C). In the remaining 41 hepatocellular carcinoma lesions, the maximal diameter of the enhancement ranged from 5 to 35 mm (mean, 16.4 mm), with all lesions being round or oval. In two of these lesions, the maximal diameters increased from 10 mm to 16 mm and from 8 mm to 15 mm, respectively, after the intraarterial prostaglandin E₁ injection (Fig. 2A,2B). However, neither the size nor shape of the enhanced area changed in the remaining 39 tumorous lesions.

View larger version (140K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —71-year-old woman with hepatocellular carcinoma. CT during arterial portography image shows round tumor (arrow) with decreased portal perfusion in segment VIII of liver.

View larger version (158K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —71-year-old woman with hepatocellular carcinoma. CT hepatic arteriogram shows area that is isodense (arrow) compared with normal liver parenchyma, corresponding to area of decreased portal perfusion seen on CT during portography.

View larger version (151K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C. —71-year-old woman with hepatocellular carcinoma. CT hepatic arteriogram obtained after intraarterial prostaglandin E1 injection shows round enhancement of tumor (arrow) that is 20 mm in diameter. CT attenuation of enhancement of this lesion is 353.0 H, whereas CT attenuation of corresponding area on CT hepatic arteriogram before prostaglandin E1 injection was 91.0 H.

View larger version (137K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A. —70-year-old man with hepatocellular carcinoma. CT hepatic arteriogram shows enhanced area of tumor (arrow) that is 8 mm in diameter. CT attenuation of tumor enhancement is 197.0 H.

View larger version (125K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B. —70-year-old man with hepatocellular carcinoma. CT hepatic arteriogram obtained after intraarterial prostaglandin E1 injection shows 15-mm-diameter tumor (arrow). Tumor is visualized to greater extent and with more dense enhancement than without prostaglandin E1. CT attenuation of tumor enhancement on CT hepatic arteriography after prostaglandin E1 injection is 251 H.

In 91% (39/43) of the pathologically confirmed hepatocellular carcinoma lesions, CT attenuation on CT hepatic arteriography increased after the intraarterial prostaglandin E₁ injection, with the overall change ranging from -7.0 H to +262.0 H (mean ± SD, 30.1 ± 53.8 H). As shown in Figure 3, the mean values for all hepatocellular carcinoma lesions significantly increased from 176.4 ± 59.0 H (range, 91.0-392.0 H) to 206.6 ± 72.5 H (range, 97.0-419.0 H; p = 0.0006, paired t test) after the intraarterial prostaglandin E1 injection.

View larger version (16K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —Diagram shows CT attention of hepatocellular carcinoma on lesions seen on CT hepatic arteriography before and after intraarterial prostaglandin E1 (PGE1) injection. Line in each box represents median value of CT attenuation of lesions before (170.0 H) and after (204.0 H) prostaglandin E1 injection. Boxes represent 25th-75th percentile. Lines outside boxes represent 10th and 90th percentiles. Plots show lesions with CT attenuations that fall outside 10th and 90th percentile. Mean CT attenuation of lesions before and after intraarterial prostaglandin E1 injection is 176.4 ± 59.0 H and 206.6 ± 2.5 H, respectively.

The mean CT attenuation on CT hepatic arteriography of the normal liver parenchyma adjacent to each tumor significantly decreased from 94.8 ± 14.9 H (range, 74.0-162.0 H) to 92.0 ± 12.1 H (range, 76.0-140.0 H) after the intraarterial prostaglandin E₁ injection (p = 0.0166, paired t test). This change ranged from -22.0 to +12.0 H (mean, -2.8 ± +7.5 H). The CT attenuation of normal liver parenchyma near a tumor on CT hepatic arteriography decreased in 58% (25/43) of tumors.

The difference in CT attenuation between hepatocellular carcinoma lesions and surrounding liver parenchyma (i.e., lesion conspicuity) increased in 91% (39/43) of lesions after the prostaglandin E₁ injection. The overall change ranged from -17.0 to +266.0 H (mean, 33.1 ± 53.3 H). Notably, in 11 lesions, the actual difference in CT attenuation between the lesion and liver parenchyma before and after the prostaglandin E₁ injection changed by more than 30.0 H (Fig. 4A,4B,4C). The mean lesion conspicuity value on CT hepatic arteriography of all tumors significantly increased from 81.6 ± 60.6 H (range, -20.0 to +302.0 H) to 114.7 ± 70.2 H (range, 13.0-315.0 H; p = 0.0002, paired t test).

View larger version (135K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A. —69-year-old woman with hepatocellular carcinoma. CT during arterial portography image shows round tumor (arrow) with decreased portal perfusion in segment V of liver.

View larger version (119K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B. —69-year-old woman with hepatocellular carcinoma. CT hepatic arteriogram shows enhanced area (arrow) of tumor with unclear margin. CT attenuation of tumor enhancement is 211.0 H and that of surrounding liver parenchyma is 162.0 H.

View larger version (121K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4C. —69-year-old woman with hepatocellular carcinoma. CT hepatic arteriogram obtained after intraarterial prostaglandin E1 injection shows round, 22-mm diameter tumor (long arrow) with distinct border. CT attenuation of tumor enhancement on CT hepatic arteriography after prostaglandin E1 injection is 222.0 H and that of surrounding liver parenchyma (thick arrow) is 140.0 H.

Discussion

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The liver is a unique organ with a dual blood supply from the portal vein and hepatic artery with mutual compensation between them [4, 7]. Blood is supplied to most liver tumors, including those of hepatocellular carcinoma, exclusively by the hepatic artery [4]. An imaging study of hepatocellular carcinoma tumors using single-level dynamic CT during hepatic arteriography showed that arterial blood flowed into the tumor via the hepatic artery, penetrated the tumor capsule, ran through the surrounding liver parenchyma, and went into the portal branches [15].

Considering these hemodynamics in hepatocellular carcinoma lesions and the surrounding liver [15], our findings of both an increase in CT attenuation in as many as 91% of the enhanced areas of hepatocellular carcinoma lesions and an increase in lesion conspicuity in as many as 91% of hepatocellular carcinoma lesions on CT hepatic arteriography after the prostaglandin E₁ injection can be explained as follows: The muscular layer of the hepatic artery contracts and expands freely in the normal liver. When the vascular wall contracts in response to an increase in portal blood flow, arterial blood flow decreases in the normal liver. These dynamics were shown by our finding that, on CT hepatic arteriography, the CT attenuation of the liver surrounding hepatocellular carcinoma statistically decreased after the intraarterial prostaglandin E₁ injection, even though contrast material had been used twice before this infusion. In hepatocellular carcinoma, on the contrary, blood vessels have no muscular layers and cannot respond to changes in portal blood flow, as Murata et al. [6] described. The autoinjector perfuses the same amount of contrast medium in CT hepatic arteriography both with and without the prostaglandin E₁ injection. Arterial blood flow into the hepatocellular carcinoma lesion increases after the reduction of hepatopetal arterial blood flow into the surrounding normal liver in response to increased portal blood flow after the prostaglandin E₁ injection.

Possibly, the increased CT attenuation and lesion conspicuity in hepatocellular carcinoma on CT hepatic arteriography with prostaglandin E₁ can also be explained by increases in blood pressure in portal branches—the drainage veins of hepatocellular carcinoma—after the prostaglandin E₁ injection [10]. In other words, blood outflow from the tumor to the surrounding liver parenchyma may be delayed, resulting in congestion of arterial blood containing contrast medium in the tumor.

In two lesions, the size of enhancement increased. The good visualization of the entire tumor in these cases after the intraarterial prostaglandin E₁ injection may have been caused by congestion or increased arterial blood in the tumor attributed to the increase in portal blood flow in the surrounding liver parenchyma.

Angiographically assisted CT has a serious disadvantage in that pseudolesions can be seen [11,12,13,14]. Nontumorous defects of portal perfusion in the liver adjacent to the gallbladder [11, 12, 16, 17] or in the hepatic hilum [11, 13, 14] are the most common pseudolesions seen on CT during arterial portography, the majority of which have been reported to be enhanced on CT hepatic arteriography [13, 16, 17]. Recently, using the same method we described [8], we found reductions in the size of the enhanced area of pseudolesions around the gallbladder or in the hepatic hilum on CT hepatic arteriography in 69% of pseudolesions and decreased CT attenuation in 86% of pseudolesions after the intraarterial injection of prostaglandin E₁. Those results [8] and the results of this study lead us to this conclusion: Among the contrast-enhanced lesions visualized on CT hepatic arteriography that had shown decreased portal perfusion on CT during arterial portography, hepatocellular carcinoma lesions became more conspicuous after the prostaglandin E₁ injection, whereas most pseudolesions became more blurred. Hence, the intraarterial prostaglandin E₁ injection via the superior mesenteric artery during CT hepatic arteriography was found to be useful in differentiating hepatic tumors from pseudolesions revealed by angiographically assisted CT, especially in sites in the liver parenchyma with a predilection for pseudolesions, such as around the gallbladder and in the hepatic hilum. Of course, the addition of intraarterial prostaglandin E₁ injection is also useful when a hepatocellular carcinoma lesion cannot be distinctly visualized on CT hepatic arteriography.

Acknowledgments
 
We thank Yuji Itai of the Department of Radiology, Institute of Clinical Medicine, University of Tsukuba, for valuable advice regarding this study.

References

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