Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization

Changes in Hepatic Lobe Volume in Biliary Tract Cancer Patients After Right Portal Vein Embolization MASATO NAGINO,1 YUJI NIMURA,1 JUNICHI KAMIYA,1 SATOSHI KONDO,1 KATSUHIKO UESAKA,1 YUKOH KIN, ~ NAOKAZU HAYAKAWA,2 AND HIDEO YAMAMOTO2

Changes in lobar v o l u m e of the liver and in total hepatic function were studied in 19 patients w i t h biliary tract eancer w h o u n d e r w e n t right portal v e i n embolization as preoperative m a n a g e m e n t for extensive liver resection. C o m p u t e d t o m o g r a p h y (CT) w a s performed to estimate liver v o l u m e before and approximately 11 days after embolization. An i n d o c y a n i n e green (ICG) test was performed before and 11 to 13 days after embolization. The calculated v o l u m e of the right lobe decreased from 761 _+ 181 cm a to 625 _+ 110 cm 3 11 days after embolization (P < .0001), w h e r e a s the v o l u m e of the left lobe increased from 420 _+ 94 cm a to 555 ± 110 cm 8 (P < .0001). Thus, portal e m b o l i z a t i o n p r o d u c e d a gain in left lobe v o l u m e of 136 _+ 62 cm 8 and an almost equivalent loss in right lobe volume. The h y p e r t r o p h y ratio of the left lobe, expressed as percentage of p o s t e m b o l i z a t i o n v o l u m e of the left lobe to preembolization size, of the 5 patients with diabetes mellitus (DM) was lower than that of the 14 patients w i t h o u t diabetes (116.7 +_ 6.3% vs. 140.4 ± 18.4%; P < .005). The ICG disappearance rate in 16 patients i m p r o v e d from 0.163 ± 0.034 to 0.177 ± 0.027 (P ~ .05). The i m p r o v e m e n t was especially e v i d e n t in 9 of 14 postjaundice patients, although the rate decreased slightly in 2 patients w i t h o u t jaundice. We conclude that right portal v e i n embolization can produce a c o m p e n s a t o r y h y p e r t r o p h y of the left lobe w i t h i n 11 days w i t h o u t seriously affecting hepatic function. In diabetic patients, however, a longer interval b e t w e e n e m b o l i z a t i o n and operation m a y be n e e d e d to a c h i e v e sufficient hypertrophy of the left lobe. (I-IEPATOLOGY1995;21:434-439.)

sponding hepatic lobe with contralateral hypertrophy. 4 The purpose of preoperative portal vein embo]ization is to initiate compensatory h y p e r t r o p h y in the future r e m n a n t liver in an a t t e m p t to counteract liver failure after major hepatectomy. We likewise applied this technique in patients with biliary tract cancer at high risk for posthepatectomy liver failure 5 and described a new approach of percutaneous t ranshepat i c portal embolization (PTPE). 6 Portal embolization has become imp o r t a n t in the preoperative m a n a g e m e n t of patients undergoing extensive liver resection. However, only a few clinical reports 7's have described the dynamics of hepatic lobe volume and function after portal embolization. How, and to w h a t extent, does the embolized lobe become atrophied? Conversely, how does the nonembolized lobe become hypertrophied? How does hepatic function change after embolization? The recent advent of computed tomography (CT) makes it possible to accurately determine liver volume. 9'1° This easy-to-repeat, noninvasive technique has been used in the clinical m a n a g e m e n t of hepatic resection and regeneration 11-~3 and of liver transplantation, especially to assess the graft size before transplantation. ~4~7 In this study, we evaluated volume alterations of the embolized and the nonembolized lobes of the liver by pre- and postembolization CT scan. In addition, we investigated functional changes as assessed by indocyanine green (ICG) clearance.

Preoperative portal vein embolization, a procedure devised by Makuuchi et al ~'2 and Kinoshita et al, 3 is a clinical application of the experimental observation t h a t portal branch ligation causes at r ophy of the corre-

PATIENTS AND METHODS

Abbreviations: PTPE, percutaneous transhepatic portal embolization; CT, computed tomography; ICG, indocyanine green; DM, diabetes mellitus; TB, total bilirubin; PTBD, percutaneous transhepatic biliary drainage; AST, aspartate transaminase; ALT, alanine transaminase; K~cc, ICG disappearance rate. From the ~First Department of Surgery, Nagoya University School of Medicine; and 2Department of Surgery, Tohkai Hospital, Nagoya, Japan. Received June 28, 1994; accepted September 14, 1994. Supported in part by the Grant-in-Aid for General Scientific Research (grant no. 04404050) from the Ministry of Education, Science and Culture, Japan, and grants from the Uehara Memorial Foundation. Address reprint requests to: Masato Nagino, MD, Assistant Professor, First Department of Surgery, Nagoya University School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya 466, Japan. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2102-002553.00/0

We studied 19 patients with biliary tract cancer (14 with advanced gallbladder carcinoma and 5 with hilar bile duct carcinoma) who underwent PTPE of the right portal vein as preoperative management for extensive liver resection. The subjects were 9 men and 10 women, with an average age of 61 _+ 10 years (range, 35 to 72 years). Five patients had diabetes mellitus (DM). All patients were noncirrhotic, but 16 (84.2%, 11 without DM and 5 with DM) were jaundiced. The jaundiced patients had an average total bilirubin (TB) concentration of 12.7 _+ 6.2 mg/dL on admission, and it decreased to 1.1 ± 0.4 mg/dL at the time of PTPE after percutaneous transhepatic biliary drainage (PTBD). Because advanced carcinomas often separate the intrahepatic bile ducts into a few to several units at the hepatic confluence, 11 of the 16 patients received multiple PTBD to drain the entire biliary system, is Consequently, in our series, the effect of intrahepatic segmental biliary obstruction on lobar volume imbalance was negligible, iv After PTPE, 13 of the 19 patients underwent extended right lobectomy with or without pancre-

434

HEPATOLOGYVo]. 21, No. 2, 1995

NAGINO ET AL 435 volumes of individual slices. The volume of the caudate lobe was calculated as part of the left lobe because the caudate lobe was not embolized. ICG tests were performed 1 to 3 days before and 11 to 13 days after PTPE. ICG (0.5 mg/kg of body weight) was administered via a peripheral vein, and venous blood samples were taken before and 5, 10, and 15 minutes after the injection. After dilution with saline, the specimens were analyzed for ICG concentration on a spectrophotometer at 805 nm. Other liver function parameters, such as TB, aspartate transaminase (AST), and alanine transaminase (ALT), were examined regularly before and after PTPE. Besides these subjects, the liver volume was determined by CT preoperatively in 5 other patients with biliary tract cancer (4 men and I women; 60 _+ 11 years) who had complete obstruction of the right portal vein caused by cancerY The obstruction was confirmed by percutaneous transhepatic portography, and patency of the right hepatic artery was verified by celiac angiography. No patients had DM. Four patients were jaundiced on admission, but their TB concentrations decreased to ~2.0 mg/dL at the time of surgery after PTBD. All 5 patients eventually underwent extended right lobectomy with or without portal vein resection and reconstruction, 21 and they were discharged from the hospital in good condition. Results were expressed as mean _+ SD. Statistical analysis was performed through appropriate use of the Wilcoxon test and the Mann-Whitney test. A level ofP < .05 was considered statistically significant.

FIG. 1. Portograms after right portal vein embolization. The right anterior (A) and posterior (P) portal branches are embolized completely with fibrin glue mixed with iodized oil.

aticoduodenectomy2° or portal vein resection and reconstruction, 21 as scheduled. Eleven patients who had undergone hepatectomy were discharged from the hospital in good condition, but 2 patients, who had DM, died of posthepatectomy liver failure and bleeding, respectively. The remaining 6 patients underwent only laparotomy, as associated peritonitis carcinomatosa or liver metastasis prevented further treatment. PTPE was performed 2 weeks before the operation, 1'2 according to the previously reported method. ~ Under fluoroscopic control, a 5.5-French triple-lumen balloon catheter (Clinical Supply Co., Gifu, Japan) was advanced into the right portal vein through a 6-French catheter sheath introduced by ultrasound-guided puncture of the umbilical portion of the left portal vein (contralateral approach: n = 6) or of the anterior branch of the right portal vein (ipsilateral approach: n = 13). As the embolic material, fibrin glue (Beriplast P; Hoechst Japan, Tokyo) was used with iodized oil (Lipiodol; Kodama Pharmaceutical Co., Tokyo) added for radiopacity (Fig. 1). 6'22 CT of the liver for volume determination was performed before and 11.1 _+ 1.4 days (range, 9 to 13 days) after PTPE in all subjects. In addition, CT was performed more than a month after PTPE in 2 of the 6 unresected cases. Serial transverse scans at l-cm intervals from the dome of the liver to the most inferior part of the organ were obtained, with enhancement by intravenous bolus injection of contrast medium. Each slice of the liver was traced with the cursor, and the corresponding area was calculated by computer. The middle hepatic vein and gallbladder were used as landmarks to define the border between the right (embolized) lobe and the left (nonembolized) lobe of the liver. The total volumes of each lobe and of the whole liver were obtained by adding the

RESULTS

Liver Volume Changes. The calculated v o l u m e of the r i g h t lobe significantly (P ~ .0001) decreased, from 761 + 181 cm 3 (range, 465 to 1123 cm 3) before P T P E to 625 _+ 110 cm ~ (range, 404 to 851 cm 8) after P T P E (Fig. 2A). However, the v o l u m e of the left lobe significantly (P ~ .0001) increased, from 420 _+ 94 cm 3 (range, 260 to 661 cm 3) to 555 _+ 110 cm 3 (range, 421 to 752 cm 3) (Fig. 2B). The v o l u m e of the whole liver exhibited no significant changes; it was 1,181 _+ 227 cm 3 (range, 865 to 1,620 cm 3) before P T P E a n d 1,180 _+ 178 cm 3 (range, 835 to 1451 cm 3) a f t e r w a r d (Fig. 2C). Thus, the r i g h t lobe lost 137 _+ 93 cm 3 in volume, a n d the left lobe g a i n e d 136 _+ 62 cm 3. The ratio of each lobar volume to the total liver v o l u m e was significantly (P < .0001) changed, as follows: r i g h t lobe, from 64.2 + 6.3% (range, 53.8% to 74.5%) before P T P E to 53.0 _+ 5.4% (range, 45.3% to 63.5%) after P T P E ; left lobe, from 35.8 _+ 6.3% (range, 25.5% to 46.9%) to 47.0 _+ 5.4% (range, 36.5% to 54.8%). The liver v o l u m e of the subjects after P T P E was comp a r e d w i t h t h a t of the 5 p a t i e n t s w i t h r i g h t portal vein o b s t r u c t i o n by cancer. F o r the cancer patients, the r i g h t lobar v o l u m e was 612 + 117 cm 3 (range, 441 to 735 cm ~) (Fig. 2A), the left lobar v o l u m e w a s 635 _+ 119 cm 3 (range, 498 to 789 cm 3) (Fig. 2B), a n d t h e whole liver v o l u m e w a s 1,248 _+ 219 cm ~ (range, 1,026 to 1,524 cm ~) (Fig. 2C). The ratio of the r i g h t lobar v o l u m e to the total liver v o l u m e w a s 49.1 _+ 4.1% (range, 43.0% to 53.2%) a n d t h a t of the left lobe was 50.9 +_ 4.1% (range, 46.8% to 57.0%). None of t h e s e values s h o w e d significant differences from the c o r r e s p o n d i n g values of the subjects a f t e r P T P E .

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-.7333; P = .0004) (Fig. 4), the hypertrophy ratio did not exhibit significant correlation with pre-embolization volume of the left lobe. Microscopically, diffuse atrophy of hepatocytes and dilatation of the sinusoid were characteristic of the resected embolized lobe, whereas mildly hypertrophic, vigorous hepatocytes were observed in the nonembolized lobe (Fig. 5). L i v e r F u n c t i o n Changes. ICG tests before and after PTPE could be performed in only 16 patients. The ICG disappearance rate (KIcG) significantly (P < .05) improved, from 0.163 _+ 0.034 (range, 0.116 to 0.239) before PTPE to 0.177 __ 0.027 (range, 0.115 to 0.212) after PTPE (Fig. 6). Whereas KICG improved in 9 of the 14 patients with jaundice on admission, it became worse in 2 patients without jaundice. AST and ALT levels were slightly elevated (less t h a n double) in 5 patients, but the values usually returned to baseline levels within a week. TB remained near pre-embolization levels in all patients. Follow-up Volumetry in Two Unresected Cases. I n one patient followed with repeat CT (case no. 1; Fig.

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HEPATOLOGY Vol. 21, No. 2, 1995

NAGINO ET AL

437

the process of liver regeneration after hepatectomy. 25'26 Studies are needed to evaluate quantitative differences in the regeneration trigger between portal blood depletion and liver resection. 7 In addition, further studies focusing on the embolic materials are needed, as it has been reported t h a t different types of embolic materials show different effects on hypertrophy of the nonembolized lobe. ~'s'27 There was no significant difference in the lobar volume of the liver between subjects after PTPE and patients with portal vein obstruction by cancer. This finding was contrary to our expectations, because the FIG. 5. Microscopic findings of the embolized lobe (A) and the nonembolized lobe (B). Atrophy of hepatocytes and dilatation of sinusoid are characteristic of the embolized lobe.

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0.240 7), each lobar volume and its ratio to the whole liver volume (shown in parentheses) changed 102 days after PTPE, as follows: right lobe, from 701 cm 3 (65.8%) to 410 cm ~ (38.5%); left lobe, from 364 cm 3 (34.2%) to 654 cm 3 (61.5%). In the other patient (case no. 2; Fig. 7), who had DM, CT 54 days after PTPE showed the following change: right lobe, from 465 cm 3 (53.8%) to 333 cm 3 (37.3%); left lobe, from 400 cm 3 (46.2%) to 559 cm 3 (62.7%). The whole liver volume was almost unchanged in both patients.

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DISCUSSION

CT estimation of liver volume in vivo m a y be affected by some potential sources of error, such as partial volume effect, respiratory phase, or interobserver variabili t y . 9'1°'14 Nevertheless, m a n y studies show a close linear relationship between CT-estimated volumes and actual volumes. 9'1°'16'~7 The average difference is within + 3% to 5%, 9 indicating t h a t the CT method of estimating volume is sufficiently accurate to be applicable for clinical use. Therefore, we believe t h a t CT volumetric studies lacking comparisons with actual volume, ~1~ including this study, are fully credible. In the present study, we found t h a t the volume gain of the ]eft lobe approximately 11 days after PTPE was 136 cm 3 on average, almost equivalent to the volume loss of the right lobe. Consequently, it can be thought t h a t right portal vein embolization caused a movement of volume from the right to the left lobe at the rate of about 12 cm3/d. Y a m a n a k a et a113 reported t h a t the hepatic regeneration rate during the first month after hepatectomy of 50% or more was 20 _+ 5.0 cm~/d in the normal liver, 11 -- 6.5 cm3/d in patients with chronic hepatitis, and 8.5 _+ 6.5 cm3/d in patients with cirrhosis. Considering both the inclusion of m a n y postjaundice cases in our series and the difference between liver resection and portal embolization, our result seems to be consistent with theirs. Liver mitochondrial enhancement, both in quality and in quantity, is essential to liver regeneration. 24'25From the viewpoint of mitochondrial function, we experimentally showed t h a t a process of compensatory hypertrophy caused by ligation or embolization of the portal vein was analogous to

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438

NAGINO ET AL

HEPATOLOGYFebruary 1995

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FIG. 7. Volume changes in 2 unresected cases on follow-up CT. Solid line, case no. 1; dotted line, case no. 2 (with DM); ©, right lobe; Q, left lobe; [3, whole liver.

obstruction or the preceding stenosis by cancer was thought to have started at least a few months earlier. 23 The lack of difference implies that a period of 11 days after right portal embolization is enough to cause hypertrophy of the left lobe, and this fact gives strong support to the efficacy of PTPE. It is well known that liver regeneration is impaired in animals rendered diabetic by pancreatectomy or drugs, such as streptozotocin or alloxan, and it is restored by insulin administration. 2s~° In addition, several clinical studies ~'3~ pointed out that glucose intolerance, including DM, was an important risk factor for posthepatectomy liver failure. These reports are compatible with our observation that the hypertrophy ratio of the left lobe after PTPE was significantly lower in patients with DM. Even in diabetic patients, however, hypertrophy of the left lobe was obtained about 2 months after PTPE, as shown in Fig. 7. Consequently, in diabetic patients it m a y be necessary to advance the date of PTPE or to postpone a scheduled operation, if possible, to achieve sufficient hypertrophy. The atrophy ratio of the right lobe showed a negative correlation with its original volume; that is, the larger the original volume, the more it atrophied after PTPE. This finding m a y be explained by the portal venous blood flow volume. K~CG value is thought to correlate with the whole liver volume. However, despite unchanged whole liver volume, K~CG significantly ameliorated after PTPE. Caution must be exercised when interpreting this result because many postj aundice patients were included in the study. It has been reported that full recovery of hepatic mitochondrial function after relief of obstructive jaundice lags behind improvement of TB and re. qmres a long period of time. 32 '33 Like this, amelioration of K~cG, which was observed in postjaundice patients, represents successive functional recovery from obstructive jaundice, not a potential effect of PTPE. The deterioration of K~CGin 2 patients without jaundice suggests that right portal vein embotization is a burden to the liver, b u t its influence on hepatic function appears to be minimal. It remains to be demonstrated whether the function of each lobe after PTPE changes in propor-

tion to its volume change. We are doing research on this issue. In conclusion, right portal vein embolization can result in a sizable compensatory hypertrophy of the left lobe within approximately 11 days, without seriously influencing hepatic function. The volume gain per day obtained by this method seemed to approximate that after major hepatectomy. The hypertrophy ratio of diabetic patients was significantly lower, suggesting that a longer interval between embolization and operation m a y be needed for patients with DM.

Acknowledgment: We thank John W. Braasch, MD, of the Lahey Clinic Medical Center, Burlington, MA, for his critical comments on this manuscript. REFERENCES

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