Brief Article Open Access
Copyright ©2010 Baishideng. All rights reserved.
World J Gastroenterol. Jul 7, 2010; 16(25): 3202-3205
Published online Jul 7, 2010. doi: 10.3748/wjg.v16.i25.3202
Perfusion CT findings in liver of patients with tumor during chemotherapy
Qing Zhang, Jun Tang, Zuo-Qin Liu, Department of Interventional Radiology, Shandong Medical Imaging Research Institute, Shandong University, 324#, Jingwu Road, Jinan 250021, Shandong Province, China
Qing Zhang, Dao-Qing Wang, Department of Radiology, Affiliated Hospital of Shandong Academy of Medical Science, 38#, Wuyingshan Road, Jinan 250031, Shandong Province, China
Zhen-Guo Yuan, Department of MRI, Shandong Medical Imaging Research Institute, Shandong University, 324#, Jingwu Road, Jinan 250021, Shandong Province, China
Zhi-Hui Yan, Anti-Senility Research Center, Shandong Academy of Medical Sciences, 89#, Jingshi Road, Jinan 250062, Shandong Province, China
Author contributions: Zhang Q, Yuan ZG, Tang J and Liu ZQ designed the research; Zhang Q and Wang DQ performed the research; Zhang Q and Yan ZH analyzed the data; Zhang Q and Yuan ZG wrote the paper.
Correspondence to: Zuo-Qin Liu, Professor, Department of Interventional Radiology, Shandong Medical Imaging Research Institute, Shandong University, 324#, Jingwu Road, Jinan 250021, Shandong Province, China. radio-lzq@163.com
Telephone: +86-531-85958637 Fax: +86-531-85958637
Received: April 4, 2010
Revised: April 26, 2010
Accepted: May 3, 2010
Published online: July 7, 2010

Abstract

AIM: To investigate the microcirculation changes in liver of patients with tumor during chemotherapy by perfusion computed tomography (CT).

METHODS: Sixty patients with tumor and 20 controls were enrolled in this study. Perfusion CT parameters of patients and controls were compared, including hepatic perfusion index (HPI), mean transit time (MTT), and permeability-surface area product (PS). Correlation between perfusion CT parameters, treatment cycle and alanine aminotransferase (ALT) level was studied.

RESULTS: No difference was found in HPI (25.68% ± 7.38% vs 26.82% ± 5.13%), MTT (19.67 ± 5.68 s vs 21.70 ± 5.43 s) and PS (17.00 ± 4.56 mL/100 mL per min vs 19.92 ± 6.35 mL/100 mL per min) between patients and controls. The HPI and MTT were significantly higher in patients undergoing 2 cycles of chemotherapy than in controls and those undergoing 1 cycle of chemotherapy (29.76% ± 5.87% vs 25.68% ± 7.38% and 25.35% ± 4.05%, and 25.61 ± 5.01 s vs 19.67 ± 5.68 s and 19.74 ± 4.54 s, respectively, P < 0.05). The HPI was higher in patients with hepatic steatosis than in controls and those without hepatic steatosis (30.85% ± 6.17% vs 25.68% ± 7.38% and 25.70% ± 4.24%, P < 0.05). Treatment cycle was well correlated with HPI and MTT (r = 0.40, r = 0.50, P < 0.01). ALT level was not correlated with perfusion CT parameters.

CONCLUSION: HPI and MTT are significantly increased in patients with tumor during chemotherapy and well correlated with treatment cycle. Chemotherapy affects hepatic microcirculation in patients with tumor. Changes in hepatic microcirculation can be quantitatively assessed by perfusion CT.

Key Words: Liver; Microcirculation; Chemotherapy; Tomography, X-ray computed; Perfusion imaging



INTRODUCTION

Liver damage secondary to chemotherapy in patients with tumor is common, and hepatic toxicity differs from mild inflammatory changes of nonspecific hepatitis to fibrosis and marked cirrhosis[1,2]. Although early liver damage causes no symptoms and is reversible in most patients, it occasionally progresses to more severe liver impairment, which may be irreversible. It is, therefore, necessary to demonstrate the presence and severity of drug-related parenchymal changes with effective imaging.

Early liver damage cannot be demonstrated by traditional computed tomography (CT). Perfusion CT is a noninvasive method showing hemodynamic changes in living tissue and has been used in evaluation of liver diseases. However, microcirculation changes in liver on perfusion CT image during chemotherapy have not been described. In this study, we investigated the hemodynamic changes in liver during chemotherapy, and estimated the correlation between the perfusion CT parameters and alanine aminotransferase (ALT) level.

MATERIALS AND METHODS
Patients and study design

Eighty consecutive individuals including 60 patients with tumor and 20 controls were enrolled in this study. Although history, physical examination, laboratory test, and Doppler sonography of liver showed that the 20 controls including 8 women at a mean age of 47.3 ± 8.6 years (range 35-64 years) had no evidence of liver disease, they underwent abdominal perfusion CT for unrelated causes. Inclusion criteria included patients with tumor confirmed by appropriate clinical and laboratory examinations, those still on chemotherapy when perfusion CT was performed, those with hepatic carcinoma or metastasis who had an adequate space in liver parenchyma for later calculation, those who had no history of alcohol abuse, viral hepatitis, liver cirrhosis or other hepatic/biliary diseases, and those who had adequate heart, renal and liver function for perfusion CT. The 60 patients including 24 women at a mean age of 53.2 ± 7.1 years (range 25-71 years) met the criteria. All patients received 1-2 cycles of chemotherapy (6-8 courses in one treatment cycle). Perfusion CT parameters were compared between controls and patients. The diagnostic criteria for hepatic steatosis were the density of liver parenchyma lower than that of spleen or the CT value of liver parenchyma less than 40 Hu on CT image without contrast agent.

The study was approved by the institutional ethics committee. Written informed consent was obtained from each patient or his or her family members after the nature of procedures was fully explained.

Perfusion CT imaging and data processing

Perfusion CT was performed for patients at the end of each treatment cycle. After an overnight fast, patients and controls lying supine on a table underwent perfusion CT with a 64-row multi-detector CT scanner (Light Speed VCT, GE Healthcare, Chalfont St. Giles, UK). Before perfusion CT, patients underwent an abdominal scan without contrast medium during a breath hold at the end of expiration. We selected a slice with the right hepatic lobe, spleen and portal trunk clearly visualized. Then, multiple-slice dynamic sequences lasting 80 s were scanned 8 s after injection of a contrast material (iohexol, 350 mg I/mL, Changfujiejing Pharmaceutical Co. Ltd., Shandong, China). The CT perfusion protocol comprised 80 scans, for 320 images. Because blood vessels of patients with tumor during chemotherapy became too fragile to endure a high injection pressure, a bolus infusion of 40 mL contrast material was given at a speed of 2.5-3.0 mL/s via a 20-gauge intravenous catheter in the antecubital vein with a power injector (SCT-210, Medrad Inc., Indianola, PA, USA). The patients kept normal respiration during the perfusion study. The CT parameters used in this study were 120 kV, 250 mA, 5-mm slice thickness, 1-s cycle time and standard reconstruction algorithm.

After image acquisition, the data were transferred to an image processing workstation (AW4.1, GE Healthcare, Chalfont St. Giles, UK) and analyzed with the integrated software of CT Perfusion 3. Four regions of interest (ROI) were set on the abdominal aorta, portal vein trunk, spleen and right liver lobe. The ROI of right liver lobe was drawn on the whole visible right lobe carefully, avoiding blood vessels, margin of liver parenchyma and possible lesions. Hepatic perfusion index (HPI), mean transit time (MTT), and permeability-surface area product (PS) were calculated.

Statistical analysis

All data were expressed as mean ± SD. Independent-sample t test was used to determine differences between patients and controls. Data about controls and patients were compared by one-way ANOVA. Spearman correlation coefficient was used to assess the correlation between perfusion parameters, treatment cycle and ALT level. All tests were two-tailed. P < 0.05 was considered statistically significant. Data processing and analysis involved use of SPSS v11.5 (SPSS Inc., Chicago, IL, USA).

RESULTS
Differences in perfusion parameters

No significant difference was found in HPI (25.68% ± 7.38% vs 26.82% ± 5.13%, t = 0.77, P = 0.44), MTT (19.67 ± 5.68 s vs 21.70 ± 5.43 s, t = 1.43, P = 0.16) and PS (17.00 ± 4.56 mL/100 mL per min vs 19.92 ± 6.35 mL/100 mL per min, t = 1.90, P = 0.06) between patients and controls.

Patients were divided into two subgroups: one receiving 1 cycle of chemotherapy (n = 40) and the other receiving 2 cycles of chemotherapy (n = 20). The HPI and MTT were higher in patients receiving 2 cycles of chemotherapy than in those receiving 1 cycle of chemotherapy and controls (29.76% ± 5.87% vs 25.35% ± 4.05% and 25.68% ± 7.38%, and 25.61 ± 5.01 s vs 19.74 ± 4.54 s and 19.67 ± 5.68 s, P < 0.05). No significant difference was observed in HPI and MTT between patients receiving 1 cycle of chemotherapy and controls, and in PS between patients and controls (F = 1.78, P = 0.18) (Table 1).

Table 1 Comparison of perfusion parameters between controls and patients by treatment cycle (mean ± SD).
ParametersControls (n = 20)1 cycle (n = 20)2 cycles (n = 40)F valueP value
HPI (%)25.68 ± 7.3825.35 ± 4.0529.76 ± 5.874.620.01
MTT (s)19.67 ± 5.6819.74 ± 4.5425.61 ± 5.0110.59< 0.01
PS (mL/100 mL per min)17.00 ± 4.5619.95 ± 6.7619.86 ± 5.601.780.18

Of the 60 patients, 13 (21.7%) showed hepatic steatosis. The incidence of hepatic steatosis was higher in patients receiving 2 cycles of chemotherapy than in those receiving 1 cycle of chemotherapy (P = 0.01). The HPI was higher in patients with hepatic steatosis than in those without hepatic steatosis and controls (30.85% ± 6.17% vs 25.70% ± 4.24% and 25.68% ± 7.38%, P < 0.05). No significant difference was found in HPI between patients without hepatic steatosis and controls, and in MTT or in PS between patients and controls (Table 2).

Table 2 Comparison of perfusion parameters between controls and patients with or without hepatic steatosis (mean ± SD).
ParametersControls (n = 20)Patients without steatosis (n = 47)Patients with steatosis (n = 13)F valueP value
HPI (%)25.68 ± 7.3825.70 ± 4.2430.85 ± 6.174.790.01
MTT (s)19.67 ± 5.6821.33 ± 5.3123.03 ± 5.831.520.23
PS (mL/100 mL per min)17.00 ± 4.5620.23 ± 6.0818.79 ± 7.432.090.13
Correlation between CT perfusion parameters, treatment cycle and ALT level

Treatment cycle was well correlated with HPI (r = 0.40, P < 0.01) and MTT (r = 0.50, P < 0.01) but not with PS (r = 0.02, P = 0.89). ALT level was not correlated with treatment cycle (r = -0.05), HPI (r = -0.06), MTT (r = 0.19), and PS (r = 0.18).

DISCUSSION

Hepatic toxicity is often encountered in patients with tumor following chemotherapy. Chemotherapy agents can impair many vital functions of liver cells and cause their death[3]. Severe cell death is followed by nodular regeneration and obstruction of sinusoids, including transformation of fenestrated sinusoids into continuous capillaries and deposition of collagen in extravascular tissue spaces located between sinusoidal endothelium and hepatocytes[4,5]. These morphologic alterations modify blood transit time and distribution volume of small and large molecules[6,7], increase vascular resistance and reduce portal perfusion[8,9]. The reduction in portal perfusion is then buffered by liver arterialization, thereby increasing the arterial fraction of liver perfusion[8,10,11]. These alterations following chemotherapy are non-specific and can mimic any form of acute or chronic liver disease.

Perfusion CT can be used to evaluate the hemodynamic changes in liver disease. However, since the results of previous studies are varied[12-14], no established conclusion is available on the change in liver perfusion, especially in early chronic liver disease. Some studies showed that HPI and MTT values are significantly increased in patients or rats with chronic liver disease[12,13]. However, another study showed that the MTT is lower while the PS is higher in patients than in controls[14]. In the present study, the hepatic HPI and MTT values were higher in patients during chemotherapy than in controls, and well correlated with treatment cycle. No significant difference was observed in PS between patients and controls.

Steatosis is a common manifestation of drug hepatotoxicity and a form of liver damage most readily recognized on CT image. Several studies have shown that the incidence of hepatic steatosis is increased in patients undergoing chemotherapy[15-18]. In this study, hepatic steatosis was observed in 13 (21.7%) of the 60 patients, which was higher in patients receiving 2 cycles of chemotherapy than in those receiving 1 cycle of chemotherapy. The HPI was higher in patients with hepatic steatosis than in those without hepatic steatosis and controls. No difference was found in MTT or in PS between patients and controls.

At present, ALT level is the main index of drug-induced hepatic damage[19]. However, the ALT level was found to be a less sensitive index of hepatic damage and could not thoroughly reflect hepatic toxicity in this study. In clinical practice, many liver function tests remain normal despite obvious liver changes seen on CT images. In the present study, only 4 of 13 patients with hepatic steatosis had abnormal ALT, which was not correlated with HPI, MTT or PS. However, it has been shown that perfusion CT parameters are correlated with the severity of hepatic disease[13], indicating that further study is needed to classify the severity of liver damage with perfusion CT parameters.

Our study has some limitations. First, the injection rate of contrast agent was low. Because the detection of perfusion parameters is affected by many factors such as the type and injection rate of contrast agent, drawing of ROI and calculation method[20,21], the low injection rate may be a major obstacle to comparison with other results. Second, our sample size was small. Third, we only investigated the changes in perfusion CT in liver of patients during chemotherapy, and did not observe the entire changing characteristics of hepatic microcirculation during and after chemotherapy.

In conclusion, hepatic microcirculation is changed in patients with tumor during chemotherapy and can be quantitatively assessed by perfusion CT. Perfusion CT may be used as a noninvasive tool in detection of hepatic toxicity.

COMMENTS
Background

Liver damage is common in patients with tumor following chemotherapy. Although early liver damage causes no symptoms and is reversible in most patients, it occasionally progresses to more severe liver impairment, which may be irreversible, it is thus necessary to demonstrate the presence and severity of drug-related parenchymal changes.

Research frontiers

Hepatic microcirculation changes in patients with tumor during chemotherapy were evaluated by perfusion computed tomography (CT). The hotspot of this research is whether hepatic microvascular changes can be quantified with perfusion CT and what kind of modifications can be detected.

Innovations and breakthroughs

At present, alanine aminotransferase (ALT) level is the main index in diagnosis of drug-induced hepatic damage. In this study, however, ALT level was found to be a less sensitive index and could not thoroughly reflect hepatic toxicity. The aim of this study was to investigate the microcirculation changes in liver of patients with tumor during chemotherapy, showing that hepatic perfusion index and mean transit time are significantly increased in patients undergoing 2 cycles chemotherapy.

Applications

The findings of this study may underscore the possibility of using perfusion CT parameters as indicators of hepatic microcirculation alteration in drug-induced liver damage. Perfusion CT may be used as a noninvasive tool in detection of hepatic toxicity.

Peer review

The paper is a concise documentation of a good study.

Footnotes

Peer reviewer: Paul E Sijens, PhD, Associate Professor, Radiology, UMCG, Hanzeplein 1, 9713GZ Groningen, The Netherlands

S- Editor Tian L L- Editor Wang XL E- Editor Ma WH

References
1.  Hutter RV, Shipkey FH, Tan CT, Murphy ML, Chowdhury M. Hepatic fibrosis in children with acute leukemia: a complication of therapy. Cancer. 1960;13:288-307.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Perry MC. Hepatotoxicity of chemotherapeutic agents. Semin Oncol. 1982;9:65-74.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Kaplowitz N, Aw TY, Simon FR, Stolz A. Drug-induced hepatotoxicity. Ann Intern Med. 1986;104:826-839.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Horn T, Christoffersen P, Henriksen JH. Alcoholic liver injury: defenestration in noncirrhotic livers--a scanning electron microscopic study. Hepatology. 1987;7:77-82.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Martinez-Hernandez A. The hepatic extracellular matrix. II. Electron immunohistochemical studies in rats with CCl4-induced cirrhosis. Lab Invest. 1985;53:166-186.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Huet PM, Goresky CA, Villeneuve JP, Marleau D, Lough JO. Assessment of liver microcirculation in human cirrhosis. J Clin Invest. 1982;70:1234-1244.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Varin F, Huet PM. Hepatic microcirculation in the perfused cirrhotic rat liver. J Clin Invest. 1985;76:1904-1912.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Leen E, Goldberg JA, Anderson JR, Robertson J, Moule B, Cooke TG, McArdle CS. Hepatic perfusion changes in patients with liver metastases: comparison with those patients with cirrhosis. Gut. 1993;34:554-557.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Tsushima Y, Blomley JK, Kusano S, Endo K. The portal component of hepatic perfusion measured by dynamic CT: an indicator of hepatic parenchymal damage. Dig Dis Sci. 1999;44:1632-1638.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Kleber G, Steudel N, Behrmann C, Zipprich A, Hübner G, Lotterer E, Fleig WE. Hepatic arterial flow volume and reserve in patients with cirrhosis: use of intra-arterial Doppler and adenosine infusion. Gastroenterology. 1999;116:906-914.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol. 1985;249:G549-G556.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Guan S, Zhao WD, Zhou KR, Peng WJ, Mao J, Tang F. CT perfusion at early stage of hepatic diffuse disease. World J Gastroenterol. 2005;11:3465-3467.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Van Beers BE, Leconte I, Materne R, Smith AM, Jamart J, Horsmans Y. Hepatic perfusion parameters in chronic liver disease: dynamic CT measurements correlated with disease severity. AJR Am J Roentgenol. 2001;176:667-673.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Chen ML, Zeng QY, Huo JW, Yin XM, Li BP, Liu JX. Assessment of the hepatic microvascular changes in liver cirrhosis by perfusion computed tomography. World J Gastroenterol. 2009;15:3532-3537.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Kooby DA, Fong Y, Suriawinata A, Gonen M, Allen PJ, Klimstra DS, DeMatteo RP, D’Angelica M, Blumgart LH, Jarnagin WR. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg. 2003;7:1034-1044.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA. Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy. J Clin Oncol. 1993;11:2386-2390.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Peppercorn PD, Reznek RH, Wilson P, Slevin ML, Gupta RK. Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer. Br J Cancer. 1998;77:2008-2011.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Sørensen P, Edal AL, Madsen EL, Fenger C, Poulsen MR, Petersen OF. Reversible hepatic steatosis in patients treated with interferon alfa-2a and 5-fluorouracil. Cancer. 1995;75:2592-2596.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11:272-276.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Kapanen M, Halavaara J, Häkkinen AM. Comparison of liver perfusion parameters studied with conventional extravascular and experimental intravascular CT contrast agents. Acad Radiol. 2007;14:951-958.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Nakashige A, Horiguchi J, Tamura A, Asahara T, Shimamoto F, Ito K. Quantitative measurement of hepatic portal perfusion by multidetector row CT with compensation for respiratory misregistration. Br J Radiol. 2004;77:728-734.  [PubMed]  [DOI]  [Cited in This Article: ]