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Serum and Biliary Insulin-like Growth Factor I and Vascular Endothelial Growth Factor in Determining the Cause of Obstructive Cholestasis
- Domenico Alvaro, MD;
- Gianpiero Macarri, MD;
- Maria Grazia Mancino, MD, PhD;
- Marco Marzioni, MD;
- MariaConsiglia Bragazzi, MD;
- Paolo Onori, MD;
- Stefano Ginanni Corradini, MD, PhD;
- Pietro Invernizzi, MD, PhD;
- Antonio Franchitto, PhD;
- Adolfo F. Attili, MD;
- Eugenio Gaudio, MD; and
- Antonio Benedetti, MD
- From the University of Rome “Sapienza,” Rome, Italy; Polytechnic University of Marche, Ancona, Italy; State University of L'Aquila, L'Aquila, Italy; and San Paolo Hospital School of Medicine, University of Milan, Milan, Italy.
Abstract
Background: Cholangiocarcinoma cells express and secrete insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF).
Objective: To measure IGF-I and VEGF in bile and serum of patients with extrahepatic cholangiocarcinoma and to evaluate their performance as diagnostic markers.
Design: Cross-sectional study.
Setting: Inpatients at the Division of Gastroenterology, University Hospital, Ancona, Italy.
Patients: 73 patients who consecutively had endoscopic retrograde cholangiopancreatography (ERCP), including patients with extrahepatic cholangiocarcinoma (n = 29), pancreatic cancer (n = 19), and benign biliary abnormalities (n = 25; bile duct stones, primary sclerosing cholangitis, and cholangitis).
Measurements: Diagnosis was based on conventional radiology, ERCP, and follow-up. Insulin-like growth factor I and VEGF were measured by using enzyme-linked immunosorbent assay.
Results: The biliary IGF-I concentration was 15- to 20-fold higher (P < 0.001) in extrahepatic cholangiocarcinoma (mean, 84.6 nmol/L [95% CI, 74.0 to 95.2 nmol/L]) than in pancreatic cancer (5.8 nmol/L [CI, 4.0 to 7.5 nmol/L]) or benign biliary abnormalities (4.1 nmol/L [CI, 3.1 to 5.2 nmol/L]). The area under the receiver-operating characteristic curve was 1 when biliary IGF-I values in the extrahepatic cholangiocarcinoma were compared with benign biliary abnormalities or pancreatic cancer. In contrast, biliary VEGF concentration was similar in the 3 groups. Serum IGF-I levels were similar among the groups, whereas serum VEGF levels were higher in the cholangiocarcinoma (0.97 ng/mL [CI, 0.59 to 1.35 ng/mL]; P = 0.0016) and pancreatic cancer groups (0.66 ng/mL [CI, 0.43 to 0.88 ng/mL]; P < 0.001) compared with patients with benign biliary abnormalities (0.28 ng/mL [CI, 0.17 to 0.37 ng/mL]).
Limitations: Data were obtained in a small sample, the study was performed in a single center, and few patients had a tissue diagnosis.
Conclusions: Biliary IGF-I levels in patients undergoing ERCP for biliary obstruction may differentiate extrahepatic cholangiocarcinoma from either pancreatic cancer or benign biliary abnormalities.
Article and Author Information
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Acknowledgments: The authors thank Tracie Dornbusch for English-language editing and AnnaRita Vestri and Alfredo Cantafora for assistance with statistical analysis. They also thank Italo Bearzi for support in the histologic characterization of cholangiocarcinomas and Livio Capocaccia for critical revision of the manuscript.
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Grant Support: By Italian Ministry of Education, University and Research grants PRIN 2005 2005069739_003 and 2005067975_002 to Drs. Alvaro and Attili; PRIN 2005 2005067975_001, 2005069739_002; and Biomedicina, Cluster C04, progetto numero 5 MIUR grants and ex 60% grants to Drs. Gaudio and Onori; Cofin 2006 2006068958_002 to Dr. Corradini; a Cofin 2004 2004068113_002 grant to Dr. Invernizzi; and Cofin 2005 2005067975_004 and 2005062350_003 grants to Drs. Marzioni, Macarri, and Benedetti.
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Potential Financial Conflicts of Interest: None disclosed.
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Requests for Single Reprints: Domenico Alvaro, MD, Division of Gastroenterology, Department of Clinical Medicine, University of Rome “Sapienza,” Via Roberto Rossellini 51, 00137 Rome, Italy; e-mail, domenico.alvaro{at}uniroma1.it.
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Current Author Addresses: Dr. Alvaro: Division of Gastroenterology Polo Pontino, Department of Clinical Medicine, University of Rome “Sapienza,” Via Roberto Rossellini 51, 00137 Rome, Italy.
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Dr. Macarri: Università Politecnica delle Marche, Clinica di Gastroenterologia, Via Tronto, 60020 Ancona, Italy.
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Dr. Mancino: University of Rome “Sapienza,” Viale Università 37, 00185 Rome, Italy.
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Dr. Marzioni: Università Politecnica delle Marche, Clinica di Gastroenterologia, Via Tronto, 60020 Ancona, Italy.
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Drs. Bragazzi, Corradini, and Attili: University of Rome “Sapienza,” Viale Università 37, 00185 Rome, Italy.
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Dr. Onori: State University of L'Aquila, L'Aquila, Italy.
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Dr. Invernizzi: Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Via Rudini 8, 20142 Milan, Italy.
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Drs. Franchitto and Gaudio: Department of Anatomy, University of Rome “Sapienza,” Via A. Borelli 50, 00185 Rome, Italy.
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Dr. Benedetti: Università Politecnica delle Marche, Clinica di Gastroenterologia, Via Tronto, 60020 Ancona, Italy.
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Author Contributions: Conception and design: D. Alvaro, M. Marzioni, A. Benedetti.
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Analysis and interpretation of the data: D. Alvaro, M.G. Mancino, M. Marzioni.
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Drafting of the article: D. Alvaro.
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Critical revision of the article for important intellectual content: M. Marzioni, P. Invernizzi, E. Gaudio.
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Final approval of the article: G. Macarri, M.G. Mancino, M. Marzioni, M.C. Bragazzi, P. Onori, S.G. Corradini, P. Invernizzi, A. Franchitto, A.F. Attili, E. Gaudio, A. Benedetti.
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Statistical expertise: S.G. Corradini, A.F. Attili.
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Administrative, technical, or logistic support: D. Alvaro.
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Collection and assembly of data: M.G. Mancino.
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