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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
[+] Article and Author Information

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.


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.

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.

Potential Financial Conflicts of Interest: None disclosed.

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@uniroma1.it.

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.

Dr. Macarri: Università Politecnica delle Marche, Clinica di Gastroenterologia, Via Tronto, 60020 Ancona, Italy.

Dr. Mancino: University of Rome “Sapienza,” Viale Università 37, 00185 Rome, Italy.

Dr. Marzioni: Università Politecnica delle Marche, Clinica di Gastroenterologia, Via Tronto, 60020 Ancona, Italy.

Drs. Bragazzi, Corradini, and Attili: University of Rome “Sapienza,” Viale Università 37, 00185 Rome, Italy.

Dr. Onori: State University of L'Aquila, L'Aquila, Italy.

Dr. Invernizzi: Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Via Rudini 8, 20142 Milan, Italy.

Drs. Franchitto and Gaudio: Department of Anatomy, University of Rome “Sapienza,” Via A. Borelli 50, 00185 Rome, Italy.

Dr. Benedetti: Università Politecnica delle Marche, Clinica di Gastroenterologia, Via Tronto, 60020 Ancona, Italy.

Author Contributions: Conception and design: D. Alvaro, M. Marzioni, A. Benedetti.

Analysis and interpretation of the data: D. Alvaro, M.G. Mancino, M. Marzioni.

Drafting of the article: D. Alvaro.

Critical revision of the article for important intellectual content: M. Marzioni, P. Invernizzi, E. Gaudio.

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.

Statistical expertise: S.G. Corradini, A.F. Attili.

Administrative, technical, or logistic support: D. Alvaro.

Collection and assembly of data: M.G. Mancino.


Ann Intern Med. 2007;147(7):451-459. doi:10.7326/0003-4819-147-7-200710020-00003
Text Size: A A A

The Table shows patient characteristics. Patients with benign biliary abnormalities were, on average, 12 to 13 years younger (Table) than the patients in the other 2 groups. Patients with extrahepatic cholangiocarcinoma had greater cholestasis than the other 2 groups. Total and direct (conjugated) serum bilirubin and serum alkaline phosphatase levels were statistically significantly higher (Table) in patients with cholangiocarcinoma than in patients with pancreatic cancer or benign biliary abnormalities. Accordingly, total biliary bile salt concentration was statistically significantly lower (Table) in the cholangiocarcinoma group than in the other 2 groups.

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Figures

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Figure 1.
Insulin-like growth factor I (IGF-I) concentration in bile and serum.P

The biliary IGF-I concentration was significantly (  < 0.001) higher in patients with extrahepatic cholangiocarcinoma than in those with pancreatic cancer or benign biliary abnormalities. IQR = interquartile range.

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Figure 2.
Vascular endothelial growth factor (VEGF) concentration in bile and serum.PP

Serum levels of VEGF were significantly higher in patients with extrahepatic cholangiocarcinoma (  = 0.002) or pancreatic cancer (  < 0.001) than in patients with benign biliary abnormalities. IQR = interquartile range.

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Biliary IGF-I in patients with extrahepatic cholangiocarcinoma
Posted on October 4, 2007
Tetsuji Fujita
Jikei University School of Medicine
Conflict of Interest: None Declared

TO THE EDITOR: I read with interest and surprise the paper by Dr Alvaro and colleagues, who concluded that the biliary insulin-like growth factor I (IGF-I) level can completely discriminate extrahepatic cholangiocarcinoma from benign biliary abnormalities and pancreatic cancer (1). In the article, biliary IGF-I levels were 10- to 15-fold higher in patients with extrahepatic cholangiocarcinoma than in those with benign biliary abnormalities or pancreatic cancer. The authors showed that the greater degree of cholestasis associated with cholangiocarcinoma did not influence the diagnostic availability of biliary IGF-I. Serum levels of IGF-I were similar among the 3 groups.

More than 75 %of the serum IGF-I circulates in a relatively stable complex bound to IGF-specific binding proteins and the remaining proportions of IGF-I are associated with the other binding proteins (2). Reliable determination of IGF-I requires dissociation and removal of these binding proteins before analysis. I would like to ask the authors whether an ELISA kit used for the determination of serum IGF-I levels is also suitable for measurement of IGF-I level in bile.

Normal extrahepatic biliary epithelium release secretory immunoglobulin A (sIgA) into the bile. We have previously revealed that serum sIgA levels were correlated with cholestasis after major abdominal surgery (3). We think that the regurgitation of sIgA from bile to the circulation due to disorganized biliary tree must be responsible for the elevation of circulating sIgA levels because a positive correlation between biliary and serum sIgA levels was found. Human IGF-I molecule, a basic globular polypeptide consisting of 70 amino acids, is smaller than sIgA, each of whose chains contains more than 100 amino acids. I assume that cholestasis leads to the regurgitation of IGF-I from bile into the systemic circulation. I would like to ask the authors the relation of biliary IGF-I levels to serum IGF-I levels, and whether serum IGF-I levels were correlated with the degree of cholestasis.

Tetsuji Fujita, MD, Department of Surgery Jikei University School of Medicine Tokyo, Japan 105-8461

References

1. Alvaro D, Macarri G, Mancino MG, et al. Serum and biliary insulin- like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med. 2007; 147: 451-9

2. Khosravi J, Diamandi A, Mistry J, Lee PDK. Noncompetitive ELISA for human serum insulin-like growth factor-I. Clin Chem. 1996; 42: 1147- 54.

3. Fujita T, Kobayashi S, Saeki T, Itsubo K. Relationship between circulating secretory immunoglobulin A levels and portal blood cytokine levels during major abdominal surgery. Arch Surg. 1997; 132: 124-7.

Conflict of Interest:

None declared

Re: Biliary IGF-I in patients with extrahepatic cholangiocarcinoma
Posted on October 5, 2007
Domenico ALVARO
Univerity of Rome Sapienza,
Conflict of Interest: None Declared

To the Editor.

We thank Dr. Tetsuji Fujita for his interest in our study (1).

We measured bile IGF1 by using a commercial Elisa kit consisting, as preliminary step, in extraction and separation of IGF-I from binding proteins (see pag. 452 of the article) and, therefore, interferences of binding proteins could rationally be excluded. A similar kit was previously used for IGF1 measurements in different biologic fluids (2-4).

Bile samples were collected, after intubation (during ERCP) of the main bile duct, downstream the site of obstruction. For that reason, it is very likely that most of bile IGF1 responsible for the large differences between cholangiocarcinoma and other pathologies originates from the neoplastic mass rather than from cholestatic bile. The IGF1 present in the collected bile fluid cannot regurgitate into serum since, downstream the obstruction, luminal pressure should be even lower than normal. Most importantly, the comparison between IgA and IGF1 is conceptually unlikely for the following reasons: a)IGF1 is synthesized and secreted by both hepatocytes and cholangiocytes mostly under GH (growth hormone) control (4); b) hepatocytes (95% of total liver cells) react to obstructive cholestasis with damage and depression of GH/IGF1 axis and IGF1 secretion (5); c) cholangiocytes (2-3% of total liver cells) respond to obstructive cholestasis with proliferation and increased expression and secretion of IGF1 (4); c)neoplastic proliferating cholangiocytes overexpress and secrete IGF1 (3). From all these considerations, since the serum and biliary IGF1 levels are influenced in opposite directions by many variables, a direct correlation between serum IGF1, biliary IGF1 and the degree of cholestasis was not found neither in our study (1) nor in previous studies (5-7). Indeed, opposite to serum IgA, several studies have demonstrated, in complete agreement, decreased IGF1 serum levels in both experimental and human cholestasis (5-7).

We hope these considerations helped in clarifying the raised issues.

Domenico ALVARO, MD Antonio BENEDETTI, MD

References:

1. Alvaro D, Macarri G, Mancino MG, et al. Serum and biliary insulin- like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med. 2007; 147: 451-9

2. Drudi Metalli V, Mancino MG, Mancino A, et al. Bile salts regulate proliferation and apoptosis of liver cells by modulating the IGF1 system. Dig Liver Dis. 2007; 39: 654-62.

3. Alvaro D, Barbaro B, Franchitto A, et al. Estrogens and insulin-like growth factor 1 modulate neoplastic cell growth in human cholangiocarcinoma. Am J Pathol. 2006;169: 877-88.

4. Alvaro D, Metalli VD, Alpini G, et al. The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis. J Hepatol. 2005;43:875-83.

5. Held MA, Cosme-Blanco W, Difedele LM, et al. Alterations in growth hormone receptor abundance regulate growth hormone signaling in murine obstructive cholestasis. Am J Physiol Gastrointest Liver Physiol 2005; 288:G986-93.

6. de Albuquerque Taveira AT, Fernandes MI, Galvão LC, et al. Impairment of bone mass development in children with chronic cholestatic liver disease.: Clin Endocrinol (Oxf). 2007; 66: 518-23.

7. Descos BP, Berry SA, Sharp HL, et al. Growth failure in cholestatic rats: the effect of malnutrition on insulin-like growth factor I. Pediatr Res. 1989; 26: 410-4.

Conflict of Interest:

None declared

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