RSS Feeds
-
Re: Biliary IGF-I in patients with extrahepatic cholangiocarcinoma
Submit responseTo 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
-
Biliary IGF-I in patients with extrahepatic cholangiocarcinoma
Submit responseTO 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