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Helicobacter pylori in the bile could play a facilitating role in the pathogenesis of the some types of gallstones
April 2000
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BRADYKININ INDUCED CONTRACTION OF HUMAN GALL· BLADDER MUSCLE IN VITRO. Hugh J. Brennan, Colin D. Johnson, Southampton Gen Hosp, Southampton, United Kingdom. Aim To examine the mechanisms of Bradykinin (BK)-induced contraction on human gallbladder muscle and to investigate possible receptors that may mediate this action. Methods A full-thickness segment from the anterior aspect of healthy and stone-hearing gallbladders was removed and placed in cold Krebs solution in an organ bath. Concentration-response curves (CRCs) were obtained for BK (0.1-100/LM). The BK response curves were repeated in the presence of a number of antagonists and channel blockers - BI & B2 receptor antagonists, SR 27897 (0.5nM,a CCK-A receptor antagonist), mepyramine (l/LM, a histamine receptor antagonist), atropine (l/LM, a muscarinic receptor antagonist), prazosin (O.l/LM,a adrenoceptor blocker), tetrodotoxin (O.03/LM, a Na channel blocker), quinidine (l/LM, a K channel blocker) and indomethacin (3/LM, a cyclo-oxygenase inhibitor). Extracellular Ca involvement was examined by use of Ca free medium. Ryanodine (lO/LM) was used to examine intracellular involvement. Ethics committee approval for tissue sampling was obtained. Statistical significance was performed using t-test, P < .05 or less was considered as indicative of significance. Results Healthy (n=6) and stone-bearing (n=9) gallbladders showed similar and repeatable CRCs to BK (EDso=4.95 & 5.5/LM). The BK response was significantly reduced only in healthy strips by BI receptor blockade (EDso=31.5/LM) and in both tissue types by B2 receptor blockade (EDso=37.2 & 29./LM). Neither antagonist affected the maximum BK response. No significant rightward shift of the response to BK was observed in the presence of mepyramine (n=4), atropine (n=), prazosin (n=6), tetrodotoxin (n=), quinidine (n=7) or SR27897 (n=5). A significant rightward shift of the curve was noted in the presence of indomethacin (n=20,EDso=55/LM). BK-induced contraction was not modified in Ca-free medium (n=7), however the presence of ryanodine caused a significant rightward shift of the BK dose-response curve (n=7,ED so=46/LM. Conclusion Gallbladder strips contract to BK in a dose-dependent manner. A difference in receptor population seems to exist between normal and stone-bearing gallbladders. BK appears to have a direct myogenic effect on the human gallbladder and this may be mediated by a third BK receptor or a BK-independent mechanism. The contraction occurs independently of extracellular Ca but intracellular Ca is vital. In addition, part of this BK-induced contraction is probably mediated by the release of a cyclo-oxygenasc-dcrived product from the arachidonic acid pathway.
INTRAHEPATIC GALLSTONES ASSOCIATED WITH CONGEN· ITAL BILE DUCT DILATATION RESTRICTED TO THE INTRAHEPATIC DUCTS (CAROLI'S DISEASE) ARE FREQUENTLY CHOLESTEROL AND SOMETIMES RESEMBLE IN SHAPE THE CAST OF DILATED DUCTS. Francesco Cetta, Claudio Baldi, Giulia Montalto, Michele Zuckermann, Antonio De Martino, Angelo De Nisi, Gennaro Nuzzo, Yuji Nimura, Institute of Surg Clinics, Siena, Italy; Institute of Surg Pathology, Roma, Italy; First Dept of Surg, Nagoya, Japan. Background/Aims: Hepatolithiasis has usually been considered synonymous with brown pigment gallstones (GS). The aims of the study was to analyze the types and composition of GS associated with congenital bile duct dilatation (CBDD) restricted to the intrahepatic ducts (Caroli s disease). Patients and Methods: 122 patients had GS within the intrahepatic ducts (1.5%). All patients had bile culture and stone analysis. Results: 67 patients had intrahepatic GS concomitant with GS in the common duct and/or in the gallbladder, in the absence of evident CBDD. GS were cholesterol in 26, mixed in 39 and brown in 2 cases. 37 patients had intrahepatic GS cranially to a postsurgical stricture. GS were brown in 19 patients, brown plus mixed in 11, black in I, mixed or cholesterol in 6. Seven patients had CBDD involving the extrahepatic ducts. GS were brown in 4, mixed in 2 and cholesterol in 1 case. Eleven patients had Caroli s disease, i.e. CBDD restricted to the intrahepatic ducts. GS associated with "pure" Caroli s disease were cholesterol in 8 cases and composite, i.e. mixed cholesterol plus brown pigment in 3. No patient had brown GS as unique stones. Bile culture was positive in 3 cases (27%). Interestingly, it was negative at ERCP and subsequently became positive at operation. In particular, in 3 of the 11 patients, not only GS were cholesterol, but they resembled in shape a true cast of the main intrahepatic segmental ducts. Conclusion: Patients with "pure" Caroli s disease have more frequently cholesterol GS (8 of II) (72%) and rarely positive bile culture (27%) (p< 0.0 I) than patients with postsurgical stricture. In particular, none of these patients had "pure" brown GS. In the absence of bile infection, cholesterol GS, sometimes resembling in shape the cast of dilated intrahepatic ducts frequently occur as primary intrahepatic GS, due to sectorial bile stasis.
289 PORCELAIN GALLBLADDER: A POSSIBLE LONG· TERM SIDE· EFFECT OF CHEMOTHERAPY INCLUDING SOMATOSTATIN FOR LIVER METASTASES FROM CARCINOIDS? Francesco Cetta, Antonio De Martino, Angelo De Nisi, Claudio Baldi, Michele Zuckermann, Maurizio Amoroso, Giulia Montalto, Institute of Surg Clinics, Siena, Italy. Background Neuroendocrine tumors and, in particular, carcinoids from the appendix are considered tumors with a relatively good prognosis, even in the presence of liver metastases. Methods During the analysis of 2000 consecutive surgical patients with gallstone disease, 15 patients with "porcelain gallbladder" (PGB), i.e. a completely or partially calcified gallbladder, were found. There were 3 men, 12 women, female-male ratio 4:1, mean age 66, range 49-88 years. Results All patients had at least one stone impacted in the infundibulum. Stones were single cholesterol ovoidal in 2 cases, combination stones in 5 and composite in 8 patients. Bile culture was positive in 4 of 15 cases. None of these patients had gallbladder carcinoma. In addition to these patients, there was a 49-year-old male, who 13 years before had appendicectomy and ileal resection for a neoplasm, which was diagnosed histologically as a "carcinoid of the appendix". During the same operation liver metastases were detected. The patient had no gallstones at that time. This patient underwent chemotherapy. Somatostatin was added as a part of the therapeutic regimen since 1992. In may 1999, the patient underwent surgery because of abdominal pain, in the presence of multiple liver metastases and a liver calcification, resembling in shape the gallbladder. At operation multiple liver metastases were found and one of them was resected to confirm diagnosis. However, symptoms were mainly caused by "intestinal occlusion" due to a small bowel loop strictly adherent to a porcelain-gallbladder, containing large faceted gallstones. Bile culture was negative. The patient recovered from operation and is still alive and well. Conclusion Somatostatinoma or long-term treatment with somatostatin is known to be associated with gallstones, mainly due to bile stasis, a well know effect of somatostatin. PGB can be a long-term side-effect of gallstones, but is infrequent before age 50 (only one 49-year-old woman in the series of 15 patients). With the increased use of somatostatin as a part of the therapeutic regimen and the increased survival of patients with liver metastases from carcinoids, not only gallstones, but also PGB can occur, even in males, as a side-effect of prolonged treatment with somatostatin.
291 HELICOBACTER PYLORI IN THE BILE COULD PLAYA FACIL· ITATING ROLE IN THE PATHOGENESIS OF THE SOME TYPES OF GALLSTONES. Francesco Cetta, Natale Figura, Giulia Montalto, Donatella Cetta, Claudio Baldi, Maurizio Amoroso, Angelo De Nisi, Michele Zuckermann, Institute of Surg Clinics, Siena, Italy; Institute of Internal Medicine, Siena, Italy. Background and aims.: Gallstones (GS) are not a unique entity, but a heterogeneous disease, including cholesterol, mixed and pigment GS (black and brown). In particular, brown GS can be considered as a true infectious disease, mainly due to bile infection by E. Coli. Helicobacter Pylori (HP) has many similarities with E. Coli: (i) it produces enzymes responsible for hydrolysis of some constituents of the bile and calcium salt precipitation; (ii) determines chronic inflammation, possibly altering gallblader motility; (iii) produces Ig and other "nucleating proteins"; (iv) acting as a foreign body, can facilitate heterologous nucleation. The aim of the study has been to establish whether HP infection: (i) is associated with GS and in particular with which types of GS; (ii) could playa role in GS formation. Methods: 50 consecutive patients (pts) with different types of GS were analyzed for the presence of HP antibodies, antigens and/or genes in the bile obtained at operation. All pts had blood samples to detect HP infection in the serum. Western blotting and PCR were used to determine presence of antigens and genes. Results: 37 pts (74%) were seropositive for HP. HPB antibodies in the bile were only found in pts with HP antibodies in the blood. In particular, at least one of the markers of HP presence in the bile was found in I of 4 pts with black stones; 1 of 5 pts with solitary Ch stones; 2 of 7 with multiple spherical Ch GS; 5 of 7 with faceted stones; 9 of II with composite OS, i.e. stones of different types within the same gallbladder; 3 of 3 with brown GS in the common duct (p<0.05). In particular, antigens were always found in pts with HP infection in the common duct bile after sphincterotomy. Conclusions: Ptesent data are preliminary and further confirmation is required in larger series. They suggest that HP presence in the bile is non homogeneously associated with the various types of GS. Even if HP certainly does not playa pathogenetic role similar to that of E.Coli in brown stone formation, the hypothesis that HP could be a co-factor for the formation of some subtypes of GS, namely multiple Ch, mixed or composite GS, cannot be excluded.
AGAA7
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BRADYKININ INDUCED CONTRACTION OF HUMAN GALL· BLADDER MUSCLE IN VITRO. Hugh J. Brennan, Colin D. Johnson, Southampton Gen Hosp, Southampton, United Kingdom. Aim To examine the mechanisms of Bradykinin (BK)-induced contraction on human gallbladder muscle and to investigate possible receptors that may mediate this action. Methods A full-thickness segment from the anterior aspect of healthy and stone-hearing gallbladders was removed and placed in cold Krebs solution in an organ bath. Concentration-response curves (CRCs) were obtained for BK (0.1-100/LM). The BK response curves were repeated in the presence of a number of antagonists and channel blockers - BI & B2 receptor antagonists, SR 27897 (0.5nM,a CCK-A receptor antagonist), mepyramine (l/LM, a histamine receptor antagonist), atropine (l/LM, a muscarinic receptor antagonist), prazosin (O.l/LM,a adrenoceptor blocker), tetrodotoxin (O.03/LM, a Na channel blocker), quinidine (l/LM, a K channel blocker) and indomethacin (3/LM, a cyclo-oxygenase inhibitor). Extracellular Ca involvement was examined by use of Ca free medium. Ryanodine (lO/LM) was used to examine intracellular involvement. Ethics committee approval for tissue sampling was obtained. Statistical significance was performed using t-test, P < .05 or less was considered as indicative of significance. Results Healthy (n=6) and stone-bearing (n=9) gallbladders showed similar and repeatable CRCs to BK (EDso=4.95 & 5.5/LM). The BK response was significantly reduced only in healthy strips by BI receptor blockade (EDso=31.5/LM) and in both tissue types by B2 receptor blockade (EDso=37.2 & 29./LM). Neither antagonist affected the maximum BK response. No significant rightward shift of the response to BK was observed in the presence of mepyramine (n=4), atropine (n=), prazosin (n=6), tetrodotoxin (n=), quinidine (n=7) or SR27897 (n=5). A significant rightward shift of the curve was noted in the presence of indomethacin (n=20,EDso=55/LM). BK-induced contraction was not modified in Ca-free medium (n=7), however the presence of ryanodine caused a significant rightward shift of the BK dose-response curve (n=7,ED so=46/LM. Conclusion Gallbladder strips contract to BK in a dose-dependent manner. A difference in receptor population seems to exist between normal and stone-bearing gallbladders. BK appears to have a direct myogenic effect on the human gallbladder and this may be mediated by a third BK receptor or a BK-independent mechanism. The contraction occurs independently of extracellular Ca but intracellular Ca is vital. In addition, part of this BK-induced contraction is probably mediated by the release of a cyclo-oxygenasc-dcrived product from the arachidonic acid pathway.
INTRAHEPATIC GALLSTONES ASSOCIATED WITH CONGEN· ITAL BILE DUCT DILATATION RESTRICTED TO THE INTRAHEPATIC DUCTS (CAROLI'S DISEASE) ARE FREQUENTLY CHOLESTEROL AND SOMETIMES RESEMBLE IN SHAPE THE CAST OF DILATED DUCTS. Francesco Cetta, Claudio Baldi, Giulia Montalto, Michele Zuckermann, Antonio De Martino, Angelo De Nisi, Gennaro Nuzzo, Yuji Nimura, Institute of Surg Clinics, Siena, Italy; Institute of Surg Pathology, Roma, Italy; First Dept of Surg, Nagoya, Japan. Background/Aims: Hepatolithiasis has usually been considered synonymous with brown pigment gallstones (GS). The aims of the study was to analyze the types and composition of GS associated with congenital bile duct dilatation (CBDD) restricted to the intrahepatic ducts (Caroli s disease). Patients and Methods: 122 patients had GS within the intrahepatic ducts (1.5%). All patients had bile culture and stone analysis. Results: 67 patients had intrahepatic GS concomitant with GS in the common duct and/or in the gallbladder, in the absence of evident CBDD. GS were cholesterol in 26, mixed in 39 and brown in 2 cases. 37 patients had intrahepatic GS cranially to a postsurgical stricture. GS were brown in 19 patients, brown plus mixed in 11, black in I, mixed or cholesterol in 6. Seven patients had CBDD involving the extrahepatic ducts. GS were brown in 4, mixed in 2 and cholesterol in 1 case. Eleven patients had Caroli s disease, i.e. CBDD restricted to the intrahepatic ducts. GS associated with "pure" Caroli s disease were cholesterol in 8 cases and composite, i.e. mixed cholesterol plus brown pigment in 3. No patient had brown GS as unique stones. Bile culture was positive in 3 cases (27%). Interestingly, it was negative at ERCP and subsequently became positive at operation. In particular, in 3 of the 11 patients, not only GS were cholesterol, but they resembled in shape a true cast of the main intrahepatic segmental ducts. Conclusion: Patients with "pure" Caroli s disease have more frequently cholesterol GS (8 of II) (72%) and rarely positive bile culture (27%) (p< 0.0 I) than patients with postsurgical stricture. In particular, none of these patients had "pure" brown GS. In the absence of bile infection, cholesterol GS, sometimes resembling in shape the cast of dilated intrahepatic ducts frequently occur as primary intrahepatic GS, due to sectorial bile stasis.
289 PORCELAIN GALLBLADDER: A POSSIBLE LONG· TERM SIDE· EFFECT OF CHEMOTHERAPY INCLUDING SOMATOSTATIN FOR LIVER METASTASES FROM CARCINOIDS? Francesco Cetta, Antonio De Martino, Angelo De Nisi, Claudio Baldi, Michele Zuckermann, Maurizio Amoroso, Giulia Montalto, Institute of Surg Clinics, Siena, Italy. Background Neuroendocrine tumors and, in particular, carcinoids from the appendix are considered tumors with a relatively good prognosis, even in the presence of liver metastases. Methods During the analysis of 2000 consecutive surgical patients with gallstone disease, 15 patients with "porcelain gallbladder" (PGB), i.e. a completely or partially calcified gallbladder, were found. There were 3 men, 12 women, female-male ratio 4:1, mean age 66, range 49-88 years. Results All patients had at least one stone impacted in the infundibulum. Stones were single cholesterol ovoidal in 2 cases, combination stones in 5 and composite in 8 patients. Bile culture was positive in 4 of 15 cases. None of these patients had gallbladder carcinoma. In addition to these patients, there was a 49-year-old male, who 13 years before had appendicectomy and ileal resection for a neoplasm, which was diagnosed histologically as a "carcinoid of the appendix". During the same operation liver metastases were detected. The patient had no gallstones at that time. This patient underwent chemotherapy. Somatostatin was added as a part of the therapeutic regimen since 1992. In may 1999, the patient underwent surgery because of abdominal pain, in the presence of multiple liver metastases and a liver calcification, resembling in shape the gallbladder. At operation multiple liver metastases were found and one of them was resected to confirm diagnosis. However, symptoms were mainly caused by "intestinal occlusion" due to a small bowel loop strictly adherent to a porcelain-gallbladder, containing large faceted gallstones. Bile culture was negative. The patient recovered from operation and is still alive and well. Conclusion Somatostatinoma or long-term treatment with somatostatin is known to be associated with gallstones, mainly due to bile stasis, a well know effect of somatostatin. PGB can be a long-term side-effect of gallstones, but is infrequent before age 50 (only one 49-year-old woman in the series of 15 patients). With the increased use of somatostatin as a part of the therapeutic regimen and the increased survival of patients with liver metastases from carcinoids, not only gallstones, but also PGB can occur, even in males, as a side-effect of prolonged treatment with somatostatin.
291 HELICOBACTER PYLORI IN THE BILE COULD PLAYA FACIL· ITATING ROLE IN THE PATHOGENESIS OF THE SOME TYPES OF GALLSTONES. Francesco Cetta, Natale Figura, Giulia Montalto, Donatella Cetta, Claudio Baldi, Maurizio Amoroso, Angelo De Nisi, Michele Zuckermann, Institute of Surg Clinics, Siena, Italy; Institute of Internal Medicine, Siena, Italy. Background and aims.: Gallstones (GS) are not a unique entity, but a heterogeneous disease, including cholesterol, mixed and pigment GS (black and brown). In particular, brown GS can be considered as a true infectious disease, mainly due to bile infection by E. Coli. Helicobacter Pylori (HP) has many similarities with E. Coli: (i) it produces enzymes responsible for hydrolysis of some constituents of the bile and calcium salt precipitation; (ii) determines chronic inflammation, possibly altering gallblader motility; (iii) produces Ig and other "nucleating proteins"; (iv) acting as a foreign body, can facilitate heterologous nucleation. The aim of the study has been to establish whether HP infection: (i) is associated with GS and in particular with which types of GS; (ii) could playa role in GS formation. Methods: 50 consecutive patients (pts) with different types of GS were analyzed for the presence of HP antibodies, antigens and/or genes in the bile obtained at operation. All pts had blood samples to detect HP infection in the serum. Western blotting and PCR were used to determine presence of antigens and genes. Results: 37 pts (74%) were seropositive for HP. HPB antibodies in the bile were only found in pts with HP antibodies in the blood. In particular, at least one of the markers of HP presence in the bile was found in I of 4 pts with black stones; 1 of 5 pts with solitary Ch stones; 2 of 7 with multiple spherical Ch GS; 5 of 7 with faceted stones; 9 of II with composite OS, i.e. stones of different types within the same gallbladder; 3 of 3 with brown GS in the common duct (p<0.05). In particular, antigens were always found in pts with HP infection in the common duct bile after sphincterotomy. Conclusions: Ptesent data are preliminary and further confirmation is required in larger series. They suggest that HP presence in the bile is non homogeneously associated with the various types of GS. Even if HP certainly does not playa pathogenetic role similar to that of E.Coli in brown stone formation, the hypothesis that HP could be a co-factor for the formation of some subtypes of GS, namely multiple Ch, mixed or composite GS, cannot be excluded.