- Email: [email protected]
Loss of inositol 1,4,5-trisphosphate receptors from cholangiocytes is a final common pathway for cholestasis
rejection episodes (p=0.04) in patients wire received CDU[(15/29) compared to LDLT(I/ 8) All subscales except tor global mental health improved over trine alter transplantation for both groups Donor type was trot a significant predictor of heahh related quality of file in any of the multivariate models developed Male patients experienced a significantly t~tster increase in quality of life afier hver transplantation At one year, the number of inpatient admissions negatively" eorrdated with perceived bodily pain (p
HBV serology may be an important tactor In donor selection and allocation The presence of anti-HBs in recipient may have a protective effect to prevent HAC. HBV vaccine in LT candidates to generate anti-HBs should be pursued to decrease morbidity" arising from HAC.
19 Analysis of Intrahepatic Biliary Strictures Without Hepatic Artery Thrombosis in 1113 Liver Transplantation Nobom Nakamura, Seigo Nishida, David LevL Tomoaki gato, Jose Nery, Juan Madariaga, Anti Vaidya, Andreas Tzakis Background. intrahepatic bihary strictures (IHBS) without hepatic artery thrombosis iHAT) after orthotopic liver transplantation (OLT) have been reported relevant to many conditions. Those Included prolonged cold ischemia ume (CIT), preservauon injury, recurrence of primary schlerosing cholangins (PSC), ABO incompaubflity, chronic rejection and cytomegalovims (CMV) infection. The aim of this study is to assess the incidence, risk factor, and outcome of the treatment in IHBS. Patients and Methods. A retrospecuve review of 1113 cadaveric whole OLT in 974 adult patients between June 1994 and February- 2002 at a single center was performed All grafts were preserved in University of Wisconsin solution. Diagnosis of IHBS was confirmed by" cholangingram Patency of hepatic ariel7 was documented by Doppler ultrasound and angmgram if indicating The incidence, type of strictures~ background data, and outcome of the management were analyzed. The data was compared to the control group without IHBS. Results. The overall incidence of IHBS was 1.5 %(17/ 1113) Mean CIT was 71 hours, warm iscben'~ic time was 33.4 minutes, donor age was 44.5 years and recipient age was 49.1 years In patients with IHBS, The primary disease Included 6 Laennecs cirrhosis, 6 HCV, 1 HBV, 1 HAV, 1 PSC, 1 Autuimmune hepatitis, 1 Sickle cell anemia. There was no ABO incompatible and CMV Intection cases. No recipient or donor factors were identified as risk tactors. Of 17 patients, 16 patients had muhiple strictures and 1 had a single stricture of right intrahepatic duct. The mean time interval which IHBS developed in the patients was 297 (,range 24-1517) days after OLT. All 17 patients were interventionaly radioloDcal treatment with multiple stricture dilatations, 3 of whom underwent retransplant and are alive well. Five (294%) died within 1 year due to Nfiary sepsis, 2 died between 1 to 2years, 1 died between 5 to 6years. Four (24%) are ahve without manipulation of biliary catheter, 2 developed graft dysfunction and were listed tbr retransplant Conclusions IHBS without HAT is a rare complication of OLT that may present bfliary sepsis. Our data revealed that no significant background data was identified as risk of IHBS. A total of 24% survived in the long term without a retransplant and 29.4% died within 1 year. The decision of appropriate Uming of retransplant is important and might improve the mortality rate for the patients with IHBS.
17
Living Donor Liver Transplantation:The Majority"of Donors Have Histologic Abnormalities on Liver Biopsy" lram 'I[an, Chanikarn Changsri Andrea Peterson Fred Poordad, John Vierhng, Nick Nissen, Steven Colquhoun, Christopher Shackleton, Stephen A. Geller, Paul Martin Background: Li~r biopsy is usually done to evaluate clinical or biochemical hepatic dysfunction, but can provide Inrportant Intormation even in the setting of normal serum liver tests, such as in assessing fibrosis in normal ALT-HCV infection Living donor liver transplantation (ID1,T) outcmnes can be impacted by donor grail abnorma/ines which may be undetectable by clinical, radiologica/or laboratory assessment, thus histologlc assessment is important. Aim: To evaluate hepatic histology in candidate donors tar aduh-to-aduh, or aduh-to-chfld L D I [ Methods: Percutaneons liver biopsies were performed on 56 donor candidates from May 2001- Oct 2002 as part of our screening protocol LDLT evaluation Included history and physical exam, screening for viral hepatitis and comprehensive biochemical tests. Liver biopsies ,sere then performed if no contraindlcation to donation was identified. Formalin* fixed, parathn-embeddad specimens were stained with H&E, diastase PAS, Masson's trichrome, reticulin silver, and ".Actoria bIue.Two patbologists assessed each biopsy. Results: The 56 candidates (29M/27F), nman age 43, had an average BMI of' 25 kg/m2. Biochemical test means were within no~nal reference ranges:AIX= 27 IU, AST = 28 IU and total bill = 061 m}/dL. No candtdale reported significant alcohol consumption and 9/56 had a history of bypen riglyceridemia A variety of histopathologic abnormalities were tound Including steatosts and steatohapantis, gmnulomas of unknown etiology, Intlarmnation possibly representative of drug reaction and a microabscess.(TABLE) Conclusions: Among potential dcmor candidates tar LDLT, all of whom had normal labm'atory and clinical screening, only 27% bad norn~al liver biopsies The most common abnormality was steatos*s (30%) The precise signibcance of these changes remains to be determined, including which of these changes are contraindications to liver transplantation These findings suggest that all potential candidates fbr LDLT should undergo sereening lwer biopsy
44 Loss of lnositol 1,4,5-Trisphosphate Receptors from Cholangiocytes Is a Final Common Pathway for Cholestasis Kazunon Sbibao, Keiji Hirata, Marie E. Robert, Michad H Nathanson
B~o~y Results
Unable
15/56
(:Z?%)
~ea~,Is (3/17 >30%lobule) Steatohep~s Chronic h e ~ N o n ~ n g grandoma Microab~cess Other: glycogenated nuclei, aonspectf'mInflammlaioa, blnucleate hepc,o ~ e , . . . . . . . . . . . . . .
17156
(30%) (1J%) (7%)
1t56 4/56 ~ 1/56 t3/56
Cholestasis is one of the principal complications of hver disease and oken results from disorders invoMng c:holanglocytes However, no unifying pathophysiological event in the cholangiocyte has been identified. Certain secretory" pathways are mediated by Ca> in cholangiocytes, and the type III isoform of the Inositol 1,4,5-trisphosphate receptor (InsP3R) is the predominant Ca > release channel in these calls. The type III InsP3R is lost from rat cholangiocytes after bile duct ligurian, but it is unknown whether other conlponents of the Ca> signaling pathway are lost as well, or whether similar molecular changes occur in patients with choIestatic disorders. To investigate these questions, we examined expression of each isoform of the InsP3R, plus expression of upstream components of the Ca> signahng pathway in rat cholangiocytes betore and after bile duct ligation. We a/so examined expression of the type lit InsP3R in liver biopsies from patients with cholestatic and non-cholestatic liver diseases. In rats, confocal immunofluoreseence and immunoblots botfi demonstrated that expression of type I, II and IlI InsP3R each was decreased after bile duct ligation In contrast, there was no decrease In expression of M3 muscarinic ace@choline receptors, Gaq/ll protein, or PLCI3 after bile duct ligation. Examination of human liver biopsy specimens by confocal immunofluorescence demonstrated that type III InsP3Rs were expressed in normal cholangtocytes and were localized to the apical region, just as in normal mt cholangiocytes. In contrast, InsP3Rs were lost from patients with biliary atresia (n= 8), primary" bfliary cirrhosis (n = 5), sclerosing cholangitis (n = 5), and chronic bile duct obstruction ( n = 5 ) However, InsP3R expression was preserved in specimens from patients with Hepatitis C viral refection (n = 5) lmmunolabeling for the cystic fibrosis trausmembrane conductance regulator (CFTR) was preserved in all biopsy specimm~. These findings demonsrrate that impailment of Ca `'+ signaling and of Ca2+-mediated ductular secretion after bile duct ligation specifically results frmn loss of lnsP3 receptors, rather than loss of other components of the Ca> signaling pathway. Moreover, loss of InsP3 receptors is a common but specific teature in a range of human cholestatic diseases, and thus may be important for the pathophysmlogy of cbolestasis
(9%)
(17%) (23%)
18 Association between Hepatitis B Virus and Hepatic Arterial Complications after Liver Transplantation Andrzej Marzec, Surakit Pungpapong, Challa Alit, Kenned1 D. Rotbstein, Victor Araya, Santiago J Mum:)z Background Recent evidence demonstrating an association between donor hepatitis B Virus (HBV) exposure and accelerated allograti vasculopatby afier liver transplantation (LT) was reported However, the impact of using HBV-exposed donors on LT is urfemown. Methods: Between May 1995 - SeptenfOer 2002, 341 LT were periormed at our institution Thirty-eight patients (11 2%) developed hepatic arterial complications (HAC) dmpatic artery thrombosis (HAT) ,~ 22(6 5%), bepatie artery" stenosis = 13(3 8%) and hepatic artery" aneurysm = 3(09%)< Patient demographics, donor and recipient HBV and cytomegalovirus (CMV) serology were analyzed, P
AASLD Abstracts
45 Inhibitor of Growth 1 (ING1) Represses Alpha-Fetoprotein (AFP) Gene Transcription by p53 Activation and Direct DNA Binding Hiromi Kataoka, Karl Riabowol (Background) The Inhibitor of Growtfi (ING) family of proteins are class li tumor suppressors that affect regulation of the cell cycle, oncogenesis and cell aging They are associated wid't acetylationqinked chromatin remodeling and their expression lends are dem'eased in cancer cells. Despite reports linking ING to p53 activation, the molecular basis of how ING activates p53 thnction and the biochemical regulatory dd'ferences among ING fami]y members has not been ducidated. Recent reports have shown that the Silent Intormation Regulator 2
A-692
HBV serology may be an important tactor In donor selection and allocation The presence of anti-HBs in recipient may have a protective effect to prevent HAC. HBV vaccine in LT candidates to generate anti-HBs should be pursued to decrease morbidity" arising from HAC.
19 Analysis of Intrahepatic Biliary Strictures Without Hepatic Artery Thrombosis in 1113 Liver Transplantation Nobom Nakamura, Seigo Nishida, David LevL Tomoaki gato, Jose Nery, Juan Madariaga, Anti Vaidya, Andreas Tzakis Background. intrahepatic bihary strictures (IHBS) without hepatic artery thrombosis iHAT) after orthotopic liver transplantation (OLT) have been reported relevant to many conditions. Those Included prolonged cold ischemia ume (CIT), preservauon injury, recurrence of primary schlerosing cholangins (PSC), ABO incompaubflity, chronic rejection and cytomegalovims (CMV) infection. The aim of this study is to assess the incidence, risk factor, and outcome of the treatment in IHBS. Patients and Methods. A retrospecuve review of 1113 cadaveric whole OLT in 974 adult patients between June 1994 and February- 2002 at a single center was performed All grafts were preserved in University of Wisconsin solution. Diagnosis of IHBS was confirmed by" cholangingram Patency of hepatic ariel7 was documented by Doppler ultrasound and angmgram if indicating The incidence, type of strictures~ background data, and outcome of the management were analyzed. The data was compared to the control group without IHBS. Results. The overall incidence of IHBS was 1.5 %(17/ 1113) Mean CIT was 71 hours, warm iscben'~ic time was 33.4 minutes, donor age was 44.5 years and recipient age was 49.1 years In patients with IHBS, The primary disease Included 6 Laennecs cirrhosis, 6 HCV, 1 HBV, 1 HAV, 1 PSC, 1 Autuimmune hepatitis, 1 Sickle cell anemia. There was no ABO incompatible and CMV Intection cases. No recipient or donor factors were identified as risk tactors. Of 17 patients, 16 patients had muhiple strictures and 1 had a single stricture of right intrahepatic duct. The mean time interval which IHBS developed in the patients was 297 (,range 24-1517) days after OLT. All 17 patients were interventionaly radioloDcal treatment with multiple stricture dilatations, 3 of whom underwent retransplant and are alive well. Five (294%) died within 1 year due to Nfiary sepsis, 2 died between 1 to 2years, 1 died between 5 to 6years. Four (24%) are ahve without manipulation of biliary catheter, 2 developed graft dysfunction and were listed tbr retransplant Conclusions IHBS without HAT is a rare complication of OLT that may present bfliary sepsis. Our data revealed that no significant background data was identified as risk of IHBS. A total of 24% survived in the long term without a retransplant and 29.4% died within 1 year. The decision of appropriate Uming of retransplant is important and might improve the mortality rate for the patients with IHBS.
17
Living Donor Liver Transplantation:The Majority"of Donors Have Histologic Abnormalities on Liver Biopsy" lram 'I[an, Chanikarn Changsri Andrea Peterson Fred Poordad, John Vierhng, Nick Nissen, Steven Colquhoun, Christopher Shackleton, Stephen A. Geller, Paul Martin Background: Li~r biopsy is usually done to evaluate clinical or biochemical hepatic dysfunction, but can provide Inrportant Intormation even in the setting of normal serum liver tests, such as in assessing fibrosis in normal ALT-HCV infection Living donor liver transplantation (ID1,T) outcmnes can be impacted by donor grail abnorma/ines which may be undetectable by clinical, radiologica/or laboratory assessment, thus histologlc assessment is important. Aim: To evaluate hepatic histology in candidate donors tar aduh-to-aduh, or aduh-to-chfld L D I [ Methods: Percutaneons liver biopsies were performed on 56 donor candidates from May 2001- Oct 2002 as part of our screening protocol LDLT evaluation Included history and physical exam, screening for viral hepatitis and comprehensive biochemical tests. Liver biopsies ,sere then performed if no contraindlcation to donation was identified. Formalin* fixed, parathn-embeddad specimens were stained with H&E, diastase PAS, Masson's trichrome, reticulin silver, and ".Actoria bIue.Two patbologists assessed each biopsy. Results: The 56 candidates (29M/27F), nman age 43, had an average BMI of' 25 kg/m2. Biochemical test means were within no~nal reference ranges:AIX= 27 IU, AST = 28 IU and total bill = 061 m}/dL. No candtdale reported significant alcohol consumption and 9/56 had a history of bypen riglyceridemia A variety of histopathologic abnormalities were tound Including steatosts and steatohapantis, gmnulomas of unknown etiology, Intlarmnation possibly representative of drug reaction and a microabscess.(TABLE) Conclusions: Among potential dcmor candidates tar LDLT, all of whom had normal labm'atory and clinical screening, only 27% bad norn~al liver biopsies The most common abnormality was steatos*s (30%) The precise signibcance of these changes remains to be determined, including which of these changes are contraindications to liver transplantation These findings suggest that all potential candidates fbr LDLT should undergo sereening lwer biopsy
44 Loss of lnositol 1,4,5-Trisphosphate Receptors from Cholangiocytes Is a Final Common Pathway for Cholestasis Kazunon Sbibao, Keiji Hirata, Marie E. Robert, Michad H Nathanson
B~o~y Results
Unable
15/56
(:Z?%)
~ea~,Is (3/17 >30%lobule) Steatohep~s Chronic h e ~ N o n ~ n g grandoma Microab~cess Other: glycogenated nuclei, aonspectf'mInflammlaioa, blnucleate hepc,o ~ e , . . . . . . . . . . . . . .
17156
(30%) (1J%) (7%)
1t56 4/56 ~ 1/56 t3/56
Cholestasis is one of the principal complications of hver disease and oken results from disorders invoMng c:holanglocytes However, no unifying pathophysiological event in the cholangiocyte has been identified. Certain secretory" pathways are mediated by Ca> in cholangiocytes, and the type III isoform of the Inositol 1,4,5-trisphosphate receptor (InsP3R) is the predominant Ca > release channel in these calls. The type III InsP3R is lost from rat cholangiocytes after bile duct ligurian, but it is unknown whether other conlponents of the Ca> signaling pathway are lost as well, or whether similar molecular changes occur in patients with choIestatic disorders. To investigate these questions, we examined expression of each isoform of the InsP3R, plus expression of upstream components of the Ca> signahng pathway in rat cholangiocytes betore and after bile duct ligation. We a/so examined expression of the type lit InsP3R in liver biopsies from patients with cholestatic and non-cholestatic liver diseases. In rats, confocal immunofluoreseence and immunoblots botfi demonstrated that expression of type I, II and IlI InsP3R each was decreased after bile duct ligation In contrast, there was no decrease In expression of M3 muscarinic ace@choline receptors, Gaq/ll protein, or PLCI3 after bile duct ligation. Examination of human liver biopsy specimens by confocal immunofluorescence demonstrated that type III InsP3Rs were expressed in normal cholangtocytes and were localized to the apical region, just as in normal mt cholangiocytes. In contrast, InsP3Rs were lost from patients with biliary atresia (n= 8), primary" bfliary cirrhosis (n = 5), sclerosing cholangitis (n = 5), and chronic bile duct obstruction ( n = 5 ) However, InsP3R expression was preserved in specimens from patients with Hepatitis C viral refection (n = 5) lmmunolabeling for the cystic fibrosis trausmembrane conductance regulator (CFTR) was preserved in all biopsy specimm~. These findings demonsrrate that impailment of Ca `'+ signaling and of Ca2+-mediated ductular secretion after bile duct ligation specifically results frmn loss of lnsP3 receptors, rather than loss of other components of the Ca> signaling pathway. Moreover, loss of InsP3 receptors is a common but specific teature in a range of human cholestatic diseases, and thus may be important for the pathophysmlogy of cbolestasis
(9%)
(17%) (23%)
18 Association between Hepatitis B Virus and Hepatic Arterial Complications after Liver Transplantation Andrzej Marzec, Surakit Pungpapong, Challa Alit, Kenned1 D. Rotbstein, Victor Araya, Santiago J Mum:)z Background Recent evidence demonstrating an association between donor hepatitis B Virus (HBV) exposure and accelerated allograti vasculopatby afier liver transplantation (LT) was reported However, the impact of using HBV-exposed donors on LT is urfemown. Methods: Between May 1995 - SeptenfOer 2002, 341 LT were periormed at our institution Thirty-eight patients (11 2%) developed hepatic arterial complications (HAC) dmpatic artery thrombosis (HAT) ,~ 22(6 5%), bepatie artery" stenosis = 13(3 8%) and hepatic artery" aneurysm = 3(09%)< Patient demographics, donor and recipient HBV and cytomegalovirus (CMV) serology were analyzed, P
AASLD Abstracts
45 Inhibitor of Growth 1 (ING1) Represses Alpha-Fetoprotein (AFP) Gene Transcription by p53 Activation and Direct DNA Binding Hiromi Kataoka, Karl Riabowol (Background) The Inhibitor of Growtfi (ING) family of proteins are class li tumor suppressors that affect regulation of the cell cycle, oncogenesis and cell aging They are associated wid't acetylationqinked chromatin remodeling and their expression lends are dem'eased in cancer cells. Despite reports linking ING to p53 activation, the molecular basis of how ING activates p53 thnction and the biochemical regulatory dd'ferences among ING fami]y members has not been ducidated. Recent reports have shown that the Silent Intormation Regulator 2
A-692