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The effect of preoperative biliary drainage on the abnormal lipoprotein spectrum in obstructive jaundice: a protective effect of drainage?
Abstracts /Netherlands
A9
Journal of Medicine 48 (1996) Al -A42
from 2 or more EPP patients in 9 families. Genomic DNA fragments were isolated by PCR using different primers chosen in the flanking intron regions. Reported mutations (from England, France, Japan and the USA) were then looked for, using single strand conformational polymorphism, and mutations confirmed by nucleotide sequencing. Results: A mutation in intron-1, located -23 bp near the acceptor site bat not localized in the consensus donor splice junction sequence of an intron, which has been reported to give rise to exonl-2skipping, was found in EPP patients from 5 of the 9 Dutch families. However, in EPP patients from 2 families, both FC alleles were found to have this mutation, and this ISVl-:!3 mutation was also found to be present in one allele of some normal controls. In two families we found a G to A mutation at the first position of the splice donor site of intron-7 (ISV7+ 11, leading to skipping of exon-7. In addition in these EPP patients there was a silent G to C mutation at nucleotide 798 @DNA bnr), which would not result in conversion of amino acid. Conclusion: Our results show that skipping of exon-2, due to the ISVl-23 (c + t) mutation must still give rise to reasonable amounts of normal FC mRNA and active FC. It is of interest that the only mutations found so far are identical to those reported by Nakhashi et al. (1992,1993) from Japan, including the combination of ISV7 + 1 (g + a) mutation and the silent mutation at position 798 (G + C). From the 17th to 19th century the Dutch were the only Europeans allowed to trade with Japan. The timing of hnsplantation for cholestatic liver disease. S. de Rave for the Liver Transplantation Group, Departments of Internal Medicine II and Surgery, University Hospital Dijkzigt, Rotterdam, Netherlands.
Currently patients with primary biliary cirrhosis (PBC) are considered caudidates for liver transplantation when they score at leasl. 8.19 points in the Mayo model [0.871x ln(bilirubin in mg/dl) - 2.53 x ln(albumin in g/dl) + 0.039 x (age in years) + 2.38 x lnfprothrombin time in s) + 0.859 x (oedema score)], corresponding to an estimated median survival of 1 year or less. A similar model for patients with primary sclerosing cholangitis (PSC) [OS35 x ln(bilirubin in mg/dl) + 0.486 X (histological stage, modified) + 0.041 x (age in years) + 0.705 >((splenomegaly score)] gives an estimated median survival o’f 1 year at a score of 5.95. We have performed orthotopic liver transplantations in 11 patients with PBC with a l-year survival of 81% (ELTR 79%) and in 11 patients with PSC with a 1-,yearsurvival of 76% (ELTR 80%). There have been no deaths at more than 1 year after transplantation. The actual survival in PBC patients can be compared with the Mayo model ‘estimates. In PBC patients with an estimated median survival of up to 2 years a gain in survival becomes apparent at 1 year after transplantation. For patients with an estimated median survival of 5 years this point is reached at just over 2 years. In patients with PSC the situation is almost identical. In our series 6 out of 17 PBC patients and 2 out of 13 PSC patieuts have died either during work-up or on the waiting list for liver transplantation. Five of the 8 patients who
died without transplantation had an estimated median survival under 1 year. Conclusion: For patients with an estimated survival of less than 1 year liver transplantation should have been considered earlier. This would have reduced mortality in the preoperative phase and probably also have improved the results of transplantation. For patients with an estimated median survival between 1 and 2 years liver transplantation is the treatment of choice. In patients with an estimated median survival between 2 and 5 years and a poor quality of life, liver transplantation should be considered a realistic option. The current policy is too restrictive.
Late effects of liier transplantation on bone mass. J.D. van Bergeijk *, S. de Rave ‘, R.A. de Man ‘, J.N.M. IJzermans ‘, H.W. Tilanus ‘, H.J. Metselaar ‘. Departments of zInternal Medicine II (Hepatology Section) and 2 Surgery, University Hospital, Rotterdam, Netherlands.
Osteopenic bone disease is a major problem after liver transplantation (LTx), with a cumulative occurrence of spontaneous vertebral fracture up to 40% in patients with cholestatic liver disease and up to 15% in other patients. Data on the long-term effects of LT on bone mass are scarce. For this reason we retrospectively analyzed the bone mineral density (BMD) of the lumbar spine (I&L41 in patients before and 6-60 months after LTx. BMD was measured by dual-energy X-ray densitometry. Between 1989 and 1995 68 patients underwent LTx; 55 (81%) patients had a follow-up of > 6 months and were selected for this study. Spontaneous vertebral fractures occurred in 4/16 (25%) patients with cholestatic liver disease and in 2/39 (5%) patients with non-cholestatic liver disease. Fractures were only observed in the first year after LTx. Only one of these patients with a vertebral fracture had a BMD below the osteoporosis threshold (Z-score < - 2). Of the patients without vertebral fractures 3 had Z-scores < - 2. BMD data are given in the table (g/cm’, mean f SD). Follow-up
All patients
Before Ltx 6 months
0.988& 0.240 0.851+ 0.190 1.146_+0.193 0.957kO.250
0.725kO.105
1.085*0.209
1 yr
1.009~0.205 1.038+0.189 1.064+0.152 1.001* 0.089
0.827+0.144 0.910+0.141 0.991+0.093 0.975 * 0.104
1.105&0.165 1.153iO.151 1.152,0.171 1.046* 0.037
1.0391kO.078
1.019&0.086
1.065 kO.073
2yr 3 yr 4yr 5v
PBC/PSC
Non-cholestatic
Conclusion: Bone mass tends to decrease in the first 6 months after LTx for cholestatic and non-cholestatic liver disease. Thereafter there is an increase in BMD, which levels off after 3 years. Spontaneous vertebral fractures occur relatively early after LTx, and are not predicted by BMD values below the osteoporosis threshold.
The effect of preoperative biliary drainage on the abnormal lipoprotein spectrum in obstructive jaundice: a protective effect of drainage? A.N. Kimmings *,*, S.J.H. van Deventer 2,
AI0
Abstracts/Netherlands
Journal of Medicine 48 f 19%) Al -A42
H. Obertop ‘, E.A.J. Rauws ‘, D.J. Gouma ‘. t Department of Surgery, ’ Laboratory for InfZammation Research and .’Department of Gastroenterology, Academic Medical Centre, Amsterdam, Netherlands. Abnormalities of lipid composition are frequently observed in patients with cholestatic disease. Usually an increase in the low-density lipoprotein (LDL) fraction is found, with accumulation of abnormal LDL. In addition, the major subfraction of high-density lipoprotein (HDL) is considerably diminished and abnormal in particle size, morphology and composition. Postoperative complications, especially sepsis after major surgery in patients with obstructive jaundice (OJ). are thought to be due to an increased susceptibility to endotoxin. HDL has been shown to bind endotoxin in serum in vitro, and is thought to play a role in normal host protection against endotoxin (scavenger receptor). Administration of reconstituted HDL protected animals in experimental endotoxaemia. Internal biliary drainage in animals showed a clear reduction of the inflammatory response, with significant reductions in endotoxaemia and therefore in cytokine induction and depression of immunity. The aim of this study was to determine the effect of preoperative bihary drainage on the (relative) lipoprotein levels in patients with OJ, as these levels could play an important role in the endotoxin-neutralising capacity of the blood and therefore in susceptibility to endotoxin. Patients (n = 15) were included with obstructive jaundice due to a “resectable” distal obstruction for which endoprosthesis placement was possible. Blood was taken at t = 0 before stent placement and t = 3 weeks, after 3 weeks drainage. Drainage was adequate as measured by bilirubin levels at timepoints 0 and 3 weeks of respectively 244 (SD 112) and 50 (SD 60) (p = 0.002). Relative lipoprotein levels were determined using electrophoresis, and showed a significant change in relative levels towards that of normal control serum: LDL 91.3% (SD 6.8) to 77.3% (SD 14.5) (p = 0.003), VLDL 2.1% (SD 2.1) to 5.2% (SD 5.9) (p = 0.13), and HDL 6.5% (SD 5.3) to 17.6% (SD 11) (p = 0.003). Conclusions: Preoperative internal biliary drainage by endoprosthesis affects the abnormal relative lipoprotein spectrum in serum from patients with OJ leading to a spectrum more comparable to normal serum. This effect of drainage could influence the endotoxin-neutralising capacity of plasma in these patients and therefore their susceptibility to endotoxin. P.J. Wahab, T.J. Wiersma, G.B. ten Haken, G. den Hartog, C.J.J. Mulder.
Percutaneous stenting in bile duct obstruction.
Department of Hepatogastroenterology and Radiology, Rimstate Hospital, Arnhem, Netherlands.
Several operative and non-operative options are available for patients with biliary obstruction. Percutaneous transhepatic cholangiography with stenting can be used to treat biliary obstruction when endoscopic attempts have failed. We report our experiences with percutaneous stenting after failure of endoscopic treatment. The biliary drainage procedure starts by introducing a sheath (12.0 french, 4 mm, radiopaque teflon) over an introducer-needle into a dilated intrahepatic bile
duct, guided by ultrasound. After decompression a guidewire is manipulated through the obstruction into the duodenum. Using the guidewire, a double mushroom endoprosthesis is positioned through the sheath (12.0 french, 6.0-12.0 cm, percutaneous double mushroom endoprosthesis set, William Cook, Bjaeverskov, Denmark). Antibiotic prophylaxis is given for 24 h. Between March 1992 and April 1995 percutaneous stenting for bile duct obstruction was attempted in 35 patients after failure of drainage by the endoscopic approach. Thirty patients had malignancy, 4 had intraductal stones and I had an obstructing duodenal diverticulum. The procedure was successful in 29 patients (83%), 1 patient needing endoscopic repositioning of the stent because of dislocation. another needing a 2nd stent for adequate drainage and in a third patient subcapsular fluid was recognised by ultrasound after the procedure. One patient stented for a Klatskin tumour died a few days after the procedure due to septicaemia after laparotomy for bleeding related to the stenting. In 5 patients stenting was impossible because of problems in dilatation of bile ducts (2), obstructing tumour (I), obstructing stones (1) and agitation (1). Endoscopic removal of stones and the stent was performed a few days after stenting 2 patients for biliary stones. During follow-up 3 patients needed repeated stenting due to obstruction by tumour growth after resp. 3 and 5, 7 and 9 months. Two patients received surgical choledochojejunostomy for obstructing tumour growth after resp. 3 and 10 months. Conclusion: Percutaneous stenting of biliary obstruction by a double mushroom endoprosthesis is a reasonable alternative when endoscopic treatment fails. Hepatitis B transmission among heart transplant recipients: an underestimated risk? R.A. de Man ‘, S.W. Schalm ‘,
A.H.H.M. Balk *, MC. Vos 3, Ph.H. Rothbarth 4, J.W. Mouton 3, H.G.M. Niesters 4. A.D.M.E. Osterhaus 4, H.A. Verbrugh ‘. Departments of ’ Internal Medicine II, ’ Cardiology, 3 Infectious Disease Control and 4 Virology, Erasmus University Hospital, Rotterdam, Netherlands.
Right-sided endomyocardial biopsy via the jugular vein is the gold standard for monitoring graft rejection in heart transplant recipients. As the risk of severe graft rejection is inversely related to the time post-transplantation, in the first year post-transplantation approximately 15 biopsy procedures per patient are performed. In our centre right-sided endomyocardial biopsy sessions are run thrice weekly and include up to 10 patients each. In 1994 abnormal liver tests led to the detection of HBsAg in 2 patients; both patients were also HBeAg-positive. Two further cases in 1995 prompted screening of all 251 heart transplant recipients: 16 other highly viraemic (HBeAg and HBV-DNA positive) but clinically asymptomatic infections were uncovered. Testing of stored sera indicated that heart transplant recipients were infected in 1993-1994, unrelated to the surgery itself. 19/20 heart transplant recipients had subtype ayw3, identical to another heart transplant recipient known to have had chronic HBV since 1989. All health care personnel invoked in heart transplant recipients were HBsAg-negative. In a case control
A9
Journal of Medicine 48 (1996) Al -A42
from 2 or more EPP patients in 9 families. Genomic DNA fragments were isolated by PCR using different primers chosen in the flanking intron regions. Reported mutations (from England, France, Japan and the USA) were then looked for, using single strand conformational polymorphism, and mutations confirmed by nucleotide sequencing. Results: A mutation in intron-1, located -23 bp near the acceptor site bat not localized in the consensus donor splice junction sequence of an intron, which has been reported to give rise to exonl-2skipping, was found in EPP patients from 5 of the 9 Dutch families. However, in EPP patients from 2 families, both FC alleles were found to have this mutation, and this ISVl-:!3 mutation was also found to be present in one allele of some normal controls. In two families we found a G to A mutation at the first position of the splice donor site of intron-7 (ISV7+ 11, leading to skipping of exon-7. In addition in these EPP patients there was a silent G to C mutation at nucleotide 798 @DNA bnr), which would not result in conversion of amino acid. Conclusion: Our results show that skipping of exon-2, due to the ISVl-23 (c + t) mutation must still give rise to reasonable amounts of normal FC mRNA and active FC. It is of interest that the only mutations found so far are identical to those reported by Nakhashi et al. (1992,1993) from Japan, including the combination of ISV7 + 1 (g + a) mutation and the silent mutation at position 798 (G + C). From the 17th to 19th century the Dutch were the only Europeans allowed to trade with Japan. The timing of hnsplantation for cholestatic liver disease. S. de Rave for the Liver Transplantation Group, Departments of Internal Medicine II and Surgery, University Hospital Dijkzigt, Rotterdam, Netherlands.
Currently patients with primary biliary cirrhosis (PBC) are considered caudidates for liver transplantation when they score at leasl. 8.19 points in the Mayo model [0.871x ln(bilirubin in mg/dl) - 2.53 x ln(albumin in g/dl) + 0.039 x (age in years) + 2.38 x lnfprothrombin time in s) + 0.859 x (oedema score)], corresponding to an estimated median survival of 1 year or less. A similar model for patients with primary sclerosing cholangitis (PSC) [OS35 x ln(bilirubin in mg/dl) + 0.486 X (histological stage, modified) + 0.041 x (age in years) + 0.705 >((splenomegaly score)] gives an estimated median survival o’f 1 year at a score of 5.95. We have performed orthotopic liver transplantations in 11 patients with PBC with a l-year survival of 81% (ELTR 79%) and in 11 patients with PSC with a 1-,yearsurvival of 76% (ELTR 80%). There have been no deaths at more than 1 year after transplantation. The actual survival in PBC patients can be compared with the Mayo model ‘estimates. In PBC patients with an estimated median survival of up to 2 years a gain in survival becomes apparent at 1 year after transplantation. For patients with an estimated median survival of 5 years this point is reached at just over 2 years. In patients with PSC the situation is almost identical. In our series 6 out of 17 PBC patients and 2 out of 13 PSC patieuts have died either during work-up or on the waiting list for liver transplantation. Five of the 8 patients who
died without transplantation had an estimated median survival under 1 year. Conclusion: For patients with an estimated survival of less than 1 year liver transplantation should have been considered earlier. This would have reduced mortality in the preoperative phase and probably also have improved the results of transplantation. For patients with an estimated median survival between 1 and 2 years liver transplantation is the treatment of choice. In patients with an estimated median survival between 2 and 5 years and a poor quality of life, liver transplantation should be considered a realistic option. The current policy is too restrictive.
Late effects of liier transplantation on bone mass. J.D. van Bergeijk *, S. de Rave ‘, R.A. de Man ‘, J.N.M. IJzermans ‘, H.W. Tilanus ‘, H.J. Metselaar ‘. Departments of zInternal Medicine II (Hepatology Section) and 2 Surgery, University Hospital, Rotterdam, Netherlands.
Osteopenic bone disease is a major problem after liver transplantation (LTx), with a cumulative occurrence of spontaneous vertebral fracture up to 40% in patients with cholestatic liver disease and up to 15% in other patients. Data on the long-term effects of LT on bone mass are scarce. For this reason we retrospectively analyzed the bone mineral density (BMD) of the lumbar spine (I&L41 in patients before and 6-60 months after LTx. BMD was measured by dual-energy X-ray densitometry. Between 1989 and 1995 68 patients underwent LTx; 55 (81%) patients had a follow-up of > 6 months and were selected for this study. Spontaneous vertebral fractures occurred in 4/16 (25%) patients with cholestatic liver disease and in 2/39 (5%) patients with non-cholestatic liver disease. Fractures were only observed in the first year after LTx. Only one of these patients with a vertebral fracture had a BMD below the osteoporosis threshold (Z-score < - 2). Of the patients without vertebral fractures 3 had Z-scores < - 2. BMD data are given in the table (g/cm’, mean f SD). Follow-up
All patients
Before Ltx 6 months
0.988& 0.240 0.851+ 0.190 1.146_+0.193 0.957kO.250
0.725kO.105
1.085*0.209
1 yr
1.009~0.205 1.038+0.189 1.064+0.152 1.001* 0.089
0.827+0.144 0.910+0.141 0.991+0.093 0.975 * 0.104
1.105&0.165 1.153iO.151 1.152,0.171 1.046* 0.037
1.0391kO.078
1.019&0.086
1.065 kO.073
2yr 3 yr 4yr 5v
PBC/PSC
Non-cholestatic
Conclusion: Bone mass tends to decrease in the first 6 months after LTx for cholestatic and non-cholestatic liver disease. Thereafter there is an increase in BMD, which levels off after 3 years. Spontaneous vertebral fractures occur relatively early after LTx, and are not predicted by BMD values below the osteoporosis threshold.
The effect of preoperative biliary drainage on the abnormal lipoprotein spectrum in obstructive jaundice: a protective effect of drainage? A.N. Kimmings *,*, S.J.H. van Deventer 2,
AI0
Abstracts/Netherlands
Journal of Medicine 48 f 19%) Al -A42
H. Obertop ‘, E.A.J. Rauws ‘, D.J. Gouma ‘. t Department of Surgery, ’ Laboratory for InfZammation Research and .’Department of Gastroenterology, Academic Medical Centre, Amsterdam, Netherlands. Abnormalities of lipid composition are frequently observed in patients with cholestatic disease. Usually an increase in the low-density lipoprotein (LDL) fraction is found, with accumulation of abnormal LDL. In addition, the major subfraction of high-density lipoprotein (HDL) is considerably diminished and abnormal in particle size, morphology and composition. Postoperative complications, especially sepsis after major surgery in patients with obstructive jaundice (OJ). are thought to be due to an increased susceptibility to endotoxin. HDL has been shown to bind endotoxin in serum in vitro, and is thought to play a role in normal host protection against endotoxin (scavenger receptor). Administration of reconstituted HDL protected animals in experimental endotoxaemia. Internal biliary drainage in animals showed a clear reduction of the inflammatory response, with significant reductions in endotoxaemia and therefore in cytokine induction and depression of immunity. The aim of this study was to determine the effect of preoperative bihary drainage on the (relative) lipoprotein levels in patients with OJ, as these levels could play an important role in the endotoxin-neutralising capacity of the blood and therefore in susceptibility to endotoxin. Patients (n = 15) were included with obstructive jaundice due to a “resectable” distal obstruction for which endoprosthesis placement was possible. Blood was taken at t = 0 before stent placement and t = 3 weeks, after 3 weeks drainage. Drainage was adequate as measured by bilirubin levels at timepoints 0 and 3 weeks of respectively 244 (SD 112) and 50 (SD 60) (p = 0.002). Relative lipoprotein levels were determined using electrophoresis, and showed a significant change in relative levels towards that of normal control serum: LDL 91.3% (SD 6.8) to 77.3% (SD 14.5) (p = 0.003), VLDL 2.1% (SD 2.1) to 5.2% (SD 5.9) (p = 0.13), and HDL 6.5% (SD 5.3) to 17.6% (SD 11) (p = 0.003). Conclusions: Preoperative internal biliary drainage by endoprosthesis affects the abnormal relative lipoprotein spectrum in serum from patients with OJ leading to a spectrum more comparable to normal serum. This effect of drainage could influence the endotoxin-neutralising capacity of plasma in these patients and therefore their susceptibility to endotoxin. P.J. Wahab, T.J. Wiersma, G.B. ten Haken, G. den Hartog, C.J.J. Mulder.
Percutaneous stenting in bile duct obstruction.
Department of Hepatogastroenterology and Radiology, Rimstate Hospital, Arnhem, Netherlands.
Several operative and non-operative options are available for patients with biliary obstruction. Percutaneous transhepatic cholangiography with stenting can be used to treat biliary obstruction when endoscopic attempts have failed. We report our experiences with percutaneous stenting after failure of endoscopic treatment. The biliary drainage procedure starts by introducing a sheath (12.0 french, 4 mm, radiopaque teflon) over an introducer-needle into a dilated intrahepatic bile
duct, guided by ultrasound. After decompression a guidewire is manipulated through the obstruction into the duodenum. Using the guidewire, a double mushroom endoprosthesis is positioned through the sheath (12.0 french, 6.0-12.0 cm, percutaneous double mushroom endoprosthesis set, William Cook, Bjaeverskov, Denmark). Antibiotic prophylaxis is given for 24 h. Between March 1992 and April 1995 percutaneous stenting for bile duct obstruction was attempted in 35 patients after failure of drainage by the endoscopic approach. Thirty patients had malignancy, 4 had intraductal stones and I had an obstructing duodenal diverticulum. The procedure was successful in 29 patients (83%), 1 patient needing endoscopic repositioning of the stent because of dislocation. another needing a 2nd stent for adequate drainage and in a third patient subcapsular fluid was recognised by ultrasound after the procedure. One patient stented for a Klatskin tumour died a few days after the procedure due to septicaemia after laparotomy for bleeding related to the stenting. In 5 patients stenting was impossible because of problems in dilatation of bile ducts (2), obstructing tumour (I), obstructing stones (1) and agitation (1). Endoscopic removal of stones and the stent was performed a few days after stenting 2 patients for biliary stones. During follow-up 3 patients needed repeated stenting due to obstruction by tumour growth after resp. 3 and 5, 7 and 9 months. Two patients received surgical choledochojejunostomy for obstructing tumour growth after resp. 3 and 10 months. Conclusion: Percutaneous stenting of biliary obstruction by a double mushroom endoprosthesis is a reasonable alternative when endoscopic treatment fails. Hepatitis B transmission among heart transplant recipients: an underestimated risk? R.A. de Man ‘, S.W. Schalm ‘,
A.H.H.M. Balk *, MC. Vos 3, Ph.H. Rothbarth 4, J.W. Mouton 3, H.G.M. Niesters 4. A.D.M.E. Osterhaus 4, H.A. Verbrugh ‘. Departments of ’ Internal Medicine II, ’ Cardiology, 3 Infectious Disease Control and 4 Virology, Erasmus University Hospital, Rotterdam, Netherlands.
Right-sided endomyocardial biopsy via the jugular vein is the gold standard for monitoring graft rejection in heart transplant recipients. As the risk of severe graft rejection is inversely related to the time post-transplantation, in the first year post-transplantation approximately 15 biopsy procedures per patient are performed. In our centre right-sided endomyocardial biopsy sessions are run thrice weekly and include up to 10 patients each. In 1994 abnormal liver tests led to the detection of HBsAg in 2 patients; both patients were also HBeAg-positive. Two further cases in 1995 prompted screening of all 251 heart transplant recipients: 16 other highly viraemic (HBeAg and HBV-DNA positive) but clinically asymptomatic infections were uncovered. Testing of stored sera indicated that heart transplant recipients were infected in 1993-1994, unrelated to the surgery itself. 19/20 heart transplant recipients had subtype ayw3, identical to another heart transplant recipient known to have had chronic HBV since 1989. All health care personnel invoked in heart transplant recipients were HBsAg-negative. In a case control