acetaminophen metabolism in patients with different cyp2e1 genotypes div. of gastroent., dept. of...

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HEPATOLOGY Vol. 22, No. 4, Pt. 2, 1995 AASLD ABSTRACTS 503A 1585 ACETAMINOPHEN METABOLISM IN PATIENTS WITH DIFFERENT CYP2E1 1586 GENOTYPES. M Tsutsumi, Y Ueshima, S Takase, Y Matsuda, H Kawahara. Div. of Gastroent., Dept. of Int. Med., Kanazawa Med, Univ., Ishikawa, Japan. Recently, the presence of genetic polymorphisms of cytochrome P4502E1 (2E1) was confirmed. However, it is not known whether the metabolism of ethanol and other drugs is influenced by CYP2E1 genotype. Acetaminophen (AA) is metabolized mainly by 2E1, while it is also metabolized by other P450 enzymes, th order to clarify whether the CYP2E1 genotype affects the metabolism of ethanol, the elimination rate (ER) of hA, as a substrate for 2E1, in both alcoholic and non-alcoholic subjects with different CYP2E1 genotypes. Methods: CYP2E1 genotypes, type A (cl/cl), type B (cl/c2), and type C (c2/ c2) were determined by PCR amplification of 5'-upstream region of the CYP2E1 gene, followed by restriction enzyme digestion of the amplified DNA fragments. While fasting, lg of AA was given orally and blood hA levels were determined sequentially by the fluoropolarizatinn immunoassay. ER was calculated by the disappearance curve of blood AA levels using one-compartment model. Genatype n Haft-life (hr) Elimination rate' Results: Normal Subject PaSents with ALD $ A 4 1.734-0.20 0.3034- 0.034 B 4 1.S1±0A7 0.2994-0.111 C 2 1.53 0.8 A 2 t .82 0.33 B 9 1.45±0.66 0.5084-0,250 $: measurement withinoneweek a~er abstinence, #: IJhr/Kg B.W. In normal subjects, ER in type C was more than twice that of type A and type B. In type A, ER was not different between in patients with alcoholic liver disease (ALD) within one week after abstinence and in normal subjects. In type A with ALD, there was no difference in ER within one week and six weeks after abstinence. On the other hand, in type B, ER was greater in ALD patients within one week after abstinence than in ALD patients with type A and in normal subjects with type B. In ALD patients with type B, ER were greater within one week after abstinence than 4 to 6 weeks after abstinence, Cormluslons: These results suggest that alcohol metabolism in individuals with c2 gone may be greater than that with cl gane and that the induction of 2E1 by ethanol in type B may occur more markedly than that in type A. RISK FACTORS FOR GALLSTONE RECURRENCE J. Tudyka, J.G. Wechsler, W. Kratzer, Ch. Mater, R. Mason. G. Adler Krankenhaus der Berreherzige~ Briider, Department of Internal Medlelne, Romanstra~ 93, D- 80639 Munich * University Clinic of Ulm. Departmem of Internal Medicine I, Robert-Koch-Strasse 8, D- 89081 Ulm Background: The search for etiological factors in gallstone recummca is focussing increasingly on nucleation time, biliary protein and glycoprotein concentration and biliary lipids. Patients: 137 gallstone patients 009 with initially solitary, 48 with initially multiple stones) with complete stone clearence after extracorporeal shock wave lithotripsy (ESWL) were followed up for 24 - 84 (median 36,3) months. Prior to therapy and at stone recurrence gallbladder bile samples were taken for measuring billary phospholipids (PL), bile acids (BA), cholesterol (CL), cholesterol saturation index (CSI), total lipid concentration (TLC), nucleation time (NT), total protein- (TPC) and glycoprotein con~on (GPC). Results: Gallstone recurrence (20, 13, 9 and 4 cases afmr 12, 24, 36 and 48 months, respectively) was more frequent in patterers with intially multiple stones and short NT as compared to those with solitary stones and longer NT (3.1 ± 1.4 days versus 7.9 • 2.0 days, p < 0.01). Furthermore, NT was foand to be negatively correlated with the number of stones, TPC and GPC, both prior to therapy and alter stone recurrence [r = - 0.65 (p < 0.01), r = - 0.55 (I 3 < 0.01) and r = - 0.49 (p < 0.05) versus r = - 0.71 (p < 0.01), r = - 0.49 (p < 0.01) and r = - 0.59 (p < 0.05)]. Patients with reeurrem stones had significantly higher values for TPC and GPC as compared to those without stone recurrence (p < 0.01 and p < 0.05). In the case of recurrmt stones NT, TPC and (}PC were similar to their pretre~mant values, whereas for CSI, PL, BA and TLC no significant ~ences were found between patients with and without stone recurrence. Conclusio m The higher risk for gallstone recurr~ce in patiemts with initial multiple stones as compared to those with solitary stones is due to a short nucleation time and increased biliary conce, rtrations of TPC and GPC. 1587 LIVER TRANSPLANTATION AFTER TRANSJUGULAR INTRAHEPATIC PORTO-SYSTEMIC SHUNT (TIPSS): TECHNICAL COMPLICATIONS. A Tzakis, J Nery, M Webb, G Ciancio, W Deferia, A Gvamfi, R Reddy, J Miller, and E Sehiff. University of Miami School of Medicine, Miami, Florida. One hundred and forty-eight patients underwent orthotopie liver transplants at the University of Miami between June 94 and June 95. Nine patients had undergone a previous TIPSS procedure for control of varieeal bleeding. The liver was transplanted orthotopically using the piggy-back technique (preservation of the native IVC). Immunosuppression was based on FK 506 and Prednisone. In 4 patients the TIPSS presented no technical difficulties as it was located well within the liver and was not associated with thrombosis of either the portal vein or the hepatic vein. In fact it may have facilitated the transplant by alleviating the portal hypertension. In 3 patients the TIPSS extended beyond the hepatic veins; in 1 case it was only loosely attached to the IVC and the atrium, and was removed uneventfully, in 1 it was embedded in the wall of the IVC and R atrium necessitating extensive dissection of the 1VC to well within the pericardium, and in 1 the IVC had to be reconstructed with a donor vein patch. In 1 case the stent extended to the confluence of the superior mesenteric and splenic veins and was embedded in the vessel wall. Removal necessitated the use of a venous interposition graft (donor lilac vein) for reconstruction. Finally, in 3 patients, although the stent appeared to be in a perfect position, there was partial thrombosis of the extrahepatic portal vein (n=2) or complete thrombosis (n=l), necessitating a venous interposition graft in the latter case. All patients are alive and well. One patient required retransplantation for hepatic artery thrombosis due to intimal dissection of the donor hepatic artery. Conclusion: TIPSS can complicate orthotopic liver transplantation either because of imperfect placement or by precipitating vascular thrombosis. Judicious use of it is recommended if liver transplantation is anticipated. 1588 ONE STAGE OPERATIVE MANAGEMENT OF GALLSTONE ILEUS AK Upadhvay. J Maurer. J Turner Department of Surgery, New York Hospital Medical Center of Queens, Flushing, New York Gallstone ileus (GSI) is an uncommon condition that requires emergency surgery. The diagnosis is often delayed and most of the patients with GSI are elderly with concomitant medical diseases. These facts result in the high morbidity and mortality rate previously reported in patients undergoing surgery for GSI. This led several authors to suggest that enterolithotomy alone should be the emergency procedure of choice, followed by a second stage, elective operation for the biliary tract disease. We retrospectivelly reviewed and report on seven cases of GSI operated on at our institution. Four of these patients presented in a five months time period. Despite a heightened awareness of GSI, the diagnosis was delayed in more than half the patients. The youngest patient was 57 years and the oldest was 87. Four of the patients were female. All seven patients had a diagnosis of GSI documented at laparotomy. In six cases a "one-stage" strategy was used; the biliary tract surgery was carried out simultaneously with the emergency small bowel operation. Six patients had needle catheter jejunostomies placed for post operative nutrition. There was no death in this series. The post operative complications included pneumonia in two patients and a brief period of acute renal failure in one patient. All patients recovered completely and were discharged to home. Our experience shows that definitive surgery canbe safely done in most patients with GSI with a low morbidity rate. We suggest that enteral nutrition be used postoperatively.

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HEPATOLOGY Vol. 22, N o . 4, P t . 2, 1995 A A S L D A B S T R A C T S 503A

1585 ACETAMINOPHEN METABOLISM IN PATIENTS WITH DIFFERENT CYP2E1 1586 GENOTYPES. M Tsutsumi, Y Ueshima, S Takase, Y Matsuda, H Kawahara. Div. of Gastroent., Dept. of Int. Med., Kanazawa Med, Univ., Ishikawa, Japan.

Recently, the presence of genetic polymorphisms of cytochrome P4502E1 (2E1) was confirmed. However, it is not known whether the metabolism of ethanol and other drugs is influenced by CYP2E1 genotype. Acetaminophen (AA) is metabolized mainly by 2E1, while it is also metabolized by other P450 enzymes, th order to clarify whether the CYP2E1 genotype affects the metabolism of ethanol, the elimination rate (ER) of hA, as a substrate for 2E1, in both alcoholic and non-alcoholic subjects with different CYP2E1 genotypes. Methods: CYP2E1 genotypes, type A (c l /c l ) , type B (cl/c2), and type C (c2/ c2) were determined by PCR amplification of 5'-upstream region of the CYP2E1 gene, followed by restriction enzyme digestion of the amplified DNA fragments. While fasting, lg of AA was given orally and blood hA levels were determined sequentially by the fluoropolarizatinn immunoassay. ER was calculated by the disappearance curve of blood AA levels using one-compartment model.

Genatype n Haft-life (hr) Elimination rate' Results: Normal Subject

PaSents with ALD $

A 4 1.734-0.20 0.3034- 0.034

B 4 1.S1±0A7 0.2994-0.111 C 2 1.53 0.8 A 2 t .82 0.33 B 9 1.45±0.66 0.5084-0,250

$: measurement within one week a~er abstinence, #: IJhr/Kg B.W. In normal subjects, ER in type C was more than twice that of type A and type B. In type A, ER was not different between in patients with alcoholic liver disease (ALD) within one week after abstinence and in normal subjects. In type A with ALD, there was no difference in ER within one week and six weeks after abstinence. On the other hand, in type B, ER was greater in ALD patients within one week after abstinence than in ALD patients with type A and in normal subjects with type B. In ALD patients with type B, ER were greater within one week after abstinence than 4 to 6 weeks after abstinence, Cormluslons: These results suggest that alcohol metabolism in individuals with c2 gone may be greater than that with cl gane and that the induction of 2E1 by ethanol in type B may occur more markedly than that in type A.

RISK FACTORS FOR GALLSTONE RECURRENCE J. Tudyka, J.G. Wechsler, W. Kratzer, Ch. Mater, R. Mason. G. Adler Krankenhaus der Berreherzige~ Briider, Department of Internal Medlelne, Romanstra~ 93, D- 80639 Munich * University Clinic of Ulm. Departmem of Internal Medicine I, Robert-Koch-Strasse 8, D- 89081 Ulm Background: The search for etiological factors in gallstone recummca is focussing increasingly on nucleation time, biliary protein and glycoprotein concentration and biliary lipids. Patients: 137 gallstone patients 0 0 9 with initially solitary, 48 with initially multiple stones) with complete stone clearence after extracorporeal shock wave lithotripsy (ESWL) were followed up for 24 - 84 (median 36,3) months. Prior to therapy and at stone recurrence gallbladder bile samples were taken for measuring billary phospholipids (PL), bile acids (BA), cholesterol (CL), cholesterol saturation index (CSI), total lipid concentration (TLC), nucleation time (NT), total protein- (TPC) and glycoprotein c o n ~ o n (GPC). Results: Gallstone recurrence (20, 13, 9 and 4 cases afmr 12, 24, 36 and 48 months, respectively) was more frequent in patterers with intially multiple stones and short NT as compared to those with solitary stones and longer NT (3.1 ± 1.4 days versus 7.9 • 2.0 days, p < 0.01). Furthermore, NT was foand to be negatively correlated with the number of stones, TPC and GPC, both prior to therapy and alter stone recurrence [r = - 0.65 ( p < 0 . 0 1 ) , r = - 0.55 (I 3 < 0.01) and r = - 0.49 (p < 0.05) versus r = - 0.71 (p < 0.01), r = - 0.49 (p < 0.01) and r = - 0.59 (p < 0.05)]. Patients with reeurrem stones had significantly higher values for TPC and GPC as compared to those without stone recurrence (p < 0.01 and p < 0.05). In the case of recurrmt stones NT, TPC and (}PC were similar to their pretre~mant values, whereas for CSI, PL, BA and TLC no significant ~ e n c e s were found between patients with and without stone recurrence. Conclusio m The higher risk for gallstone recurr~ce in patiemts with initial multiple stones as compared to those with solitary stones is due to a short nucleation time and increased biliary conce, rtrations of TPC and GPC.

1587 L I V E R T R A N S P L A N T A T I O N A F T E R T R A N S J U G U L A R INTRAHEPATIC PORTO-SYSTEMIC SHUNT (TIPSS): TECHNICAL COMPLICATIONS. A Tzakis, J Nery, M Webb, G Ciancio, W Deferia, A Gvamfi, R Reddy, J Miller, and E Sehiff. University of Miami School of Medicine, Miami, Florida.

One hundred and forty-eight patients underwent orthotopie liver transplants at the University of Miami between June 94 and June 95. Nine patients had undergone a previous TIPSS procedure for control of varieeal bleeding. The liver was transplanted orthotopically using the p i g g y - b a c k techn ique (p r e se rva t i on of the na t ive IVC). Immunosuppression was based on FK 506 and Prednisone.

In 4 patients the TIPSS presented no technical difficulties as it was located well within the liver and was not associated with thrombosis of either the portal vein or the hepatic vein. In fact it may have facilitated the transplant by alleviating the portal hypertension. In 3 patients the TIPSS extended beyond the hepatic veins; in 1 case it was only loosely attached to the IVC and the atrium, and was removed uneventfully, in 1 it was embedded in the wall of the IVC and R atr ium necessitating extensive dissection of the 1VC to well within the pericardium, and in 1 the IVC had to be reconstructed with a donor vein patch.

In 1 case the stent extended to the confluence of the superior mesenteric and splenic veins and was embedded in the vessel wall. Removal necessitated the use of a venous interposition graf t (donor lilac vein) for reconstruction. Finally, in 3 patients, although the stent appeared to be in a perfect position, there was partial thrombosis of the extrahepatic portal vein (n=2) or complete thrombosis (n=l), necessitating a venous interposition graft in the latter case.

All patients are alive and well. One patient required retransplantation for hepatic artery thrombosis due to intimal dissection of the donor hepatic artery. Conclusion: TIPSS can complicate orthotopic liver transplantation either because of imperfect placement or by precipitating vascular thrombosis. Judicious use of it is recommended if liver transplantation is anticipated.

1588 O N E S T A G E O P E R A T I V E M A N A G E M E N T O F G A L L S T O N E ILEUS AK Upadhvay. J Maurer. J Turner Department o f Surgery, New York Hospital Medical Center o f Queens, Flushing, New York

Gallstone ileus (GSI) is an uncommon condition that requires emergency surgery. The diagnosis is often delayed and most of the patients with GSI are elderly with concomitant medical diseases. These facts result in the high morbidity and mortality rate previously reported in patients undergoing surgery for GSI. This led several authors to suggest that enterolithotomy alone should be the emergency procedure o f choice, followed by a second stage, elective operation for the biliary tract disease.

We retrospectivelly reviewed and report on seven cases o f GSI operated on at our institution. Four o f these patients presented in a five months time period. Despite a heightened awareness o f GSI, the diagnosis was delayed in more than half the patients. The youngest patient was 57 years and the oldest was 87. Four o f the patients were female. All seven patients had a diagnosis o f GSI documented at laparotomy. In six cases a "one-stage" strategy was used; the biliary tract surgery was carried out simultaneously with the emergency small bowel operation. Six patients had needle catheter jejunostomies placed for post operative nutrition. There was no death in this series. The post operative complications included pneumonia in two patients and a br ief period o f acute renal failure in one patient. All patients recovered completely and were discharged to home.

Our experience shows that definitive surgery canbe safely done in most patients with GSI with a low morbidity rate. We suggest that enteral nutrition be used postoperatively.