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Predictors of shunt stenosis following transjugular intrahepatic portosystemic shunt (TIPS) placement
Al110
AASLD ABSTRACTS
GALLBLADDER LITHIASIS IN PATIENTS WITH A L C O H O L I C C I R R H O S I S O F THE L I V E R : P R O S P E C T I V E STUDY O F A E T I O L O G I C AND P A T H O G E N I C F A C T O R S IN 56 CASES. Liebaert-Bories MP, Mendler M, Cessot F, Sauterean D, Venot J, Parneix JL, Le Sidaner A, Cazelles-Boudier MC, Pillegand B. Department of Gastroenterology and Liver Diseases, Dupuytren University Hospital, 2 avenue Martin-Luther-King, F-870a2 Limoges Cedex, FRANCE. Patients with alcoholic cirrhosis have a significantly higher frequency of gallbladder lithiasis (20 to 30%) as compared to the general population (10 to 15%). The aim of this study was to detect possible epidemiologic, biological or clinical factors leading to gallbladder lithiasis in alcoholic cirrhosis. Patients and methods: Fifty-five patients with alcoholic cirrhosis of the liver were included in the study from November 1993 to March 1994. Thirty patients had uhrasonographic signs of gallbladder lithiasis (Group A) and in 26 (Group B) these signs were absent. Age, sex, body surface, alcohol intake, duration of cirrhosis, signs of portal hypertension ( u l t r a s o n o g r a p h y , upper digestive endoscopy), signs of hepatic insufficiency, Child-Pugh score, hepatic fibrosis score (PIIINP, APO-A1, PGA score, a 2 - m a c r o g l o b u l i n ) , signs of hemolysis (reticulosis >150000/mm 3, haptoglobin <1g/l, total serum bilirubin >20 mmoles/1 with non-conjugated bilirubin (NCB) > conjugated bilirubin), and signs of hyperspienism (platelet count <150000/mm3, neutrophil count <1800/1, splenomegaly) were studied in each patient. The X2 and Student tests were used for smustical analysis of data. Results : 1) In this study ~he frequency of gallbladder lithiasis was higher (53.6%) than that found in previously published studies. 2) Of the parameters studied, only hemolysis differed significantly between Group A (n=24, 80%) and Group B (n=6, 9_3%) (p < 0.01). 3) Average serum NCB (Group A, n=27.3 ±20.19 mmoles/l; Group B, n=21 ±14.02 mmoles/l) and presence of hypersplenism (Group A, n=18, 60%; Group B, n=10, 38%) did not however differ significantly. Conclusion: These results indicate that hemolysis is an important factor implicated in the pathophysiology of gallbladder lithiasis in alcoholic cirrhosis. Hypersplenism does not seem to be the sole cause of increased hemolysis.
• SERUM LOW DENSITY LIPOPROTEIN OF ALCOHOLIC PATIENTS IS CHEMICALLY MODIFIED I N V I V O BY ACETALDEHYDE AND LIPID PEROXIDATIVE PRODUCTS A N D IT INDUCES APOLIPOPROTEIN E S Y N T H E S I S BY MACROPHAGES. R.C. Lin, J. Dai, L. Lumeng, M-Y. Zhang. Indiana Univ Sch M e d / V A Med Center, Indianapolis, IN Liver and blood proteins (e.~. a 37KD protein recently identified as A 4 - 3 - k e t o s t e r o i d 5~-reduetase, a key enzyme in bile acid synthesis, and hemoglobin) are known to form adducts w i t h acetaldehyde (ach) in vivo during chronic alcohol exposure. Liver proteins are also modified by lipid p e r o x i d a t i v e products e.~. 4-hydroxynonenal (4-HNE) in animals fed alcohol chronically. Since the incidence of atherosclerosis decreases with moderate alcohol intake while death rate due to heart disease increases with heavy drinking, we report herein the effects of heavy alcohol drinking on serum LDL. A g a r o s e gel electrophoresis showed that LDL samples from alcoholic patients without serious liver disease were more negatively charged (relative mobility: 0 . 4 6 3 ± 0 . 0 6 6 , n=75) than LDL from non-drinking control subjects (0.3965:0.046, nffi92) (p<0.O01). Antibodies raised by keyhole limpet hemocyanin (KLH) modified in v i t r o by 4-HNE or by ach as immunogen reacted m o r e strongly with patients' LDL than with control LDL (p<0.01 for anti-KLH-4-HNE and p<0.05 for anti-KLH-ach), indicating oxidatively modified epitopes and ach-adducts are present in LDL of alcoholics. LDL of alcoholics also has decreased vitamin E ( 6 . 9 9 ~ 2 . 0 9 ~g/mg vs. 8 . 6 3 ± 2 . 0 4 pg/mg LDL, p<0.05). Electromobility of LDL from alcoholics normalized in 2 wk of abstinence, but vitamin E did not. Macrophages (M~) possess scavenger receptors that are not d o w n - r e g u l a t e d by cellular cholesterol contents. When incubated w i t h mouse peritoneal M~, patients' LDL induced apolipoprotein E secretion by 3-fold over control LDL with a concomitant increase in M ~ cholesterol. Statistical analyses on LDL chemical compositions of alcoholics showed no dependency on age, gender or AST levels. CONCLUSIONS: LDL of alcoholics has lower vitamin E contents, is chemically modified by ach and 4-HNE in v i v o and exhibits altered biological function. These changes in heavy alcohol drinkers may render LDL m o r e atherogenic and thereby may overcome the protective effects of moderate alcohol intake.
GASTROENTEROLOGY, Vol. 108, No. 4
• EFFECTS OF CHRONIC ADMINISTRATION OF OCTREOTIDE ON HEMODYNAMICS, PLASMA GLUCAGON AND NOREPINEPFIRINE LEVELS AND VASCULAR cAMP CONTENT IN PORTAL VEIN STENOSED RATS. H.C. Lin, C.M. Yang, Y.T. Tsai, S.M. Lee, P.C. Yu, F.C. Cheng, J.S. Kuo, S.D. Lee. Div. of Gastroenterology, Dept. of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C. Hemodynamic studies in cirrhotic patients showed that acute administration of octreotide (Oc) decreased hepatic and azygos blood flows with a minimal effect on portal pressure. However, the mechanism of action and the effect of chronic, long-term administration of Oc in portal hypertension have not yet been established. Recently, in rats with portal vein stenosis (PVS), a 4-day course of Oc treatment ameliorated vasodilatation and Na + retention. The present study was undertaken to evaluate the chronic effects of d e in PVS rats and its possible mechanism of action in portal hypertension. Experiment 1: Both PVS (n=7, respectively) and sham-operated (SO) (n=6, respectively) rats were divided into 2 groups and received a 100 gg/kg of Oc or a placebo s.c. every 12 hr for 14 consecutive days. Cardiac output and regional bemodynamics were measured using the radioactive microsphere technique. Experiment 2: Both PVS (n=7, respectively) and SO (n=7, respectively) were divided into 2 groups and received either Oc or placebo as described above for 14 consecutive days. Plasma glucagon (Ghi) and norepinephrine (NE) were determined from blood samples obtained via decapitation and using a RIA & HPLC method, respectively, cAMP was determined using RIA from vascular smooth muscle Cells obtained from a segment of tail artery. Basically, PVS rats showed the presence of portal hypertension and hyperdynamic circulation associated with a hyperglucagonemia when compared to SO rats. Accordingly, an increased vascular cAMP content was found in PVS rats. NE was no different between PVS & SO rats. In PVS rats receiving chronic Oc, portal pressure (-23%), portal inflow (-18%), renal blood flow (-31%), cardiac index (-25%) & Glu (-26%) were significantly decreased while mean arterial pressure (+10%), systemic (+28%), splanchnic arterial (+20%) and renal (447%) vascular resistances and NE (+62%) were significantly increased compared to rats receiving placebo, cAMP showed a decreasing trend after Oc treatment. However, after Oc treatment, the portal pressure & portal inflow were still higher in PVS rats than in SO rats. In contrast, in SO rats, there were no differences in any of the parameters between rats receiving de & placebo. We concluded that chronic Oc treatment corrected the systemic hyperdynamic circulation with partial reversal of splanchnic hyperemia. The possible mechanism of action of Oc may be resulted from a decreased Glu level together with an increased NE concentration which in turn induced a marked vasoconstrictive effect.
• PREDICTORS OF SHUNT STENOSIS FOLLOWING TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS) PLACEMENT. C.D. Lind, W.K. Chong, W.O. Richards, C.W. Pinson, S.G. Meranze and M. Mazer. Departments of Medicine, Surgery and Radiology, Vanderbilt University, Nashville, TN 37232. Transjugular intrahepatic portosystemic shunt (TIPS) placement has been used for the management of portal hypertension and variceal hemorrhage. Long term efficacy has been limited by the high incidence of shunt stenosis within 1 year after TIPS placement. Aims: 1) To determine whether the clinical parameters of Child's-Pugh score, prothrombin time (PT), or platelet count (pit ct) influence the subsequent development of TIPS stenosis. 2) To determine whether early angiographic or doppler ultrasound parameters of TIPS function predict the development of TIPS stenosis. Methods: 35 patients with recurrent variceal hemorrhage were treated with TIPS placement and have completed 2-year followup. Pre- and post-procedure evaluation included: clinical assessment, upper GI endoscopy, portal pressure measurement, portal angiography and color doppler ultrasonography. Follow-up assessment was performed at 3 and 12 months postTIPS and when clinically indicated. Pre-procedure clinical parameters (Child'sPugh score, PT, pit ct), post-TIPS portal-hepatic vein gradient (grad), and doppler ultrasound maximal flow velocity (MFV) 1 month after TIPS placement were retrospectively evaluated based upon the eventual development of TIPS stenosis. Results: Of 35 TIPS patients, 6/35 died before 3 month angiography, 7/35 developed early shunt occlusion, and 1/35 has done well for 33 months without angiographic follow-up. 10/35 patients developed shunt stenosis during follow-up and 11/35 patients have had no evidence of shunt stenosis. Comparison of clinical, angiographic and doppler ultrasound parameters based upon shunt status shows: Parameter Shunt Stenosis (n= 10) No Stenosis (n= 11) Child's-Pugh score 8.6+0.6* 10.7_+0.8" Prothrombin time (sec) 14.6_+0.3" 16.05:0.5" Platelet count (x 1,000) 121.9-1-23.2 79.25:9.0 Post-TIPS grad(mmHg) 10+ 1.2 105:0.8 MFV (cm/s) 99 5:11.7 97 _+14.4 Values expressed as MEAN _+ S.E.M.;* p < 0.05 by unpaired t-test Conclusions: 1) The development of shunt stenosis after TIPS is influenced by Child's-Pugh class and prothrombin time. Patients with prolonged PT or worse Child's class are less likely to develop stenosis. 2) Early angiographic and doppler ultrasound parameters of TIPS function do not predict the development of shunt stenosis. 3) TIPS stenosis is more likely to occur in patients with liver disease that carries a good prognosis (Child's-Pugh class A or B; normal prothrombin time). This observation may be important in making decisions regarding the use of TIPS vs. surgical shunts in this patient population.
AASLD ABSTRACTS
GALLBLADDER LITHIASIS IN PATIENTS WITH A L C O H O L I C C I R R H O S I S O F THE L I V E R : P R O S P E C T I V E STUDY O F A E T I O L O G I C AND P A T H O G E N I C F A C T O R S IN 56 CASES. Liebaert-Bories MP, Mendler M, Cessot F, Sauterean D, Venot J, Parneix JL, Le Sidaner A, Cazelles-Boudier MC, Pillegand B. Department of Gastroenterology and Liver Diseases, Dupuytren University Hospital, 2 avenue Martin-Luther-King, F-870a2 Limoges Cedex, FRANCE. Patients with alcoholic cirrhosis have a significantly higher frequency of gallbladder lithiasis (20 to 30%) as compared to the general population (10 to 15%). The aim of this study was to detect possible epidemiologic, biological or clinical factors leading to gallbladder lithiasis in alcoholic cirrhosis. Patients and methods: Fifty-five patients with alcoholic cirrhosis of the liver were included in the study from November 1993 to March 1994. Thirty patients had uhrasonographic signs of gallbladder lithiasis (Group A) and in 26 (Group B) these signs were absent. Age, sex, body surface, alcohol intake, duration of cirrhosis, signs of portal hypertension ( u l t r a s o n o g r a p h y , upper digestive endoscopy), signs of hepatic insufficiency, Child-Pugh score, hepatic fibrosis score (PIIINP, APO-A1, PGA score, a 2 - m a c r o g l o b u l i n ) , signs of hemolysis (reticulosis >150000/mm 3, haptoglobin <1g/l, total serum bilirubin >20 mmoles/1 with non-conjugated bilirubin (NCB) > conjugated bilirubin), and signs of hyperspienism (platelet count <150000/mm3, neutrophil count <1800/1, splenomegaly) were studied in each patient. The X2 and Student tests were used for smustical analysis of data. Results : 1) In this study ~he frequency of gallbladder lithiasis was higher (53.6%) than that found in previously published studies. 2) Of the parameters studied, only hemolysis differed significantly between Group A (n=24, 80%) and Group B (n=6, 9_3%) (p < 0.01). 3) Average serum NCB (Group A, n=27.3 ±20.19 mmoles/l; Group B, n=21 ±14.02 mmoles/l) and presence of hypersplenism (Group A, n=18, 60%; Group B, n=10, 38%) did not however differ significantly. Conclusion: These results indicate that hemolysis is an important factor implicated in the pathophysiology of gallbladder lithiasis in alcoholic cirrhosis. Hypersplenism does not seem to be the sole cause of increased hemolysis.
• SERUM LOW DENSITY LIPOPROTEIN OF ALCOHOLIC PATIENTS IS CHEMICALLY MODIFIED I N V I V O BY ACETALDEHYDE AND LIPID PEROXIDATIVE PRODUCTS A N D IT INDUCES APOLIPOPROTEIN E S Y N T H E S I S BY MACROPHAGES. R.C. Lin, J. Dai, L. Lumeng, M-Y. Zhang. Indiana Univ Sch M e d / V A Med Center, Indianapolis, IN Liver and blood proteins (e.~. a 37KD protein recently identified as A 4 - 3 - k e t o s t e r o i d 5~-reduetase, a key enzyme in bile acid synthesis, and hemoglobin) are known to form adducts w i t h acetaldehyde (ach) in vivo during chronic alcohol exposure. Liver proteins are also modified by lipid p e r o x i d a t i v e products e.~. 4-hydroxynonenal (4-HNE) in animals fed alcohol chronically. Since the incidence of atherosclerosis decreases with moderate alcohol intake while death rate due to heart disease increases with heavy drinking, we report herein the effects of heavy alcohol drinking on serum LDL. A g a r o s e gel electrophoresis showed that LDL samples from alcoholic patients without serious liver disease were more negatively charged (relative mobility: 0 . 4 6 3 ± 0 . 0 6 6 , n=75) than LDL from non-drinking control subjects (0.3965:0.046, nffi92) (p<0.O01). Antibodies raised by keyhole limpet hemocyanin (KLH) modified in v i t r o by 4-HNE or by ach as immunogen reacted m o r e strongly with patients' LDL than with control LDL (p<0.01 for anti-KLH-4-HNE and p<0.05 for anti-KLH-ach), indicating oxidatively modified epitopes and ach-adducts are present in LDL of alcoholics. LDL of alcoholics also has decreased vitamin E ( 6 . 9 9 ~ 2 . 0 9 ~g/mg vs. 8 . 6 3 ± 2 . 0 4 pg/mg LDL, p<0.05). Electromobility of LDL from alcoholics normalized in 2 wk of abstinence, but vitamin E did not. Macrophages (M~) possess scavenger receptors that are not d o w n - r e g u l a t e d by cellular cholesterol contents. When incubated w i t h mouse peritoneal M~, patients' LDL induced apolipoprotein E secretion by 3-fold over control LDL with a concomitant increase in M ~ cholesterol. Statistical analyses on LDL chemical compositions of alcoholics showed no dependency on age, gender or AST levels. CONCLUSIONS: LDL of alcoholics has lower vitamin E contents, is chemically modified by ach and 4-HNE in v i v o and exhibits altered biological function. These changes in heavy alcohol drinkers may render LDL m o r e atherogenic and thereby may overcome the protective effects of moderate alcohol intake.
GASTROENTEROLOGY, Vol. 108, No. 4
• EFFECTS OF CHRONIC ADMINISTRATION OF OCTREOTIDE ON HEMODYNAMICS, PLASMA GLUCAGON AND NOREPINEPFIRINE LEVELS AND VASCULAR cAMP CONTENT IN PORTAL VEIN STENOSED RATS. H.C. Lin, C.M. Yang, Y.T. Tsai, S.M. Lee, P.C. Yu, F.C. Cheng, J.S. Kuo, S.D. Lee. Div. of Gastroenterology, Dept. of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C. Hemodynamic studies in cirrhotic patients showed that acute administration of octreotide (Oc) decreased hepatic and azygos blood flows with a minimal effect on portal pressure. However, the mechanism of action and the effect of chronic, long-term administration of Oc in portal hypertension have not yet been established. Recently, in rats with portal vein stenosis (PVS), a 4-day course of Oc treatment ameliorated vasodilatation and Na + retention. The present study was undertaken to evaluate the chronic effects of d e in PVS rats and its possible mechanism of action in portal hypertension. Experiment 1: Both PVS (n=7, respectively) and sham-operated (SO) (n=6, respectively) rats were divided into 2 groups and received a 100 gg/kg of Oc or a placebo s.c. every 12 hr for 14 consecutive days. Cardiac output and regional bemodynamics were measured using the radioactive microsphere technique. Experiment 2: Both PVS (n=7, respectively) and SO (n=7, respectively) were divided into 2 groups and received either Oc or placebo as described above for 14 consecutive days. Plasma glucagon (Ghi) and norepinephrine (NE) were determined from blood samples obtained via decapitation and using a RIA & HPLC method, respectively, cAMP was determined using RIA from vascular smooth muscle Cells obtained from a segment of tail artery. Basically, PVS rats showed the presence of portal hypertension and hyperdynamic circulation associated with a hyperglucagonemia when compared to SO rats. Accordingly, an increased vascular cAMP content was found in PVS rats. NE was no different between PVS & SO rats. In PVS rats receiving chronic Oc, portal pressure (-23%), portal inflow (-18%), renal blood flow (-31%), cardiac index (-25%) & Glu (-26%) were significantly decreased while mean arterial pressure (+10%), systemic (+28%), splanchnic arterial (+20%) and renal (447%) vascular resistances and NE (+62%) were significantly increased compared to rats receiving placebo, cAMP showed a decreasing trend after Oc treatment. However, after Oc treatment, the portal pressure & portal inflow were still higher in PVS rats than in SO rats. In contrast, in SO rats, there were no differences in any of the parameters between rats receiving de & placebo. We concluded that chronic Oc treatment corrected the systemic hyperdynamic circulation with partial reversal of splanchnic hyperemia. The possible mechanism of action of Oc may be resulted from a decreased Glu level together with an increased NE concentration which in turn induced a marked vasoconstrictive effect.
• PREDICTORS OF SHUNT STENOSIS FOLLOWING TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS) PLACEMENT. C.D. Lind, W.K. Chong, W.O. Richards, C.W. Pinson, S.G. Meranze and M. Mazer. Departments of Medicine, Surgery and Radiology, Vanderbilt University, Nashville, TN 37232. Transjugular intrahepatic portosystemic shunt (TIPS) placement has been used for the management of portal hypertension and variceal hemorrhage. Long term efficacy has been limited by the high incidence of shunt stenosis within 1 year after TIPS placement. Aims: 1) To determine whether the clinical parameters of Child's-Pugh score, prothrombin time (PT), or platelet count (pit ct) influence the subsequent development of TIPS stenosis. 2) To determine whether early angiographic or doppler ultrasound parameters of TIPS function predict the development of TIPS stenosis. Methods: 35 patients with recurrent variceal hemorrhage were treated with TIPS placement and have completed 2-year followup. Pre- and post-procedure evaluation included: clinical assessment, upper GI endoscopy, portal pressure measurement, portal angiography and color doppler ultrasonography. Follow-up assessment was performed at 3 and 12 months postTIPS and when clinically indicated. Pre-procedure clinical parameters (Child'sPugh score, PT, pit ct), post-TIPS portal-hepatic vein gradient (grad), and doppler ultrasound maximal flow velocity (MFV) 1 month after TIPS placement were retrospectively evaluated based upon the eventual development of TIPS stenosis. Results: Of 35 TIPS patients, 6/35 died before 3 month angiography, 7/35 developed early shunt occlusion, and 1/35 has done well for 33 months without angiographic follow-up. 10/35 patients developed shunt stenosis during follow-up and 11/35 patients have had no evidence of shunt stenosis. Comparison of clinical, angiographic and doppler ultrasound parameters based upon shunt status shows: Parameter Shunt Stenosis (n= 10) No Stenosis (n= 11) Child's-Pugh score 8.6+0.6* 10.7_+0.8" Prothrombin time (sec) 14.6_+0.3" 16.05:0.5" Platelet count (x 1,000) 121.9-1-23.2 79.25:9.0 Post-TIPS grad(mmHg) 10+ 1.2 105:0.8 MFV (cm/s) 99 5:11.7 97 _+14.4 Values expressed as MEAN _+ S.E.M.;* p < 0.05 by unpaired t-test Conclusions: 1) The development of shunt stenosis after TIPS is influenced by Child's-Pugh class and prothrombin time. Patients with prolonged PT or worse Child's class are less likely to develop stenosis. 2) Early angiographic and doppler ultrasound parameters of TIPS function do not predict the development of shunt stenosis. 3) TIPS stenosis is more likely to occur in patients with liver disease that carries a good prognosis (Child's-Pugh class A or B; normal prothrombin time). This observation may be important in making decisions regarding the use of TIPS vs. surgical shunts in this patient population.