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What is the clinical relevance of portal hypertensive gastropathy (PHG) in patients with compensated liver cirrhosis?
534A
AASLD ABSTRACTS
HEPATOLOGYOctober 2001
1447
1448
SHOULD W E ROUTINELY MEASURE HVPG TO ASSESS RESPONSE OF PRIMARY PROPHYLAXIS IN PATIENTS W I T H CIRRHOSIS? A DECISION ANALYTIC STUDY. Bret Hicken, Miguel R Arguedas, Gary A Abrams,
W H A T IS THE CLINICAL RELEVANCE OF PORTAL HYPERTENSIVE G A S T R O P A T I ~ (PHG) IN PATIENTS W I T H COMPENSATED LIVER CIRRHOSIS?. Filippo Schepis, UniversitCt Magna Graecia, Catanzaro, Catan-
Michael B Fallon, University of Alabama at Birmingham, Birmingham, AL
zaro Italy; Calogero Camm/L ISMEDA, CNR Palermo, Palermo Italy; Roberto De Franchis, Dipartimento di Medieina Interna, Mflano, Milano italy; Domenico Niceforo, Antonio Magnano, Socrate Pallio, Maurizio Cinquegrani, Dipartimento di Medicina Interna, Messina, Messina Italy; Luca Carpinelli, Dipartimento di Medicina Interna, Milano, Milano Italy; Giovanni Tuccari, Daniela vfllari, Istituto di Anatomia Patologica, Messina, Messina italy; Antonio Craxi, Divisione di Gastroenterologia, Palermo, Palermo Italy; Giovanni Raimondo, Dipartimento di Medicina Interna, Messina, Messina Italy
BACKGROUND: Varieeal bleeding (VB) is the most lethal consequence of cirrhosis and portal hypertension. Therefore, primary prophylaxis with beta-blockers is recommended in patients with varices considered at high-risk for bleeding and is associated with an average risk reduction of approximately 45%. Optimal prevention is achieved when beta-blocker therapy reduces hepatic venous pressure gradient (HVPG) to less than 12 mmHg or results in a 20% reduction compared to baseline levels. Therefore, HVPG measurements may be useful to identify patients who do not respond to beta-blockers so that alternate forms of treatment maybe considered. However, the cost-effectiveness of such a strategy has not been evaluated in guiding primary prophylaxis in patients with high-risk varices. DESIGN & METHODS: A decision analysis model was constructed with specialized software (DATA 3.5, Williamstown, MA). We evaluated the use of HVPG measurement as a guide to primary prophylaxis in a hypothetical cohort of patients with high-risk varices. We compared two HVPG strategies: 1) measurement of HVPG 4 weeks after initiating betablocker therapy with the endpoint of achieving a reduction in HVPG to 12 mmHg or less and 2) measurement of HVPG prior to initiating medical therapy and 4 weeks after with the endpoint of achieving a 20% reduction in HVPG compared to baseline levels. Each strategy was separately compared to beta-blocker therapy without HVPG measurements Patients considered to have an inadequate HVPG response to beta-blockers underwent endoscopic variceal ligation (average 4 sessions). The total costs and number of episodes of VB were accrued over a time horizon of 1 year. Transition probabilities (probability of VB on medical therapy and according to HVPG, probability of endoscopic complications, probability of death from cirrhosis and its complications and from endoscopic complications) were obtained from the medical literature. Costs were obtained from Medicare reimbursement at our institution and are expressed in 2000 US dollars. We assumed the perspective of a third party payer. For analyses extending beyond one year, a 3% discount was performed to costs and benefits. RESULTS: At one year, a strategy of HVPG measurement 4 weeks after institution of primary prophylaxis was associated with a total cost of $5,426 and resulted in 3 episodes of VB per 100 patients. Medical therapy without HVPG measurement resulted in total costs of $2,202 and resulted in 13 episodes of VB per 100 patients. Therefore, the incremental cost per VB prevented was $46,057. if two HVPG measurements are performed (one at baseline and one 4 weeks after initiating therapy), the incremental cost per VB prevented increased to $98,071 compared to medical therapy. As the time horizon was extended, the incremental cost per bleed prevented of HVPG measurement 4 weeks after institution of primary prophylaxis improved: $25,700 (2 years) and $19,500 (3 years). HVPG would become a cost-saving strategy only at a cost of $450 or less. CONCLUSIONS: Performing a single HVPG measurement 4 weeks after institution of primary prophylaxis with beta-blockers to identify patients with a reduction to less than 12 mmHg can substantially decrease the risk of VB but at a si;lg~nificantincrease in costs. Performing 2 HVPG measurements is expensive as a result of high upfront procedural costs.
Aims: To assess the clinical value of PHG as a marker of liver dysfunction and its quantitative correlation with non-invasive or endoscopic indicators of portal hypertension (PHT). To evaluate whether endoscopic grades of PHG correlate with the severity of liver disease and PHT. To verify whether the severity of endoscopic elementary lesions of PHG has any impact on the prognosis of patients with cirrhosis. Patients and Methods: 142 consecutive compensated cirrhotics underwent upper endoscopy. Patients were grouped according to their endoscopic class (EC-0 = PHG and esophageal varices lEVI both absent; EC-1 = only PHG present; EC-2 = PHG and EV both presen0; to the New Italian Endoscopic Club (NIEC) grades of PHG (mild, severe); and to their endoscopic pattern (EP) of association beetwen the most common elementary endoscopic lesions of PHG (mosaic-like pattern [MLP], and red-point lesions [RPLs]) (EP-1 = RPLs alone; EP-2 ~ MLP mild with or without RPLs; EP-3: MLP moderate/severe with or without RPLs). Results: PHG was diagnosed in 61.3% of patients. It was mild in 23.9% and severe in 37.3%. EV were detected in 44.3% of subjects. At multivariate analysis, no predictor of PHG grade was found, while prothrombin activity (OR: 0.96, 95% CI 0.94-0.99) and ultrasonographic portal vein diameter (OR: 36.8, 95% CI 4.9-275) were the significant variables explaining the differences among endoscopic classes (ECs). Bflirubin was the only independent predictor of EP (OR: 0.54, 95% CI 0.36 0.81). These findings have been validated on cohort of cirrhotic patients included in the NIEC study recently published *. Conclusions: Patients with PHG alone (EC-2) represent an "intermediate" group integrated among patients without any indicator of PHT and with a normal liver function, and those with stable PHT and a more advanced liver disease. The NIEC grades of PHG do not parallele the severity of liver dysfunction arid PHT. Patients presenting with moderate/severe MLP should be considered as having a severe PHG. *Gastroenterology 2000;119:181-187.
1449
1450
INADEQUATE HEPATOPORTAL COLLOIDOSMOTIC PRESSURE AS A RESULT OF TRANSCAPILLARY WATERFLUX IN PORTAL HYPERTENSION. Karl-Georg Petersen, Andreas G Ochs, Volker Siegerstetter, Martin
COMBINATION OF ENDOSCOPIC VARICEAL LIGATION PLUS PROPRANOLOL VERSUS ENDOSCOPIC VARICEAL LIGATION ALONE IN THE PRIMARY PROPHYLAXIS OF OESOPHAGEAL VARICEAL BLEEDING: AN INTERIM ANALYSIS. Shriram Agarwal, Jagdeep Singh, G B Pant
Roessle, Med Uniklinik II, Freiburg Germany Hepatoportal colloidosmotic pressure regulates the synthesis of albumin and the release of antidiuretic hormone. In portal hypertension (PH) predominant filtration of water and small solutes could increase portal and intrahepatic protein concentrations and thus colloidosmotic pressure. Serum choline esterase was measured as a marker protein. Simultaneous right atrium samples were compared to portal and hepatic vein samples taken in patients undergoing TIPS or with a functioning portosystemic stent shunt. The percentage of differences is shown (AChe). In 20 patients with chronic PH and hepatopetal portal blood flow (928 + 327 ml/min AChe was 1.1 +- 1.3% (p<0.02). Reduction of portal pressure by TIPS (29 • 4 to 17 + 5 mmHg)reduced AChe to 0.3 ± 1.7% (p<0.02). Hepatic vein AChe was 1.8 -+ 1.2% (p<0.001). Balloon occlusion of 16 functioning shunts increased portal pressure (15 ~ 4 to 29 --3 mmHg, p<0.001) and AChe (4.0 -+ 3.7%, p<0.001). AChe correlated with total protein (r = 0.86, p<0.002) and albumin (r = 0.81, p<0.002). A albumin (MW 67000) was 18% lower than AChe (MW 230000) indicating size depending filtration. AChe can be used as a filtration fraction to calculate transcapillary waterfluxes from the serum flow. The preportal intestinal flux of 5 ]/day is in good accordance with previous intraoperative measurements of intestinal lymph flow in cirrhosis. Hepatic artery flow and hepatic lymph data were taken into account to determine the transhepatic waterflnx into the peritoneal cavity (6 l/day) from hepatic vein AChe. Conclusion: Intestinal preportal transcapillary waterflux and transhepatic waterflux can be determined from portal and hepatovenons serum protein concentrations. The waterfluxes increase portal and hepatic intravascular serum proteins and hence local colloidosmotic pressure. This may contribute to inadequate osmoregulation via antidiuretic hormone and albumin synthesis.
Hospital, New Delhi India; Shashi Sharma, ICPO, New Delhi India; Shiv K Sarin, G B Pant Hospital, New Delhi India Background And Aim: This prospective, randomized controlled trial compared a combination of endoscopic variceal ligation (EVL) with propranolol and EVL alone in the prevention of first oesophageal variceal bleed in patients with high risk varices ( > 5 m m with red color signs). Interim results o f the ongoing trial are presented. Patients and Methods: Consecutive eligible patients were randomly allocated to EVL plus propranolol (46 patients) or EVL (46 patients) roup. Patients in the combination group received propranolol at a dose sufcient to decrease the base line heart rate by 25% or to 55 beats/min, beginning on the day of randomization followed by EVL on the same day or within 24 hours while those in the EVL group underwent ligation beginning the day of randomization or within 24 hours. Variceal ligation was performed every 1-2 weeks until the varices were obliterated. In the combination group, propranolol was continued after the variceal eradication. The end-point of the study was bleeding or death. Data were analyzed according to intention-to-treat strategy. The actuarial probabilities of bleeding and death were calculated by the Kaplan-Meier method and comparisons made using log-rank test. Results: Baseline patient characteristics, age, sex, Child-Pugh score, frequency of alcoholic cirrhosis were comparable in the two groups. The mean dose of propranolol was 92 mg/day. The median duration of follow-up was 8 months in both groups. Four patients (8.7 o~) in the combination group and five (10.9 o~) in the EVL group had bleeding. All the patients bled before obliteration of varices. After 18 months, the actuarial probability of first bleed was 10.5% in the combination and 15,8% in the EVL group (p=0.82). None of the patients bled from portal hypertensive gastropathy. Four patients died in the EVL group; 2 from post-EVL ulcer bleed. In the combination group, two patients died due to non-bleed related cause. The actuarial probability of survival at 18 months was 92% in the EVL and 90% in the combination group (p=0.60). At the end of follow-up, 7 of 42 (17%) surviving patients in the EVL group and 2 of 44 (4.5%) in the combination group had recurrence of varices (p=0.06). There were no serious complications of variceal ligation; propranolol was stopped in 3 patients because of side-effects in the combination group. Conclusions: (i) Both EVL alone and a combination of EVL plus propranolol are effective in the primary prophylaxis of bleed from high-risk varices, (ii) the addition of propranolol does not decrease the actuarial probability of first variceal bleed and death over 18 month period, but shows a tendency to reduction in the incidence of variceal recurrence.
AASLD ABSTRACTS
HEPATOLOGYOctober 2001
1447
1448
SHOULD W E ROUTINELY MEASURE HVPG TO ASSESS RESPONSE OF PRIMARY PROPHYLAXIS IN PATIENTS W I T H CIRRHOSIS? A DECISION ANALYTIC STUDY. Bret Hicken, Miguel R Arguedas, Gary A Abrams,
W H A T IS THE CLINICAL RELEVANCE OF PORTAL HYPERTENSIVE G A S T R O P A T I ~ (PHG) IN PATIENTS W I T H COMPENSATED LIVER CIRRHOSIS?. Filippo Schepis, UniversitCt Magna Graecia, Catanzaro, Catan-
Michael B Fallon, University of Alabama at Birmingham, Birmingham, AL
zaro Italy; Calogero Camm/L ISMEDA, CNR Palermo, Palermo Italy; Roberto De Franchis, Dipartimento di Medieina Interna, Mflano, Milano italy; Domenico Niceforo, Antonio Magnano, Socrate Pallio, Maurizio Cinquegrani, Dipartimento di Medicina Interna, Messina, Messina Italy; Luca Carpinelli, Dipartimento di Medicina Interna, Milano, Milano Italy; Giovanni Tuccari, Daniela vfllari, Istituto di Anatomia Patologica, Messina, Messina italy; Antonio Craxi, Divisione di Gastroenterologia, Palermo, Palermo Italy; Giovanni Raimondo, Dipartimento di Medicina Interna, Messina, Messina Italy
BACKGROUND: Varieeal bleeding (VB) is the most lethal consequence of cirrhosis and portal hypertension. Therefore, primary prophylaxis with beta-blockers is recommended in patients with varices considered at high-risk for bleeding and is associated with an average risk reduction of approximately 45%. Optimal prevention is achieved when beta-blocker therapy reduces hepatic venous pressure gradient (HVPG) to less than 12 mmHg or results in a 20% reduction compared to baseline levels. Therefore, HVPG measurements may be useful to identify patients who do not respond to beta-blockers so that alternate forms of treatment maybe considered. However, the cost-effectiveness of such a strategy has not been evaluated in guiding primary prophylaxis in patients with high-risk varices. DESIGN & METHODS: A decision analysis model was constructed with specialized software (DATA 3.5, Williamstown, MA). We evaluated the use of HVPG measurement as a guide to primary prophylaxis in a hypothetical cohort of patients with high-risk varices. We compared two HVPG strategies: 1) measurement of HVPG 4 weeks after initiating betablocker therapy with the endpoint of achieving a reduction in HVPG to 12 mmHg or less and 2) measurement of HVPG prior to initiating medical therapy and 4 weeks after with the endpoint of achieving a 20% reduction in HVPG compared to baseline levels. Each strategy was separately compared to beta-blocker therapy without HVPG measurements Patients considered to have an inadequate HVPG response to beta-blockers underwent endoscopic variceal ligation (average 4 sessions). The total costs and number of episodes of VB were accrued over a time horizon of 1 year. Transition probabilities (probability of VB on medical therapy and according to HVPG, probability of endoscopic complications, probability of death from cirrhosis and its complications and from endoscopic complications) were obtained from the medical literature. Costs were obtained from Medicare reimbursement at our institution and are expressed in 2000 US dollars. We assumed the perspective of a third party payer. For analyses extending beyond one year, a 3% discount was performed to costs and benefits. RESULTS: At one year, a strategy of HVPG measurement 4 weeks after institution of primary prophylaxis was associated with a total cost of $5,426 and resulted in 3 episodes of VB per 100 patients. Medical therapy without HVPG measurement resulted in total costs of $2,202 and resulted in 13 episodes of VB per 100 patients. Therefore, the incremental cost per VB prevented was $46,057. if two HVPG measurements are performed (one at baseline and one 4 weeks after initiating therapy), the incremental cost per VB prevented increased to $98,071 compared to medical therapy. As the time horizon was extended, the incremental cost per bleed prevented of HVPG measurement 4 weeks after institution of primary prophylaxis improved: $25,700 (2 years) and $19,500 (3 years). HVPG would become a cost-saving strategy only at a cost of $450 or less. CONCLUSIONS: Performing a single HVPG measurement 4 weeks after institution of primary prophylaxis with beta-blockers to identify patients with a reduction to less than 12 mmHg can substantially decrease the risk of VB but at a si;lg~nificantincrease in costs. Performing 2 HVPG measurements is expensive as a result of high upfront procedural costs.
Aims: To assess the clinical value of PHG as a marker of liver dysfunction and its quantitative correlation with non-invasive or endoscopic indicators of portal hypertension (PHT). To evaluate whether endoscopic grades of PHG correlate with the severity of liver disease and PHT. To verify whether the severity of endoscopic elementary lesions of PHG has any impact on the prognosis of patients with cirrhosis. Patients and Methods: 142 consecutive compensated cirrhotics underwent upper endoscopy. Patients were grouped according to their endoscopic class (EC-0 = PHG and esophageal varices lEVI both absent; EC-1 = only PHG present; EC-2 = PHG and EV both presen0; to the New Italian Endoscopic Club (NIEC) grades of PHG (mild, severe); and to their endoscopic pattern (EP) of association beetwen the most common elementary endoscopic lesions of PHG (mosaic-like pattern [MLP], and red-point lesions [RPLs]) (EP-1 = RPLs alone; EP-2 ~ MLP mild with or without RPLs; EP-3: MLP moderate/severe with or without RPLs). Results: PHG was diagnosed in 61.3% of patients. It was mild in 23.9% and severe in 37.3%. EV were detected in 44.3% of subjects. At multivariate analysis, no predictor of PHG grade was found, while prothrombin activity (OR: 0.96, 95% CI 0.94-0.99) and ultrasonographic portal vein diameter (OR: 36.8, 95% CI 4.9-275) were the significant variables explaining the differences among endoscopic classes (ECs). Bflirubin was the only independent predictor of EP (OR: 0.54, 95% CI 0.36 0.81). These findings have been validated on cohort of cirrhotic patients included in the NIEC study recently published *. Conclusions: Patients with PHG alone (EC-2) represent an "intermediate" group integrated among patients without any indicator of PHT and with a normal liver function, and those with stable PHT and a more advanced liver disease. The NIEC grades of PHG do not parallele the severity of liver dysfunction arid PHT. Patients presenting with moderate/severe MLP should be considered as having a severe PHG. *Gastroenterology 2000;119:181-187.
1449
1450
INADEQUATE HEPATOPORTAL COLLOIDOSMOTIC PRESSURE AS A RESULT OF TRANSCAPILLARY WATERFLUX IN PORTAL HYPERTENSION. Karl-Georg Petersen, Andreas G Ochs, Volker Siegerstetter, Martin
COMBINATION OF ENDOSCOPIC VARICEAL LIGATION PLUS PROPRANOLOL VERSUS ENDOSCOPIC VARICEAL LIGATION ALONE IN THE PRIMARY PROPHYLAXIS OF OESOPHAGEAL VARICEAL BLEEDING: AN INTERIM ANALYSIS. Shriram Agarwal, Jagdeep Singh, G B Pant
Roessle, Med Uniklinik II, Freiburg Germany Hepatoportal colloidosmotic pressure regulates the synthesis of albumin and the release of antidiuretic hormone. In portal hypertension (PH) predominant filtration of water and small solutes could increase portal and intrahepatic protein concentrations and thus colloidosmotic pressure. Serum choline esterase was measured as a marker protein. Simultaneous right atrium samples were compared to portal and hepatic vein samples taken in patients undergoing TIPS or with a functioning portosystemic stent shunt. The percentage of differences is shown (AChe). In 20 patients with chronic PH and hepatopetal portal blood flow (928 + 327 ml/min AChe was 1.1 +- 1.3% (p<0.02). Reduction of portal pressure by TIPS (29 • 4 to 17 + 5 mmHg)reduced AChe to 0.3 ± 1.7% (p<0.02). Hepatic vein AChe was 1.8 -+ 1.2% (p<0.001). Balloon occlusion of 16 functioning shunts increased portal pressure (15 ~ 4 to 29 --3 mmHg, p<0.001) and AChe (4.0 -+ 3.7%, p<0.001). AChe correlated with total protein (r = 0.86, p<0.002) and albumin (r = 0.81, p<0.002). A albumin (MW 67000) was 18% lower than AChe (MW 230000) indicating size depending filtration. AChe can be used as a filtration fraction to calculate transcapillary waterfluxes from the serum flow. The preportal intestinal flux of 5 ]/day is in good accordance with previous intraoperative measurements of intestinal lymph flow in cirrhosis. Hepatic artery flow and hepatic lymph data were taken into account to determine the transhepatic waterflnx into the peritoneal cavity (6 l/day) from hepatic vein AChe. Conclusion: Intestinal preportal transcapillary waterflux and transhepatic waterflux can be determined from portal and hepatovenons serum protein concentrations. The waterfluxes increase portal and hepatic intravascular serum proteins and hence local colloidosmotic pressure. This may contribute to inadequate osmoregulation via antidiuretic hormone and albumin synthesis.
Hospital, New Delhi India; Shashi Sharma, ICPO, New Delhi India; Shiv K Sarin, G B Pant Hospital, New Delhi India Background And Aim: This prospective, randomized controlled trial compared a combination of endoscopic variceal ligation (EVL) with propranolol and EVL alone in the prevention of first oesophageal variceal bleed in patients with high risk varices ( > 5 m m with red color signs). Interim results o f the ongoing trial are presented. Patients and Methods: Consecutive eligible patients were randomly allocated to EVL plus propranolol (46 patients) or EVL (46 patients) roup. Patients in the combination group received propranolol at a dose sufcient to decrease the base line heart rate by 25% or to 55 beats/min, beginning on the day of randomization followed by EVL on the same day or within 24 hours while those in the EVL group underwent ligation beginning the day of randomization or within 24 hours. Variceal ligation was performed every 1-2 weeks until the varices were obliterated. In the combination group, propranolol was continued after the variceal eradication. The end-point of the study was bleeding or death. Data were analyzed according to intention-to-treat strategy. The actuarial probabilities of bleeding and death were calculated by the Kaplan-Meier method and comparisons made using log-rank test. Results: Baseline patient characteristics, age, sex, Child-Pugh score, frequency of alcoholic cirrhosis were comparable in the two groups. The mean dose of propranolol was 92 mg/day. The median duration of follow-up was 8 months in both groups. Four patients (8.7 o~) in the combination group and five (10.9 o~) in the EVL group had bleeding. All the patients bled before obliteration of varices. After 18 months, the actuarial probability of first bleed was 10.5% in the combination and 15,8% in the EVL group (p=0.82). None of the patients bled from portal hypertensive gastropathy. Four patients died in the EVL group; 2 from post-EVL ulcer bleed. In the combination group, two patients died due to non-bleed related cause. The actuarial probability of survival at 18 months was 92% in the EVL and 90% in the combination group (p=0.60). At the end of follow-up, 7 of 42 (17%) surviving patients in the EVL group and 2 of 44 (4.5%) in the combination group had recurrence of varices (p=0.06). There were no serious complications of variceal ligation; propranolol was stopped in 3 patients because of side-effects in the combination group. Conclusions: (i) Both EVL alone and a combination of EVL plus propranolol are effective in the primary prophylaxis of bleed from high-risk varices, (ii) the addition of propranolol does not decrease the actuarial probability of first variceal bleed and death over 18 month period, but shows a tendency to reduction in the incidence of variceal recurrence.