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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

      

American Association for the Study of Liver Diseases 50th Annual Meeting

Portal Hypertensive Bleeding

 

Steven K. Herrine, MD

 

Background

Bleeding from esophageal varices occurs in approximately 30% of patients with chronic liver disease and portal hypertension. Gastrointestinal bleeding due to portal hypertension is estimated to cost approximately $1.2 billion per year in the US.[1]

Nonselective beta-blockade with propranolol or nadolol has been shown in meta-analyses to decrease the risk of first variceal hemorrhage in those patients with high-risk varices.[2] Despite advances in endoscopic and pharmacological approaches to treatment and prevention of variceal hemorrhage, mortality of a first-time bleed remains in excess of 30%. Among pharmacological agents available in the US, octreotide has the most favorable profile in acute variceal hemorrhage.[3] In recent years, endoscopic variceal band ligation (EVL) has emerged as the therapy of choice for variceal hemorrhage over endoscopic injection sclerotherapy, yielding similar efficacy rates with fewer complications.[4] Combination sclerotherapy and band ligation does not appear to improve patient outcome.[5] Results of randomized trials have discouraged the use of sclerotherapy as prophylaxis against index bleed in patients with high-risk varices.[6] The use of prophylactic band ligation to prevent first variceal bleed remains under investigation.[7] In bleeding that persists despite medical and endoscopic intervention, portal decompression by way of TIPS (transvenous intrahepatic portosystemic shunt) has proven effective.[8] In selected cases, surgical shunts or esophageal transection is useful in the control of variceal hemorrhage.[9,10]

Leon Schiff Lecture

Dr. Roberto Groszmann elegantly painted the backdrop for the clinical reviews that are to follow in this text during his delivery of the Leon Schiff State-of-the-Art Lecture entitled "Pathophysiology of Portal Hypertension" on Monday, November 8, 1999. Dr. Groszmann placed the topic of portal hypertension in an historical context, then elucidated our current understanding of the causes of the splanchnic vasodilatation and the subsequent retention of water and sodium. Much of his attention was turned to nitric oxide (NO), particularly endothelial NO, the production of which appears to be increased by vascular wall stress. Bringing his comments into the clinical realm, Dr. Groszmann theorized that nitrates will likely continue to play a role in the therapy of portal hypertension because of the ability of these compounds to donate NO. However, because the action of nitrates is systemic, rather than selectively splanchnic, currently available compounds are likely to be of limited value.[11]

Endoscopic Therapy of Variceal Hemorrhage

From an endoscopic standpoint, it seems clear that endoscopic band ligation (EBL) is supplanting endoscopic sclerotherapy as the most effective and safe technique for control of hemorrhage and serial eradication of varices. Gastric varices (GV) have proven more difficult to treat, often requiring portosystemic shunting. Williams and colleagues from University of Virginia provide a report of the early US experience with enbucrilate injection for control of GV bleeding. Of 11 patients treated, 10 had resolution of index bleed, while 1 had recurrence. Two patients died from previously identified malignancy during the period of observation. There was no damage to endoscopic equipment, a concern given the adhesive nature of enbucrilate. Cost of care compared favorably with standard care of these patients.[12] Such a technique, if successful in control and eradication of GV, will prove most useful.

Pharmacologic Therapy of Variceal Hemorrhage

Beta adrenergic blockade is accepted as effective primary prophylaxis against variceal hemorrhage in patients with large esophageal varices. The studies that have shown this benefit used sufficient beta-blockade to lower pulse by 25% or to 55 beats per minute. Some investigators have suggested that even these parameters are insufficient to insure adequate lowering of the portosystemic gradient, thereby preventing hemorrhage. Peron and his French group used hepatic venous pressure gradient (HVPG) to assess adequacy of primary and secondary prophylaxis in 22 patients with cirrhosis and varices. Propranolol at 160 mg/day lowered the portosystemic gradient in 15/22 patients to below 12 mmHg or reduced it by 20%. Four more patients were classified as responders by these criteria, with the addition of isosorbide mononitrate (IMN) 60 mg qd. Four patients bled during follow-up, including 2 "responders," suggesting that reduction of HVPG by 20% may be an inadequate parameter in prophylaxis of variceal hemorrhage.[13]

Dr. Minyana and colleagues presented data comparing EBL to nadolol (NAD) plus IMN in the prevention of variceal rebleeding once primary hemostasis had been achieved. Five days after control of bleeding, 139 patients were randomized to EBL versus NAL (reducing HR [heart rate] by 25% but > 55 beats per minute) plus IMN (up to 40 mg bid). Drug therapy was as successful in preventing rebleeding as EBL in this patient population, with fewer complications. These data must be interpreted with caution, however, because the 43% rebleeding rate observed in the EVL group was rather high.[14]

    

Lopez-Balaguer and colleagues presented a careful hemodynamic study in cirrhotic patients given a combination of somatostatin and IMN. Somatostatin has been shown to decrease splanchnic pressure and has proven useful in control of variceal hemorrhage. In addition, IMN provides further vasodilatation, presumably through its role as a NO donor, as discussed previously. In this study, 39 patients were given IMN in addition to somatostatin. Significant decreases were seen in mean arterial pressure and hepatic venous pressure gradient, the latter primarily due to a decrease in wedged hepatic vein pressure. Despite these results, decrease in mean arterial pressure may limit the usefulness of this combination.[15]

Cales reported on 196 patients admitted for variceal hemorrhage or portal hypertensive bleeding randomized to vapreotide, a somatostatin analogue, or placebo, within a mean of 2.2 hours. Endoscopic therapy was provided within a mean of 3.1 hours after admission. Less bleeding was observed at the time of endoscopy, with associated higher hemostasis rates and less blood transfusion. No significant difference in 5- or 42-day survival was seen. Time will tell if this compound will become available for trials in the US.[16]

El Atti and coworkers took an alternative pharmacologic approach to variceal hemorrhage. Recognizing the known action of sumatriptan in raising lower esophageal sphincter pressure by its peripheral action of 5HT receptor, these investigators theorized a lowering of variceal pressure with this agent. Ten patients were given sumatriptan, 10 mg sq. There was a significant lowering of variceal pressure as measured with pressure-sensitive gauge, but no effect on portal or systemic pressure. The researchers speculate that variceal pressure is lowered by the elevation of lower esophageal sphincter pressure.[17]

Primary Prophylaxis of Variceal Hemorrhage

Clearly, primary prophylaxis of variceal hemorrhage cannot take place unless the appropriate patients are selected and tested. Dr. Arguedas and colleagues from the University of Alabama reported on 69 consecutive patients undergoing evaluation for orthotopic liver transplantation (OLT). Of these patients, 33% presented with variceal bleeding as original presentation of liver disease. Twelve others developed bleeding after the diagnosis of cirrhosis, only 1 of whom had undergone screening exam. Only 55% of the remaining patients in the cohort have been screened to date. The researchers correctly call for more vigilant screening of patients with cirrhosis for varices to allow primary prophylaxis.[18] Saeian and associates attempted to provide us with information to ease that screening process by demonstrating the acceptability of unsedated transnasal and peroral endoscopy (5.3 mm outer diameter) for variceal screening in 9 patients.[19]

Dr. Merkel and his colleagues in Padua reported a primary prophylaxis trial comparing NAD monotherapy with NAD plus IMN. One hundred forty-six patients with cirrhosis and known esophageal varices, but no bleeding, were treated for 7 years. Sixteen in the NAD group and 8 in the combination therapy group bled. The cumulative bleeding risk was higher in the NAD group (29%) versus the NAD/IMN group (12%). Addition of IMN did not increase incidence of liver failure, development of ascites, or renal insufficiency; however, 4 patients requested discontinuation of IMN due to side effects.[20]

During the plenary sessions, Dr. Lui outlined the experience of his group from Scotland regarding the best approach to primary prophylaxis. Previous experiences with sclerotherapy as a means of prophylaxis have proven disappointing. The role of EBL in this capacity is as yet unproven. In their study, 172 patients with cirrhosis and no history of bleeding were stratified by treatment into EBL, propranolol, or isosorbide mononitrate groups. Band ligation was found to be superior to IMN, but not significantly different from propranolol, despite a 24% withdrawal from the propranolol group due to side effects. During a rather lively question and answer session following the presentation, concerns with the high bleeding rate in the pharmacologic groups were expressed. Clearly, further investigation into the role of endoscopic prophylaxis of variceal hemorrhage is warranted.[21]

Issues in TIPS

The use of TIPS has proven invaluable in the therapy of refractory variceal hemorrhage by lowering the portosystemic gradient. More recently, this method of portal decompression has been employed in the management of patients with refractory ascites. Unfortunately, TIPS has been associated with the development of portosystemic encephalopathy. Furthermore, stenosis of the shunt occurs in nearly half of patients undergoing the procedure within the first 6 months.

Russo and associates looked at 90 consecutive patients who underwent TIPS over a 6-year period. Those with relatively maintained synthetic function had higher incidence of TIPS stenosis, determined angiographically, than those with abnormal INR. The researchers suggested that TIPS is not indicated in those patients with portal hypertension and relatively preserved prothrombin time.[22]

Further data on predicting the complications of TIPS were provided in a poster presented by El Atti in which 79 patients with emergently placed TIPS for variceal hemorrhage were analyzed. Twenty-one of 79 were determined to have bled from gastric fundal varices (GV), while 58 bled from esophageal varices (EV). Fifty-two percent of patients with GV had large spontaneous portosystemic shunts, half of which required embolization to control hemorrhage. Forty percent of the GV group with large spontaneous shunts versus 8% of the EV group had early TIPS thrombosis. The investigators suggested that anticoagulation may therefore be warranted in the group with large spontaneous portosystemic shunts.[23]

Pomier-Layrargues and colleagues provided data to help predict which patients who undergo TIPS will have resistant encephalopathy. In their study, 219 patients who underwent TIPS were reported. One hundred eighteen subjects had preprocedure flow, while 31 had either hepatofugal, back-and-forth flow, or portal vein thrombosis. No patient in the second group had severe encephalopathy after TIPS, while 16.5% of the first group did. The researchers speculated that reversed or absent portal flow is protective against severe post-TIPS encephalopathy.[24]

These papers, which illuminate the difficulties in managing the patient after TIPS, support the current trend to view this procedure as a temporizing therapy or as a bridge toward ultimate OLT.

    

References

1.      Roberts LR, Kamath PS. Pathophysiology and treatment of variceal hemorrhage. Mayo Clin Proc 1996;71(10):973-983.

2.      Poynard T, Cales P, Pasta L, et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med 1991;324(22):1532-1538.

3.      Sung JJ, Chung SC, Lai CW, et al. Octreotide infusion or emergency sclerotherapy for variceal hemorrhage. Lancet 1993;342:637-641.

4.      Hou MC, Lin HC, Kuo BIT, et al. Comparison of endoscopic variceal injection sclerotherapy and ligation for the treatment of esophageal variceal hemorrhage: a prospective randomized trial. Hepatology 1995;21:1517-1522.

5.      Laine L, Stein C, Sharma V. Randomized comparison of ligation versus ligation plus sclerotherapy in patients with bleeding esophageal varices. Gastroenterology 1996;110:529-533.

6.      Van Ruiswyk J, Byrd JC. Efficacy of prophylactic sclerotherapy for prevention of first variceal hemorrhage. Gastroenterology 1992;102:587-597.

7.      Sarin SK, Gupten RKC, Jain AK, Sundaram KR. A randomized controlled trial of endoscopic variceal band ligation for primary prophylaxis of variceal bleeding. Eur J Gastroenterol Hepatol 1996;8:337-342.

8.      Rossle M, Haag K, Ochs A, et al. The transjugular intrahepatic portosystemic stent-shunt procedure for variceal bleeding. N Engl J Med 1994;330:165-171.

9.      Collins JC, Rypins EB, Sarfeh IJ. Narrow-diameter portocaval shunts for management of variceal bleeding. World J Surg 1994;18:211-215.

10.  Burroughs AK, Hamilton G, Phillips A, et al. A comparison of sclerotherapy with acute transection of the esophagus for the emergency control of bleeding from esophageal varices. N Engl J Med 1989;321:857-862.

11.  Groszmann RJ. Pathophysiology of portal hypertension. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas.

12.  Williams JM, Hespenheide EE, Lucas LJ, et al. Enbucrilate (histoacryl) for the treatment of bleeding gastric varices: a cost analysis. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 231.

13.  Peron JM, Asnacios A, Sanchez J, et al. Adjustment of portal hypertension medical treatment according to the hemodynamic response: prospective study of 22 patients. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 229.

14.  Minyana J, Gallego A, Vera JS, et al. Endoscopic ligation versus naldolol plus isosorbide-s-mononitrate for the prevention of variceal rebleeding. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 215.

15.  Lopez-Balaguer JM, Sola-Vera J, Minyana J, et al. Hemodynamic effects of combined therapy with somatostatin and isosorbide-s-mononitrate in patients with cirrhosis and portal hypertension. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 222.

16.  Cales P. Early administration of vapreotide, a new somatostatin analogue, and endoscopic therapy for acute portal hypertensive bleeding in patients with cirrhosis. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 1035.

17.  El Atti EA, Nevens F, Couli B, et al. Sumatriptan reduces variceal pressure without affecting portal pressure. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 238.

18.  Arguedas MR, McGuire BM, Fallon MB, et al. The use of screening and preventive therapies for esophageal varices in patients referred for evaluation of orthotopic liver transplantation. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 220.

19.  Saeian K, Staff DM, Townsend W, et al. A new approach to screening for esophageal varices. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 219.

20.  Merkel C, Marin R, Sacerdoti D, et al. Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 217.

21.  Lui HF, Stanley AJ, Forrest EH, et al. Primary prophylaxis of variceal haemorrhage: a randomised controlled trial comparing band ligation, propranolol and isosorbide mononitrate. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 632.

22.  Russo MW, Honeycutt K, Jacques PF, et al. Prothrombin time, but not platelet count, predicts stenosis after transjugular intrahepatic portosystemic shunt (TIPS). Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 225.

23.  El Atti EA, Stockx L, Maleux G, et al. Patients with fundal variceal bleeding have frequently large portosystemic shunts which makes them at risk for stent thrombosis and encephalopathy after TIPS. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 226.

24.  Pomier-Layrargues G, Hassoun Z, Lafortune M, et al. Relationship between pre-TIPS liver perfusion by the portal vein and the incidence of post-TIPS chronic recurrent hepatic encephalopathy. Program and abstracts of the 50th Annual Meeting and Postgraduate Courses of the American Association for the Study of Liver Diseases; November 5-9, 1999; Dallas, Texas. Abstract 529.