Elevation of ascitic cholesterol level by itself was notspecific as it was also identified in two patients with purulentperitonitis and one patient with congestive heart failure.These findings diminished the specificity of elevation ofascitic cholesterol.

Because a large number of patients in this study withascites had primary liver cancer without peritoneal involve-ment, it would have been quite interesting to determinewhether serum �-fetoprotein determination at the time ofparacentesis for cytology could have increased the sensitiv-ity of obtaining a proper diagnosis among these patientswith ascites.

The results of this present study are therefore somewhatdisappointing. It does appear that in a patient with ascites ofindeterminant origin, if the analysis of ascitic fluid is non-specific and cytologic examination of ascitic fluid is nega-tive, the clinician should continue to image the liver. Ifimaging of the liver is noncontributory, the decision toproceed to a more invasive technique will continue to in-volve judging whether it is likely that hepatic cirrhosis ispresent.

Timothy R. Koch, M.D.Section of Gastroenterology

West Virginia UniversityMorgantown, West Virginia

Combined Therapy for SecondaryProphylaxis of Variceal Rebleeding?Villanueva C, Minana J, Ortiz J, et al.Endoscopic ligation compared with combined treatment withnadolol and isosorbide mononitrate to prevent recurrentvariceal bleeding.N Engl J Med 2001;345:647–55

Villanueva et al., utilized a randomized trial to compareendoscopic variceal band ligation (EVBL) with combinedpharmacological treatment with nadolol and isosorbidemononitrate (IM) for secondary prevention of esophagealvariceal rebleeding. One hundred forty-four patients whowere hospitalized with cirrhosis and variceal bleeding wererandomly assigned (stratified according to Child-Pugh clas-sification and history of previous variceal bleeding) to re-ceive combined medical therapy (72 patients) or EVBL (72patients). The initial dose of nadolol was 80 mg/day, with anaim to decrease the heart rate bay 25% over a period of 5days; the mean dose was 95 � 56 mg/day. The initial doseof IM was 20 mg/day and was increased over a period of 1wk to 40 mg b.i.d. unless side effects appeared. Endoscopicvariceal ligation sessions were performed every 2 to 3 wk,utilizing up to eight bands per session, and were repeateduntil the varices were eradicated. The mean duration offollow up was 21 months and the primary end points of thestudy were recurrent bleeding, complications, and death.Hepatic venous pressure gradient (HVPG) was measured

before randomization and 1 to 3 months after the start ofcombined medical treatment or once EVBL had been com-pleted. Hemodynamic response to therapy was defined as adecrease of the HVPG to less than 12 mm Hg or a decreaseof more than 20% from the baseline. They found that thefrequency of recurrent bleeding was 49% (35 out of 72patients) in the ligation group versus 33% (24 out of 72patients) in the medication group (p � 0.04). Severe treat-ment related complications occurred in 12% of patients inthe ligation group compared with 3% in the medicationgroup (p � 0.05). The probability of survival at 2 yr wassimilar in the two groups, 74% in the medication groupversus 65% in the ligation group (p � 0.52). A high Child-Pugh score at the third month of follow up was found to bean independent predictor of death. In patients with hemo-dynamic response to therapy (HVPG �12 mm Hg or 20%less than the baseline), there was a significant reduction ofthe risk of recurrent bleeding (p � 0.001) and death (p �0.02), which occurred in 51% of patients in the medicationgroup compared with only 15% in the EVBL group (p �0.05).

The author concluded that combined medical therapysignificantly decreases the recurrence of variceal bleeding,and lowers the rate of major complications related to treat-ment.

COMMENT

Patients who survive an initial episode of hemorrhage due tothe rupture of esophageal varices, have up to an 80% risk ofexperiencing further bleeding, with a resulting mortality ofup to 30% (1–3). This occurs most commonly within thefirst 6 wk after the initial episode of variceal bleeding (4, 5).Clinical, endoscopic, and hemodynamic predictors of earlyrecurrence have been well identified (1, 6–10) and could beuseful for the triage of high-risk patients. Secondary pro-phylaxis for variceal rebleeding in patients with cirrhosis isessential and includes endoscopic and pharmacologic mo-dalities. The endoscopic modalities include injection scle-rotherapy and variceal ligation therapy. Several controlledtrials have shown that endoscopic variceal ligation hashigher efficacy in preventing variceal rebleeding (11, 12),less complications, lower costs, and higher rates of survival(13–15) compared with endoscopic injection sclerotherapy.Medical therapy for secondary prevention of variceal re-bleeding includes non-selective beta-blockers (16, 17),alone or in combination with isosorbide mononitrate. Themechanism of action is reduction of blood flow, portalpressure, and subsequently gastroesophageal blood flow(18, 19). Nadolol has been used instead of propanolol forthis propose because is not metabolized by the liver and isonly administered once a day (20). Improved efficacy ofmedical therapy is related to induction of hemodynamicchanges, specifically, the reduction in HVPG less than 12mm Hg or with a 20% decrease from the baseline (21–24).Unfortunately, nonselective beta-blockers achieve target re-

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duction in HVPG in only one third of treated patients (22,25).

Recent randomized trials have suggested that the additionof isosorbide mononitrate to beta-blockers improves theefficacy of medical therapy in preventing variceal rebleed-ing (20, 26–28). Several trials compared this combinedpharmacologic therapy to endoscopic ligation (24, 29) andto sclerotherapy (27), and showed benefits without an in-crease in the risk of ascites or impaired renal function (27,28).

This study suggests that once acute esophageal varicealbleeding has been controlled, combined pharmacologictherapy with nadolol and isosorbide mononitrate has signif-icant advantages over endoscopic ligation therapy alone inpreventing recurrence of variceal hemorrhage. In addition, itwas associated with fewer major treatment-related compli-cations. The limitations of this study were that: 1) it wasconducted in a single center, therefore, it could be associatedwith selection bias; 2) even though they utilized pharmaco-logic therapy this was not a double blind study and, there-fore, it could be associated with observer bias; and 3) one ofthe exclusion criteria before randomization was advancedliver disease, therefore, the majority of patients included inthe study were in Child-Pugh class A and B. However, thedifferences between the two therapies were more pro-nounced among patients whose liver function was wellpreserved. This study corroborates the results of other trials,stating that the risk of variceal rebleeding is extremely lowwhen the hemodynamic targets are achieved and concludedthat monitoring HVPG identifies patients with a poor re-sponse, in whom more aggressive alternative therapies maybe warranted.

Given the high risk of recurrence after an initial varicealhemorrhage and considering the cost-effectiveness of vari-ous methods of treatment, combined therapy (endoscopicvariceal ligation plus combined pharmacologic therapy)could include the elements of an ideal treatment. A potentialadvantage of combination therapy is that the modalitiesacting through different mechanisms may be additive interms of their benefit or even synergistic. Therefore, me-chanical obstruction of esophageal varices utilizing endo-scopic ligation combined with a pharmacologic reduction ofthe portal blood flow could, by two different mechanisms,be additive and decrease the risk of rebleeding and mortal-ity. Further preventive strategies should be directed towardthis combined therapy.

Diego Maldonado, M.D.Jamie S. Barkin, M.D., F.A.C.P., M.A.C.G.

University of Miami, School of Medicine/Mt. Sinai Medical Center, Miami, Florida

REFERENCES

1. Sharara Al, Rockey DC. Gastroesophageal variceal hemor-rhage. N Engl J Med 2001;345:669–81.

2. Bosch J, Burrhoughs AK. Clinical manifestations and man-agement of bleeding episodes in cirrhotic patients. In: Rodes J,Mclntyre N, Benhamou JP, Bircher J, Rizetto M, eds: Oxfordtextbook of clinical hepatology, 1998;671–93.

3. Graham DY, Smith JL. The course of patients after varicealhemorrhage. Gastroenterology 1981;80:800–9.

4. The Copenhagen Esophageal Varices Sclerotherapy Project.Sclerotherapy after first variceal hemorrhage in cirrhosis: Arandomized multicenter trial. New Engl J Med 1984;311:1594–1600.

5. Smith JL, Graham DY. Variceal hemorrhage: A critical evalua-tion of survival analysis. Gastroenterology 1982;82:968–73.

6. Schepis F, Camma C, Niceforo D, et al. Which patients withcirrhosis should undergo endoscopic screening for esophagealvarices detection? Hepatology 2001;33:333–8.

7. Moitinho E, Escorsall A, Bandi JC, et al. Prognostic value ofearly measurements of portal pressure in acute variceal bleed-ing. Gastroenterology 1999;117:626–31.

8. Lebrec D, De Fleury P, Rueff B, et al. Portal hypertension, sizeof esophageal varices, and risk of gastrointestinal bleeding inalcoholic cirrhosis. Gastroenterology 1980;79:1139–44.

9. De Franchis R, Primignani M. Why do varices bleed? Gas-troentrol Clin North Am 1992;21:85–101.

10. Vinel JP, Cassigneul J, Levade M, et al. Assessment of shortterm prognosis after variceal bleeding in patients with alco-holic cirrhosis by early measurement of portohepatic gradient.Hepatology 1986;6:116–17.

11. Lo GH, Lai KH, Cheng JS, et al. Emergency banding ligationversus sclerotherapy for the control of active bleeding fromesophageal varices. Hepatology 1999;25:1101–04.

12. Stiegman GV, Goff JS, Michaletz-Onody PA, et al. Endoscopicsclerotherapy as compared with endoscopic ligation for bleedingesophageal varices. N Engl J Med 1992;326:1527–32.

13. Laine L, el-Newihi HM, Migikovsky B, et al. Endoscopicligation compared with sclerotherapy for the treatment ofbleeding esophageal varices. Ann Intern Med 1993;119:1–7.

14. Lo GH, Lal KH, Cheng JS, et al. A prospective, randomizedtrial of sclerotherapy versus ligation in the management ofbleeding esophageal varices. Hepatology 1995;22:466–71.

15. Laine L, Cook D. Endoscopic ligation compared with sclero-therapy for treatment of esophageal varices bleeding: A meta-analysis. Ann Intern Med 1995;123:280–87.

16. Lebrec D, Poynard T, Hillon P, Benharnou JP. Propanolol forprevention of recurrent gastrointestinal bleeding in patients withcirrhosis: A controlled study. N Engl J Med 1981;305:1371–74.

17. Teres J, Bosh J, Bordas JM, et al. Propranolol versus sclero-therapy in preventing variceal rebleeding: A randomized con-trolled trial. Gastroenterology 1993;105:1508–14.

18. Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short termeffects of propranolol on portal venous pressure. Hepatology1986;6:101–6.

19. Labrec D, Hillon P, Munoz C, et al. The effect of propranololon portal hypertension in patients with cirrhosis: A hemody-namic study. Hepatology 1982;2:523–27.

20. Merkel C, Merin R, Sacerdoti D, et al. Long term results of aclinical trial of nadolol with or without isosorbide mononitratefor primary prophylaxis of variceal bleeding in cirrhosis.Hepatology 2000;31:324–9.

21. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamicsevents in a prospective randomized trial of propranolol versusplacebo in a prevention of a first variceal hemorrhage. Gas-troenterology 1980;99:1401–07.

22. Feu F, Garcia-Pagan JC, Bosch J, et al. Relation betweenportal pressure response to pharmacotherapy and risk of re-current variceal hemorrhage in patients with cirrhosis. Lancet1995;346:1056–58.

23. Markel C, Bolognesi M, Sacerdoti D, et al. The hemodynamic

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response to medical treatment of portal hypertension as apredictor of clinical effectiveness in the primary prophylaxisof variceal bleeding in cirrhosis. Hepatology 2000;32:930–4.

24. Sarin SK, Lamba GS, Kumar M, et al. Comparison of endo-scopic ligation and propranolol for the primary prevention ofvariceal bleeding. N Engl J Med 1999;340:988–93.

25. Bosch J, Mastal R, Kravatz D, et al. Effect of propranolol onazygous venous blood flow and hepatic and systemic hemo-dynamics in cirrhosis. Hepatology 1984;4:1200–5.

26. Merkel C, Sacerdoti D, Bolognesi M, et al. Hemodynamicevaluation of the addition of isosorbide-5-Mononitrate tonadolol in cirrhotic patients with insufficient response to thebeta-blocker alone. Hepatology 1997;26:34–9.

27. Villanueva C, Balanzo J, Novella MT, et al. Nadolol plusisosorbide mononitrate compared with sclerotherapy for theprevention of variceal rebleeding. N Engl J Med 1996;334:1624–9.

28. Goumay J, Masliah C, Martin T, et al. Isosorbide mononitrateand propranolol compared with propranolol alone for the pre-vention of variceal rebleeding. Hepatology 2000;31:1239–45.

29. Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligationplus nadolol and sucarifate compared with ligation alone forthe prevention of variceal rebleeding: A prospective, random-ized trial. Hepatology 2000;32:461–6.

Surveillance and Surgeryfor Barrett’s Esophagus:More Results From SwedenOberg S, Johansson J, Wenner J, et al.Endoscopic Surveillance of Columnar-Lined Esophagus;Frequency of Intestinal Metaplasia Detection and Impact ofAntireflux SurgeryAnn Surg 2001;234:619–26

ABSTRACTThis study evaluated the prevalence of intestinal metaplasia(IM) in patients with varying lengths of columnar-linedesophagus (CLE) during long-term endoscopic and his-topathologic surveillance. A total of 177 patients were fol-lowed for a median surveillance period of 5.1 yr and amedian four endoscopies per patient. Fifty-two percent ofthe patients had IM at first surveillance endoscopy. Theprevalence of IM increased with increasing number of en-doscopies, and after six endoscopies the IM prevalence hadincreased from �30% to �64% in patients with a 1–2 cmCLE length, and from �45% to �89% in those with a 3–4cm length. IM was found in longer CLE segments early inthe surveillance period, whereas detection of IM was evenlyspread out over the surveillance period in the short segmentpatients.

A second aim of this study was to compare the effective-ness of antireflux surgery with acid suppressant therapy inpreventing the development of IM. Studying patients with-out IM at the first two endoscopies, the investigators foundthat IM developed significantly less frequently among the20 surgically treated patients compared with the 49 medi-cally treated patients (PPI therapy in 45 out of 49). The time

to development of IM was shorter in the medically treatedgroup (p � 0.001, log-rank test) and in a multivariablelogistic analysis, prior antireflux surgery was the only sig-nificant factor associated with a reduced risk of intestinal-ization (10.3-fold decreased risk). (Am J Gastroenterol2002;97:2136–2137. © 2002 by Am. Coll. of Gastroenter-ology)

COMMENT

This study is the first to quantify the frequency and timingof the development of intestinal metaplasia during endo-scopic surveillance in patients with CLE. That this studyshould originate from Sweden is not surprising, firstly be-cause the medical system in that country greatly facilitatesthe collection of thorough follow-up data, and secondlybecause in other places prolonged follow-up of patientswithout IM is unlikely. The study’s principal finding, thatthe pattern of detection of IM differed according to thelength of the columar segment, has some important impli-cations. As the authors conclude, the fact that the cumulativeprevalence of IM in long segment CLE rapidly reached100% suggests that goblet cells are always or almost alwayspresent in long segment CLE, but even with a rigorousbiopsy protocol the false negative sampling error rate is 20%or more.

Intestinal metaplasia developed gradually over time inshort segment CLE. This finding supports the hypothesisthat Barrett’s esophagus develops from areas of non-intes-tinalized metaplastic columnar cells. According to this hy-pothesis, normal squamous epithelium in the esophagus isreplaced first by a simple columnar epithelium termed car-diac mucosa, within which, in a second cellular alteration,IM develops in some patients. Although the acquired natureof cardiac mucosa has been disputed (1), there is someevidence that the presence of this epithelium is associatedwith abnormal gastroesophageal reflux (2, 3).

The clinical implications of these findings are that pa-tients with a long segment of columnar epithelium probablyhave Barrett’s esophagus and should be entered in a sur-veillance program regardless of the presence or absence ofgoblet cells at initial endoscopy. These findings also suggestthat patients with short non-IM CLE should have at least onefollow-up endoscopy (at 5 yr, suggest Oberg et al.) becausethey can develop Barrett’s esophagus. Finally, the findingthat non-IM patients treated medically were significantlymore likely to develop IM than those treated surgicallyagain raises the question of whether the antireflux control(4) offered by a properly performed fundoplication has anybeneficial effect on the natural history of this disease that isnot provided by medical therapy alone. Ye et al. (5) recentlyreported another Swedish study, this one including morethan 10,000 post-antireflux surgery patients, which foundthat surgery did not protect against the development of

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