SELECTED SUMMARIESHenry J. Binder, M.D.

Selected Summaries EditorYale University School of MedicineNew Haven, Connecticut 06520-8019

STAFF OF CONTRIBUTORS

Laurence Blendis, Toronto, CanadaRobert Bresalier, Detroit, MIGuadalupe Garcıa-Tsao, New Haven, CTWilliam L. Hasler, Ann Arbor, MICyrus Kapadia, New Haven, CT

Ronald L. Koretz, Sylmar, CAKris V. Kowdley, Seattle, WAWayne Lencer, Boston, MAPankaj Pasricha, Galveston, TXWilliam Sandborn, Rochester, MN

Mitchell L. Schubert, Richmond, VAFergus Shanahan, Wilton, Cork, IrelandJacques Van Dam, Boston, MADavid C. Whitcomb, Pittsburgh, PA

AN ADVANCE IN THE TREATMENT OF PORTALHYPERTENSION?

Banares R, Moitinho E, Piqueras B, Casado M, Garcia-Pagan J-C,de Diego A, Bosch J (Hepatic Hemodynamics Laboratory, LiverUnit, Hospital General Universitario Gregorio Maranon, Uni-versidad Complutense, Madrid, Spain; and Hepatic Hemody-namics Laboratory, Liver Unit, Institut de Malalties Digestives,Hospital Clinic, Institut de Investigacio, Biomedica August Pii Sunyer, Universitat de Barcelona, Spain). Carvedilol, a newnonselective b-blocker with intrinsic anti–a-1-adrenergic ac-tivity, has a greater portal hypertensive effect than propranololin patients with cirrhosis. Hepatology 1999;30:79–83.

About one third of cirrhotic patients with esophageal variceswill bleed over the course of a 10-year follow-up period. Thosewho survive the initial variceal bleed have a 70% risk ofrebleeding in 1 year if left untreated. Propranolol, a nonselec-tive b-blocker, has been shown to be effective as primary andsecondary prophylaxis against esophageal variceal bleeds, butthe response to its portal hypotensive effect is variable. Banareset al. studied the acute effects of carvedilol, a new nonselectiveb-blocker with a-blocking activity, to determine whether thecombined a- and b-blocking actions could result in a greaterreduction in the portal pressure, thereby conferring a greaterprotection against variceal bleeding. Fourteen cirrhotic pa-tients were treated with 25 mg oral carvedilol, and theirsystemic and splanchnic hemodynamics were assessed beforeand 1 hour after carvedilol administration. The 25-mg dose ofcarvedilol was chosen because the 12.5-mg dose did notproduce a significant reduction of the hepatic venous pressuregradient (HVPG) in a similar group of cirrhotic patients. Theresults of the 25-mg dose of carvedilol were compared withthose of another 14 patients, who were given an intravenous0.15-mg/kg bolus of propranolol followed by a continuousinfusion of 0.2 mg/kg, and with those of a third group of 7patients given placebo. Both carvedilol and propranolol pro-duced a significant reduction in HVPG, hepatic blood flow(HBF), and azygos blood flow compared with the placebogroup who showed no change. However, the reduction inHVPG achieved with carvedilol (from 19.5 6 1.3 to 15.4 6 1.0mm Hg) was significantly greater than that achieved withpropranolol (from 20.4 6 1.1 to 17.7 6 0.8 mm Hg). Also,

64% of patients in the carvedilol group had a decrease inHVPG either by <20% or to a level #12 mm Hg, thethreshold for esophageal variceal bleeding, compared with 14%of patients in the propranolol group (P , 0.05). The reduc-tions in cardiac output and heart rate were similar between thecarvedilol and propranolol groups. However, carvedilol pro-duced more systemic hypotension. Mean arterial pressuredecreased significantly from 89 6 4 to 73 6 3 mm Hg(P , 0.05); systemic vascular resistance also decreased signifi-cantly from 938 6 51 to 845 6 54 dyn · s · cm25 (P , 0.05).In contrast, no such systemic hypotensive effects were observedwith propranolol. The investigators therefore concluded thatcarvedilol potentially could be more beneficial than a portalhypotensive agent. However, its potential benefits as a treat-ment for complications of portal hypertension need to beevaluated carefully against its significant systemic hypotensiveeffects.

Comment. Bleeding from esophageal varices is associated withmortality rates ranging from 3% to 70% (Gastroenterology 1981;81:944–952). Therefore, many pharmacological agents capable of reduc-ing portal pressure have been used as primary prophylaxis against theinitial bleed and as secondary prophylaxis against rebleeding after theinitial bleed. Nonselective b-blockers such as propranolol or nadololcan reduce portal pressure by reducing the portal inflow (PharmacolTher 1994;64:65–107). This is achieved by blocking the b1-adrenergic receptors of the heart, leading to a reduction in cardiacoutput and therefore regional blood flow. In addition, blockage of theb2-vasodilatory adrenergic receptors in the splanchnic circulationallows unopposed a-adrenergic–mediated vasoconstriction in thesplanchnic capillary bed, further reducing the splanchnic inflow(Hepatology 1982;2:528–531). With this, propranolol was shown tobe more effective than placebo in both the prevention of the indexvariceal bleed (Ann Intern Med 1992;117:59–70, N Engl J Med1991;324:1532–1538) and in reducing recurrent variceal bleeds(Hepatology 1997;25:64–70, Lancet 1990;336:153–156). However,the portal hypotensive effect of propranolol is not universal (Hepatol-ogy 1984;4:1200–1205), with only one third of patients achieving an<20% reduction in HVPG or a decrease of HVPG to a value of,12mm Hg, the critical threshold portal pressure for varicealbleeding (Hepatology 1985;5:419–424). Therefore, many other thera-pies, whether singly or in combination with propranolol, have beentried to reduce portal pressure further. For example, the combinationof isosorbide-5-mononitrate (ISMN) and propranolol has been shownto significantly reduce the risk of variceal rebleeding (N Engl J Med1996;334:1624–1629).

GASTROENTEROLOGY 2000;118:802–805

Recently the combination of an a-adrenergic blocker, prazosin, andpropranolol has been studied (Gastroenterology 1998;115:116–123).The a-adrenergic–blocking action reduces intrahepatic resistancewhile leaving the hepatic blood flow unchanged. The authors foundthat this combination had a greater portal hypotensive effect than thecombination of propranolol plus ISMN. However, the development ofsignificant systemic hypotensive effects and clinical fluid retentionwere major disadvantages. Thus, the recent development of a b-adren-ergic blocker with a milder a-adrenergic–blocking action, such ascarvedilol, looked more promising. Milligram for milligram, carve-dilol is 2–4 times as potent as propranolol as a b-adrenergic antagonist(Therapiewoche 1982;32:5714). Because the ratio of its a1-adrenergicand b-adrenergic–blocking activities is 1:10 (Eur J Pharmacol1990;38[suppl 2]S112–S114), it has significantly less side effects thanother a- and b-adrenergic antagonists such as lebatolol. Therefore, itsfirst assessment as a portal hypotensive agent in patients with cirrhosis( J Hepatol 1996;25:909–915) showed that carvedilol caused asignificant reduction in the HVPG. This was mainly caused by areduction in the wedged hepatic venous pressure (approximately220%), probably reflecting a reduction in intrahepatic resistance.Carvedilol also caused a significant reduction in cardiac output andheart rate through its b-adrenergic–blocking action. However, trouble-some systemic hypotension was observed in both studies, especially inpatients with ascites; this was significantly more severe than that seenwith propranolol alone ( J Hepatol 1996;25:909–915). This may bebecause patients with severe liver disease tend to have higher plasmaconcentrations of carvedilol, because its metabolism primarily occursin the liver (N Engl J Med 1998;339:1759–1765). As with prazosin(Gastroenterology 1995;109:1257–1265 and 1998;115:116–123),carvedilol may also rarely cause edema and reversible deterioration inrenal function (N Engl J Med 1996;334:1349–1355), especially in thesetting of low systemic blood pressure or renal insufficiency (N Engl JMed 1998;339:1759–1765). In a single-dose study, carvedilol did notproduce a decrease in renal plasma flow (J Hepatol 1996;25:909–915)in a small number of cirrhotic patients. In a recent study, carvedilol,25 mg orally, was administered for 4 weeks. The reduction of 20% inHVPG was maintained, and renal function was unaffected. However,the dropout rate was high (41%), mostly because of systemichypotension (J Hepatol 1999;30:479–484).

In summary, it seems that carvedilol may not be a medicaltherapeutic alternative for the long-term management of esophagealvarices in patients with cirrhosis.

FLORENCE WONG

LAURENCE BLENDIS

Reply. We entirely agree with the concern of Drs. Wong andBlendis on the potential adverse effects on renal function and sodiumretention of any drug causing systemic hypotension in patients withcirrhosis. This was emphasized in the discussion part of our study.Actually, our group was the first to describe this important limitationfor the use of vasodilators in treatment of portal hypertension(Hepatology 1993;17:800–806 and 1994;20:1502–1508, Gastroenter-ology 1995;109:1257–1265), which is widely recognized today(Gastroenterology 1997;113:1794–1797). While we agree with theircomments, we think that their final conclusion that ‘‘carvedilol maynot be a medical therapeutic alternative’’ probably is a little bit avantla lettre, and that this question should be answered by appropriateclinical trials. To provide an example supporting our view, if we hadfollowed the above recommendations by Drs. Wong and Blendis, thecombination of propranolol (or nadolol) with ISMN would have neverbeen used clinically, because the hypotension caused by this drug

combination in our first, short-term administration study (Hepatol-ogy 1990;11:230–238) was similar to that caused by carvedilol.Subsequent studies during long-term administration showed that thehypotensive effects were much less when ISMN was slowly titratedagainst arterial blood pressure and clinical tolerance, and that therewere no adverse effects on renal function (Hepatology 1994;20:1502–1508). To some extent, the same happened with prazosin (Gastroenter-ology 1995;109:1257–1265 and 115:116–123), which caused muchless hypotension and adverse renal effects when given in combinationwith propranolol on a long-term basis. This is probably becauseb-blockade suppresses renin release, which plays an important roletriggering sodium retention. It is very unfortunate that we do not havea vasodilator acting solely in the liver and devoid of systemic effects,because such a drug would be the drug to use in portal hypertension,alone or associated with b-blockers. Meanwhile, we cannot discard theuse of b-blockers with small doses of vasodilators. Perhaps carvedilolwill not be the final answer, but it is worth to keep trying.

RAFAEL BANARES, M.D.

JUAN C. GARCIA–PAGAN, M.D.

JAIME BOSCH, M.D.

SALMONELLA PATHOGENESIS: THE TROJANHORSE OR THE NEW YORK SHUTTLE?

Vazquez-Torres A, Jones-Carson J, Baumler AJ, Falkow S, ValdiviaR, Brown W, Le M, Berggren R, Parks WT, Fang FC. (Depart-ments of Medicine, Pathology, and Microbiology, University ofColorado Health Sciences Center, Denver, Colorado; Depart-ment of Immunology, National Jewish Center for Immunologyand Respiratory Medicine, Denver, Colorado; Department ofMedical Microbiology and Immunology, Texas A&M Univer-sity, College Station, Texas; Department of Microbiology andImmunology, Stanford University School of Medicine, Stan-ford, California; Department of Medicine, Veterans AffairsMedical Center, Denver, Colorado; and Laboratory of CellRegulation and Carcinogenesis, National Cancer Institute,National Institutes of Health, Bethesda, Maryland). Extraintes-tinal dissemination of Salmonella by CD18-expressing phago-cytes. Nature 1999;401:804–808.

The intestine functions as an effective barrier againstinvasion of 108–1010 bacteria that normally colonize theintestinal lumen. However, certain bacterial pathogens, such asSalmonella, Shigella, and Yersinia, opportunistically invade thehealthy intestine. These pathogens first breach the epithelialbarrier by exploiting the transepithelial transport activity of Mcells located in the so-called dome epithelium that coversorganized lymphoid follicles of the intestine. In the case ofSalmonella, entry into the mucosa via M cells, or invasion ofcultured epithelial cells, requires the coordinate action ofspecific bacterial virulence factors. On the other hand, there isevidence that certain Salmonella typhimurium strains deficient insuch virulence factors can still invade the host intestine, spreadto the liver and spleen, and cause lethal disease.

Vazquez-Torres et al. tested the idea that S. typhimurium maycross the intestinal barrier and disseminate from the intestineby invading CD18-positive mucosal macrophages or dendritic

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