could have been caused by coinfection with hepatitis A and non-A, non-B hepatitis viruses, with the latter being responsible for the subsequent chronic liver disease. This possibility can be confirmed or refuted by testing for antibody to hepatitis C virus. However, even if hepatitis C virus infection is confirmed, the persistence of serum IgM anti-HAV may still indicate concomitant persistent HAV infection in this patient. It has been suggested by a recent study on hepatitis delta virus infection that instead of viral interference, coreplication of two viruses may accelerate the progression of the liver disease (10). By analogy, it is an intriguing possibility that HAV may coreplicate with another associated virus and induce progressive liver disease. Another possibility that deserves consideration is that the progressive clinical and histological course in this patient may have been the results of an HAV-triggered autoimmune reaction, as has been observed in HBV infections. However, it is not a likely possibility because the autoantibodies were negative and serum electrophoresis was normal. Obviously, the cause of the chronic hepatitis in this patient is uncertain. The concept that HAV infection does not lead to chronic hepatitis is still valid unless HAAg can be demonstrated in the second or third liver biopsy of this patient. One thing that is quite certain, however, is that steroid therapy is not indicated in acute viral hepatitis of any type. Indeed, it may be contraindicated.
YUN-FANLIAW,M.D. Liver Unit Chang Gung Memorial Hospital Chang Gung Medical College Taipei, Taiwan REFERENCES 1. Routenberg JA, Dienstag JL, Harrison WO, Kilpatrick ME, Hooper RR, Chisari FV,Purcell RH, et al. Foodborne outbreak of hepatitis A clinical and laboratory features of acute and protracted illness. Am J Med Sci 1989;278:123-131. 2. Weir WRL, Mellor JA, Smith H, Tyrell DAJ. Significance of hepatitis enzyme levels at discharge in acute viral hepatitis. J Infect Dis 1981;3:309-315. 3. Gruer LD, McKendrick MW,Beeching NJ, Geddes AM. Relapsing hepatitis associated with hepatitis Avirus. Lancet 1982;2:163-165. 4. Jacobson IM, Nath BJ,Diestag JL. Relapsing viral hepatitis type A. J Med Virol 1985;16:163-169. 5. Tanno H, Jay OH, Rojman JA, Palazzi J. Biphasic form of hepatitis A virus infection: a frequent variant in Argentina. Liver 1988;9: 53-57. 6. Kao HW, Ashcavai M, Redeker AG. The persistence of hepatitis A IgM antibody after acute clinical hepatitis A. HEPATOLOGY 1984;4: 933-936. 7. Liaw YF', Yang CY, Chu CM, Huang MJ. Appearance and persistence of hepatitis A IgM antibody in acute clinical hepatitis A observed in an outbreak. Infection 1986;14:156-158. 8. Frosner GG, Gauss-Miller V, Siegl G, Scheid R, Messelberger V, Traschin JD, Deinhardt F. Adaptation of human hepatitis A virus to growth in tissue culture and development of chronic persistent infection. In: Szmuness W, Alter HJ, Maynard JE,eds. Viral hepatitis. Philadelphia: Franklin Institute Press, 1982: 803-804.
9. Mathiesen LR, Feinstone SM, Purcell RH, Wagner JA. Detection of hepatitis A antigen by immunofluorescence. Infect Immunol 1977;18:524-530. 10. Scaglioni PP, Pasquinelli C, Marchegiano P, Mellegari M, Mao GP, Manenti F, Villa E. Hepatitis D virus (HDV) and hepatitis B virus (HBV) co-replication results in a rapidly progressive disease [Abstract]. J Hepatology 1989;9:S220.
PROPRANOLOL-INDUCEDREDUCTION IN RECURRENT VARICEAL HEMORRHAGE IN SCHISTOSOMIASIS Kiire CR. Controlled trial of propranolol to prevent recurrent variceal bleeding in patients with noncirrhotic portal fibrosis. Br Med J 1989;298:1363-1365.
ABSTRACT Fifty patients with non-cirrhotic portal fibrosis who were admitted to hospital because of upper gastrointestinal bleeding were randomly assigned to treatment with either oral propranolol given in doses that reduced the resting pulse rate by 25%(26 patients) or with a placebo (25 patients). One year after the start of the study 20 patients in the propranolol group and five patients in the placebo group were free from recurrent gastrointestinal bleeding (p < 0.0001). Giving continuous oral propranolol treatment is therefore effective in preventing recurrent upper gastrointestinal bleeding in patients with noncirrhotic portal fibrosis. COMlVIENTS
Out of Africa
The paper by Kiire is a remarkable document. It reports the results of a randomized clinical trial (RCT) from Zimbabwe in which P-adrenergic blockade was used to prevent recurrent hemorrhage from varices in patients with noncirrhotic portal hypertension. In a group of 50 patients, three fourths of whom had schistosomiasis, this article reports a fourfold reduction in the prevalence of recurrent bleeding from varices and from acute gastric erosions (p < 0.001). Mortality was also decreased by a factor of four (16% to 4%), but this difference is not statistically significant. This investigation is remarkable for several reasons. It is the first RCT of P-blockade performed predominantly in noncirrhotic patients. Second, it provides important clinical observations about the pathogenesis of variceal bleeding and its prevention. Third, it was performed in what is generally referred to as an emerging nation in darkest Africa, an unlikely birthplace of RCTs. In addition to Kiire's paper eight RCTs that were designed to compare the effects of p-blockade and placebo in the prevention of rebleeding in patients who had survived the first episode of hemorrhage have been published in peer-reviewed journals (1-9). All were performed in patients with cirrhosis, most of which was of alcoholic origin. Noncirrhotic portal hypertension includes schistosomiasis, chronic hepatitis, portal vein obstruction,
Vol. 11, No. 6, 1990
Indian childhood fibrosis, idiopathic portal hypertension and a variety of other lesions. This diverse group of disorders is characterized by presinusoidal portal hypertension. Alcoholic cirrhosis causes sinusoidalpostsinusoidal portal hypertension, but all other types of cirrhotic or noncirrhotic portal hypertension have some degree of presinusoidal portal hypertension (10). Schistosomiasis is the prototype of presinusoidal portal hypertension, although in its more advanced stages it may have components of sinusoidal or postsinusoidal portal hypertension as well. It is not clear that the mechanism of variceal development and rupture is identical in cirrhotic and noncirrhotic portal hypertension, although it is often assumed that a varix is a varix and that portal hypertension is portal hypertension. At best, that hypothesis is null. Although there is nothing inherently difficult in designing RCTs, their performance in an objective manner is an extremely complex exercise. They require careful prospective organization, the creation of a modus operandi, close contact with and clinical control of many patients and health care personnel, careful recording of diverse data and much leg work to keep track of the patients and to assemble all the information. The author and associates deserve our applause. What was required in this study? Initially, an endoscopical diagnosis of the original bleeding episode was needed. This procedure was performed in all 50 patients. It required explanation of the concept of a new, experimental therapy to each of a sizable group of patients and the securing of the patients’ interest and trust. It required that the patients have a liver biopsy to document the hepatic histological findings. All the patients apparently agreed to participate. Now comes the tricky part. It required explaining to the patients the complex concept of random selection so that half the patients would receive the presumably beneficial new treatment and half would be treated by older, traditional methods (i.e., by no specific therapy). To admit and diagnose the patients, to stabilize them, to invite or convince them to participate, to biopsy them and to randomize them all within 2 days of emergency admission requires superb organization. Finally, if and when the patients rebled from varices, as half of them did, it required repeat, urgent endoscopy during the bleeding episode to establish the source of the recurrent hemorrhage. Such investigations, which are performed in addition to the actual treatment, must be carried out over a period of months, at least. All the patients must be seen periodically, their medications renewed, their side effects assessed and their compliance calculated. This is an impressive performance that requires a well-disciplined team. Such complicated investigations require careful detailed organization that is not usually the forte of emerging nations. Such investigations are difficult to conduct even at clinical centers in developed nations. From personal experience I know that conducting such RCTs in the urban United States requires
persistent, meticulous attention. Is it, somehow, less so in Harare, Zimbabwe? Or is it even more difficult? Incidentally, in undeveloped countries portal hypertension is caused almost invariably by infections or infestations. In the developed- or perhaps more accurately, over-developed- nations, the usual cause is alcohol. Were there any mitigating circumstances? Were the patients selected for compliance or for residence close to the hospital, as they were in the study of Lebrec et al. (l)?Were the patients, and/or the endoscopists, or both, incarcerated in the hospital to ensure availability at times of need? How many endoscopists were involved? Despite the applause for this fine investigation, it is not a perfect study. Indeed, the perfect study has not yet been performed or reported. It does, however, have many of the virtues and vices of the study of Lebrec et al. (11, which it carefully copied. Bleeding from both acute gastric erosions and varices were considered endpoints of the study. This causes some confusion because the two lesions have not been proved to be equivalent, although they both appear to march to the same drummer. Propranolol dosage was based on the resting heart rate, which is not the most precise index of its effects on portal pressure. Although a placebo was administered, it was not a double-blinded study. Complications of therapy were not mentioned. Although portal pressure was not measured, it is difficult to do under ideal circumstances because pressure levels in patients with presinusoidal portal hypertension are artifactually low when measured by hepatic vein catheterization. Perhaps, it is not necessary to have done so, since prior studies have shown that all alcoholic cirrhotic patients with varices have hepatic vein pressure gradients of at least 12 mm Hg (11).Do all patients with schistosomiasis and varices have significant portal hypertension? Finally, this study was performed in relatively healthy “patients with good liver function” who were considered equivalent to Child’s class A patients. Indeed, the authors suggest that in patients withpoor liver function elevated levels of catecholamines may have vasoconstriction that counterbalances the propranolol-induced reduction in pressure. This hypothesis deserves testing. For those who have the need to keep score, Pblockade has significantly reduced the risks of recurrent hemorrhage in seven of the 10 RCTs, including the investigation under discussion. In sport parlance propranolol has won seven and tied three. There have been no losses. This trial shows that propranolol can decrease rebleeding from varices in presinusoidal portal hypertension, as well as in the sinusoidal portal hypertension of alcoholic cirrhosis. It does not, however, explain the mechanism of the beneficial effects of propranolol, since P-blockade can reduce portal venous pressure, intravariceal pressure and azygous blood flow, each of which has been implicated as a critical factor in the pathogenesis of hemorrhage from varices.
Although there were fewer deaths in the propranolol group than in the placebo group, this difference is not statistically significant. It would be a surprise if it were, because in only one study did propranolol appear to improve survival in cirrhotic patients (1).In schistosomiasis the loss of portal venous blood flow is partly compensated for by an increase in hepatic arterial flow. Furthermore, in schistosomiasis the absence of abnormal hepatic function, coagulopathy and impaired ammonia tolerance, which are characteristic of cirrhosis, should result in improved survival. Clearly, confirmation of these observations is needed, but in the meantime, based on the cumulative evidence cited, it seems reasonable to treat selected patients with large varices of almost any etiology with p-blockade. Most such controlled investigations have shown pblockade to be beneficial. Although several have not, none has shown it to increase the prevalence of bleeding or to be severely toxic. The differences in the results in individual studies appear to be related to patient selection, although prognostic markers have not been clearly identified. Use of p-blockade may also be extrapolated to those patients with schistosomiasis who have not yet bled from varices, a group in whom there may be even more to gain and less to lose (Conn HO, Unpublished observations).
0. CONN, M.D. West Haven Veterans Administration Medical Center Yale University School of Medicine New Haven, Connecticut 06510 HAROLD
REFERENCES 1. Lebrec D, Poynard T, Bernuau J , Bercoff E, Nouel 0,Capron J-P, Poupon R, et al. A randomized controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with 1984;4:355-358. cirrhosis: a final report, HEPATOLOGY 2. Burroughs AK, Jenkins WJ, Sherlock S, Dunk AB, Walt RP, Osuafor TOK, Mackie S, et al. Controlled trial of propranolol for the prevention of recurrent variceal hemorrhage in patients with cirrhosis. N Engl J Med 1983;309:1539-1542. 3. Villeneuve JP, Pomier-Layrargues G, Infante-Rivard C, Willems B, Michel Huet P, Marleau D, Viallet A. Propranolol for the prevention of recurrent variceal hemorrhage: a controlled trial. HEPATOLOGY 1986;6:1239-1243. 4. Gatta A, Merkel D, Sacerdoti M, Bolognesi L, Calegaro R, Zuin P, Angeli A, et al. Nadolol for prevention of variceal rebleeding in cirrhosis: a controlled clinical trial. Digestion 1987;37:22-28. 5. Queuniet AIM, Czernichow P, Lerebours E, Ducrotte P, Trauvonez JL, Colin R. Etude controlee du propranolol dans la prevention des recidives hemorrhagiques chez les patients cirrhotiques. Gastroenterol Clin Biol 1987;11:41-47. 6. Marbet UA, Straumann G, Gyr KE, Bedlinger C, Schaub N, Vogtlin J , Loosli J , et al. Reduction in early recurrence of variceal bleeding by propranolol. Scand J Gastroenterol 1988;23:369-374. 7. Colombo M, deFranchis R, Tommasini M, Sangiovanni A, Dioguardi N. P-Blockade prevents recurrent gastrointestinal bleeding in well-compensated patients with alcoholic cirrhosis: a multicenter randomized controlled trial. HEPATOLQGY 1989;9:433-438. 8. Sheen IS, Chen TY, Liaw YF. Randomized controlled study of propranolol for prevention of recurrent esophageal varices bleeding in patients with cirrhosis. Liver 1989;9:1-5. 9. Garden OJ, Mills PR, Birnie GG, Murray GD, Carter DC. Propranolol in the prevention of recurrent variceal hemorrhage in cirrhotic patients. Gastroenterology 1990;98:185-190. 10. Conn HO, Groszmann RJ. Pathophysiology of portal hypertension. In: The liver: biology and pathobiology. Arias IM, Popper H, Schacter D, Shafritz D., eds. New York Press, 1982:821-848. 11. Garcia-Tsao G, Grace ND,Groszmann RJ,Conn HO, Fisher RR, Atterbury CE, Glickman M. Portal pressure, presence of gastro1985;5:419-424. esophageal varices and bleeding. HEPATOLOGY