Hepatitis B surface antigen carriers — To biopsy or not to biopsy

00~65085/78/7506086~02.00/0 75:08604303. 1978 Copyright0 1978 by the American Gastroenterological Association

Vol. 75,No. 5

~ASTROENTEROLOGY

Printed in U.S.A.

HEPATITIS B SURFACE ANTIGEN CARRIERS-TO TO BIOPSY RONALD L. KORETZ, M.D.,

KLAUS J. LEWIN, M.D.,

BIOPSY OR NOT

DONALD J. REBHUN, M.S.P.H.,

AND GARY L. GITNICK, M.D. Division of Gastroenterology, Department of Medicine and Department Sciences, University of California, Los Angeles, California

of Pathology,

Center for the Health

In order to assess the frequency of significant liver disease in hepatitis B surface antigen carriers with normal liver tests, 54 such individuals were identified and prospectively followed for 4 to 48 months with monthly liver tests. Upon testing, 4 were found to carry e antigen and 14 carried e antibody (anti-e). During follow-up, only 4 patients, none of whom were e antigen-positive, developed persisting abnormalities in liver tests. Of the 23 patients who underwent percutaneous liver biopsies, normal histologies were found in 2, nonspecific changes (ground glass hepatocytes, focal necrosis, fatty changes, etc.) in 18, and chronic persistent hepatitis (with or without other nonspecific changes) in 3. Chronic active hepatitis and/or cirrhosis, lesions which may carry more serious prognostic implications, were not seen in any biopsies. Two of the 4 e antigen-positive patients consented to biopsy, both of whom had chronic persistent hepatitis. All 6 patients with anti-e who underwent biopsy had ground glass hepatocytes, which were found in only about 50% of the remaining patients. It is concluded that hepatitis B surface antigen carriers should be followed with serial liver tests, and those whose tests remain normal should not be considered for liver biopsy. Approximately 0.5% of the population of the United States, or one million people, are carriers of the hepatitis B surface antigen (HBsAg).’ In some other areas of the world, the carrier rate is substantially higher.2 Many carriers of HBsAg are asymptomatic when examined clinically. Serum transaminase levels may or may not be abnormal. Liver biopsies have revealed a range of histological appearances from normal or nonspecific changes through chronic active hepatitis with cirrhosis.2-1y In view of the existence of cirrhosis in some of these individuals, and in view of the possibility that immunosuppressive treatment may be offered to those who have histological chronic active hepatitis,20 the medical implications of liver biopsy in these patients are significant. On the other hand, the expense and potential risk of biopsy in a large population also requires consideration. When studies in Western Europe were contrasted with those in the United States, it was observed that the American patient is more likely to have significant Received February 27, 1978.Accepted May 15, 1978. Address requests for reprints to: Gary L. Gitnick, M.D., Division ofGastroenterology, Department of Medicine, Center for the Health Sciences, University of California, 10833 Le Conte Avenue, Los Angeles, California 90034. This study was supported by Grant RR00865 from the United States Public Health Service. The authors wish to express their gratitude to Olive Stone, Kris Hauss, Maria Rrezina, Susie Ritman, Joanne Dierck, Lynn Puhek, Cindy Jarvis, Dennis Bell, Al Bodt, and David Iwaoka for their cooperation and diligence in obtaining specimens and performing laboratory procedures.

and progressive liver disease. lo*12,l3 One earlier American study suggested that “a substantial proportion, perhaps the majority of Au-positive [i.e., HBsAg-positivel blood donors will have liver disease”.“j The questions arose, therefore, concerning who should undergo liver biopsy or whether all HBsAg-positive patients in the United States should have liver biopsies. One simple screening device might be biochemical liver tests. Some authors have noted an association between abnormal transaminase levels and histological liver disease in HBsAg carriers.7,**13,I5921Others have stated that normal liver tests are not satisfactory in excluding the presence of severe liver disease. g, lo, 14*22,23 In order to ascertain the status of asymptomatic carriers with normal liver biochemical tests, a series of such patients were identified and studied. This report presents the results of that study. Materials and Methods Volunteer blood donors who were found to be HBsAgpositiveby the Los Angeles-OrangeCountyRed Crosswere so notified and offered the opportunity to participate in this study. Those who agreed were interviewedand had blood drawn to confirm HBsAg positivity (Ausria II, Abbott Laboratories, South Pasadena, Calif.) and to determine SGPT levels. Patients who had abnormal SGPT values or were transientHBsAg carrierswere referredto their private physicians. Fifty-four patients who were asymptomaticHBsAg carriersand maintaineda normal SGPI’and positiveHBsAg statuson 4 successive specimens drawn at least 1 month apart

were enrolled into the study. They represented one-half of the HBsAg-positive individuals evaluated for this study. All participants were followed on a monthly basis with SGFI’and HBsAg determinations. They also were tested fore 860

November

HEPATITIS

1978

B SURFACE

antigen and antibody to e antigen (anti-e) by rheophoresis.24 “Biochemical hepatitis” was defined as an otherwise unexplained rise in the SGPT on two consecutive blood tests. Twenty-three patients were admitted to the UCLA Clinical Research Center where they underwent percutaneous liver biopsy. Their slides were mixed with those from other liver biopsies of patients with chronic hepatitis; five slides were submitted in duplicate and the entire set was coded. They were then reviewed by a pathologist (K. J. L.) who had no clinical information and was unaware that extra slides were included in the set. There was exact agreement when the code was broken in the five instances of duplicate slides. There was also exact agreement with the coded interpretation and the clinical interpretation in the cases of the biopsies from the chronic hepatitis patients. Criteria for the histological classification of the liver biopsies were as follows: chronic persistent hepatitis: intact hepatic architecture, widening of the portal tracts with mononuclear (lymphocytes and plasma cells) infiltrate and occasional fibrosis, and foci of hepatocytolysis and acidophilic degeneration; and chronic active hepatitis: widening of the portal tract with severe inflammation, destruction of the limiting plate, and marked fibrosis associated with evidence of intralobular hepatocytolysis. This study was approved by the Human Subject Protection Committee at the Center for the Health Sciences, University of California, Los Angeles.

Results Thirty-six of these patients were men and 18 were women; the mean age was 39 years (ranging from 22 to 64 years). Fifteen of the patients were of Oriental background. None had symptoms referable to hepatic dysfunction, and neither did any have a history of acute hepatitis or drug abuse. The patients were followed for 4 to 48 months with a mean follow-up of 19 months. During the period of follow-up, 12 individuals developed an abnormal SGFT on at least one occasion. However, only 4 of these patients had an unexplained persistently abnormal SGF’T on repeat testing (i.e., biochemical hepatitis). Furthermore, 3 of these 4 patients developed these abnormal SGF’T values only after 2 years of follow-up. (Twenty-one patients have been followed for more than 2 years.) Four of the 54 patients were found to be positive for e antigen and 14 carried anti-e. The remaining 36 were negative for both e and anti-e. One of the 4 patients who developed late SGPT elevation carried anti-e. The other 3 had neither e antigen nor anti-e. The results of liver biopsy are listed in table 1. Characteristics of chronic active hepatitis and/or cirrhosis were not seen in any of the 23 specimens. Although only two biopsies were considered normal, most of the abnormalities were of a nonspecific nature. Only 3 patients had chronic persistent hepatitis. The “nonspecific changes” included fatty changes, focal necrosis of hepatocytes, and collections of lymphocytes without evidence of hepatocellular destruction. Only 2 e antigen-positive patients consented to liver biopsy (table 2). Both had chronic persistent hepatitis, the most sever& histological lesion seen in the series (P < 0.02). However, one of the 6 patients with anti-e who agreed to biopsy also had chronic persistent hepatitis. Of interest, all 6 of these individuals had ground

ANTIGEN

861

CARRIERS TABLE 1. Results of liver biopsy

Normal Groundglass hepatocytesonly Nonspecific changes only Ground glass hepatocyte and nonspecific Chronic persistent hepatitis _~.

e status

TABLE 2. Liver biopsy and v stutus” __-. _._ .._- _~~ Normal GGH NS CPH NO.

are:

0 6 8

2 1 0

2 6 15

e antigen positive Anti-e positive Neither ‘I Abbreviations

changes

CPH,

chronic

persistent

0 5 9 hepatitis;

0 0 2”

GGH.

ground glass hepatocytes; NS, nonspecific changes. )i Four additional patients had only ground glass hepatocytes

as

an abnormality.

glass hepatocytes, a finding seen in only 50% of the remaining patients (P = 0.05). Three of the 4 patients who developed biochemical hepatitis underwent liver biopsy 6 to 26 months before their SGPT became abnormal. Ground glass hepatocytes (as the only abnormality) were seen in one of the specimens, and fatty changes only were seen in the other two. One of these patients underwent a second biopsy after his SGF’T became abnormal, and chronic persistent hepatitis was seen. Discussion The 54 patients followed in this study had no apparent clinical illness. Additionally, only 4 of them developed sustained elevations in SGPT indicating biochemical disease, and even these SGF’T abnormalities were low grade (less than 5 times the upper limit of normal). If the data are computed by an actuarial method,‘” the risk of developing even these low grade transaminase abnormalities over a 3-year period is 16%. Finally, in those patients who consented to undergo liver biopsy, no evidence of liver disease either carrying a poor prognosis (cirrhosis) or tempting some physicians to intervene with immunosuppressive therapy (chronic active hepatitis) was observed. Because of the conflicting views on the reliability of biochemical liver studies, the reported experience”-“’ was reviewed and the data were extracted, where possible, comparing the results of liver biopsy and liver tests. The results of this review are displayed in table 3. As can be seen, the frequency of finding “significant” liver disease (chronic active hepatitis or cirrhosis) in patients with normal transaminase levels is 2% (5 of 2371, whereas this frequency rises to 19% (35 of 189) if the transaminase level is abnormal. It should be pointed out that many of the patients with normal transaminase levels in these series had abnormal liver biopsies (in particular, chronic persistent hepatitis) and, therefore, evidence of liver “disease.” However, these findings are not associated with symptoms, do not progress to significant clinical illness, and have a good prognosis if not treated. Thus, from the patient’s point of view, “disease” does not exist. It should be pointed out that one particular subgroup

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Vol. 75, No. 5

KORETZ ET AL. TABLE

3. SGPT and histology in HBsAg carriersa Normal SGpT

Reference

3 4 5 6 7 8 9 2 10 11 12

13 14 15 16 17 18 19 Current paper

country Denmark Germany Italy Belgium Sweden England Scotland Taiwan Australia Denmark Canada Canada Canada United States United States United States United States United States United States

Carrier population Donors Donors Donors Donors Donors Donors Military personnel Prisoners Acute hepatitis Donors Donors Donors Donors Donors Donors Military personnel Donors

20 34 6 7 17

are: CAH, chronic active hepatitis;

Cirrhosis or CAR

CPH, NS, or norma1

1

No.

Cirrhosis or CAH

4

CPH, NS, or norma1 4

10 5 31

19 34 6 7 17 10 5 31

10

7

2 5 15

2 5 15

4 24 9

3 24 9

15 23

15 23

14

4

10

232

189

35

154

237

Total a Abbreviations

No.

Abnormal SGPT

5

CPH, chronic persistent hepatitis;

of HBsAg carriers, parenteral drug abusers, were not included in this study. As such, one cannot assume that this correlation between normal SGPT and the absence of clinically significant liver disease can be extrapolated to this subgroup. The usefulness of the e antigen system in providing prognostic information could not be thoroughly evaluated in this group of patients because most of them were either anti-e-positive or negative for both e antigen and anti-e. Only 4 patients were found to be carriers of e antigen; 2 of these consented to liver biopsy and both were found to have chronic persistent hepatitis. The presence of anti-e correlated with the presence of ground glass hepatocytes. Ground glass hepatocytes have been correlated with cytoplasmic HBsAg and “inactive” hepatitis126 and the anti-e carrier state has also been associated with a nonprogressive condition.27 In conclusion, chronic HBsAg carriers who are not parenteral drug abusers can be followed with serial SGPT levels only. Those who have repeatedly abnormal values should undergo liver biopsy. The incidence of significant liver disease in the carriers with normal transaminase levels is too low to justify the risk and expense of liver biopsy. REFERENCES Chalmers TC, Alter HJ: Management of the asymptomatic carrier of the hepatitis-associated (Australia) antigen. N Engl J Med 285:613-616, 1972 Anderson KE, Sun S, Berg HS, et al: Liver function and histology in asymptomatic Chinese military personnel with hepatitis B antigenemia. Am J Dig Dis 19:693-703, 1974 Reinicke V, Dybkjaer E, Poulsen H, et al: A study of Australiaantigen-positive blood donors and their recipients, with special reference to liver histology. N Engl J Med 286:867-870, 1972

4 18 5 13

4

8 11 20 16 30 6 30 3

NS, nonspecific

2 15

4 14 5 12 6 9 5 19 14 30 4 15 3

changes.

4. Holtermuller KH, Baumeister HG, Schafer A, et al: Prospective study of hepatitis B antigen (HBsAg) positive carriers (abstr). Gastroenterology 69:830, 1975 Ricci G, De Bat C, Caramia F: Liver disease in Australia antigen carriers. Lancet 1:494, 1972 LaBacq E: Liver disease in carriers of Au antigen. Lancet 2:977978, 1971 Iwarson S, Lindholm A, Lundin P, et al: Hepatitis-associated antigen and antibody in Swedish blood donors. VOX Sang 22:501509, 1972 8. Woolf IL, Boyes BE, Jones DM, et al: Asymptomatic liver disease in hepatitis B antigen carriers. J Clin Path01 27:348-352, 1974 9. Russell RI, Goldberg DM, Allan JG, et al: A study of hepatic disease in Australia antigen and antibody-positive blood donors. Am J Dig Dis 19113-121, 1974 10. Bolin TD, Davis AE, Liddelow AG: Liver disease and cellmediated immunity in hepatitis-associated antigen (HAA) carriers. Gut 14:365-368, 1973 0, Elling P, et al: Incidence and 11. Nielsen JO, Dietrichson meaning of persistence of Australia antigen in patients with acute viral hepatitis: development of chronic hepatitis. N Engl J Med 285:1157-1160, 1971 12. Simon JB, Pate1 SK: Liver disease in asymptomatic carriers of hepatitis B antigen. Gastroenterology 661020-1028, 1974 13. Feinman SV, Cooter N, Sinclair JC, et al: Clinical and epidemiological significance of the HBsAg (Australia antigen) carrier state. Gastroenterology 68:113-120, 1975 14. Villeneuve JP, Richer G, Cote J, et al: Chronic carriers of hepatitis B antigen (HBsAg). Am J Dig Dis 21:18-25, 1976 15. Vittal SB, Sourdourekas D, Shobassy N, et al: Asymptomatic hepatic disease in blood donors with hepatitis B antigenemia. Am J Clin Path01 62649-654, 1974 16. Singleton JW, Fitch RA, Merrill DA, et al: Liver disease in Australia-antigen-positive blood donors. Lancet 2:785-787, 1971 17. Schaefer RA, Finlayson NDC, Prince AM: Liver disease in asymptomatic hepatitis B antigen carriers (abstr). J Clin Invest 53:71, 1974

November I978 18. Griffin

FM: Hepatitis B antigenemia donors. JAMA 226:753-755, 1973

HEPATITIS

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in apparently

healthy

19. Hamilton PA, Sampliner RE, Boitnott JK, et al: Liver disease in relation to liver enzymes in chronic HBsAg carriers (abstr). Gastroenterology 70:983, 1976 20. Schalm SW, Summerskill WHJ, Gitnick GL, et al: Contrasting features and responses to treatment of chronic active liver disease with and without hepatitis B antigen. Gut 17:781-786, 1976 21. Sun S, Beasley RP, Anderson KE, et al: Serial liver biopsy observations in hepatitis B antigen carriers by light and electron microscopy. Am J Dig Dis 21:366-369, 1976 22. Fainaru M, Levii IS: Asymptomatic hepatitis B antigen carriers: a clinicopathological study. Acta Hepatogastroenterol 21:186191. 1974

ANTIGEN CARRIERS 23. Editorial: 24. 25.

26.

27.

What shall we do with the HBAg carrier?

863 Br Med J

4~427-428, 1974 Van Oss CH, Bronson PM: Immunorheophoresis. Immunochemistry 6:775-778, 1969 Greenstein AJ, Sachar DB, Pasternack BS, et al: Reoperation and recurrence in Crohn’s colitis and ileocolitis. Crude and cumulative rates. N Engl J Med 293:685-690, 1975 Ray MB, Desmet VJ, Bradburne AF, et al: Differential distribution of hepatitis B surface antigen and hepatitis B core antigen in the liver of hepatitis B patients. Gastroenterology 71:462-467, 1976 Smith JL, Murphy BL, Auslander MO, et al: Studies of the “e” antigen in acute and chronic hepatitis. Gastroenterology 71:208209, 1976