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Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis
GASTROENTEROLOGY 1985;89:732-5
Hepatic Decompensation Associated With Hepatitis B e Antigen Clearance in Chronic Type J3 Hepatitis I-SHYAN SHEEN, YUN-FAN LIAW, DAR-IN TAI, and CHIA-MING CHU ’ Liver Unit, Chang-Gung Memorial Hospital, Lin-Kou Medical Center, Taipei, Taiwan, Republic of China
To examine hepatic decompensation associated with acute exacerbation preceding hepatitis B e antigen clearance in chronic type B hepatitis, 376 patients with chronic hepatitis who were hepatitis B e antigen-positive were prospectively studied for up to 7 yr (mean 25 mo). Among the 165 patients who underwent hepatitis B e antigen clearance, 4 patients experienced hepatic decompensation and one of them eventually developed hepatic encephalopathy and died. The incidence of hepatic decompensation associated with hepatitis B e antigen cIearante was 2.4%. We suggest that such an event in previously unrecognized chronic hepatitis B carriers could have been erroneously interpreted as acute or subacute hepaticfailure, and that it might have been the result of a stronger enhancement of the host immune response.
It has been well documented that hepatitis B e antigen (HBeAg) seroconversion to its antibody occurs frequently during the course of chronic type B hepatitis (l-4). Our previous study has indicated that about two-thirds ,of such HBeAg clearances are preceded by an abrupt elevation of serum glutamic pyruvic transaminase (SGPT) level and by histologic changes compatible with lpbular hepatitis or even bridging hepatic necrosis (BHN), which was suspected to be the result of enhanced host immune responses (4,5). In other words, acute exacerbations Received June 18, 1984. Accepted April 20, 1985. Address requests for reprints to: Yun-Fan Liaw, M.D., Chief, Liver Unit, Chang-Gung Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan, 105, Republic of China. This work was supported in part by a Grant from the Prosperous Foundation, Taipei, Taiwan, Republic of China. The authors thank Y: C. Ou and L. Y. Wang for their excellent technical assistance and S. W. Hwu for her help in the preparation of this manuscript. 0 1985 by the American Gastroeaterological Association 0016-5085/85/$3.30
of chronic type B hepatitis preceding HBeAg clearance are similar to acute viral hepatitis not only in biochemical and histologic respects, but also, probably, in immunologic mechanisms as well. It is therefore conceivable that hepatic decompensation could also occur in acute exacerbations preceding HBeAg clearance. This study examines hepatic decompensation during the course of chronic type B hepatitis. Materials and Methods The prospective follow-up study of chronic type B hepatitis in the Liver Unit of Chang-Gung Memorial Hospital, as described elsewhere (a$), has been extended to a 7-yr period. A total of 376 HBeAg-positive patients with clinicopathologically verified chronic hepatitis were monitored during this time. The patients were seen by us every 3-6 mo, or more frequently if need be, for a minimum of 6 mo to a maximum of 7 yr. Routine follow-up studies included clinical assessment, conventional liver function tests, assay of serologic hepatitis markers, and (Yfetoprotein level determinations. Follow-up liver biopsy was performed if indicated. Clinical status and liver function tests within 1 mo before and after HBeAg clearance were analyzed. Hepatic decompensation was defined as a syndrome comprising the following features: (a) obvious subjective symptoms, (b) jaundice, (c) ascites, (d) hepatic encephalopathy, and (e) blood coagulation disorders (6). Hepatitis B markers, including hepatitis B surface antigen (HBsAg) and antibody, hepatitis B core antibody, HBeAg, and hepatitis B e antibody, as well as immunoglobulin M class anti-hepatitis A virus antibody, were assayed by commercially available radioimmunoassay (Ausria-II, Ausab, Corab; HBeAg-RIA; HAVAB-M; Abbott Laboratories, North Chicago, Ill.). Anti-6 antibody was assayed by Abbott anti-8 research kits [generously supplied by R & D Department, Abbott Laboratories).
Abbreviation used in this paper: BHN, bridging hepatic necrosis.
HEPATIC DECOMPENSATION WITH HBeAg CLEARANCE
October 1985
733
Table 1. Clinical Features of Patients With Hepatic Decompensation Associated With Hepatitis B e Antigen Clearance
in Chronic
Type B Hepatitis Peak changes during HBeAg clearance
Patient No.
Age (yrl
1
22
2
31 54 40
3 4
Sex
Prior history (mol
Prior histology”
Alb (gidl)
M
12
CAH (4)
2.7
M M M
8 23 16
CLH (0.5) CAH (10) CLH (lo]
3.2 3.0
2.0
Bil (mgidl) 40 8.7 3.8
22
PT (s) 7.5 3 6 6
AFP (ngiml) 754
88 106 1337
SGOTI SGPT (IV/L)
Ascites
Encephalopathy
282670
+++
+
11111965 2861281 315012890
+
_
++ +
_
Histology Massive necrosisb ND ND
Multilobular BHk
Clinical outcome Died Improved Improved
Improved
AFP, a-Fetoprotein; Alb, albumin; BHN; bridging hepatic necrosis; Bil, bilirubin; CAH, chionic active hepatitis; CLH, chronic lobular hepatitis; HBeAg, hepatitis B e antigen; ND, not done; PT, prothrombin time (seconds longer than control]; +, indicates presence; -, b Necropsy. c Biopsy just before decompensation. indicates absence. a Number in parentheses is months before hepatic decompensation.
a-Fetoprotein was assayed by a-feto-RIA-II (Dainabot, Tokyo, Japan). Conventional liver function tests were performed using a sequential multiple autoanalyzer. Prothrombin time was studied using a BBL fibrometer (Becton, Dickinson & Co., Cockeysville, Md.). All liver biopsy specimens were obtained using Menghini needles; specimens were fixed in 10% formalin and stained with hematoxylin and eosin, Masson’s trichrome, and silver impregnation. Hepatic histopathology was interpreted according to the standard criteria (7). Bridging hepatic necrosis was defined as a lesion on a liver biopsy specimen showing at least one confluent area of necrosis bridging a portal triad to a central vein, or three bands of central-tocentral bridging necrosis (8,9).
Results During a 7-yr period (mean 25 mo), HBeAg clearance was observed in 165 patients (149 men and 16 women) with an annual HBeAg clearance rate similar to that of our previous reports (4,5). Among the 165 patients who underwent HBeAg clearance, 4 patients developed hepatic decompensation immediately (l-3 wk) before HBeAg clearance, and 1 of the 4 finally developed hepatic encephalopathy and died. Hepatic decompensation was not observed in any of the 8 patients who cleared HBeAg after antiviral therapy using adenine arabinoside (IO mg/kg . day, 5 dayslwk for two consecutive weeks), nor in the 211 patients who did not clear HBeAg. The incidence of hepatic failure associated with HBeAg clearance in chronic type B hepatitis was 2.4%. The clinical features of the 4 patients who developed hepatic decompensation are shown in Table 1. The clinical course of the patient who died (patient 1) is shown in Figure 1. Patients 1, 2, and 4 were free of any symptoms and signs, except for a mild elevation of SGPT (less than four times the normal level), and no clinical evidence of cirrhosis
was observed l-2 mo before the abrupt development of hepatic decompensation. Two weeks before decompensation, a liver biopsy specimen was obtained from patient 2, which showed features of chronic lobular hepatitis. Patient 3 had had persistent symptoms and a moderate elevation of SGPT, bilirubin, and y-globulin (22 g/dl) for 5 mo before the development of hepatic decompensation. Except for the patient who died, hepatitis B e antibody appeared and SGPT returned to predecompensation levels within 1 mo. Patient 2 underwent a follow-up liver biopsy 6 mo after recovery, and no evidence of chronic active hepatitis or cirrhosis was observed. Liver biopsy specimens were obtained within the 3 mo preceding or during HBeAg clearance in 71 patients. Bridging hepatic necrosis was noted in 38 of the patients (53.5%), including 2 patients who developed hepatic decompensation. No evidence of hepatitis A virus of &superinfection was found in those patients tested, including the 4 patients with hepatic decompensation.
IXscussion This prospective study suggests that acute exacerbation preceding spontaneous HBeAg clearance in chronic type B hepatitis could be so severe as to cause hepatic decompensation and even death. This could occur in patients without prior evidence of chronic active hepatitis or cirrhosis (Table 1). Although it has not been emphasized in the literature, hepatic decompensation after withdrawal of steroid therapy has been mentioned (10). Clinically severe illness associated with spontaneous reactivation of chronic hepatitis B virus (HBV) infectibn has also been reported, but ascites and variceal bleeding occur only in patients with preexisting cirrhosis (11). This study also suggests that the clinical and histologic features of hepatic decompensation asso-
734
SHEEN ET AL.
GASTROENTEROLOGY Vol. 89, No. 4
HBeAg Anti-HBe AFP
\ -2
+
+
+
+
+
191
50
10
10
754
-15;
9
10
11
2
3
Time
Period
-
-
Figure
BOO
+
L%600 I
400 200
2
8
12
1
Month
of Follow-Up
ciated with HBeAg clearance in chronic type B hepatitis are clinically indistinguishable from fulminant hepatitis (x), or subacute hepatic failure (13,14) except for the time scale and better prognosis of chronic hepatitis B infection. It is therefore conceivable that such hepatic decompensation in previously unrecognized HBsAg carriers could have been erroneously classified as type B fulminant hepatitis or subacute hepatic failure. This is particularly likely in Taiwan, an endemic area of HBV infection, where many HBsAg-positive “acute hepatitis”-like episodes are actually acute exacerbations in undiagnosed chronic HBsAg carriers (9,15). Superinfection with other viral agents in chronic HBsAg carriers may induce a far more severe liver injury than single-agent infection (16),and such superinfection may suppress HBV replication (17). Hepatic decompensation associated with HBeAg clearance in chronic type B hepatitis may, therefore, be the result of such superinfection, particularly by the S-agent, which has been advocated as the cause of fulminant course in some cases of HBV (18,19). The possibility of F-superinfection being the cause of hepatic decompensation in this study was excluded. However, the possibility of superinfection with nonA, non-B hepatitis viruses cannot be determined until specific markers become available. Our previous studies have suggested that acute exacerbation with greater severity, as reflected by the elevation of cr-fetoproteins to >lOO ng/ml and the presence of BHN, may represent stronger enhancement of the host immune response, and such exacerbation may predict subsequent HBeAg clearance (5,20,21). This study further demonstrates that the host may have to pay a price as high as multilobular BHN or even massive hepatic necrosis for the inactivation of HBV replication. In contrast, HBeAg clearance after antiviral therapy is usually not pre-
1. The clinical course of the patient (patient 1) with fatal hepatic failure associated with hepatitis B e antigen (HBeAg) clearance. The striped area represents the normal zone of serum glutamic pyruvic transaminase (SGPT) and bilirubin; arrows indicate timing of tissue study: solid and empty bar indicate ascites and variceal bleeding, respectively. Hepatitis B e antigen and hepatitis B e antibody (anti-HBe) are shown as positive (+) or negative (-); a-fetoprotein (AFP) is measured in nanograms per milliliter.
ceded by acute exacerbation (21), and is not accompanied by hepatic decompensation (21-23),as observed in this study. Further examination, however, is required to determine the efficacy of antiviral therapy in the alleviation of such a severe and possibly fatal complication.
References 1. Realdi
2.
3.
4.
5.
6.
7. 8.
9.
10.
G, Alberti A, Rugge M, et al. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology 1980;79:195-9. Lofgren B, Nordenfelt E. Evaluation of a new radioimmunoassay for detecting hepatitis B e antigen and its antibody. J Med Virol 1980;5:323-30. Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981;94:744-8. Liaw YF, Chu CM, Su IJ, Huang MJ, Lin DY, Chang-Chien CS. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology 1983;84:216-9. Liaw YF, Chu CM, Huang MJ, Sheen IS, Yang CY, Lin DY. Determinants for hepatitis B e antigen clearance in chronic type B hepatitis. Liver 1984;4:301-6. Sherlock S. Hepato-cellular failure. In: Sherlock S, ed. Diseases of the liver and biliary system. 6th ed. London: Blackwell Scientific, 1981:79-90. International Group. Acute and chronic hepatitis revisited. Lancet 1977;ii:914-9. Ware AJ, Cuthbert JA, Shorey J, et al. A prospective trial of steroid therapy in severe viral hepatitis: the prognostic significance of bridging necrosis. Gastroenterology 1981;80: 219-24. Liaw YF, Chu CM, Chen TJ, et al. A prospective study on the prognostic significance of bridging hepatic necrosis in acute viral hepatitis. Chin J Gastroenterol 1984;1:13-7. Nair P, Tong MJ, Stevenson D, Roskamp D, Boone C. Pulse prednisone treatment of patients with chronic active hepatitis B: results of a controlled clinical trial. Hepatology 1983;3:877.
October 1985
11. Davis GL, Hoofnagle JH, Waggoner JG. Spontaneous reactivation of chronic hepatitis B virus infection. Gastroenterology 1984;86:230-5. 12. Redeker AG. Viral hepatitis: clinical aspect. Am J Med Sci 1975;270:9-16. 13. Tandon BN, Joshi FAMS, Krishnamurthy L, Tandon HD. Subacute hepatic failure: is it a distinct entity? J Clin Gastroenterol 1982;4:343-6. 14. Sheen IS, Liaw YF, Chu CM, Chen TJ. Subacute hepatic failure. J Formosan Med Assoc 1984;83:1268-73. 15. Liaw YF, Chu CM, Huang MJ, et al. The etiology of adult acute viral hepatitis in an endemic area of hepatitis A and B. Am J Trop Med Hyg 1983;32:1401-6. 16. Dienes HP, Purcell RH, Popper H, Bonino F, Ponzetto A. Simultaneous infection of chimpanzees with more than one hepatitis virus. Hepatology 1981;1:506. 17. Tsiquaye KN, Portmann B, Tovey G, et al. Non-A, non-B hepatitis in persistent carriers of hepatitis R virus. J Med Virol 1983;11:179-89. 18. Rizzetto M, Canese MG, Gerin JL, et al. Transmission of
HEPATIC DECOMPENSATION WITH HBeAg CLEARANCE
19. 20.
21.
22.
23.
735
hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis 1980;141:590-602. Smedile A, Farci P, Verme G, et al. Influence of delta infection on severity of hepatitis B. Lancet 1982;ii:945-7. Liaw YF, Yang SS, Chen TJ, Chu CM. Acute exacerbation in HBeAg-positive chronic type B hepatitis: a clinicopathological study. J Hepatol 1985;1:227-33. Liaw YF, Lin DY, Chen TJ, Chu CM, Sheen IS. Clinicopathological response of HBsAg-positive chronic active hepatitis to adenine arabinoside: lack of correlation with DNA polymerase response. Infection 1984;12:248-50. Scullard GH, Pollard RB, Smith JL, Sacks SL, Gregory PB, Robinson WS, Merigan TC. Antiviral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside. J Infect Dis 1981;143:772-3. Weller IVD, Bassendine MF, Craxi A, et al. Successful treatment of HBsAg and HBeAg positive chronic liver disease: prolonged inhibition of viral replication by highly soluble adenine arabinoside, 5’-monophosphate (ARA-AMP). Gut 1982;23:717-23.
Hepatic Decompensation Associated With Hepatitis B e Antigen Clearance in Chronic Type J3 Hepatitis I-SHYAN SHEEN, YUN-FAN LIAW, DAR-IN TAI, and CHIA-MING CHU ’ Liver Unit, Chang-Gung Memorial Hospital, Lin-Kou Medical Center, Taipei, Taiwan, Republic of China
To examine hepatic decompensation associated with acute exacerbation preceding hepatitis B e antigen clearance in chronic type B hepatitis, 376 patients with chronic hepatitis who were hepatitis B e antigen-positive were prospectively studied for up to 7 yr (mean 25 mo). Among the 165 patients who underwent hepatitis B e antigen clearance, 4 patients experienced hepatic decompensation and one of them eventually developed hepatic encephalopathy and died. The incidence of hepatic decompensation associated with hepatitis B e antigen cIearante was 2.4%. We suggest that such an event in previously unrecognized chronic hepatitis B carriers could have been erroneously interpreted as acute or subacute hepaticfailure, and that it might have been the result of a stronger enhancement of the host immune response.
It has been well documented that hepatitis B e antigen (HBeAg) seroconversion to its antibody occurs frequently during the course of chronic type B hepatitis (l-4). Our previous study has indicated that about two-thirds ,of such HBeAg clearances are preceded by an abrupt elevation of serum glutamic pyruvic transaminase (SGPT) level and by histologic changes compatible with lpbular hepatitis or even bridging hepatic necrosis (BHN), which was suspected to be the result of enhanced host immune responses (4,5). In other words, acute exacerbations Received June 18, 1984. Accepted April 20, 1985. Address requests for reprints to: Yun-Fan Liaw, M.D., Chief, Liver Unit, Chang-Gung Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan, 105, Republic of China. This work was supported in part by a Grant from the Prosperous Foundation, Taipei, Taiwan, Republic of China. The authors thank Y: C. Ou and L. Y. Wang for their excellent technical assistance and S. W. Hwu for her help in the preparation of this manuscript. 0 1985 by the American Gastroeaterological Association 0016-5085/85/$3.30
of chronic type B hepatitis preceding HBeAg clearance are similar to acute viral hepatitis not only in biochemical and histologic respects, but also, probably, in immunologic mechanisms as well. It is therefore conceivable that hepatic decompensation could also occur in acute exacerbations preceding HBeAg clearance. This study examines hepatic decompensation during the course of chronic type B hepatitis. Materials and Methods The prospective follow-up study of chronic type B hepatitis in the Liver Unit of Chang-Gung Memorial Hospital, as described elsewhere (a$), has been extended to a 7-yr period. A total of 376 HBeAg-positive patients with clinicopathologically verified chronic hepatitis were monitored during this time. The patients were seen by us every 3-6 mo, or more frequently if need be, for a minimum of 6 mo to a maximum of 7 yr. Routine follow-up studies included clinical assessment, conventional liver function tests, assay of serologic hepatitis markers, and (Yfetoprotein level determinations. Follow-up liver biopsy was performed if indicated. Clinical status and liver function tests within 1 mo before and after HBeAg clearance were analyzed. Hepatic decompensation was defined as a syndrome comprising the following features: (a) obvious subjective symptoms, (b) jaundice, (c) ascites, (d) hepatic encephalopathy, and (e) blood coagulation disorders (6). Hepatitis B markers, including hepatitis B surface antigen (HBsAg) and antibody, hepatitis B core antibody, HBeAg, and hepatitis B e antibody, as well as immunoglobulin M class anti-hepatitis A virus antibody, were assayed by commercially available radioimmunoassay (Ausria-II, Ausab, Corab; HBeAg-RIA; HAVAB-M; Abbott Laboratories, North Chicago, Ill.). Anti-6 antibody was assayed by Abbott anti-8 research kits [generously supplied by R & D Department, Abbott Laboratories).
Abbreviation used in this paper: BHN, bridging hepatic necrosis.
HEPATIC DECOMPENSATION WITH HBeAg CLEARANCE
October 1985
733
Table 1. Clinical Features of Patients With Hepatic Decompensation Associated With Hepatitis B e Antigen Clearance
in Chronic
Type B Hepatitis Peak changes during HBeAg clearance
Patient No.
Age (yrl
1
22
2
31 54 40
3 4
Sex
Prior history (mol
Prior histology”
Alb (gidl)
M
12
CAH (4)
2.7
M M M
8 23 16
CLH (0.5) CAH (10) CLH (lo]
3.2 3.0
2.0
Bil (mgidl) 40 8.7 3.8
22
PT (s) 7.5 3 6 6
AFP (ngiml) 754
88 106 1337
SGOTI SGPT (IV/L)
Ascites
Encephalopathy
282670
+++
+
11111965 2861281 315012890
+
_
++ +
_
Histology Massive necrosisb ND ND
Multilobular BHk
Clinical outcome Died Improved Improved
Improved
AFP, a-Fetoprotein; Alb, albumin; BHN; bridging hepatic necrosis; Bil, bilirubin; CAH, chionic active hepatitis; CLH, chronic lobular hepatitis; HBeAg, hepatitis B e antigen; ND, not done; PT, prothrombin time (seconds longer than control]; +, indicates presence; -, b Necropsy. c Biopsy just before decompensation. indicates absence. a Number in parentheses is months before hepatic decompensation.
a-Fetoprotein was assayed by a-feto-RIA-II (Dainabot, Tokyo, Japan). Conventional liver function tests were performed using a sequential multiple autoanalyzer. Prothrombin time was studied using a BBL fibrometer (Becton, Dickinson & Co., Cockeysville, Md.). All liver biopsy specimens were obtained using Menghini needles; specimens were fixed in 10% formalin and stained with hematoxylin and eosin, Masson’s trichrome, and silver impregnation. Hepatic histopathology was interpreted according to the standard criteria (7). Bridging hepatic necrosis was defined as a lesion on a liver biopsy specimen showing at least one confluent area of necrosis bridging a portal triad to a central vein, or three bands of central-tocentral bridging necrosis (8,9).
Results During a 7-yr period (mean 25 mo), HBeAg clearance was observed in 165 patients (149 men and 16 women) with an annual HBeAg clearance rate similar to that of our previous reports (4,5). Among the 165 patients who underwent HBeAg clearance, 4 patients developed hepatic decompensation immediately (l-3 wk) before HBeAg clearance, and 1 of the 4 finally developed hepatic encephalopathy and died. Hepatic decompensation was not observed in any of the 8 patients who cleared HBeAg after antiviral therapy using adenine arabinoside (IO mg/kg . day, 5 dayslwk for two consecutive weeks), nor in the 211 patients who did not clear HBeAg. The incidence of hepatic failure associated with HBeAg clearance in chronic type B hepatitis was 2.4%. The clinical features of the 4 patients who developed hepatic decompensation are shown in Table 1. The clinical course of the patient who died (patient 1) is shown in Figure 1. Patients 1, 2, and 4 were free of any symptoms and signs, except for a mild elevation of SGPT (less than four times the normal level), and no clinical evidence of cirrhosis
was observed l-2 mo before the abrupt development of hepatic decompensation. Two weeks before decompensation, a liver biopsy specimen was obtained from patient 2, which showed features of chronic lobular hepatitis. Patient 3 had had persistent symptoms and a moderate elevation of SGPT, bilirubin, and y-globulin (22 g/dl) for 5 mo before the development of hepatic decompensation. Except for the patient who died, hepatitis B e antibody appeared and SGPT returned to predecompensation levels within 1 mo. Patient 2 underwent a follow-up liver biopsy 6 mo after recovery, and no evidence of chronic active hepatitis or cirrhosis was observed. Liver biopsy specimens were obtained within the 3 mo preceding or during HBeAg clearance in 71 patients. Bridging hepatic necrosis was noted in 38 of the patients (53.5%), including 2 patients who developed hepatic decompensation. No evidence of hepatitis A virus of &superinfection was found in those patients tested, including the 4 patients with hepatic decompensation.
IXscussion This prospective study suggests that acute exacerbation preceding spontaneous HBeAg clearance in chronic type B hepatitis could be so severe as to cause hepatic decompensation and even death. This could occur in patients without prior evidence of chronic active hepatitis or cirrhosis (Table 1). Although it has not been emphasized in the literature, hepatic decompensation after withdrawal of steroid therapy has been mentioned (10). Clinically severe illness associated with spontaneous reactivation of chronic hepatitis B virus (HBV) infectibn has also been reported, but ascites and variceal bleeding occur only in patients with preexisting cirrhosis (11). This study also suggests that the clinical and histologic features of hepatic decompensation asso-
734
SHEEN ET AL.
GASTROENTEROLOGY Vol. 89, No. 4
HBeAg Anti-HBe AFP
\ -2
+
+
+
+
+
191
50
10
10
754
-15;
9
10
11
2
3
Time
Period
-
-
Figure
BOO
+
L%600 I
400 200
2
8
12
1
Month
of Follow-Up
ciated with HBeAg clearance in chronic type B hepatitis are clinically indistinguishable from fulminant hepatitis (x), or subacute hepatic failure (13,14) except for the time scale and better prognosis of chronic hepatitis B infection. It is therefore conceivable that such hepatic decompensation in previously unrecognized HBsAg carriers could have been erroneously classified as type B fulminant hepatitis or subacute hepatic failure. This is particularly likely in Taiwan, an endemic area of HBV infection, where many HBsAg-positive “acute hepatitis”-like episodes are actually acute exacerbations in undiagnosed chronic HBsAg carriers (9,15). Superinfection with other viral agents in chronic HBsAg carriers may induce a far more severe liver injury than single-agent infection (16),and such superinfection may suppress HBV replication (17). Hepatic decompensation associated with HBeAg clearance in chronic type B hepatitis may, therefore, be the result of such superinfection, particularly by the S-agent, which has been advocated as the cause of fulminant course in some cases of HBV (18,19). The possibility of F-superinfection being the cause of hepatic decompensation in this study was excluded. However, the possibility of superinfection with nonA, non-B hepatitis viruses cannot be determined until specific markers become available. Our previous studies have suggested that acute exacerbation with greater severity, as reflected by the elevation of cr-fetoproteins to >lOO ng/ml and the presence of BHN, may represent stronger enhancement of the host immune response, and such exacerbation may predict subsequent HBeAg clearance (5,20,21). This study further demonstrates that the host may have to pay a price as high as multilobular BHN or even massive hepatic necrosis for the inactivation of HBV replication. In contrast, HBeAg clearance after antiviral therapy is usually not pre-
1. The clinical course of the patient (patient 1) with fatal hepatic failure associated with hepatitis B e antigen (HBeAg) clearance. The striped area represents the normal zone of serum glutamic pyruvic transaminase (SGPT) and bilirubin; arrows indicate timing of tissue study: solid and empty bar indicate ascites and variceal bleeding, respectively. Hepatitis B e antigen and hepatitis B e antibody (anti-HBe) are shown as positive (+) or negative (-); a-fetoprotein (AFP) is measured in nanograms per milliliter.
ceded by acute exacerbation (21), and is not accompanied by hepatic decompensation (21-23),as observed in this study. Further examination, however, is required to determine the efficacy of antiviral therapy in the alleviation of such a severe and possibly fatal complication.
References 1. Realdi
2.
3.
4.
5.
6.
7. 8.
9.
10.
G, Alberti A, Rugge M, et al. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology 1980;79:195-9. Lofgren B, Nordenfelt E. Evaluation of a new radioimmunoassay for detecting hepatitis B e antigen and its antibody. J Med Virol 1980;5:323-30. Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981;94:744-8. Liaw YF, Chu CM, Su IJ, Huang MJ, Lin DY, Chang-Chien CS. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology 1983;84:216-9. Liaw YF, Chu CM, Huang MJ, Sheen IS, Yang CY, Lin DY. Determinants for hepatitis B e antigen clearance in chronic type B hepatitis. Liver 1984;4:301-6. Sherlock S. Hepato-cellular failure. In: Sherlock S, ed. Diseases of the liver and biliary system. 6th ed. London: Blackwell Scientific, 1981:79-90. International Group. Acute and chronic hepatitis revisited. Lancet 1977;ii:914-9. Ware AJ, Cuthbert JA, Shorey J, et al. A prospective trial of steroid therapy in severe viral hepatitis: the prognostic significance of bridging necrosis. Gastroenterology 1981;80: 219-24. Liaw YF, Chu CM, Chen TJ, et al. A prospective study on the prognostic significance of bridging hepatic necrosis in acute viral hepatitis. Chin J Gastroenterol 1984;1:13-7. Nair P, Tong MJ, Stevenson D, Roskamp D, Boone C. Pulse prednisone treatment of patients with chronic active hepatitis B: results of a controlled clinical trial. Hepatology 1983;3:877.
October 1985
11. Davis GL, Hoofnagle JH, Waggoner JG. Spontaneous reactivation of chronic hepatitis B virus infection. Gastroenterology 1984;86:230-5. 12. Redeker AG. Viral hepatitis: clinical aspect. Am J Med Sci 1975;270:9-16. 13. Tandon BN, Joshi FAMS, Krishnamurthy L, Tandon HD. Subacute hepatic failure: is it a distinct entity? J Clin Gastroenterol 1982;4:343-6. 14. Sheen IS, Liaw YF, Chu CM, Chen TJ. Subacute hepatic failure. J Formosan Med Assoc 1984;83:1268-73. 15. Liaw YF, Chu CM, Huang MJ, et al. The etiology of adult acute viral hepatitis in an endemic area of hepatitis A and B. Am J Trop Med Hyg 1983;32:1401-6. 16. Dienes HP, Purcell RH, Popper H, Bonino F, Ponzetto A. Simultaneous infection of chimpanzees with more than one hepatitis virus. Hepatology 1981;1:506. 17. Tsiquaye KN, Portmann B, Tovey G, et al. Non-A, non-B hepatitis in persistent carriers of hepatitis R virus. J Med Virol 1983;11:179-89. 18. Rizzetto M, Canese MG, Gerin JL, et al. Transmission of
HEPATIC DECOMPENSATION WITH HBeAg CLEARANCE
19. 20.
21.
22.
23.
735
hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis 1980;141:590-602. Smedile A, Farci P, Verme G, et al. Influence of delta infection on severity of hepatitis B. Lancet 1982;ii:945-7. Liaw YF, Yang SS, Chen TJ, Chu CM. Acute exacerbation in HBeAg-positive chronic type B hepatitis: a clinicopathological study. J Hepatol 1985;1:227-33. Liaw YF, Lin DY, Chen TJ, Chu CM, Sheen IS. Clinicopathological response of HBsAg-positive chronic active hepatitis to adenine arabinoside: lack of correlation with DNA polymerase response. Infection 1984;12:248-50. Scullard GH, Pollard RB, Smith JL, Sacks SL, Gregory PB, Robinson WS, Merigan TC. Antiviral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside. J Infect Dis 1981;143:772-3. Weller IVD, Bassendine MF, Craxi A, et al. Successful treatment of HBsAg and HBeAg positive chronic liver disease: prolonged inhibition of viral replication by highly soluble adenine arabinoside, 5’-monophosphate (ARA-AMP). Gut 1982;23:717-23.