Clearance of HBsAg in Seven Patients with Chronic Hepatitis B HIROSHIADACHI, SHUICHI KANEKO, EIKI m T S U S H I T A , YUTAKA INAGAKI, MASASHI UNOURA AND KENICHIKOBAYASHI First Department of Internal Medicine, Kanazawa University, Kanazawa 920 Japan
The natural history of chronic hepatitis B patients who spontaneously cleared serum HBsAg was investigated. A total of 351 patients with chronic hepatitis B were obsemd in our hospital for at least 3 yr. Seven of these patients became HBsAg negative during the follow-up period. HBsAg disappeared within 6 mo (range = 11 to 169 daye, mean = 70 days) after acute elevation of ALT. ALT levels as high as 500 IU were found in three patients, whereas such elevation was not demonstrated in the other four patients. After the disappearance of HBsAg, ALT levels returned to normal in all patients. With one exception, all patients seroconverted to antibody to HBaAg; however, hepatitis B vim DNA remained detectable in serum using the polymerase chain reaction in five patients. The titer of percent inhibition of antibody to HBcAg gradually decreased to less than 70% when a 1:200 dilution of the serum of six patients was used. Four of the patients had active liver disease develop: two had chronic active hepatitie and two had cirrhosis. Three of these four patients subsequently had hepatocellular carcinoma develop. These findings suggest that patients may suffer complications of chronic hepatitis even after normalization of transaminase activities and after the clearance of HBsAg. Thus hepatitis B virus should be considered as a possible factor 8880ciated with hepatocellular carcinoma even in the absence of HBsAg, particularly if serum hepatitis B virus DNA pemists. ( H E P A T O ~ Y1992;16:1334-1337.)
who cleared serum HBsAg to understand the natural history of this disease.
MATERIALS AND METHODS
During the years 1983 to 1991,a total of 351 patients with chronic hepatitis B were observed in our hospital (Kanazawa University, Kanazawa Japan) for at least 3 yr. Seven of these patients became spontaneously HBsAg negative during the follow-up period (Table 1). None of these patients had been treated with corticosteroids, immunostimulants, immunosuppressive agents, interferon or other antiviral drugs. They did not have past history of blood transfusion or drug abuse, and were not homosexuals. These seven patients included five men and two women whose mean age was 48.9yr. Six of the seven patients were histologically diagnosed as shown in Table 1. HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc and IgM antibody to HBc (IgM-HBc) were assayed by RIA (Ausria-11, Ausab, Abbott-HBe, Abbott-HBe, Corab and Anti-HBc-M, respectively; Abbott Laboratories, North Chicago, IL). Results of HBsAg, anti-HBs and HBeAg were expressed as a ratio (sample counts per minute/mean counts per minute for negative controls). A positive result was scored for ratios of 2.1 or greater. Results for anti-HBe and anti-HBc (200-fold dilution) were expressed as percent inhibition (negative control mean counts per minute minus sample counts per minutehegative control mean counts per minute minus positive control mean counts per minute), with a positive result being 30% or greater. Serum HBV DNA was detected using the polymerase chain reaction (PCR) technique (7). The specific primers consisted of primer 1763 5'The clearance of HBsAg from serum of patients with GCTTTGGGGCATGGACATTGACCCGTATAA-3' and primer acute hepatitis B usualIy indicates recovery from in- 2032R 5'-CTGACTACTAATTCCCTGGATGCTGGGTCT-3' fection (1, 2). However, the clinical significance of the for the core gene sequence of HBV genome. Antibody to disappearance of HBsAg during the course of chronic hepatitis C virus (anti-HCV) was tested by enzyme-linked hepatitis B has not been fully explained because the immunoassay (Anti-HCV; Ortho Diagnostics, Tokyo, Japan). clearance ratio seems to be very low (3-6). Although Liver biopsy specimens were immunohistochemically exseveral investigators reported a good prognosis for such amined for the presence of HBcAg using avidin-biotin peroxpatients (3-51, some patients had liver diseases (4,6) and idase complex kit (Histofine-HBc;Nichirei, Tokyo, Japan).
related complications develop. Therefore we investigated the clinical course of chronic hepatitis B patients
RESULTS Activity
Received January 27, 1992; accepted July 24, 1992. Address reprint requests to: Hiroshi Adachi, M.D., First Department of Internal Medicine, Knnazawa University, Takara-Machi 13-1, Kanazawa 920 Japan. 31/1/41639
Of
Hepatitis and HBsAg Clearance.We found
that three patients (patients 2, 3 and 4 ) cleared HBsAg after acute exacerbation of ALT levels (Fig. 1).Peak ALT levels were between 406 and 558 IU and were seen 11to 169 days before the clearance of HBsAg. All three patients had liver disease develop before they cleared HBsAg; two had CAH and one had cirrhosis. In contrast,
1334
1335
CLEARANCE OF HBsAg
Vol. 16, No. 6. 1992
Patient no.1 &,nlmW" I
*
I
T
'
d "BY W L
I"*_.
\ 6'
75
Patient no.2
80
87
'88
'89"
Patient 110.4
Patient 170.3
I a
D Patient no.5
Patient no.6
y1
I
Patient no.7
rm
FIG.1.(A-G) Clinical, biochemical and serologmd course of seven patients who cleared HBBAg. The horizontal line represents level of Berum ALT and titer for HBsAg, HBeAg and anti-HBc. Solid bars indicate positive assays. Arrows indicate the time and the result: chronic persistent hepatitis (CPH),CAH, CAH with lobular disarray (CAH with LD), cirrhosis tI,C), HCC. HBV DNA, IgM-HBc, anti-HCV or intrahepatic HBcAg HBcAg).
TABLE 1. Chracteristics of patients who became H B d g negative during the follow-upperiod Patient
ABe (yr )
Sex
1 2 3 4 5
67 64
M M F M M
6 7
19 54
56 24 37
Blood tramfusion ~
Duration of obeervation (yr)
Histological llndhlg on admission
24
Cirrhosis" CAH Cirrhosis with CAH CAH Chronic persistent hepatitis Chronic persistent hepatitis Not obtained
-
10
-
F
-
6 5 7 7
M
-
6
-
-
"Eventually complicated by HCC
such elevations of ALT levels were not observed in the remained stable. The elevation in the ALT level of other four patients, even though ALT levels of three of patient 1, seen in 1988, was considered to be caused by these patients (patients 5, 6 and 7) were tested at least the effect of transarterial embolization for the treatment once a month (Fig. 1). Three of the four patients had of HCC because HBsAg, HBeAg, anti-HCV and DNA chronic persistent hepatitis (patient 1 was the excep- polymerase were negative. Serial Cha*ges of HBV Markers. For all patients tion). After the disappearance of HBsAg, ALT levels of all patients, except for patient 1. were normalized and HBsAg titers decreased and became less than a ratio of
1336
ADACHI ET AL. DIsa
n&
LC
pannce 01
ncc
Patient no.1
Patient no.2
Patient no.3 1
0
8
6
4
2
2
4
6
8
1012
(years) I ~ ~ I I - ~ B c ~ x z w ) , ~ ~ . ~ ~an11.nBc(xmo).70.h
FIG. 2. Relationship between disappearance of HBsAg and pathemas. Three patients (patients 1,2 and 3) had HCC develop after the disappearance of HBsAg. The horizontal axis represents the course of time, with HBsAg disappearance located as the midpoint. The pathological state and anti-HBc level are simultaneously depicted in the chart.
2.1. For patient 3 and 4, HBsAg titers fluctuated for nearly 3 yr. Five patients seroconverted to anti-HBs within 1yr of the follow-upperiod. Interestingly, HBsAg of three of these patients (patients 3 , 4 and 5 ) reappeared after the seroconversion to anti-HBs, but these patients did not have any clinical symptoms or elevation in ALT level. Two patients (patients 3 and 6) tested positive for IgM-HBc and/or intrahepatic HBcAg when acute exacerbation of ALT levels was found, whereas patient 4 was negative for both markers. Two patients (patients 4 and 6)had HBeAg disappear almost at the same time as the disappearance of HBsAg, and four patients remained negative for HBeAg for more than 2 yr. In all patients, titers of anti-HBc decreased subsequent to the decrease in HBsAg and finally yielded less than 70% inhibition assays in six patients. However, five patients remained positive for serum HBV DNA after clearance of HBsAg. Complication by HCC. Three patients (patients 1, 2 and 3) had HCC develop after the disappearance of HBsAg (Fig. 2). Although hepatitis in these patients was not active when HCC was clinically detected, all had already had liver disease develop at the time of seroconversion. Two had cirrhosis and one had CAH. For two patients, HCC developed within 4 yr after the disappearance of HBsAg. HCC in patient 1,however, was not detected until 9 yr after the disappearance of HBsAg (Fig. 2). Not only was HBsAg absent in these patients but also titers of anti-HBc yielded less than 70% inhibition in two cases. Serum HBV DNA, however, tested positive using PCR. DISCUSSION
The disappearance rate of HBsAg in 7 of the 351 patients (0.4%/yr)in our hospital was as small as that in volunteer blood donors with HBsAg (3-6).Studies using blood donors have demonstrated that seroconversion to anti-HBs indicates recovery from HBV infection and is a good prognosis for liver disease (3-5). In fact, in our study all seven patients demonstrated remission of biochemical activity of hepatitis after the disappearance of HBsAg from serum. Five of the patients tested
HEPATOLUGY
positive for HBV DNA using the PCR technique; however, these patients had normal transaminase activities, as reported previously (8). Therefore these findings suggest that the clearance of HBsAg may indicate the biological remission of hepatitis. Unfortunately, three of the four patients who had liver disease develop when HBsAg became undetectable eventually had HCC develop. Thus the disappearance of HBsAg does not necessarily indicate a good prognosis because patients may have complicationsof liver disease. HCC was detected within 2 yr after the disappearance of HBsAg in two cases and after 9 yr in a third case. Interestingly, the three patients who had HCC develop clearly had more risk factors than the remaining patients; they all had cirrhosis and were older. Although two of them (patients 2 and 3) tested positive for anti-HCV, they had blood transfusions after cirrhosis was diagnosed. The role of HCV infection in hepatocarcinogenesis in these patients is unknown. Because patients with cirrhosis are at high risk of having HCC develop (9,101,patients should be checked for HCC even if HBsAg becomes negative and hepatitis is inactive for several years. HBV DNA remained detectable in serum using the PCR technique in these patients who had HCC develop even after HBsAg became undetectable. This finding suggests that the persistence of HBV DNA may be important for the follow-up of these patients and the development of HCC. In all patients, titers of anti-HBc decreased along with HBsAg and subsequently became less than 70% inhibition when a 1 :200 dilution of samples from six of seven patients was used. Therefore it is not easy to distinguish between patients who recover from acute hepatitis B and those who have chronic hepatitis B but who have HBsAg disappear (11). HBV should be considered as a factor associated with HCC even in the absence of HBsAg. Thus patients with liver disease whose HBsAg becomes undetectable during the follow-up period should be monitored for HCC as carefully as those patients with HBsAg. REFERENCES 1. Krugman S, Giles JP. Viral hepatitis type B (MS-2-train): further
observations on natural history and prevention. N Engl J Med 1973;288:755-760. 2. Krugman S, Overby LR, Mushahwar LK, Ling C, Frosner GG,
Deinhardt F. Viral hepatitis, type B: studies on natural history and prevention re-examined. N Engl J Med 1979;300:101-106. 3. Dormeyer HH, Arnold W, Sconborn H, Braun B, Klinge 0, Pfeifer U, Knolle J, et al. The significance of serologic, histologic, and immunohistologic findings in the prognosis of 88 asymptomatic carriers of hepatitis B surface antigen. J Infect Dis 1981;144: 33-37. 4. Feinman SV, Berris B, Cooter N, Sinclair JC, Wrobel DM. Results
of a long-term prospective study of the hepatitis B surface antigen (HBsAg) carrier state. Hepatogastroenterology 1982;29:58-61. 5. Sampliner RE, Hamilton FA, Iseri OA, Tabor E, Boitnott J. The liver histology and frequency of clearance of the hepatitis B surface antigen (HBsAg) in chronic carriers. Am J Med Sci 1979;277: 17-22. 6. 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;94:744-748.
Vol 16, No 6, 1992
(‘I,EARAN(’E O F IIBsAg
7 Kaneko S, Miller KH, Feinstone S M . I:noura M . Kobayashi K. Hattori N, Purcell RH. Detection of serum hepatitis B virus DNA in patients with chronic hepatitis using the polymerase chain reaction assay. Proc Nati Acad Sci USA 1989:86:318-316. 8. Kaneko S,Miller RH, Bisceglie AM, Feinstone SM. Hoofnagle J H . Purcell RH. Detection of hepatitis R virus DNA in serum by polymerase chain reaction. application for clinical diagnosis. Gastroenterology 1990;99:799-804 9. The Liver Cancer Study Group n f ’ J a p m Primary liver cancer in
1337
Japan: clinicopathologic features and results of surgical treatment. Ann Surg 1990;211:277-287. 10. Oka H, Kurioka N, K m K, Kanno T, Kurolu T. Mizoguch Y. Kobayashi K. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis HEPATOLOGY 1990; 12: 680-687. 1 1 . Morgan TR, Redeker AG. Yamada S. Ashcavai M. HBsAg clearance in chronic active hepatitis B: a possible cause of c~yptogeniccirrhosis. Dig Dis Sci 1986;31:700-704.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes ( I f HEPATOLOGY for 1992 are available to subscribers only. They may be purchased from the publisher at a cost of $74.00 for domestic, $102.18 for Canadian and $97.00 international for Vol. 15 (January to J u n e ) and Vol. 16 (July to December). Price includes shipping charges. Each bound volume contains a subject and author index, and all advertising is removed. C,opiesare shipped within 60 days after publication of the last issue of the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 1 1830 Westline Industrial Drive, St. Louis, MO 63146-3318, USA; phone (800)325-4177.ext. 4351, or (314)453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Hk;1J.%?’Oi.o(;k’subscription.
The natural history of chronic hepatitis B patients who spontaneously cleared serum HBsAg was investigated. A total of 351 patients with chronic hepatitis B were obsemd in our hospital for at least 3 yr. Seven of these patients became HBsAg negative during the follow-up period. HBsAg disappeared within 6 mo (range = 11 to 169 daye, mean = 70 days) after acute elevation of ALT. ALT levels as high as 500 IU were found in three patients, whereas such elevation was not demonstrated in the other four patients. After the disappearance of HBsAg, ALT levels returned to normal in all patients. With one exception, all patients seroconverted to antibody to HBaAg; however, hepatitis B vim DNA remained detectable in serum using the polymerase chain reaction in five patients. The titer of percent inhibition of antibody to HBcAg gradually decreased to less than 70% when a 1:200 dilution of the serum of six patients was used. Four of the patients had active liver disease develop: two had chronic active hepatitie and two had cirrhosis. Three of these four patients subsequently had hepatocellular carcinoma develop. These findings suggest that patients may suffer complications of chronic hepatitis even after normalization of transaminase activities and after the clearance of HBsAg. Thus hepatitis B virus should be considered as a possible factor 8880ciated with hepatocellular carcinoma even in the absence of HBsAg, particularly if serum hepatitis B virus DNA pemists. ( H E P A T O ~ Y1992;16:1334-1337.)
who cleared serum HBsAg to understand the natural history of this disease.
MATERIALS AND METHODS
During the years 1983 to 1991,a total of 351 patients with chronic hepatitis B were observed in our hospital (Kanazawa University, Kanazawa Japan) for at least 3 yr. Seven of these patients became spontaneously HBsAg negative during the follow-up period (Table 1). None of these patients had been treated with corticosteroids, immunostimulants, immunosuppressive agents, interferon or other antiviral drugs. They did not have past history of blood transfusion or drug abuse, and were not homosexuals. These seven patients included five men and two women whose mean age was 48.9yr. Six of the seven patients were histologically diagnosed as shown in Table 1. HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc and IgM antibody to HBc (IgM-HBc) were assayed by RIA (Ausria-11, Ausab, Abbott-HBe, Abbott-HBe, Corab and Anti-HBc-M, respectively; Abbott Laboratories, North Chicago, IL). Results of HBsAg, anti-HBs and HBeAg were expressed as a ratio (sample counts per minute/mean counts per minute for negative controls). A positive result was scored for ratios of 2.1 or greater. Results for anti-HBe and anti-HBc (200-fold dilution) were expressed as percent inhibition (negative control mean counts per minute minus sample counts per minutehegative control mean counts per minute minus positive control mean counts per minute), with a positive result being 30% or greater. Serum HBV DNA was detected using the polymerase chain reaction (PCR) technique (7). The specific primers consisted of primer 1763 5'The clearance of HBsAg from serum of patients with GCTTTGGGGCATGGACATTGACCCGTATAA-3' and primer acute hepatitis B usualIy indicates recovery from in- 2032R 5'-CTGACTACTAATTCCCTGGATGCTGGGTCT-3' fection (1, 2). However, the clinical significance of the for the core gene sequence of HBV genome. Antibody to disappearance of HBsAg during the course of chronic hepatitis C virus (anti-HCV) was tested by enzyme-linked hepatitis B has not been fully explained because the immunoassay (Anti-HCV; Ortho Diagnostics, Tokyo, Japan). clearance ratio seems to be very low (3-6). Although Liver biopsy specimens were immunohistochemically exseveral investigators reported a good prognosis for such amined for the presence of HBcAg using avidin-biotin peroxpatients (3-51, some patients had liver diseases (4,6) and idase complex kit (Histofine-HBc;Nichirei, Tokyo, Japan).
related complications develop. Therefore we investigated the clinical course of chronic hepatitis B patients
RESULTS Activity
Received January 27, 1992; accepted July 24, 1992. Address reprint requests to: Hiroshi Adachi, M.D., First Department of Internal Medicine, Knnazawa University, Takara-Machi 13-1, Kanazawa 920 Japan. 31/1/41639
Of
Hepatitis and HBsAg Clearance.We found
that three patients (patients 2, 3 and 4 ) cleared HBsAg after acute exacerbation of ALT levels (Fig. 1).Peak ALT levels were between 406 and 558 IU and were seen 11to 169 days before the clearance of HBsAg. All three patients had liver disease develop before they cleared HBsAg; two had CAH and one had cirrhosis. In contrast,
1334
1335
CLEARANCE OF HBsAg
Vol. 16, No. 6. 1992
Patient no.1 &,nlmW" I
*
I
T
'
d "BY W L
I"*_.
\ 6'
75
Patient no.2
80
87
'88
'89"
Patient 110.4
Patient 170.3
I a
D Patient no.5
Patient no.6
y1
I
Patient no.7
rm
FIG.1.(A-G) Clinical, biochemical and serologmd course of seven patients who cleared HBBAg. The horizontal line represents level of Berum ALT and titer for HBsAg, HBeAg and anti-HBc. Solid bars indicate positive assays. Arrows indicate the time and the result: chronic persistent hepatitis (CPH),CAH, CAH with lobular disarray (CAH with LD), cirrhosis tI,C), HCC. HBV DNA, IgM-HBc, anti-HCV or intrahepatic HBcAg HBcAg).
TABLE 1. Chracteristics of patients who became H B d g negative during the follow-upperiod Patient
ABe (yr )
Sex
1 2 3 4 5
67 64
M M F M M
6 7
19 54
56 24 37
Blood tramfusion ~
Duration of obeervation (yr)
Histological llndhlg on admission
24
Cirrhosis" CAH Cirrhosis with CAH CAH Chronic persistent hepatitis Chronic persistent hepatitis Not obtained
-
10
-
F
-
6 5 7 7
M
-
6
-
-
"Eventually complicated by HCC
such elevations of ALT levels were not observed in the remained stable. The elevation in the ALT level of other four patients, even though ALT levels of three of patient 1, seen in 1988, was considered to be caused by these patients (patients 5, 6 and 7) were tested at least the effect of transarterial embolization for the treatment once a month (Fig. 1). Three of the four patients had of HCC because HBsAg, HBeAg, anti-HCV and DNA chronic persistent hepatitis (patient 1 was the excep- polymerase were negative. Serial Cha*ges of HBV Markers. For all patients tion). After the disappearance of HBsAg, ALT levels of all patients, except for patient 1. were normalized and HBsAg titers decreased and became less than a ratio of
1336
ADACHI ET AL. DIsa
n&
LC
pannce 01
ncc
Patient no.1
Patient no.2
Patient no.3 1
0
8
6
4
2
2
4
6
8
1012
(years) I ~ ~ I I - ~ B c ~ x z w ) , ~ ~ . ~ ~an11.nBc(xmo).70.h
FIG. 2. Relationship between disappearance of HBsAg and pathemas. Three patients (patients 1,2 and 3) had HCC develop after the disappearance of HBsAg. The horizontal axis represents the course of time, with HBsAg disappearance located as the midpoint. The pathological state and anti-HBc level are simultaneously depicted in the chart.
2.1. For patient 3 and 4, HBsAg titers fluctuated for nearly 3 yr. Five patients seroconverted to anti-HBs within 1yr of the follow-upperiod. Interestingly, HBsAg of three of these patients (patients 3 , 4 and 5 ) reappeared after the seroconversion to anti-HBs, but these patients did not have any clinical symptoms or elevation in ALT level. Two patients (patients 3 and 6) tested positive for IgM-HBc and/or intrahepatic HBcAg when acute exacerbation of ALT levels was found, whereas patient 4 was negative for both markers. Two patients (patients 4 and 6)had HBeAg disappear almost at the same time as the disappearance of HBsAg, and four patients remained negative for HBeAg for more than 2 yr. In all patients, titers of anti-HBc decreased subsequent to the decrease in HBsAg and finally yielded less than 70% inhibition assays in six patients. However, five patients remained positive for serum HBV DNA after clearance of HBsAg. Complication by HCC. Three patients (patients 1, 2 and 3) had HCC develop after the disappearance of HBsAg (Fig. 2). Although hepatitis in these patients was not active when HCC was clinically detected, all had already had liver disease develop at the time of seroconversion. Two had cirrhosis and one had CAH. For two patients, HCC developed within 4 yr after the disappearance of HBsAg. HCC in patient 1,however, was not detected until 9 yr after the disappearance of HBsAg (Fig. 2). Not only was HBsAg absent in these patients but also titers of anti-HBc yielded less than 70% inhibition in two cases. Serum HBV DNA, however, tested positive using PCR. DISCUSSION
The disappearance rate of HBsAg in 7 of the 351 patients (0.4%/yr)in our hospital was as small as that in volunteer blood donors with HBsAg (3-6).Studies using blood donors have demonstrated that seroconversion to anti-HBs indicates recovery from HBV infection and is a good prognosis for liver disease (3-5). In fact, in our study all seven patients demonstrated remission of biochemical activity of hepatitis after the disappearance of HBsAg from serum. Five of the patients tested
HEPATOLUGY
positive for HBV DNA using the PCR technique; however, these patients had normal transaminase activities, as reported previously (8). Therefore these findings suggest that the clearance of HBsAg may indicate the biological remission of hepatitis. Unfortunately, three of the four patients who had liver disease develop when HBsAg became undetectable eventually had HCC develop. Thus the disappearance of HBsAg does not necessarily indicate a good prognosis because patients may have complicationsof liver disease. HCC was detected within 2 yr after the disappearance of HBsAg in two cases and after 9 yr in a third case. Interestingly, the three patients who had HCC develop clearly had more risk factors than the remaining patients; they all had cirrhosis and were older. Although two of them (patients 2 and 3) tested positive for anti-HCV, they had blood transfusions after cirrhosis was diagnosed. The role of HCV infection in hepatocarcinogenesis in these patients is unknown. Because patients with cirrhosis are at high risk of having HCC develop (9,101,patients should be checked for HCC even if HBsAg becomes negative and hepatitis is inactive for several years. HBV DNA remained detectable in serum using the PCR technique in these patients who had HCC develop even after HBsAg became undetectable. This finding suggests that the persistence of HBV DNA may be important for the follow-up of these patients and the development of HCC. In all patients, titers of anti-HBc decreased along with HBsAg and subsequently became less than 70% inhibition when a 1 :200 dilution of samples from six of seven patients was used. Therefore it is not easy to distinguish between patients who recover from acute hepatitis B and those who have chronic hepatitis B but who have HBsAg disappear (11). HBV should be considered as a factor associated with HCC even in the absence of HBsAg. Thus patients with liver disease whose HBsAg becomes undetectable during the follow-up period should be monitored for HCC as carefully as those patients with HBsAg. REFERENCES 1. Krugman S, Giles JP. Viral hepatitis type B (MS-2-train): further
observations on natural history and prevention. N Engl J Med 1973;288:755-760. 2. Krugman S, Overby LR, Mushahwar LK, Ling C, Frosner GG,
Deinhardt F. Viral hepatitis, type B: studies on natural history and prevention re-examined. N Engl J Med 1979;300:101-106. 3. Dormeyer HH, Arnold W, Sconborn H, Braun B, Klinge 0, Pfeifer U, Knolle J, et al. The significance of serologic, histologic, and immunohistologic findings in the prognosis of 88 asymptomatic carriers of hepatitis B surface antigen. J Infect Dis 1981;144: 33-37. 4. Feinman SV, Berris B, Cooter N, Sinclair JC, Wrobel DM. Results
of a long-term prospective study of the hepatitis B surface antigen (HBsAg) carrier state. Hepatogastroenterology 1982;29:58-61. 5. Sampliner RE, Hamilton FA, Iseri OA, Tabor E, Boitnott J. The liver histology and frequency of clearance of the hepatitis B surface antigen (HBsAg) in chronic carriers. Am J Med Sci 1979;277: 17-22. 6. 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;94:744-748.
Vol 16, No 6, 1992
(‘I,EARAN(’E O F IIBsAg
7 Kaneko S, Miller KH, Feinstone S M . I:noura M . Kobayashi K. Hattori N, Purcell RH. Detection of serum hepatitis B virus DNA in patients with chronic hepatitis using the polymerase chain reaction assay. Proc Nati Acad Sci USA 1989:86:318-316. 8. Kaneko S,Miller RH, Bisceglie AM, Feinstone SM. Hoofnagle J H . Purcell RH. Detection of hepatitis R virus DNA in serum by polymerase chain reaction. application for clinical diagnosis. Gastroenterology 1990;99:799-804 9. The Liver Cancer Study Group n f ’ J a p m Primary liver cancer in
1337
Japan: clinicopathologic features and results of surgical treatment. Ann Surg 1990;211:277-287. 10. Oka H, Kurioka N, K m K, Kanno T, Kurolu T. Mizoguch Y. Kobayashi K. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis HEPATOLOGY 1990; 12: 680-687. 1 1 . Morgan TR, Redeker AG. Yamada S. Ashcavai M. HBsAg clearance in chronic active hepatitis B: a possible cause of c~yptogeniccirrhosis. Dig Dis Sci 1986;31:700-704.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes ( I f HEPATOLOGY for 1992 are available to subscribers only. They may be purchased from the publisher at a cost of $74.00 for domestic, $102.18 for Canadian and $97.00 international for Vol. 15 (January to J u n e ) and Vol. 16 (July to December). Price includes shipping charges. Each bound volume contains a subject and author index, and all advertising is removed. C,opiesare shipped within 60 days after publication of the last issue of the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 1 1830 Westline Industrial Drive, St. Louis, MO 63146-3318, USA; phone (800)325-4177.ext. 4351, or (314)453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Hk;1J.%?’Oi.o(;k’subscription.
