Abstract
Objective
To investigate the mechanisms and risk factors underlying postoperative reactivation of hepatitis after liver resection for hepatitis B virus-related hepatocellular carcinoma.
Summary Background Data
Although risk factors for acute hepatic failure after liver resection have been reported in patients with chronic liver disease, the issue of reactivation of hepatitis B virus replication after liver resection is unresolved.
Methods
Fifty-five patients with hepatocellular carcinoma and hepatitis B surface antigen underwent liver resection. In 25 of these 55 patients, serum levels of hepatitis B virus DNA and the type of hepatitis B virus were determined before and after surgery.
Results
Postoperative hepatitis occurred in 13 of the 55 patients (24%). Reactivation of viral replication occurred after liver resection in 7 of the 25 patients tested, and alanine aminotransferase activity increased in 6 of these 7 patients. High preoperative alanine aminotransferase activity, high levels of hepatitis B virus DNA, presence of wild-type DNA, and detection of hepatitis B core antigen in hepatocytes, all features of the immune clearance phase in the natural course of hepatitis B virus infection with no surgery, were more likely to be found in patients with reactivation than in patients without reactivation.
Conclusions
During the immune clearance phase of hepatitis B virus infection, especially the period of acute exacerbation, changes in serum hepatitis B virus DNA level should be monitored for early warnings of reactivation of viral replication, likely to cause severe postoperative hepatitis and acute hepatic failure.
Worldwide, patients with hepatitis B virus (HBV) number as many as 280 million. HBV infection is a risk factor for hepatocellular carcinoma (HCC), 1 most effectively treated by resection. Recent progress in the preoperative evaluation of liver function, surgical procedures, and perioperative management has improved the results of liver resection. 2,3 However, resection in patients with chronic liver disease still can lead to postoperative hepatic failure, resulting in decompensation and death. The Child-Pugh classification 4 has been used frequently to evaluate preoperative liver function. Risk factors for postoperative hepatic failure have been studied by many investigators, and various new methods have been proposed for evaluating preoperative liver function. 3,5–12
After undergoing liver resection for HBV-related HCC, some patients again develop hepatitis. Four years ago, we treated an HBV carrier and who underwent right lobectomy for HCC and 6 weeks later developed fatal acute hepatic failure with remarkably increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (≥3,000 IU/L). The patient had well-preserved liver function before surgery and was discharged from the hospital 4 weeks after surgery. Although acute hepatic failure has been reported to occur from reactivation of HBV replication after liver transplantation, 13 whether reactivation of HBV replication occurs after liver resection is not known, nor is the relation of such an event to postoperative hepatitis. In the present study, we retrospectively studied the incidence of postoperative hepatitis. Beginning in 1994, we also prospectively investigated reactivation of HBV replication after liver resection and factors that might be associated with reactivation.
METHODS
Patients
From November 1988 to June 1998, 56 patients with hepatitis B surface antigen (HBsAg) but without antihepatitis C virus (HCV) underwent liver resection for HCC in the Second Department of Surgery at Osaka City University Medical School. Of the 56 patients, 1 who died 27 days after resection was excluded from the study. Of the remaining 55 patients, 43 were men and 12 were women. Ages ranged from 30 to 71 years (mean 50.6). Thirty-six of the 55 patients had been treated for chronic hepatitis B (persistent positivity for HBsAg) for at least 1 year before the detection of HCC and sera obtained from the other 19 patients at any follow-up appointment (for at least 1 year) were positive for HBsAg, indicating that all subjects were HBV carriers. Bi- or trisegmentectomy, referred to here as major hepatectomy, was performed in 20 patients, segmentectomy in 8 patients, subsegmentectomy in 12 patients, and partial resection in 15 patients. Blood transfusion was performed during or after surgery in 38 of the 55 patients. In the most recently treated 25 patients, beginning in October 1994, we prospectively investigated changes in viral state by molecular biologic and histopathologic methods.
This study was conducted in accordance with the Helsinki Declaration and the guidelines of the ethics committee of our institution. Informed consent was obtained from each patient.
Viral Markers
Serum samples were obtained before and after surgery and frozen at -80°C until assay. Examinations for anti-HCV using second- or third-generation enzyme-linked immunosorbent assays (Ortho Diagnostics Systems, Tokyo, Japan) and for HCV RNA by polymerase chain reaction with reverse transcription using primers derived from a conserved 5′-untranslated region of the viral genome 14 were performed. Hepatitis B envelope antigen (HBeAg), anti-HBe, HBsAg, and anti-HBs were examined by an enzyme immunoassay (International Reagents, Kobe, Japan). Hepatitis G virus (HGV)/GB virus C was examined by a method reported previously. 15 In all patients, results of tests for antibodies to hepatitis D virus by an enzyme immunoassay (Abott, North Chicago, IL) were examined.
Postoperative Hepatitis
Serum ALT activity usually increased immediately after liver resection and then decreased gradually to preoperative levels within 3 weeks. In some patients, ALT activity showed a subsequent increase. Postoperative hepatitis was judged to be significant when a second postoperative increase in ALT activity occurred between 3 weeks and 3 months after surgery, reaching a level at least twice that seen before surgery. Causes of ALT increases other than hepatitis, particularly sepsis or thrombosis of the hepatic artery or portal vein, examined by ultrasonography, were excluded. When drug-induced hepatitis was suspected, a lymphocyte stimulation test was performed and eosinophilia was checked. When ALT activity exceeded 45 IU/L (the reference range, <45 IU/L), it was assumed to be abnormally high.
HBV DNA Level and Quantitative Analysis of Wild and Precore Mutant Types
Serum HBV DNA levels in serially obtained stored sera were quantitated by a branched DNA assay (Chiron Amplex-HBV kit; Chiron, Emeryville, CA). The cutoff value for this assay was 0.7 mEq/mL HBV DNA. Reactivation of HBV replication was judged to be significant when the value increased to five times the preoperative value within 3 months after surgery. When the value increased to 10 times the preoperative value, the increase was assumed to be remarkable.
Quantitative analysis of wild-type HBV (HBeAg-producing HBV) and the precore mutant type involved a solid-phase minisequencing assay using primer-guided incorporation of a single labeled nucleotide on an affinity-captured biotinylated amplified HBV DNA template. 16
Sera were obtained before and at 1, 2, and 4 weeks after surgery. When the HBV DNA level in the sera obtained at 4 weeks after surgery was high, sera obtained at 8 weeks after surgery were also tested.
Histologic Examination and Core Antigen Expression in the Liver
Surgical tissue specimens were fixed in 10% formalin and embedded in paraffin. Serial sections 4 μm thick were stained with hematoxylin and eosin. The severity of active hepatitis in the noncancerous hepatic tissue was graded pathologically using the histologic activity index. 17 For immunohistochemical demonstration of HB core antigen (HBcAg), an immunoperoxidase technique involving avidin-biotin peroxidase complexes (Vectastain ABC kit, Vector Laboratories, Burlingame, CA) was used according to a method reported previously 18–20 with some modifications. HBcAg was stained using a rabbit antibody to HBcAg (anti-HBc; DAKO, UK). The hepatocytes were considered positive for HBcAg when the cytoplasm or nuclei of hepatocytes stained brown in a uniform manner. When one or more hepatocytes was found per five high-power fields (approximately 400 hepatocytes per one field), the liver was considered positive for HBcAg.
Statistics
The Student t test was used to analyze differences in age. The Fisher exact test was used to compare categorical data between groups. The Mann-Whitney test was used to compare ALT activity between groups. Multiple logistic regression analysis with a stepwise procedure was used for multivariate analysis. A difference with a probability value less than 0.05 was considered significant.
RESULTS
Postoperative Hepatitis and Viral State
In all patients, results of tests for anti-HCV, HCV RNA, and antibodies to hepatitis D virus were negative. Postoperative hepatitis developed in 13 of 55 patients (24%). No patient had a documented transmission of HCV by blood transfusion. In 44 of the 55 patients, transmission of HGV could be ruled out as well. Although HGV was transmitted during or after surgery in 2 of the other 11 patients, this infection was not believed to have caused postoperative hepatitis because abnormally elevated activities of aminotransferases were not found except for the few days immediately after surgery. 21 Among patients with postoperative hepatitis, none showed eosinophilia. Of the 13 patients, 1 was readmitted to the hospital and died of acute hepatic failure, and 5 others were readmitted after surgery. The seven other patients needed to rest at home for several weeks. It took 6 to 10 weeks for ALT activity to return to the preoperative value. A typical change in ALT activity in a patient with postoperative hepatitis is shown in Figure 1. Postoperative hepatitis developed in 7 of the 16 patients with HBeAg and in 6 of the remaining 39 patients, representing a significant excess in patients with HBeAg compared with those without HBeAg (P = .0371). Preoperative ALT activities were significantly greater in patients with postoperative hepatitis (mean 79 IU/L) than in patients without postoperative hepatitis (mean 51 IU/L;P = .0190).
Figure 1. Changes in serum levels of hepatitis B virus DNA and alanine aminotransferase activity after liver resection. Open square, hepatitis B virus DNA; open circle, alanine aminotransferase activity. W/M, wild-type hepatitis B virus/mutant type hepatitis B virus.
Reactivation of HBV DNA Replication
We prospectively investigated changes in viral status by molecular biologic methods in 25 of the 55 patients. Before surgery, sera from all patients were positive for HBsAg, and sera from four patients were positive for HBeAg. Twenty-one patients had anti-HBe, and 5 of the 21 patients had anti-HBs. Wild-type HBV was detected in all 4 patients with HBeAg and in 6 of 21 patients without HBeAg. After liver resection, reactivation of HBV DNA replication occurred in 7 patients (group 1) but not in the remaining 18 patients (group 2) (Fig. 2). A remarkable increase in the HBV DNA level was seen in two patients who underwent major hepatectomy. In two of the seven patients, preoperative sera were positive for HBeAg and wild-type HBV alone was detected. In the sera of one of the seven patients, mutant-type HBV alone was detected. In three of the other four patients who had both wild- and mutant-type HBV, the percentage of wild-type HBV increased. Therefore, wild-type HBV increased predominantly in most patients.
Figure 2. Changes in serum levels of hepatitis B virus DNA after liver resection in patients with reactivation of viral replication. The results are expressed as a mean ± SE.
An increase in serum ALT activity was observed after the increase in HBV DNA level in six of the seven patients. Typical changes in serum levels of HBV DNA and ALT activity are shown in Figure 1. In the patient, the serum HBV DNA level increased on the seventh day after right lobectomy and then decreased. Serum ALT activity increased just after surgery and then decreased. ALT activity increased again and peaked on day 30 after surgery, then decreased. Percentages of wild-type and mutant-type HBV changed from 30%/70% to 40%/60% in parallel with the increase in HBV DNA. The patient’s serum, negative for HBeAg before surgery, changed to positive (reverse seroconversion) after surgery and then changed to negative. These findings indicate that reactivation of HBV replication is a cause of postoperative hepatitis. During reactivation, the increase predominantly represented wild-type HBV in most patients.
Clinicopathologic Findings in Patients With and Without Reactivated HBV DNA Replication
Clinicopathologic findings in groups 1 and 2 are shown in Table 1. Patient ages ranged from 30 to 61 years in group 1 and from 35 to 71 years in group 2. No significant difference was seen between the two groups for mean age, sex distribution, or history of alcohol abuse (defined as an estimated mean of at least 86 g daily ethanol intake for at least 10 years, according to the Liver Cancer Study Group of Japan). 22 No significant differences were noted between the two groups in the proportions of patients with HBeAg, Child-Pugh classification A, stage of HCC according to the UICC classification, 23 or histologic active hepatitis (histologic activity score from 2 to 4). Proportions of patients with abnormally high ALT activity (>45 IU/L) and a high HBV DNA level (≥0.7 meq/mL) were significantly higher in group 1 than in group 2 (P = .0213, P = .0016, respectively). The proportion of patients with wild-type HBV was significantly higher in group 1 than in group 2 (P = .0068), although the proportion of patients with mutant-type HBV was not significantly different between groups. HBcAg was stained in both cytoplasm and nuclei of hepatocytes in seven patients and in nuclei alone in three patients (Fig. 3); this marker is related to active replication of HBV. 18–20 The proportion of patients with HBcAg in hepatocytes was significantly higher in group 1 than in group 2 (P = .002). The proportion of patients with preoperative fluctuation of ALT activity, which is related to acute exacerbations during the natural course of HBV infection, tended to be higher in group 1 than in group 2, although the difference was not significant (P = .0900). No significant differences were present between groups in the type of resection. The proportion of patients who received a blood transfusion during or after surgery was not significantly different between groups. Therefore, high ALT activity, high HBV DNA level, presence of wild-type HBV, and presence of HBcAg in hepatocytes were risk factors for reactivation of HBV replication after liver resection.
Table 1. CLINICOPATHOLOGIC FINDINGS AND RESULTS OF LABORATORY TESTS IN PATIENTS WITH AND WITHOUT REACTIVATION OF HEPATITIS B VIRUS REPLICATION
HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; ALT, alanine aminotransferase; HBV, hepatitis B virus; HBcAg, hepatitis B core antigen. Numbers in the parentheses are percentages. * Stage of cancer is classified according to the UICC classification.
Figure 3. Immunohistochemical staining of hepatitis B core antigen (HbcAg) in a section of liver. Expression of HbcAg were seen in both nuclei and cytoplasm of hepatocytes (upper) or in nuclei alone (lower).
To investigate independent risk factors for reactivation, preoperative ALT activity, HBV DNA level, presence of wild-type HBV, and presence of HBcAg in the hepatocytes were studied as variables. By multivariate analysis, these factors were not found to be independent risk factors for reactivation of HBV replication.
DISCUSSION
Postoperative hepatitis includes posttransfusion hepatitis and drug-induced hepatitis. In this study, infection with HGV was not responsible for postoperative hepatitis, and blood transfusion was not a risk factor for postoperative hepatitis. We showed that reactivation of HBV replication after surgery was strongly related to postoperative hepatitis.
Acute exacerbations occur frequently during the natural course of chronic hepatitis B. 1,24 Exacerbations may be associated with clearance of HBV and HBeAg to anti-HBe seroconversion or reactivation of HBV replication and reversion from anti-HBe to HBeAg positivity. The cumulative probability of developing exacerbations has been reported to be 8.7% in patients with serum ALT activities of less than 200 IU/L. 24 In the present study, reactivation of HBV replication occurred after liver resection in 7 of 25 patients (28%), indicating that factors other than the acute exacerbation contribute to viral reactivation. Reactivation of HBV replication in patients who receive cytotoxic or immunosuppressive therapy is well recognized. 25–34 However, similar therapy, including corticosteroids, has itself been used to treat chronic hepatitis B. 35–37 The mechanism underlying such exacerbations is thought to be that although cytotoxic and immunosuppressive drugs permit enhanced viral replication, with a consequent increase in hepatocyte infection, withdrawal of the drugs results in partial restoration of immunocompetence, leading to rapid destruction of infected hepatocytes. Serum concentrations of corticosteroids, representing an endogenous immunosuppressant, increase remarkably after surgery. 38 Accordingly, we suggest the following mechanism for reactivation of HBV replication after liver resection. Resection induces immunosuppression and permits enhanced viral replication. Immune function recovers later in the postoperative course, resulting in rapid destruction of infected hepatocytes and causing postoperative hepatitis and acute hepatic failure.
In our study, high ALT activity, high level of HBV DNA, presence of wild-type HBV, and presence of HBcAg in hepatocytes were found to be risk factors for reactivation of HBV replication after liver resection. The proportion of patients with preoperative fluctuation of ALT activity, which is related to acute exacerbation, tended to be higher in group 1. These factors are related to active viral replication, and patients characterized by them were in the immune clearance phase during the natural course of HBV infection. 1,24 Change from HbeAg-negative to HbeAg-positive status (reverse seroconversion) also is related to active HBV replication. 24,29,30,32,34 By multivariate analysis, these factors were not independent risk factors because all proved to be related to active viral replication. However, normal ALT activity, low serum level of HBV DNA, absence of wild-type HBV, and lack of HBcAg in hepatocytes indicated that a patient was in the quiescent phase during the natural infection. Therefore, patients in the immune clearance phase, especially the period of acute exacerbation, at the time of liver resection were at risk for reactivation of viral replication after surgery.
Recent studies have shown that severe forms of hepatitis, including fulminant hepatitis B after transmission of the virus, are caused by HBV with mutations in the precore region. 39–42 Severe recurrent hepatitis caused by HBV with a precore mutation is a reported cause of early graft loss after liver transplantation. 13 After HBV infection by transmission or infiltration of HBV into the transplanted liver, the mutant type of HBV lacking HBeAg may spread in the liver more easily than the wild-type HBV because the mutant type can escape immune responses. However, the presence of mutant-type HBV was not a risk factor for reactivation of HBV replication after liver resection. The clinical findings in reactivation of HBV replication after liver resection or immunosuppressive therapy resemble those in acute exacerbations during the natural course of HBV infection. In fact, wild-type HBV (HbeAg-positive) and elevated ALT activity have been reported to be risk factors in acute exacerbations. 24 Therefore, the mechanism of the reactivation of HBV replication after liver resection differs from that in fulminant hepatitis B caused by HBV transmission and that for reactivation after liver transplantation.
For patients with acute hepatic failure after cytotoxic or immunosuppressive therapy, reintroduction of steroids has been attempted, 28 but this method would not in itself be expected to improve outcome if carried out at a stage when advanced hepatocyte necrosis already was present. Yoshiba et al 34 have found in postimmunosuppression patients that early institution of treatment with both interferon and cyclosporin A can prevent progressive liver destruction and avert liver failure with coma. However, interferon has been found to suppress liver regeneration after partial hepatectomy. 43 Antiviral drugs such as lamivudine or famciclovir are expected to be useful. However, whether these therapies are beneficial in acute hepatic failure after liver resection is not clear. Liver transplantation to treat acute hepatic failure after chemotherapy has been reported. 44 Remarkable increases in the HBV DNA level occurred in patients who underwent major hepatectomy, indicating that the amount of liver to be resected should probably be limited because effective therapy for the reactivation after liver resection has not been established.
For estimation of the reactivation of HBV replication, knowing whether a patient is in the immune clearance phase of HBV infection is important, and this can be assessed by investigation of changes in ALT activity before surgery, preoperative ALT activity, preoperative serum level of HBV DNA, and the presence of wild-type HBV DNA and HBeAg. Wild-type HBV DNA is a more sensitive marker than HBeAg. If a specimen can be obtained before surgery from the liver, the tissue should be examined for HBcAg. In patients in the immune clearance phase, close monitoring of changes in serum levels of HBV DNA provides an important early warning of severe postoperative hepatitis and potentially lethal acute hepatic failure. In patients at risk, the amount of liver to be resected should probably be limited if possible. Antiviral agents should be found that can suppress viral replication without side effects in the postoperative period.
Footnotes
Supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture, Japan.
Correspondence: Shoji Kubo, MD, Second Department of Surgery, Osaka City University Medical School, 1–4-3 Asahimachi, Abeno-ku, Osaka 545–8585, Japan.
Accepted for publication May 10, 1999.
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