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Keywords:

  • chronic hepatitis B;
  • inflammatory bowel disease;
  • reactivation;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background:

Little is known about the clinical features of hepatitis B virus (HBV) infection in patients with inflammatory bowel disease (IBD). We therefore evaluated the influence of immunosuppressive treatment for IBD on the course of HBV infection and the effect of HBV infection on the therapeutic strategy and clinical course of IBD patients.

Methods:

We retrospectively evaluated the incidence of and risk factors for liver dysfunction in hepatitis B surface antigen (HBsAg)-positive IBD patients. Also, the clinical course of IBD patients with HBV infection was compared with matched IBD controls without HBV infection.

Results:

Of 4153 patients diagnosed with IBD between July 1989 and May 2011, 134 were HBsAg-positive, including 54 with Crohn's disease (CD) and 80 with ulcerative colitis (UC). Liver dysfunction was observed in 23 of the 134 (17.2%) HBsAg-positive patients. Prolonged immunosuppression (>3 months) was an independent predictor of liver dysfunction (odds ratio [OR] 3.06; 95% confidence interval [CI] 1.02–9.16). The rate of use of immunosuppressants, including corticosteroids (P = 0.005), azathioprine/6-mercaptopurine (P < 0.001), and infliximab (P = 0.026), was significantly lower in HBsAg-positive than HBsAg-negative IBD patients. Clinical outcomes, including admission rate, mean number of admissions, total proctocolectomy in UC patients, and mortality were worse in HBsAg-positive than HBsAg-negative IBD patients during the follow-up period.

Conclusions:

Liver dysfunction in HBsAg-positive IBD patients was more frequent in those with prolonged immunosuppression. IBD patients with chronic HBV infection used immunosuppressants less frequently and had a worse prognosis than those without it. (Inflamm Bowel Dis 2012;)

Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of idiopathic inflammatory bowel disease (IBD) with a remitting and relapsing course. To induce and maintain remission in IBD, most patients receive immunosuppressive agents, including corticosteroids, thiopurine antimetabolites such as azathioprine and 6-mercaptopurine, and anti-tumor necrosis factor α (anti-TNF-α) agents such as infliximab.1 Reactivation of hepatitis B virus (HBV) replication is a well-known complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy.2 Because HBV infection remains highly prevalent in Asia3 and the incidence of IBD is rapidly increasing in some Asian countries,4, 5 understanding the clinical features of HBV infection in IBD patients is very important. Little is known, however, about the clinical characteristics of IBD patients with chronic HBV infection. A multicenter study from Spain showed that treatment with ≥2 immunosuppressants was an independent predictor of liver dysfunction in IBD patients infected with HBV.6 A hospital-based study in Greece indicated that IBD patients infected with HBV can be safely treated with immunosuppressants if they are also treated with preventive antiviral treatment.7 Those two studies, however, included only 25 and 11 IBD patients who were positive for hepatitis B surface antigen (HBsAg), respectively, indicating the need for further investigations of the clinical features and courses of HBV infection in patients with IBD. We therefore assessed the influence of immunosuppressants on the course of chronic HBV infection in patients with IBD. We also compared the clinical course of IBD patients with HBV infection with matched IBD controls without HBV infection at a single tertiary center in Korea.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

Between July 1989 and May 2011, a total of 4153 patients with IBD, comprising 1731 with CD and 2422 with UC (2523 men and 1630 women), were newly registered at the IBD clinic of the Asan Medical Center, a tertiary university hospital in Seoul, Korea. CD and UC were diagnosed based on conventional clinical, radiologic, endoscopic, and histopathologic criteria.4, 8, 9 All IBD patients underwent regular follow-up in the outpatient clinic every 1–3 months, including liver function tests (aminotransferase, alkaline phosphatase, r-glutamyltranspeptidase, and total bilirubin concentrations; and prothrombin time, all measured by standard laboratory techniques). We have routinely checked HBV serology in almost all IBD patients because Korea is still an endemic area of HBV. Liver dysfunction related to HBV reactivation was defined as an increase of 2-fold the upper normal limit of serum alanine transaminase (ALT) and an increase of >104 copies/mL HBV DNA levels. Liver dysfunction related to HBV reactivation was considered probable when an increase in ALT was observed in the absence of other potential causative factors but HBV DNA values were not available. Diagnoses of liver cirrhosis and hepatocellular carcinoma were made on the basis of clinical, laboratory, analytical and morphological criteria (ultrasound, computed tomography [CT] scan). Fulminant liver failure was defined as severe acute failure complicated by hepatic encephalopathy.6 Patients with liver diseases other than HBV (e.g., other types of viral hepatitis including hepatitis C, autoimmune disease and toxic hepatitis) were excluded from this study.

To perform a matched case-control study, cases (HBsAg-positive IBD) were defined as IBD patients who were also positive for HBsAg. The control group consisted of IBD patients without HBsAg, selected from the 4153 IBD patients and matched 2:1 to cases by disease (CD or UC), age (±5 years), gender, calendar year of first visit to Asan Medical Center due to symptoms or signs of IBD (±2 years), and duration of IBD prior to first visit (±2 years).

Methods

Data obtained from medical records were analyzed retrospectively. We first calculated the crude prevalence of HBV infection in patients with IBD and analyzed the factors related to liver dysfunction in HBsAg-positive IBD patients, including duration and number of immunosuppressants and prophylactic antiviral treatment. We also compared the characteristics and outcomes of HBsAg-positive and -negative IBD patients, including age at diagnosis of IBD, disease extent/location, and behavior according to the Montreal Classification of IBD,10 medical treatments, admission rate, mean number of admissions during follow-up, surgery rate (intestinal resection in CD patients and total proctocolectomy in UC patients), follow-up duration, and mortality. The study protocol was approved by the Institutional Review Board of the Asan Medical Center.

Statistics

Continuous variables were expressed as medians with ranges. Discrete data were tabulated as numbers and percentages. In univariate analysis, the chi-squared test and Fisher's exact test were used to compare proportions and Student's t-test was used to compare quantitative variables. Multivariate analysis was performed using binary logistic regression analysis. After determining relevant risk factors by univariate analysis, variables with P-values less than 0.20 were entered into multivariate analysis. All statistical analyses were performed using PASW statistics (v. 18.0; SPSS, Chicago, IL), with a P-value less than 0.05 considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Demographic and Clinical Characteristics of the IBD Patients with HBV Infection

Of the 4153 patients diagnosed with IBD during the study period, 3249 (78.2%) were assessed for HBV infection, including 1521 patients with CD and 1728 with UC. Among these, we identified 134 HBsAg-positive patients, including 54 with CD and 80 with UC. These patients consisted of 93 men and 41 women, of median age at the time of IBD diagnosis of 35 years (range, 16.7–76 years). The crude prevalence of HBV infection in our study subjects was 4.1% (134/3249): 3.6% (54/1521) in CD patients and 4.6% (80/1728) in UC patients. The clinical characteristics of the IBD patients according to the Montreal Classification are shown in Table 1.

Table 1. Demographic and Clinical Characteristics of IBD Patients with and without HBV Infection
VariablesHBV groupNon-HBV Group 
Crohn's Diseasen=54n=108P-value
Gender [male:female]43:1186:221.000a
Age at diagnosis [median (range) years]30.6 (16.7-70)29.4 (15.7-67)0.973b
Montreal location [n (%)]  0.730a
 Ileum17 (31.5)36 (33.3) 
 Colon6 (11.1)8 (7.4) 
 Ileocolon31 (57.4)64 (59.3) 
Upper GI modifier [n (%)]14 (25.9)28 (25.9)1.000a
Montreal behavior [n (%)]  0.270a
 Nonstricturing nonpenetrating22 (40.7)43 (39.8) 
 Stricturing13 (24.1)16 (14.8) 
 Penetrating19 (35.2)49 (45.4) 
Perianal fistula modifier [n (%)]29 (53.7)54 (50)0.657a
Ulcerative Colitisn=80n=160 
  • GI, gastrointestinal; HBV, hepatitis B virus; IBD, inflammatory bowel disease.

  • a

    Chi-square test.

  • b

    t-test.

Gender [male:female]50:30100:601.000a
Age at diagnosis [median (range) years]38.5 (17-76)39 (16-76)0.828b
Disease extent  0.480a
 Proctitis33 (41.3)59 (36.9) 
 Left-sided colitis19 (23.8)50 (31.3) 
 Extensive colitis28 (35.0)51 (31.9) 

Of the 134 HBsAg-positive IBD patients, 61 (45.5%) were treated with corticosteroids, 30 (22.4%) with azathioprine or 6-mercaptopurine, and six (4.5%) with infliximab during the follow-up period. No patient received adalimumab, certolizumab, methotrexate, or cyclosporine. Twenty-four patients (17.9%) received ≥2 immunosuppressants simultaneously and 39 (29.1%) received prolonged immunosuppression, defined as maintenance treatment for >3 months.

Hepatic Dysfunction Related to Immunosuppressants in HBV-infected Patients with IBD

Liver dysfunction was observed in 23 of the 134 (17.2%) HBsAg-positive patients, compared with 5 of 268 (1.9%) matched HBsAg-negative controls (P < 0.001). Of the patients who had received immunosuppressive therapy, 18 (25.7%) of 70 HBsAg-positive and 5 of 180 (2.8%) HBsAg-negative patients developed liver dysfunction (P < 0.001). HBV DNA was positive (>104 copies/mL HBV DNA levels) in 21 of 23 (91.3%) HBsAg-positive patients with liver dysfunction and in 16 of 18 (88.9%) HBsAg-positive patients with liver dysfunction who had received immunosuppressive therapy. In two patients, HBV reactivation could not be confirmed because HBV DNA was not available for analysis. However, they were considered to have probable HBV reactivation, because liver dysfunction was observed after treatment with corticosteroids, which are not associated with hepatotoxicity.

Univariate analysis showed that prolonged immunosuppression (>3 months) and treatment with corticosteroids were significantly related to liver dysfunction (Table 2). Of the variables included in Table 2, gender, age, treatment with corticosteroids, and prolonged immunosuppression, considered the most clinically relevant factors, were included in the multivariate analysis. The only factor significantly related to liver dysfunction was prolonged immunosuppression (>3 months) (odds ratio [OR] 3.06; 95% confidence interval [CI] 1.02–9.16). Among the 70 HBsAg-positive patients who had received immunosuppressants, 18 (25.7%) developed liver dysfunction, including 3 of 11 (27.3%) who received antiviral prophylaxis and 15 of 59 (25.4%) without antiviral prophylaxis (P = 0.898). Baseline HBV-DNA had been checked in 51 of 70 HBsAg-positive patients receiving immunosuppressants. Liver dysfunction was developed in 15 of 42 (35.7%) HBV-DNA positive patients and 0 of 9 (0%) HBV-DNA negative patients. Among 11 patients receiving antiviral prophylaxis, six patients including three with CD and three with UC received lamivudine, and the remaining five patients including one with CD and four with UC received entecavir (Table 3).

Table 2. Factors Related to Liver Dysfunction in Patients with IBD and Chronic HBV Infection (Univariate Analysis)
 Patients with HBV Related Liver Dysfunction (n=23)Patients without HBV Related Liver Dysfunction (n=111)P-value
  • HBV, hepatitis B virus.

  • a

    Chi-square test.

  • b

    t-test.

Gender (M/F) [n (%)]19/4 (82.6/17.4)75/36 (67.6/32.4)0.150a
Median age at diagnosis (years)33350.304b
≥ 2 immunosuppressants [n (%)]6 (26.1%)18 (16.2%)0.261a
Immunosuppression >3 months [n (%)]14 (60.9%)25 (22.5%)<0.001a
Prophylactic antiviral treatment [n (%)]3 (13.0%)8 (7.2%)0.353a
Corticosteroids [n (%)]16 (69.6%)45 (40.5%)0.011a
Azathioprine/6-mercaptopurine [n (%)]7 (30.4%)23 (20.7%)0.309a
Infliximab [n (%)]2 (8.7%)4 (3.6%)0.402a
Table 3. Characteristics of IBD Patients with HBV Infection Receiving Antiviral Prophylaxis
CasesType of IBDBaseline HBV-DNA Level (Copies/mL)Type of ImmunosuppressantsImmunosuppression >3 MonthsAntiviral AgentAdequacy of Antiviral ProphylaxisaLiver Dysfunction
  • AZA, azathioprine; CD, Crohn's disease; HBV, hepatitis B virus; IBD, inflammatory bowel disease; IFX, infliximab; 6-MP, 6-mercaptopurine; UC, ulcerative colitis.

  • a

    Strict antiviral prophylaxis in accordance with treatment guidelines.

1CD3.0X102Steroids, AZA/6-MPYesLamivudineAdequateNo
2CD1.9X103Steroids, AZA/6-MP, IFXYesEntecavirInadequateYes
3UC8.6X102SteroidsNoLamivudineAdequateNo
4UC2.9X102SteroidsYesEntecavirAdequateNo
5UC6.5X102SteroidsNoLamivudineAdequateYes
6UC1.1X104SteroidsNoLamivudineInadequateNo
7CD2.6X103Steroids, AZA/6-MPYesLamivudineInadequateYes
8CD4.8X103Steroids, AZA/6-MPYesLamivudineAdequateNo
9UC5.3X103SteroidsYesEntecavirAdequateNo
10UCUndetectableSteroidsYesEntecavirAdequateNo
11UCUndetectableSteroidsNoEntecavirAdequateNo

Seven patients (5.2%), including three with CD and four with UC, developed liver cirrhosis, with six, two with CD and four with UC, diagnosed with hepatocellular carcinoma. One patient with UC developed fulminant hepatic failure due to HBV-related liver dysfunction after immunosuppression.

Clinical Outcomes of HBsAg-positive IBD Patients compared with HBsAg-negative IBD Patients

Median follow-up duration after diagnosis of IBD was 56.1 months (range, 0.3–325.7 months) in the HBsAg-positive group and 55.1 months (range 0.3–316.7 months) in the HBsAg-negative group. There were no marked between-group differences in disease extent/location and behavior based on the Montreal Classification (including perianal fistula modifier and upper gastrointestinal modifier in patients with CD). However, univariate analysis showed that use of immunosuppressants, including corticosteroids (P = 0.005), azathioprine/6-mercaptopurine (P < 0.001), and infliximab (P = 0.026), was significantly less frequent in the HBsAg-positive than the HBsAg-negative group (Table 4). The admission rate (proportion of patients admitted during follow-up) and the mean number of admissions during the follow-up period were higher in the HBsAg-positive than the HBsAg-negative group. The risk of total proctocolectomy in UC patients was higher in the HBsAg-positive than the HBsAg-negative group (10.0% vs. 1.9%, P = 0.005), whereas the risk of intestinal resection among CD patients did not differ between these groups (46.3% vs. 44.4%, P = 0.823).

Table 4. Clinical Outcomes of IBD Patients with Chronic HBV Infection Compared with Matched IBD Controls without HBV Infection
Clinical OutcomesHBV Group (n=134)Non-HBV Group (n=268)P-value
  • CD, Crohn's disease; HBV, hepatitis B virus; IBD, inflammatory bowel disease; UC, ulcerative colitis.

  • a

    t-test

  • b

    Chi-square test.

  • c

    Number of patients admitted during follow-up.

  • d

    Number of patients who underwent surgery during follow-up.

Median follow-up after diagnosis of IBD (months)56.1 (0.3-325.7)55.1 (0.3-316.7)0.974a
Azathioprine/6-mercaptopurine [n (%)]30 (22.4)107 (39.9)< 0.001b
Corticosteroids [n (%)]61 (45.5)162 (60.4)0.005b
Infliximab [n (%)]6 (4.5)30 (11.2)0.026b
Admissionc [n (%)]78 (58.2)116 (43.3)0.005b
Mean no. of admissions during follow-up1.50.90.047a
Surgeryd [n (%)]   
 Total proctocolectomy in UC8 (10.0; 8/80)3 (1.9; 3/160)0.005b
 Intestinal resection in CD25 (46.3; 25/54)48 (44.4; 48/108)0.823b
Mortality [n (%)]7 (5.2)1 (0.4)0.001b

At final evaluation, seven HBsAg-positive IBD patients, two with CD, and five with UC had died, two from hepatic decompression, three of progression of hepatocellular carcinoma, and two of general medical conditions other than liver diseases and IBD. Only one HBsAg-negative IBD patient died, of UC-associated colorectal carcinoma. The mortality rate during the follow-up period was significantly higher in the HBsAg-positive than in the HBsAg-negative IBD group (5.2% vs. 0.4%, P = 0.001).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

To our knowledge, this study is the largest to date to assess the clinical courses of chronic HBV infection and IBD in patients with both diseases, and the first to determine the outcome of chronic HBV infection in Asian patients with IBD who were treated with immunosuppressive regimens. In Korea, the prevalence of HBV was almost 8% of the general population until the 1980s.11 After the immunization for all neonates was begun since 1991 (National Immunization Program), the prevalence of HBV infection was markedly reduced, especially in children (0.6%), adolescents (1.6%), and in their early 20s (3%).12 However, the prevalence in adults still showed no significant differences to the prevalence rates in the past.13 This study differs from previous studies, in that we included HBsAg-positive IBD patients, but excluded IBD patients with antibodies to hepatitis B core antigen (anti-HBc) alone. Although HBV may be reactivated by immunosuppressive treatment in patients with anti-HBc alone, its incidence is very rare. Therefore, we sought to include only patients at high risk of HBV reactivation. This study also differs from previous studies in that we evaluated not only the clinical outcomes of chronic HBV infection but also those of IBD by comparing IBD patients with and without HBV infection. This was possible due to our inclusion of a relatively large number of HBsAg-positive patients. We found that prolonged immunosuppression (>3 months) was significantly related to liver dysfunction, and that IBD patients with HBV infection were less frequently treated with immunosuppressants than IBD patients without HBV infection. In addition, several clinical outcomes, including hospital admissions, surgery, and mortality, were worse in IBD patients with than without HBV infection.

Reactivation of HBV has been reported in 21% to 53% of patients with chronic HBV infection who receive cytotoxic therapy for hemato-oncological malignancies.14–16 In addition, the rates of HBV reactivation in patients with HBV and rheumatoid arthritis who receive anti-TNF-α therapy were 0% in those who received antiviral prophylaxis and 63% in those who did not.17 However, less is known about the rate of HBV reactivation in IBD patients administered immunosuppressive therapy, such as corticosteroids, thiopurines, and anti-TNF-α agents.18

In a recent multicenter study from Spain, HBV reactivation was observed in 9 of 25 (36%) HBsAg-positive patients with IBD who had received immunosuppressive agents.6 Of these, six patients developed hepatic failure, with three undergoing liver transplantation and one dying. Considering the higher prevalence of chronic HBV infection in our IBD patients (4.1%) than in IBD patients in Western countries (mean prevalence 1%),18 HBV reactivation in IBD patients is likely a more common problem in Asian than in Western patients. We observed liver dysfunction related to chronic HBV infection in 17.2% of 134 HBsAg-positive patients, and in 25.7% of 70 HBsAg-positive patients who had received immunosuppressive therapy. This rate of HBV reactivation was lower than the 36% reported in Spain. In addition, only one of our patients developed fulminant hepatic failure; this patient recovered following full supportive care without liver transplantation, a finding different from the results of the Spanish study. This discrepancy may be partially explained by relatively short periods of follow-up (median 56 months) and immunosuppression (median 6 months) in our patients, and by ethnic differences in the response of carriers to HBV infection.19

Of our 70 HBsAg-positive patients receiving immunosuppressive therapy, only 11 received antiviral prophylaxis, with three (27.3%) developing liver dysfunction. This rate of liver dysfunction despite antiviral prophylaxis was higher than in previous reports,6, 17 but we observed no difference in the rate of liver dysfunction between patients who did and did not receive antiviral prophylaxis. In contrast, other studies, including the study from Spain, observed a trend toward a lower rate of HBV reactivation in patients who did than did not receive antiviral prophylaxis, although the differences were not statistically significant due to the small number of patients in earlier studies.6 Our finding, of a high rate of HBV reactivation despite antiviral prophylaxis, may have been due to patient failure to follow guidelines for antiviral prophylaxis. The consensus of the European Crohn's and Colitis Organisation recommends that chronic HBsAg carriers receive prophylactic antiviral treatment with nucleotide/nucleoside analogs, starting 2 weeks prior to the initiation of treatment with steroids, azathioprine, or anti-TNF-α, and continuing for 6 months after their withdrawal.20 We found that three patients received inappropriate antiviral prophylaxis because of a strict Korean government health insurance reimbursement policy. Until now, the cost of prophylactic antiviral treatments in patients without liver dysfunction (i.e., an increase of 2-fold the upper normal limit of serum ALT) was not reimbursed by public health insurance in Korea. For the same reason, only 11 of 70 HBsAg-positive patients who had received immunosuppressive therapy also received antiviral prophylaxis. Among the eight patients who received adequate antiviral prophylaxis, one (12.5%) experienced liver dysfunction. Therefore, our results indicate the importance of strict antiviral prophylaxis, in accordance with treatment guidelines.

We found that immunosuppressants were less frequently used for HBsAg-positive than HBsAg-negative IBD patients, likely due to the fear of HBV reactivation and to the strict Korean insurance policy on antiviral prophylaxis. A lower rate of immunosuppressant use may have an adverse effect on the prognosis of patients with IBD. We found that clinical outcomes, including admission rate, mean number of admissions per person, surgery rate for UC, and mortality were worse in HBsAg-positive than HBsAg-negative IBD patients. Especially the higher rate of total proctocolectomy in HBsAg-positive than HBsAg-negative UC patients may have been due to the desire to avoid repeated and prolonged use of immunosuppressants. Thus, the greater use of immunosuppressants, together with appropriate antiviral prophylaxis, may have reduced the rate of total proctocolectomy in HBsAg-positive UC patients.

Our findings must, however, be interpreted against the background of potential limitations. First, this was a retrospective study. Therefore, the evaluation of HBV reactivation and the use of antiviral prophylaxis were not standardized in our patients, thus precluding an accurate estimation of the frequency of HBV reactivation and of the efficacy of antiviral prophylaxis. Second, this study included ethnically distinct Korean patients only, with vertical transmission of HBV being the major mode of chronic HBV infection in Korea. Therefore, our results may not be applicable to Western populations or patients with other modes of transmission. However, there is no evidence of ethnic differences of HBV reactivation in patients with rheumatic diseases, with studies performed in both Asian and Western populations.17, 21

In conclusion, liver dysfunction in HBV-infected IBD patients was more frequent in those receiving prolonged immunosuppression. We also found that immunosuppressants were less frequently used for IBD patients with than without HBV infection, and that IBD patients with HBV infection had worse clinical outcomes than those without HBV infection. These findings suggest that HBV-infected IBD patients should receive prophylactic antiviral agents and immunosuppressants without delay. Further prospective, long-term follow-up studies are needed to confirm these observations.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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