’Original article Occult hepatitis B infection in children with chronic liver disease Anshu Srivastavaa, Amrita Mathiasa, Surender K. Yachhaa and Rakesh Aggarwalb Aims Occult hepatitis B infection (OBI) may adversely affect the outcome of patients with chronic liver disease (CLD). There are no data on OBI and CLD in children. This study determined the prevalence and effect of OBI in HBsAg-negative CLD children. Materials and methods CLD children were prospectively evaluated with a demographic, clinical, and investigative proforma. All HBsAg-negative CLD cases were tested for exposure to hepatitis B (total anti-HBc, anti-HBs). Serum hepatitis B virus DNA was measured in exposed (total anti-HBc positive) patients. Results A total of 115 HBsAg-negative CLD children (59 boys, age 9.0 ± 3.6 years) were enrolled. The etiology of CLD was known in 94 cases and 21 children had cryptogenic CLD. Of these, 45 (39.1%) had evidence of HBV exposure (23 total anti-HBc positive, 17 total anti-HBc and anti-HBs positive, five only anti-HBs positive without previous vaccination). The anti-HBc-positive children had a higher Child’s score than the anti-HBc-negative children [11 (5–13) vs. 7 (5–13); P = 0.00]. A total of 4/45 children had seropositive OBI with serum HBV DNA of 8, 36, 133, and 156 IU/ml, respectively. The proportion of total anti-HBc positivity (8/21 vs. 32/94; P = 0.8) and OBI (2/21 vs. 2/94; P = 0.1) was similar in cryptogenic CLD and known cause CLD. Conclusion Seropositive OBI is infrequent in Indian children with CLD. The prevalence is similar in cryptogenic and CLD of known etiology. Eur J Gastroenterol Hepatol 27:375–377 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
Materials and methods
Occult hepatitis B infection (OBI) has been defined as the presence of detectable hepatitis B virus (HBV) DNA in the liver or serum of HBsAg-negative patients, with or without HBV antibodies (anti-HBc, anti-HBs). The amount of viral DNA present in patients with OBI is small and sensitive HBV DNA PCR assays are required for its diagnosis [1]. OBI has been considered to play a role in the pathogenesis of cryptogenic liver disease, increased risk of progression to cirrhosis and eventually to hepatocellular carcinoma, and flare of viremia on immunosuppression [2, 3]. Studies in adults with chronic liver disease (CLD) have shown a variable prevalence of OBI ranging from 2 to 32% depending on the prevalence of HBV infection in the particular general population and the sensitivity of the assay used for detection of HBV DNA [4,5]. However, studies on OBI in children are limited largely to those with hematological disorders and HIV infection [6,7].The current study aimed to prospectively evaluate the prevalence of OBI in children with CLD.
This prospective study enrolled children with CLD evaluated in the Department of Pediatric Gastroenterology between March 2008 and June 2010. Written, informed consent was obtained from parents of participating children and the study was approved by the Institutional Ethics Committee. The study was carried out in accordance with the latest guidelines of ‘Good Clinical Practice’. CLD was diagnosed on the basis of clinical, biochemical, ultrasonographic, and endoscopic evidence with or without histology. The etiology of underlying CLD was determined according to standard criteria. Cases where no etiology was identified were labeled as cryptogenic and HBsAg-positive CLD patients were excluded from analysis. In children with HBsAg-negative CLD, those with total anti-HBc positivity with or without anti-HBs positivity, and those with only anti-HBs positivity and no history of hepatitis B vaccination were labeled as exposed to hepatitis B. This subgroup was further tested for quantitative HBV DNA using the COBAS Taqman HBV test kit (Roche Molecular Systems, Pleasanton, California, USA). This assay detects a genomic sequence within the highly conserved precore/core region of the HBV genome, with a lower limit of detection of 6 IU/ml.
European Journal of Gastroenterology & Hepatology 2015, 27:375–377
Statistical analysis
Keywords: children, chronic liver disease, hepatitis B virus, occult hepatitis B Departments of aPediatric Gastroenterology and bGastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Correspondence to Anshu Srivastava, MD, DM, Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India Tel: + 91 522 2495212; fax: + 91 522 2668017; e-mail: [email protected] Received 24 October 2014 Accepted 6 January 2015
SPSS (version 17.0; SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Continuous data were expressed as mean and SD and categorical values as proportions. Student’s ‘t’ test was used to compare continuous variables and χ2/Fisher’s exact test for categorical variables; P values of less than 0.05 were considered significant.
0954-691X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MEG.0000000000000294
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
375
376
April 2015 • Volume 27 • Number 4
European Journal of Gastroenterology & Hepatology
Results
A total of 115 (59 boys, age 9.0 ± 3.6 years) HBsAgnegative CLD children were evaluated. The etiology of CLD in these 115 cases was autoimmune liver disease (AILD) in 32 (27.8%), Wilson’s disease in 25 (21.7%), Budd–Chiari syndrome in 15 (13.0%), biliary atresia in nine (7.8%), progressive familial intrahepatic cholestasis in three (2.6%), and HCV, Indian childhood cirrhosis, primary sclerosing cholangitis, Alagille syndrome, and noncirrhotic portal fibrosis in two (1.7%) cases each; 21 (18.2%) patients had no discernible cause of CLD and they were labeled as cryptogenic CLD. A total of 40/115 (34.8%) cases were positive for total anti-HBc, suggesting exposure to the HBV, of whom 17 also had anti-HBs antibodies. Among the total of 75 antiHBc-negative CLD cases, 32 were anti-HBs positive. Twenty-seven of these 32 children had received the hepatitis B vaccine and five had not received the hepatitis B vaccine. Thus, a total of 45 children were considered exposed to hepatitis B and tested for serum HBV quantitative DNA (23 only total anti-HBc positive, 17 positive for both total anti-HBc and anti-HBs, and five only antiHBs positive cases). Four (8.8%) of these 45 HBV-exposed patients had detectable HBV DNA of 8, 36, 133, and 156 IU/ml, respectively. The details of these four cases are shown in Table 1. Of these 45 cases, 44 were negative for anti-HCV antibody and one was anti-HCV positive, but HCV RNA negative. The etiology of CLD in this case was Wilson’s disease. Of the 21 cases with cryptogenic CLD, eight (38%) were positive for total anti-HBc and two (9.5%) had detectable HBV DNA. The total anti-HBc positivity was similar in the cryptogenic CLD and CLD with known etiologies (8/21 vs. 32/94; P = 0.8). Seropositive OBI was present in a higher percentage of cryptogenic CLD cases than those with known etiologies [2/21 (9.5%) vs. 2/94 (2.1%)], but the difference was not statistically significant. None of the two HCV-related CLD children had OBI infection. The numbers of children in Child’s class A, B, and C were 34, 35, and 38 in the CLD without OBI group and 0, 1, and 3 in the CLD with OBI group, respectively. None of our 45 HBV-exposed children, including the four with occult HBV (OHBV), had undergone liver transplantation. Table 1. Details of cases with occult hepatitis B infection Characteristics
Case 1
Age (years) Sex Cause of CLD
12 Female Cryptogenic
HBsAg Anti-HBc total Anti-HBs HBV DNA (IU/ml) Hepatitis B vaccination Anti-HCV
Negative Positive Negative 156 No
Child–Pugh class
Negative
C
Case 2 9 Male Wilson’s disease Negative Positive Negative 8 No Positive (HCV RNA negative) B
Case 3 6 Female Cryptogenic
Discussion
CLD patients are at an increased risk of exposure to HBV and this is shown by the 35% positivity of total anti-HBc in children with HBsAg-negative CLD. A total of 4/45 (8.8%) patients with evidence of HBV exposure had OBI, all with low serum levels of HBV DNA. In a recent consensus, OBI has been defined as the presence of HBV DNA in the liver/serum of HBsAg-negative patients [1]. The serum HBV DNA level is very low (< 200 IU/ml) as was found in all four of our cases [1]. Cases with higher serum HBV DNA levels, similar to those observed in patients with overt HBV infection (serologically evident), should be considered ‘false OBI’ and are believed to be because of infection by mutant HBV (S gene escape mutant), which produces a modified HBsAg that is not detected by the commercial test [1]. OBI is further divided into seropositive (anti-HBc/antiHBs positive) or seronegative OBI (anti-HBc/anti-HBs negative). OBI is significantly more common in anti-HBcpositive patients than anti-HBc-negative cases and seronegative OBI accounts for only ∼ 20% of all OBI cases [1]. As we did not test the anti-HBc/anti-HBs-negative cases for HBV DNA, we cannot determine the occurrence of seronegative OBI. Overall, the OBI rate in our HBsAgnegative CLD children was low, 4/115 (3.4%), and even if we theoretically add 20% of seronegative cases, it would be estimated to increase to 5.2%. There are no published studies of OBI in CLD children. In adults, variable prevalence of OBI has been shown depending on the etiology of liver disease (maximum with chronic hepatitis C and cryptogenic CLD), HBV endemicity in the area, and PCR methods [8]. In India, OBI has been reported in 9.4% of adult CLD cases [9], which is higher than that in our study. We did not observe any significant difference in OBI among patients with cryptogenic versus other known etiology of liver disease (2/9 vs. Table 2. Comparison of total anti-HBc-positive and anti-HBc-negative children with chronic liver disease Parameters
Total anti-HBc positive (n = 40)
Total anti-HBc negative (n = 75)
P value
8 (2–16) 25 : 15 11 (5–13) 27/34
10 (2–18) 34 : 41 7 (5–13) 45/62
0.02 0.4 0.000 0.6
4.4 (0.3–41.5)
1.8 (0.4–25)
0.006
Case 4
Negative Positive Positive 36 No
8 Male Wilson’s disease Negative Positive Positive 133 No
Negative
Negative
C
Total anti-HBc positivity is considered a marker of OBI in the absence of HBV DNA testing, and a comparison of anti-HBc-positive and anti-HBc-negative children with CLD is shown in Table 2.
C
Anti-HBc, anti hepatitis B core; anti-HBs, anti hepatitis B surface; CLD, chronic liver disease; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus.
Age (years) Male : female Child’s score Esophageal varices (present/screened) Serum bilirubin (mg/ dl) SGPT (U/l) SGOT (U/l) Serum proteins (g/dl) Serum albumin (g/dl) Alkaline phosphatase (U/l) PT prolongation over control (s)
68 133 6.4 2.6 419
(7–628) (42–836) (4.7–8.1) (1.2–3.9) (49–1568)
75 100 6.8 3.3 508.5
8.0 (0.2–10)
(12–1248) (23–1940) (3.6–8.8) (1.3–4.9) (97–1545)
2.9 (0–10)
0.4 0.06 0.1 0.000 0.1 0.000
All values are represented as median (range). Anti-HBc, anti hepatitis B core; PT, prothrombin time; SGOT, serum glutamicoxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Occult hepatitis B in children with CLD Srivastava et al.
2/36; P = 0.1). Also, none of our CLD cases with OBI had hepatitis C as the etiology of CLD. The numbers of HCVrelated CLD cases were too few to evaluate the association of HCV-related CLD and OBI. The prevalence of OBI would have been higher if we had tested the liver tissue rather than serum for HBV DNA; however, as liver specimens are available only in a minority of cases, analysis of serum samples is the most common approach to identify cases of OBI [1]. OBI in CLD patients is important for various reasons. First, it may be the etiology for liver damage in cryptogenic cases [10]. However, we observed a similar prevalence in cryptogenic cases, which does not support the above observation. Second, OBI may accelerate the progression of liver fibrosis, development of cirrhosis, and increase the risk of development of hepatocellular carcinoma in CLD patients [1,3]. As the number of OBI cases in our study was very small, a comparison of Child’s score in those with and without OBI may not be appropriate. However, a comparison of all total anti-HBc-positive and total antiHBc-negative children shows that the anti-HBc-positive cases had more severe liver disease. This was evident from the significantly poorer synthetic functions (lower albumin, prolonged prothrombin time), high bilirubin, and a higher Child’s score in anti-HBc-positive children in comparison with those who were negative for anti-HBc. Third, there is a possible risk of HBV reactivation if these patients are administered immunosuppression and finally, it may lead to graft infection and reactivation of OHBV after liver transplantation [11]. None of our 32 cases of AILD on immunosuppression had OBI. Georgiadou et al. [12] found OBI in 12.2% of adults with AILD, but it did not affect the clinical and laboratory features of the disease and none of the cases with AILD and OBI deteriorated with immunosuppression during follow-up. The intensity of immune-suppression is related to the risk of reactivation. The current literature shows that the risk of reactivation of OHBV after liver transplantation is low [13]. In general, administration either of antiviral drugs or of hepatitis B immune globulin is not recommended in patients with OHBV infection undergoing liver transplantation. However, these patients may need a closer biochemical and virological monitoring in the postoperative phase. This becomes even more important if the liver graft is from an anti-HBc-positive donor [14]. However, the available literature is limited and does not allow any recommendations, and further studies are needed to clarify the management of OBI in CLD patients [15]. The most effective way to deal with OHBV is to prevent it. Hepatitis B vaccination should be administered in all non-HBV-related CLD patients at the earliest possible opportunity, preferably before decompensation of liver disease, to improve seroconversion. Also, it may be useful to verify successful immunization following such vaccination by detection of anti-HBs antibodies. The limitation of our study is that we did not measure HBV DNA in the anti-HBc/anti-HBs-negative CLD cases and thus cannot comment on the prevalence of seronegative OBI.
www.eurojgh.com
377
Conclusion
Seropositive OBI is uncommon and found only in 3.4% of CLD children. The cryptogenic CLD children did not have an increased prevalence of OBI compared with those with a known etiology of CLD. Children testing positive for total anti-HBc had poorer liver functions and more advanced liver disease than those who were anti-HBcnegative. Acknowledgements
This project was supported by an intramural grant from the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow. Conflicts of interest
There are no conflicts of interest. References 1
2
3
4
5
6
7
8 9
10
11
12
13
14
15
Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008; 49:652–657. Covolo L, Pollicino T, Raimondo G, Donato F. Occult hepatitis B virus and the risk for chronic liver disease: a meta-analysis. Dig Liver Dis 2013; 45:238–244. Shi Y, Wu YH, Wu W, Zhang WJ, Yang J, Chen Z. Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis. Liver Int 2012; 32:231–240. Chan HL, Tsang SW, Leung NW, Tse CH, Hui Y, Tam JS, et al. Occult HBV infection in cryptogenic liver cirrhosis in an area with high prevalence of HBV infection. Am J Gastroenterol 2002; 97:1211–1215. Kaviani MJ, Behbahani B, Mosallaii MJ, Sari-Aslani F, Taghavi SA. Occult hepatitis B virus infection and cryptogenic chronic hepatitis in an area with intermediate prevalence of HBV infection. World J Gastroenterol 2006; 12:5048–5050. Said ZN, El-Sayed MH, El-Bishbishi IA, El-Fouhil DF, Abdel-Rheem SE, El-Abedin MZ, Salama II. High prevalence of occult hepatitis B in hepatitis C-infected Egyptian children with haematological disorders and malignancies. Liver Int 2009; 29:518–524. Dapena M, Figueras C, Noguera-Julian A, Fortuny C, de José MI, Mellado MJ, et al. Implementation of occult hepatitis screening in the Spanish cohort of HIV infected pediatric patients. Pediatr Infect Dis J 2013; 32:e377–e379. Chemin I, Trepo C. Clinical impact of occult HBV infections. J Clin Virol 2005; 34 (Suppl 1):S15–S21. Chaudhuri V, Tayal R, Nayak B, Acharya SK, Panda SK. Occult hepatitis B virus infection in chronic liver disease: full-length genome and analysis of mutant surface promoter. Gastroenterology 2004; 127:1356–1371. Berasain C, Betés M, Panizo A, Ruiz J, Herrero JI, Civeira MP, et al. Pathological and virological findings in patients with persistent hypertransaminasemia of unknown etiology. Gut 2000; 47:429–435. Abdelmalek MF, Pasha TM, Zein NN, Persing DH, Wiesner RH, Douglas DD. Subclinical reactivation of hepatitis B virus in liver transplant recipients with past exposure. Liver Transpl 2003; 9:1253–1257. Georgiadou SP, Zachou K, Liaskos C, Gabeta S, Rigopoulou EI, Dalekos GN. Occult hepatitis B virus infection in patients with autoimmune liver diseases. Liver Int 2009; 29:434–442. Ciesek S, Helfritz FA, Lehmann U, Becker T, Strassburg CP, Neipp M, et al. Persistence of occult hepatitis B after removal of the hepatitis B virus-infected liver. J Infect Dis 2008; 197:355–360. Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: a systematic review. J Hepatol 2010; 52:272–279. Lledó JL, Fernández C, Gutiérrez ML, Ocaña S. Management of occult hepatitis B virus infection: an update for the clinician. World J Gastroenterol 2011; 17:1563–1568.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Introduction
Materials and methods
Occult hepatitis B infection (OBI) has been defined as the presence of detectable hepatitis B virus (HBV) DNA in the liver or serum of HBsAg-negative patients, with or without HBV antibodies (anti-HBc, anti-HBs). The amount of viral DNA present in patients with OBI is small and sensitive HBV DNA PCR assays are required for its diagnosis [1]. OBI has been considered to play a role in the pathogenesis of cryptogenic liver disease, increased risk of progression to cirrhosis and eventually to hepatocellular carcinoma, and flare of viremia on immunosuppression [2, 3]. Studies in adults with chronic liver disease (CLD) have shown a variable prevalence of OBI ranging from 2 to 32% depending on the prevalence of HBV infection in the particular general population and the sensitivity of the assay used for detection of HBV DNA [4,5]. However, studies on OBI in children are limited largely to those with hematological disorders and HIV infection [6,7].The current study aimed to prospectively evaluate the prevalence of OBI in children with CLD.
This prospective study enrolled children with CLD evaluated in the Department of Pediatric Gastroenterology between March 2008 and June 2010. Written, informed consent was obtained from parents of participating children and the study was approved by the Institutional Ethics Committee. The study was carried out in accordance with the latest guidelines of ‘Good Clinical Practice’. CLD was diagnosed on the basis of clinical, biochemical, ultrasonographic, and endoscopic evidence with or without histology. The etiology of underlying CLD was determined according to standard criteria. Cases where no etiology was identified were labeled as cryptogenic and HBsAg-positive CLD patients were excluded from analysis. In children with HBsAg-negative CLD, those with total anti-HBc positivity with or without anti-HBs positivity, and those with only anti-HBs positivity and no history of hepatitis B vaccination were labeled as exposed to hepatitis B. This subgroup was further tested for quantitative HBV DNA using the COBAS Taqman HBV test kit (Roche Molecular Systems, Pleasanton, California, USA). This assay detects a genomic sequence within the highly conserved precore/core region of the HBV genome, with a lower limit of detection of 6 IU/ml.
European Journal of Gastroenterology & Hepatology 2015, 27:375–377
Statistical analysis
Keywords: children, chronic liver disease, hepatitis B virus, occult hepatitis B Departments of aPediatric Gastroenterology and bGastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Correspondence to Anshu Srivastava, MD, DM, Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India Tel: + 91 522 2495212; fax: + 91 522 2668017; e-mail: [email protected] Received 24 October 2014 Accepted 6 January 2015
SPSS (version 17.0; SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Continuous data were expressed as mean and SD and categorical values as proportions. Student’s ‘t’ test was used to compare continuous variables and χ2/Fisher’s exact test for categorical variables; P values of less than 0.05 were considered significant.
0954-691X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MEG.0000000000000294
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
375
376
April 2015 • Volume 27 • Number 4
European Journal of Gastroenterology & Hepatology
Results
A total of 115 (59 boys, age 9.0 ± 3.6 years) HBsAgnegative CLD children were evaluated. The etiology of CLD in these 115 cases was autoimmune liver disease (AILD) in 32 (27.8%), Wilson’s disease in 25 (21.7%), Budd–Chiari syndrome in 15 (13.0%), biliary atresia in nine (7.8%), progressive familial intrahepatic cholestasis in three (2.6%), and HCV, Indian childhood cirrhosis, primary sclerosing cholangitis, Alagille syndrome, and noncirrhotic portal fibrosis in two (1.7%) cases each; 21 (18.2%) patients had no discernible cause of CLD and they were labeled as cryptogenic CLD. A total of 40/115 (34.8%) cases were positive for total anti-HBc, suggesting exposure to the HBV, of whom 17 also had anti-HBs antibodies. Among the total of 75 antiHBc-negative CLD cases, 32 were anti-HBs positive. Twenty-seven of these 32 children had received the hepatitis B vaccine and five had not received the hepatitis B vaccine. Thus, a total of 45 children were considered exposed to hepatitis B and tested for serum HBV quantitative DNA (23 only total anti-HBc positive, 17 positive for both total anti-HBc and anti-HBs, and five only antiHBs positive cases). Four (8.8%) of these 45 HBV-exposed patients had detectable HBV DNA of 8, 36, 133, and 156 IU/ml, respectively. The details of these four cases are shown in Table 1. Of these 45 cases, 44 were negative for anti-HCV antibody and one was anti-HCV positive, but HCV RNA negative. The etiology of CLD in this case was Wilson’s disease. Of the 21 cases with cryptogenic CLD, eight (38%) were positive for total anti-HBc and two (9.5%) had detectable HBV DNA. The total anti-HBc positivity was similar in the cryptogenic CLD and CLD with known etiologies (8/21 vs. 32/94; P = 0.8). Seropositive OBI was present in a higher percentage of cryptogenic CLD cases than those with known etiologies [2/21 (9.5%) vs. 2/94 (2.1%)], but the difference was not statistically significant. None of the two HCV-related CLD children had OBI infection. The numbers of children in Child’s class A, B, and C were 34, 35, and 38 in the CLD without OBI group and 0, 1, and 3 in the CLD with OBI group, respectively. None of our 45 HBV-exposed children, including the four with occult HBV (OHBV), had undergone liver transplantation. Table 1. Details of cases with occult hepatitis B infection Characteristics
Case 1
Age (years) Sex Cause of CLD
12 Female Cryptogenic
HBsAg Anti-HBc total Anti-HBs HBV DNA (IU/ml) Hepatitis B vaccination Anti-HCV
Negative Positive Negative 156 No
Child–Pugh class
Negative
C
Case 2 9 Male Wilson’s disease Negative Positive Negative 8 No Positive (HCV RNA negative) B
Case 3 6 Female Cryptogenic
Discussion
CLD patients are at an increased risk of exposure to HBV and this is shown by the 35% positivity of total anti-HBc in children with HBsAg-negative CLD. A total of 4/45 (8.8%) patients with evidence of HBV exposure had OBI, all with low serum levels of HBV DNA. In a recent consensus, OBI has been defined as the presence of HBV DNA in the liver/serum of HBsAg-negative patients [1]. The serum HBV DNA level is very low (< 200 IU/ml) as was found in all four of our cases [1]. Cases with higher serum HBV DNA levels, similar to those observed in patients with overt HBV infection (serologically evident), should be considered ‘false OBI’ and are believed to be because of infection by mutant HBV (S gene escape mutant), which produces a modified HBsAg that is not detected by the commercial test [1]. OBI is further divided into seropositive (anti-HBc/antiHBs positive) or seronegative OBI (anti-HBc/anti-HBs negative). OBI is significantly more common in anti-HBcpositive patients than anti-HBc-negative cases and seronegative OBI accounts for only ∼ 20% of all OBI cases [1]. As we did not test the anti-HBc/anti-HBs-negative cases for HBV DNA, we cannot determine the occurrence of seronegative OBI. Overall, the OBI rate in our HBsAgnegative CLD children was low, 4/115 (3.4%), and even if we theoretically add 20% of seronegative cases, it would be estimated to increase to 5.2%. There are no published studies of OBI in CLD children. In adults, variable prevalence of OBI has been shown depending on the etiology of liver disease (maximum with chronic hepatitis C and cryptogenic CLD), HBV endemicity in the area, and PCR methods [8]. In India, OBI has been reported in 9.4% of adult CLD cases [9], which is higher than that in our study. We did not observe any significant difference in OBI among patients with cryptogenic versus other known etiology of liver disease (2/9 vs. Table 2. Comparison of total anti-HBc-positive and anti-HBc-negative children with chronic liver disease Parameters
Total anti-HBc positive (n = 40)
Total anti-HBc negative (n = 75)
P value
8 (2–16) 25 : 15 11 (5–13) 27/34
10 (2–18) 34 : 41 7 (5–13) 45/62
0.02 0.4 0.000 0.6
4.4 (0.3–41.5)
1.8 (0.4–25)
0.006
Case 4
Negative Positive Positive 36 No
8 Male Wilson’s disease Negative Positive Positive 133 No
Negative
Negative
C
Total anti-HBc positivity is considered a marker of OBI in the absence of HBV DNA testing, and a comparison of anti-HBc-positive and anti-HBc-negative children with CLD is shown in Table 2.
C
Anti-HBc, anti hepatitis B core; anti-HBs, anti hepatitis B surface; CLD, chronic liver disease; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus.
Age (years) Male : female Child’s score Esophageal varices (present/screened) Serum bilirubin (mg/ dl) SGPT (U/l) SGOT (U/l) Serum proteins (g/dl) Serum albumin (g/dl) Alkaline phosphatase (U/l) PT prolongation over control (s)
68 133 6.4 2.6 419
(7–628) (42–836) (4.7–8.1) (1.2–3.9) (49–1568)
75 100 6.8 3.3 508.5
8.0 (0.2–10)
(12–1248) (23–1940) (3.6–8.8) (1.3–4.9) (97–1545)
2.9 (0–10)
0.4 0.06 0.1 0.000 0.1 0.000
All values are represented as median (range). Anti-HBc, anti hepatitis B core; PT, prothrombin time; SGOT, serum glutamicoxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Occult hepatitis B in children with CLD Srivastava et al.
2/36; P = 0.1). Also, none of our CLD cases with OBI had hepatitis C as the etiology of CLD. The numbers of HCVrelated CLD cases were too few to evaluate the association of HCV-related CLD and OBI. The prevalence of OBI would have been higher if we had tested the liver tissue rather than serum for HBV DNA; however, as liver specimens are available only in a minority of cases, analysis of serum samples is the most common approach to identify cases of OBI [1]. OBI in CLD patients is important for various reasons. First, it may be the etiology for liver damage in cryptogenic cases [10]. However, we observed a similar prevalence in cryptogenic cases, which does not support the above observation. Second, OBI may accelerate the progression of liver fibrosis, development of cirrhosis, and increase the risk of development of hepatocellular carcinoma in CLD patients [1,3]. As the number of OBI cases in our study was very small, a comparison of Child’s score in those with and without OBI may not be appropriate. However, a comparison of all total anti-HBc-positive and total antiHBc-negative children shows that the anti-HBc-positive cases had more severe liver disease. This was evident from the significantly poorer synthetic functions (lower albumin, prolonged prothrombin time), high bilirubin, and a higher Child’s score in anti-HBc-positive children in comparison with those who were negative for anti-HBc. Third, there is a possible risk of HBV reactivation if these patients are administered immunosuppression and finally, it may lead to graft infection and reactivation of OHBV after liver transplantation [11]. None of our 32 cases of AILD on immunosuppression had OBI. Georgiadou et al. [12] found OBI in 12.2% of adults with AILD, but it did not affect the clinical and laboratory features of the disease and none of the cases with AILD and OBI deteriorated with immunosuppression during follow-up. The intensity of immune-suppression is related to the risk of reactivation. The current literature shows that the risk of reactivation of OHBV after liver transplantation is low [13]. In general, administration either of antiviral drugs or of hepatitis B immune globulin is not recommended in patients with OHBV infection undergoing liver transplantation. However, these patients may need a closer biochemical and virological monitoring in the postoperative phase. This becomes even more important if the liver graft is from an anti-HBc-positive donor [14]. However, the available literature is limited and does not allow any recommendations, and further studies are needed to clarify the management of OBI in CLD patients [15]. The most effective way to deal with OHBV is to prevent it. Hepatitis B vaccination should be administered in all non-HBV-related CLD patients at the earliest possible opportunity, preferably before decompensation of liver disease, to improve seroconversion. Also, it may be useful to verify successful immunization following such vaccination by detection of anti-HBs antibodies. The limitation of our study is that we did not measure HBV DNA in the anti-HBc/anti-HBs-negative CLD cases and thus cannot comment on the prevalence of seronegative OBI.
www.eurojgh.com
377
Conclusion
Seropositive OBI is uncommon and found only in 3.4% of CLD children. The cryptogenic CLD children did not have an increased prevalence of OBI compared with those with a known etiology of CLD. Children testing positive for total anti-HBc had poorer liver functions and more advanced liver disease than those who were anti-HBcnegative. Acknowledgements
This project was supported by an intramural grant from the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow. Conflicts of interest
There are no conflicts of interest. References 1
2
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