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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2016  |  Volume : 27  |  Issue : 5  |  Page : 1047-1051
Delayed clearance of hepatitis B surface antigen and development of hepatitis B surface antibody in a chronic hemodialysis patient


1 Division of Nephrology, Greater Los Angeles Veterans Affairs Healthcare System; Department of Medicine, David Geffen School of Medicine at UCLA; Division of Nephrology, Olive View - UCLA Medical Center, Los Angeles, CA, USA
2 Department of Medicine, David Geffen School of Medicine at UCLA; Division of Nephrology, Olive View - UCLA Medical Center; Department of Medicine, Division of Nephrology, Cedars Sinai Medical Center, Los Angeles, CA, USA
3 Department of Medicine, David Geffen School of Medicine at UCLA; Division of Nephrology, Olive View - UCLA Medical Center, Los Angeles, CA, USA
4 Department of Nephrology, Kaiser Permanente, Panorama City, USA
5 Department of Medicine, David Geffen School of Medicine at UCLA; Division of Nephrology, Olive View - UCLA Medical Center; Surgical Consultative Nephrology, UCLA David Geffen School of Medicine, Director UCLA Stone Center, Los Angeles, CA, USA

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Date of Web Publication22-Sep-2016
 

   Abstract 

The introduction of hepatitis B vaccination and infection control in 1977 has greatly decreased the prevalence of hepatitis B. Currently, approximately 2.8% of the end-stage renal disease population is hepatitis B positive with a presence in 27.7% of the USA hemodialysis (HD) units according to the Dialysis Outcomes and Practice Patterns Study data. The behavior of hepatitis B infection differs significantly between immunocompetent and immunosuppressed hosts. Immunosuppressed hosts present more subtly with complications of chronic hepatitis B infection, being more challenging to detect. It is also well known that patients with chronic infection on HD have a small chance of clearing the virus. We report here a case of a hepatitis B positive HD patient who underwent spontaneous delayed serological clearance of hepatitis B surface antigen and development of immunity via appearance of hepatitis B surface antibody. This is a rare occurrence, and the few similar reported cases will be discussed.

How to cite this article:
Treger R, Hanna RM, Lee BM, Lopez EA, Wilson J, Corry D. Delayed clearance of hepatitis B surface antigen and development of hepatitis B surface antibody in a chronic hemodialysis patient. Saudi J Kidney Dis Transpl 2016;27:1047-51

How to cite this URL:
Treger R, Hanna RM, Lee BM, Lopez EA, Wilson J, Corry D. Delayed clearance of hepatitis B surface antigen and development of hepatitis B surface antibody in a chronic hemodialysis patient. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Nov 15];27:1047-51. Available from: http://www.sjkdt.org/text.asp?2016/27/5/1047/190886

   Introduction Top


The prevalence of hepatitis B virus (HBV) infection in chronic hemodialysis (HD) patients has greatly decreased due to the implementation of vaccination and guidelines for infection control in 1977. In 1976, there was a 7.8% prevalence of hepatitis B surface antigen (HBsAg) positivity among dialysis patients, but in 2000, it had decreased to 2.8%. Nevertheless, in 1999, 27.7% of dialysis units treated patients with hepatitis B. [1],[2]

The HBV, which belongs to Hepadnaviridae, has a lipid bilayer outer coat made from hostderived lipids. HBsAg is presented outwardly, and an inner coat with Hepatitis B core antigen (HBcAg) encloses the genome of viral deoxyribonucleic acid (DNA). [3] This DNA has only 3.2 kilobase pairs and has multiple reading frames coding for proteins such as Hepatitis B e-antigen (HBeAg). [3] Viral particles attach to host cells using the HBsAg protein to bind to host cell proteins (such as carboxypeptidase D). The viral DNA then incorporates itself into the host's DNA. [3],[4]

In immunocompetent hosts, acute hepatitis B infection may result in viral replication and initially, detection of HBeAg/HBsAg in serum. HBeAg expression is usually delayed, and the antigen is rapidly cleared. In contrast, HBsAg has a variable detection window, typically between one to two weeks of infection, but occurring as late as 11-12 weeks after the initial acute infection. [3],[5] HBV DNA remains detectable in serum as long as active infection persists. The clinical course is tracked by enzymatic biomarkers of liver injury such as serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT). Antibody response occurs in waves with IgM anti-HBc appearing first, followed by IgG anti-HBe, and finally IgG anti-HBsAg. IgG anti-HBsAg arises during the latter stages of infection as the body clears viral HBsAg and continues to provide immunity against reinfection. [3],[5]

Among immunocompetent adults, about 90- 95% of patients recover completely and develop Anti-HBsAg. [6] The risk of progressing to chronic HBV infection increases and varies inversely with the age of onset, with chronic active hepatitis B being more common in those infected during childhood. [6] About 50% of those with chronic active hepatitis have evidence of viral replication and about 15-20% proceed to cirrhosis within five years, [7] a process that worsens with increasing viral load. [8] Chronic hepatitis usually consists of two phases: an early replicating phase with active liver disease and circulating HBV DNA and HBeAg, and a late nonreplicating phase with clearance of HBV DNA and appearance of HBeAb. [9] Some patients with chronic HBV infection eventually become HBsAg negative, with the annual delayed clearance rate of HBsAg estimated to be 0.5-2%. [10]

The natural history of hepatitis B in immunocompromised populations, including patients with end-stage renal disease (ESRD), is not well known. Factors such as uremia contribute to the immunosuppressed status of dialysis patients. [11] The presentation of dialysis patients who are chronic carriers is atypical as well. It has been noted that dialysis patients with chronic HBV infection and HBsAg expression are in general anicteric, rarely develop symptomatic hepatitis and have lower aminotransferase levels, and rarely clear the virus. [12] This may interfere with the recognition of occult hepatocellular carcinoma or cirrhosis. [12]

There have been several reports of spontaneous clearance of hepatitis B in HD patients that are discussed extensively thereafter. [13],[14],[15],[16],[17] We herein report a patient who cleared the HBV after about seven years of carrier status and three years on chronic HD.


   Case Report Top


Our patient is an 82-year-old Hispanic male with a history of pancreatitis, osteoarthritis, hypertension for 15 years, and ESRD of unknown etiology, on HD since 1999, and who had been HBsAg positive since 1996. Serial laboratory follow-up continued to show positive HBsAg and negative HBsAb. Liver function tests including AST, ALT, alkaline phosphatase, and albumin were always within normal limits since presentation in 1999. A computerized tomography scan of the abdomen in 2002 did not show any evidence of cirrhosis or focal liver mass. Alpha-fetoprotein (AFP) was also followed and remained within normal limits since presentation. The patient had no clinical symptoms of active hepatitis. He was not jaundiced as is commonly noted among ESRD patients with hepatitis B. [12] Since the transaminases were normal on presentation to HD, and hepatitis B DNA polymerase chain reaction was negative in 2002, the patient was most likely in the late nonreplicating phase of chronic HBV infection. This also implies that he must have been a carrier long before his diagnosis in 1996. He had no other past medical history besides an appendectomy and hypertension, with no evident risk factors for hepatitis B seroconversion.

After having been on HD for three years, the patient developed a negative HBsAg test and subsequently developed a positive HBsAb [Table 1]. The first reading of a negative HBsAg was in May 2003; then the titers of HBsAb began to increase, until in July 2003, the patient had a detectable surface antibody level of eight. HBV DNA testing was then ordered and revealed an undetectable viral load. The clearance of HBsAg, lack of hepB DNA expression, and most importantly, the development of HBsAb strongly suggested that the patient had developed immunity and not just cleared the virus. The laboratory values noted above were processed by Spectra Laboratories and Abbott Laboratories. Further testing was then undertaken in June and September 2003, showing the patient was HBcAb positive and HBeAg negative. The patient continues to be HBsAg negative and HbsAb positive four years after the seroclearance was first noted and overall, continues to do well.
Table 1: Chart of serial serological measurements showing clearance of HBsAg and the development of a HBsAb response.

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   Discussion Top


While the clearance of HBsAg and the development of undetectable HepB viral DNA are not uncommon in patients who develop latent hepatitis B infection, the development of HBsAb is the unusual feature that strongly suggests the development of immunity in our patient. The spontaneous clearance rate of hepatitis B in immunosuppressed patients, and specifically HD patients, [18] is not well established; however, a series of patients who did clear the virus were identified by Piazza et al [13] as early as 1996. Early data on clearance of hepatitis B from HD patients with treatment were disappointing and chronic carriers who remained seropositive 12 months after the initial infection had little chance for clearing the HBV even with treatment. [16] Currently, however, studies are being conducted with newer nucleoside and nucleotide analogs.

It is well established that prevention of viral infection with immunization is the preferred strategy for HD patients and other immunosuppressed patients with concomitant viral infections such as hepatitis C. [2] It is also known that dialysis patients respond well to vaccination despite uremia. [19]

Given the difficulty in eradicating hepatitis B in immunosuppressed patients with medications, it is a reasonable expectation that spontaneous clearance of hepatitis B viremia is a rare event. An earlier letter published in 1996 suggested that this phenomenon did rarely occur; spontaneous clearance of hepatitis B was observed in five dialysis patients. [13] Four other case reports documenting this phenomenon of spontaneous serological clearance of hepatitis B in HD patients have been published since. Hinoshita et al reported on a 70-year-old male, who cleared the virus after almost 10 years on HD. [16] A patient infected with the human immunodeficiency virus with concomitant hepatitis B was reported to have cleared the virus in 1990. [15] Another case, where a hepatitis B carrier acquired immunity and surface antigen production was noted to cease, was reported in 2004. [17] Finally, a case of hepatitis B clearance was noted after 10 years of HD and carrier status, as reported by Patel et al. [14]

In immunocompromised ESRD patients on HD, individual case reports (including ours), and the aforementioned series published in 1996 bring the total known patients with spontaneous clearance of hepatitis B viremia up to 10 [13],[14],[15],[16],[17] [Table 2]. It is also noteworthy that our patient was able to mount a measurable anti-HBsAg response given that not all patients with normal immune function are noted to develop this. Although those who clear HBsAg appear to have a better prognosis, it is important to stress that clearance of HBsAg does not preclude the development of cirrhosis or hepatocellular carcinoma. [5],[20] Therefore, these patients still need to be monitored closely with serial ultrasonography and AFP measurement. Overall, our patient demonstrates an unusual case of seroclearance of HBsAg in a HD patient in the USA.
Table 2: Cases of spontaneous hepatitis B clearance in hemodialysis patients.

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There is now some data emerging on the response of the immunocompromised populations' response to various treatments including new strategies using nucleoside and nucleotide analogs in the chronic kidney disease population, where these therapies present particular toxicities and challenges. [21] New research is needed to see what the treatment response in hepatitis B patients on dialysis will be. [22] Epidemiological data on clearance of hepatitis B from a large number of HD patients may be a helpful future direction to determine the exact percentages of patients who can clear hepatitis B spontaneously on HD.

 
   References Top

1.
Burdick RA, Bragg-Gresham JL, Woods JD, et al. Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: The DOPPS. Kidney Int 2003;63: 2222-9.  Back to cited text no. 1
[PUBMED]    
2.
Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysisassociated diseases in the United States, 2002. Semin Dial 2005;18:52-61.  Back to cited text no. 2
[PUBMED]    
3.
Liang TJ. Hepatitis B: The virus and disease. Hepatology 2009;49 5 Suppl:S13-21.  Back to cited text no. 3
    
4.
Hayes CN, Zhang Y, Makokha GN, Hasan MZ, Omokoko MD, Chayama K. Early events in hepatitis B virus infection: From the cell surface to the nucleus. J Gastroenterol Hepatol 2016;31:302-9.  Back to cited text no. 4
    
5.
Chu CM. Natural history of chronic hepatitis B virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol 2000;15: E25-30.  Back to cited text no. 5
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6.
Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: Epidemiology and vaccination. Epidemiol Rev 2006; 28:112-25.  Back to cited text no. 6
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7.
Fattovich G, Brollo L, Giustina G, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294-8.  Back to cited text no. 7
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8.
Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/ Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-86.  Back to cited text no. 8
    
9.
Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: What we knew in 1981 and what we know in 2005. Hepatology 2006;43 2 Suppl 1:S173-81.  Back to cited text no. 9
    
10.
Chu CM, Liaw YF. Hepatitis B virus-related cirrhosis: Natural history and treatment. Semin Liver Dis 2006;26:142-52.  Back to cited text no. 10
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11.
Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008;3:1526-33.  Back to cited text no. 11
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12.
Molino C, Fabbian F, Cozzolino M, Longhini C. The management of viral hepatitis in CKD patients: An unresolved problem. Int J Artif Organs 2008;31:683-96.  Back to cited text no. 12
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13.
Piazza V, Efficace E, Montagna G, et al. Spontaneous hepatitis B surface antigen clearance in patients on chronic dialysis. Nephrol Dial Transplant 1996;11:1489-90.  Back to cited text no. 13
[PUBMED]    
14.
Patel C, Monga D, Alexander M, et al. Spontaneous clearance of hepatitis B surface antigenemia after long-term hemodialysis. Semin Dial 2014;27:57-9.  Back to cited text no. 14
[PUBMED]    
15.
Ortiz-Interian CJ, de Medina MD, Perez GO, et al. Recurrence and clearance of hepatitis B surface antigenemia in a dialysis patient infected with the human immunodeficiency virus. Am J Kidney Dis 1990;16:154-6.  Back to cited text no. 15
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16.
Hinoshita F, Okuda K, Asano Y. Hepatitis B surface antigen clearance long after starting hemo-dialysis in a 70-year-old maintenance hemodialysis patient. A retrospective study on hepatitis B virus markers and liver function for 10 years. J Jpn Soc Dial Ther 2001;34:263-9.  Back to cited text no. 16
    
17.
Freudiger H, Sitavanc R. Reverse seroconversion of hepatitis B in a haemodialysis patient. Nephrol Dial Transplant 2004;19:238-41.  Back to cited text no. 17
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18.
Fabrizi F, Lunghi G, Alongi G, et al. Biological dynamics of hepatitis B virus load in dialysis population. Am J Kidney Dis 2003;41:1278-85.  Back to cited text no. 18
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19.
Dervisoglu E, Simsek M, Yilmaz A. Antibody response following hepatitis B vaccination in peritoneal dialysis patients: Does normalized urea clearance matter? Clinics (Sao Paulo) 2011;66:1559-62.  Back to cited text no. 19
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20.
Adachi H, Kaneko S, Matsushita E, Inagaki Y, Unoura M, Kobayashi K. Clearance of HBsAg in seven patients with chronic hepatitis B. Hepatology 1992;16:1334-7.  Back to cited text no. 20
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21.
Pipili C, Cholongitas E, Papatheodoridis G. Review article: Nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. Aliment Pharmacol Ther 2014;39:35-46.  Back to cited text no. 21
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22.
Einollahi B. Therapy for HBV infection in hemodialysis patients: Is it possible? Hepat Mon 2012;12:153-7.  Back to cited text no. 22
[PUBMED]    

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Correspondence Address:
Ramy M Hanna
Cedars-Sinai Medical Center - Office Towers, 8635 West Third Street, Suite No. 495, Los Angeles, CA 90048
USA
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DOI: 10.4103/1319-2442.190886

PMID: 27752020

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