The many faces of positive hepatitis B surface antigen
Authors: Derek M. Tang, Theo Heller, Christopher Koh
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. This document was supported by the Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. TO THE EDITOR: Correct interpretation of laboratory test results is paramount in avoiding misdiagnosis and incorrect management that could potentially be harmful to patients. In this letter, we illustrate an unusual presentation of hepatitis B viral markers with an uncommon explanation. A Caucasian female in her mid to late fifties with primary hyperparathyroidism was referred for the evaluation of a positive hepatitis B surface antigen (HBsAg) result while undergoing examination for surgical removal of a parathyroid adenoma. She had no gastrointestinal complaints or risk factors for viral hepatitis except for possible sexual contact. Physical examination did not reveal stigmata of chronic liver disease. Liver function tests were within normal limits, including an alanine transaminase of 13, and evaluation for viral hepatitis A, C, and D were unremarkable. Serum calcium and parathyroid hormone (PTH) levels were elevated at 2.77 mmol/L (range, 2.15‐2.55) and 163.9 pg/mL (range, 15.0‐65.0), respectively. Results from three preoperative hepatitis B virus (HBV) panels obtained over 5 weeks are shown in Table 1. Table 1 - Results of Our Patient's Hepatitis B Testing Testa HBsAgb S/COc Ratio Neutralization Test Result HBcAb HBeAg HBeAb HBsAb HBV DNA 1 Positive 3.13 (average, 3.07) Nonconfirmable Not detected 2 Positive 9.24 No confirmation necessary 3 Positive 9.70 No confirmation necessary aTests 1‐3 were performed over a 5‐week period before the patient's surgery.bThe VITROS Immunodiagnostic Products HBsAg assay was performed on a VITROS ECiQ Immunodiagnostic System.cPer manufacturer (Ortho Clinical Diagnostics), S/CO ratio was reported if the HBsAg result was positive. An initial S/CO >5.0 indicated a positive result that did not require confirmation. An equivocal 0.9 ≥ S/CO ratio ≤ 5.0 underwent repeat testing (average value reported) with a subsequent neutralization test.Abbreviations: HBcAb, hepatitis B core antibody; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; S/CO, signal‐to‐cutoff. A false‐positive HBsAg was initially suspected given the patient's uncharacteristic test results. The presence of heterophilc antibodies was confirmed when a fourth preoperative HBsAg (not shown in Table 1) resulted negative after the addition of a heterophilic blocking reagent. Although elevated PTH has been shown to interfere with immunoassays,1 this was not the causative factor, because our patient's HBsAg remained positive despite normalization of serum calcium and PTH 4 weeks postsurgery. On repeat testing 7 weeks postsurgery, the HBsAg became negative, thereby supporting the notion that the responsible heterophilic antibodies circulated in the patient's serum for up to 7 weeks after adenoma removal. Therefore, it is highly suspected that the patient's false‐positive HBsAg was attributed to heterophilic interference from a paraneoplastic syndrome related to her parathyroid adenoma. To the best of our knowledge, this is the first reported case in the literature. The diagnosis and management of HBV infection relies heavily on biomarkers and laboratory values.2 Surface antigen testing is part of the initial screening to detect acute and chronic hepatitis B infection.2 Active or resolved infection would each have resulted in the presence of other detectable serologic HBV markers.2 Transiently positive HBsAg has been observed in patients for up to 2 weeks after HBV vaccination,3 but our patient had not been vaccinated and had repeatedly positive HBsAg results for more than a month. The fluctuating HBsAg titers observed in this case may have resulted from changes in secretions from the parathyroid adenoma, which also caused serum calcium and parathyroid hormone levels to fluctuate. Heterophilic antibodies have been known to cause both falsely positive (e.g., human immunodeficiency virus)4 and falsely elevated (e.g. prostate‐specific antigen)5 immunoassay results. These naturally occurring human antibodies bind to a wide variety of chemical structures, including the animal antibodies often used in immunochemistry assays,1 and can be neutralized by a reagent composed of specific inactivating binders.5 In an era of increased reliance on laboratory values in disease management and despite advances in modern assays methods, clinicians should be cognizant of the rare, but important, challenges posed by heterophilic antibodies, particularly when test results are discordant with other clinical findings.