Endocrine Abstracts

Serum or plasma human chorionic gonadotropin (hCG) immunoassays are a cornerstone in diagnosis and monitoring of pregnancy [1]. Although these assays show very satisfying performance, pathophysiological (e.g., menopause induced pituitary secretion of hCG, familial hCG syndrome, exogenous hCG injections) and analytical (e.g., interference of heterophilic antibodies or anti-hCG antibodies, lack of specificity of older assays) determinants may rarely cause false positive results and lead to wrong diagnosis of pregnancy or associated trophoblastic disease [2]. We present the case of a 40-year-old female who was admitted to the emergency department (ED) for abdominal pain for a week in a context of treated respiratory infection. The patient blood test at admission notably showed high c-reactive protein (CRP) (52.7 mg/l [URL: 5]), hyperleukocytosis (10.84 103/pL [RR: 4.00 — 10.00]), high neutrophil count (8.56 10³/qL [RR: 1.6 — 7.00]), normal urinalysis and positive total hCG (37.6 UI/l [URL: 5]). An ultrasound was performed and showed an absence of pregnancy in the uterus. The patient was released with a diagnosis of ectopic pregnancy of unknown location to be monitored. Two days later, hCG was still above the URL (39 UI/l), CRP was stable (54 mg/l), neutrophil count was still high (7.28 10³/qL) and urinalysis was normal. As controls of hCG levels at days 5 and 7 showed a slow decrease in hCG but still suggested ectopic pregnancy, a single 50 mg dose of methotrexate was administered. The following days, she presented with persistent fever, thoracic and abdominal pain and persistent increased hCG values (40.8 UI/l). The second ultrasound was still negative for pregnancy. Given the severity of the presentation, a workup was conducted, and blood cultures were found positive for Streptococcus sanguinis. Cardiac ultrasound showed a 13 mm vegetation on the mitral valve signing endocarditis and the patient underwent emergency surgery for valvuloplasty. The patient then recovered progressively and the hCG has been decreasing while still above threshold until 44 days post-surgery, when hCG was ultimately found negative. Laboratory investigations were performed alongside the clinical investigations to explain the inconsistence between hCG levels and the apparent absence of pregnancy. Routinely, hCG was measured using the Elecsys HCG+§ assay (Roche Diagnostics, Switzerland). Given the age of the patient, FSH levels were measured to exclude post-menopausal increased hCG. Free b- subunit and chromogranin were also measured to evaluate the risk of trophoblastic and neuro- endocrine malignancy, respectively. Additional investigations, based on recently published literature [3], were regularly performed on samples with positive hCG to exclude an analytical interference: testing samples using another immunoassay method, testing urinary hCG, treatment using heterophilic blocking tubes, serial dilutions, and treatment with polyethylene glycol. Given the absence of any detectable analytical interference, two hypotheses prevailed for the persistently high hCG values observed. The first was ectopic pregnancy in the peritoneum which led to infection by a digestive germ and consequent blood dissemination and endocarditis. The second is quiescent gestational trophoblastic disease (Q-GTD), which corresponds to the persistence of fully differentiated syncytiotrophoblasts [4]. It is a benign or inactive form of GTD. A persistent low serum hCG elevation is observed (usually between 50 and 200 mIU/mL), with no clinical or radiological evidence of pregnancy or tumour and often resolves spontaneously within 12 months but sometimes persists or progresses to malignant disease. Assessment of hyperglycosylated hCG (hCG-H) may help differentiate patients with Q-GTD from other causes of hCG elevation [5] but this measurement was not available for a clinical use in Belgium yet. A comprehensive algorithm would be most relevant to help both clinicians and laboratory specialists to handle suspicion of false positive hCG results and prevent harmful consequences for patients.

References: 1. Nerenz RD BJ. Pregnancy and its disorders. In: Rifai N CR, Burnham CAD, Wittwer CT. Tietz Textbook of Laboratory Medicine St. Louis, MO: Elsevier, 2022.2. Oyatogun O, Sandhu M, Barata-Kirby S, Tuller E, Schust DJ. A rational diagnostic approach to the "phantom hCG" and other clinical scenarios in which a patient is thought to be pregnant but is not Ther Adv Reprod Health 2021;15:26334941211016412.3. Wauthier L, Plebani M, Favresse J. Interferences in immunoassays: review and practical algorithm. Clin Chem Lab Med 2022;60:808-820.4. Ngu SF, Chan KK. Management of Chemoresistant and Quiescent Gestational Trophoblastic Disease. Curr Obstet Gynecol Rep 2014;3:84-90.5. Cole LA, Muller CY. Hyperglycosylated hCG in the management of quiescent and chemorefractory gestational trophoblastic diseases. Gynecol Oncol 2010;116.