Heterophile Research Articles

False-Positive Causes in Serum Cardiac Troponin Levels.

Cardiac troponins (cTns) are the most valuable and specific markers of cardiovascular diseases, including acute myocardial infarction. These biomarkers can also be used to assess the degree of myocardial damage in non-cardiac diseases that can negatively affect the cells of cardiac muscle tissue. However, in everyday clinical practice, doctors often encounter with false-positive cases of increased cTns. False-positive cases of increased cTns can contribute to incorrect diagnosis and subsequent inadequate treatment, which causes significant harm to the patient. This review discusses some common causes of a false-positive increase in the level of cTns in the blood serum. Such causes are fibrin clots, heterophilic antibodies, alkaline phosphatase, rheumatoid factor, and cross-reactions of diagnostic (anti-cTn) antibodies with skeletal troponins. Detailed attention is focused on the mechanisms of false-positive increase, and ways to identify and combat these false-positive causes of increased cTns. This has an important practical significance in modern clinical practice.

Hormone Immunoassay Interference: A 2021 Update.

Immunoassays are powerful qualitative and quantitative analytical techniques. Since the first description of an immunoassay method in 1959, advances have been made in assay designs and analytical characteristics, opening the door for their widespread implementation in clinical laboratories. Clinical endocrinology is closely linked to laboratory medicine because hormone quantification is important for the diagnosis, treatment, and prognosis of endocrine disorders. Several interferences in immunoassays have been identified through the years; although some are no longer encountered in daily practice, cross-reaction, heterophile antibodies, biotin, and anti-analyte antibodies still cause problems. Newer interferences are also emerging with the development of new therapies. The interfering substance may be exogenous (e.g., a drug or substance absorbed by the patient) or endogenous (e.g., antibodies produced by the patient), and the bias caused by interference can be positive or negative. The consequences of interference can be deleterious when clinicians consider erroneous results to establish a diagnosis, leading to unnecessary explorations or inappropriate treatments. Clinical laboratories and manufacturers continue to investigate methods for the detection, elimination, and prevention of interferences. However, no system is completely devoid of such incidents. In this review, we focus on the analytical interferences encountered in daily practice and possible solutions for their detection or elimination.

Interference from heterophilic antibodies in Ca 19-9 testing: Case report

Interference from heterophilic antibodies in Ca 19-9 testing: Case report

Analytical performance of a new immunoturbidimetric D‐dimer assay and comparison with available assays

BackgroundThe routine D‐dimer quantification to exclude venous thromboembolism has led to the development of many assays, the usefulness of which depends on their reliability and performance. ObjectiveWe evaluated the analytical performances of the immunoturbidimetric Yumizen G DDi 2 assay (HORIBA Medical, Montpellier, France) performed on the Yumizen G800 analyzer and compared it with other available D‐dimer assays. MethodsWithin‐run and between‐run imprecision were evaluated using low‐ and high‐level quality‐control plasma samples. Interference due to hemolysis, icterus, lipemia, rheumatoid factor (RF), or heterophilic antibodies (human antimouse antibodies [HAMAs]) was evaluated by spiking plasma samples with hemolysate, bilirubin, Intralipid, RF, or HAMAs. The measurements obtained with the different D‐dimer assays were compared using Passing‐Bablok regression analysis and Bland‐Altman plot method, using fresh citrated plasma samples collected from 66 consecutive routine patients with a wide range of D‐dimer concentrations. ResultsWithin‐ and between‐run variation coefficients for the Yumizen G DDi 2 assay ranged from 1.7% to 5.8% and from 2.8% to 5.5%, respectively. Hemolysis and icterus did not have any effect up to 10 g/L hemoglobin and 300 mg/L bilirubin. Lipemia seemed to generate an underestimation of D‐dimer concentration when the Intralipid concentration was >5 g/L. RF and HAMAs did not have any effect. The Passing‐Bablok and Bland‐Altman analyses showed small differences with other available D‐dimer assays, which were more pronounced with increasing values. ConclusionsIts analytical performances and main technical features indicate that the new Yumizen G DDi 2 assay is suitable for the rapid quantification of D‐dimer in clinical hemostasis laboratories.

A 3D Microfluidic ELISA for the Detection of Severe Dengue: Sensitivity Improvement and Vroman Effect Amelioration by EDC-NHS Surface Modification.

Serum is commonly used as a specimen in immunoassays but the presence of heterophilic antibodies can potentially interfere with the test results. Previously, we have developed a microfluidic device called: 3D Stack for enzyme-linked immunosorbent assay (ELISA). However, its evaluation was limited to detection from a single protein solution. Here, we investigated the sensitivity of the 3D Stack in detecting a severe dengue biomarker—soluble CD163 (sCD163)—within the serum matrix. To determine potential interactions with serum matrix, a spike-and-recovery assay was performed, using 3D Stacks with and without surface modification by an EDC–NHS (N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide/N-hydroxysuccinimide) coupling. Without surface modification, a reduced analyte recovery in proportion to serum concentration was observed because of the Vroman effect, which resulted in competitive displacement of coated capture antibodies by serum proteins with stronger binding affinities. However, EDC–NHS coupling prevented antibody desorption and improved the sensitivity. Subsequent comparison of sCD163 detection using a 3D Stack with EDC–NHS coupling and conventional ELISA in dengue patients’ sera revealed a high correlation (R = 0.9298, p < 0.0001) between the two detection platforms. Bland–Altman analysis further revealed insignificant systematic error between the mean differences of the two methods. These data suggest the potentials of the 3D Stack for further development as a detection platform.

A Diagnostic Dilemma from a Presentation of Shortness of Breath and Chest Pain.

A patient presented to hospital with chest pain and shortness of breath on 2 occasions 4 weeks apart. Clinical examination revealed an elevated jugular venous pressure consistent with heart failure or elevated filling pressures. The patient was investigated through various modalities including electrocardiogram (ECG), transthoracic echocardiogram, coronary angiography, MRI, cardiac catheterization, positron emission tomography, and an extensive laboratory workup. Serial hs TnI measurements consistently revealed grossly elevated troponin I (>10 000 ng/L). In-lab investigation of increased high sensitivity troponin I (hsTnI) showed evidence of falsely increased troponin due to the presence of heterophilic antibodies. This case demonstrates a complex patient presentation and the value of involving the laboratory medicine team when dealing with potentially discrepant results. This is a rare report of grossly elevated troponin due to heterophilic antibodies for high-sensitivity troponin Abbott assay.

Accuracy of Signs, Symptoms, and Hematologic Parameters for the Diagnosis of Infectious Mononucleosis: A Systematic Review and Meta-Analysis.

The accuracy of individual symptoms, signs, and several easily obtainable hematologic parameters for diagnosing infectious mononucleosis (IM) still needs to be confirmed. Improving the diagnosis of IM based on the clinical findings could prompt physicians to identify better which patients need a diagnostic test for IM. This study performed a systematic review to determine the accuracy of symptoms, signs, and hematologic parameters in patients with suspected IM that used heterophile antibody test or viral capsid antigen tests as the reference standard. The PubMed database was searched for all relevant articles. Two reviewers reviewed all studies in parallel and assessed the quality of the selected studies using the quality assessment of diagnostic accuracy studies 2 (QUADAS-2) criteria. The pooled measures of diagnostic performance were calculated by bivariate meta-analysis for each clinical finding, which included sensitivity, specificity, likelihood ratios, the diagnostic odds ratios, and the area under the receiver operating characteristic curve. Seventeen studies were included in our final analysis. The prevalence of IM ranged from 2.1% to 80% among prospective cohort studies. The presence of splenomegaly (positive likelihood ratio [LR+], 2.39; 95% confidence interval [CI], 1.11-5.51), palatal petechiae (LR+, 1.32-11.40), posterior cervical lymphadenopathy (LR+, 3.16; 95% CI, 1.45-5.20), and axillary or inguinal cervical lymphadenopathy (LR+, 3.05; 95 CI, 1.85-4.70) were moderately useful for ruling in IM. The most helpful hematologic parameters for ruling in IM include lymphocytes greater than 4 × 109/L and greater than 40% to 50%, or atypical lymphocytes greater than 40%. A combination of lymphocytes greater than 50% and atypical lymphocytes greater than 10% (LR+, 50.40; 95% CI, 8.43-162) was also found to be helpful to rule in disease. Most of the clinical findings have limited diagnostic value in ruling out the disease when absent. Although most symptoms and signs were unhelpful, the likelihood of IM is appreciably increased by several examination findings. Hematologic parameters were more accurate than symptoms and signs. Since most clinical findings have limited diagnostic value in ruling out the disease, physicians should not rely on the absence of any individual symptom or clinical sign for ruling out IM.

S2731 Isolated EBV-Induced Acute Hepatitis in the Absence of Infectious Mononucleosis

Introduction: Epstein-Barr virus (EBV) is a globally prevalent herpesvirus with an estimated 90-95% seropositivity rate worldwide. It is most known for causing infectious mononucleosis characterized by the classic triad of fever, pharyngitis, and lymphadenopathy. Hepatitis is a common manifestation seen in 90% of cases;however, isolated acute hepatitis in the absence of infectious mononucleosis is a rare clinical presentation. Case Description/Methods: An 18-year-old female with no medical history presented with fevers, fatigue, myalgia, and headache ongoing for one week. She had been evaluated previously with recommendations for supportive care for an unspecified viral illness. Workup at the time had been negative for urine hCG, COVID-19, heterophile antibody, Lyme disease, and bacteremia. However, symptoms worsened with the development of nausea, vomiting, and darkening of her urine. Prior to this, patient had been in her normal state of health without sick contacts, travel history, animal exposures, risky sexual practices, or substance use. Exam revealed cervical lymphadenopathy and hepatosplenomegaly. Labs showed normal leukocyte count 8.4 thou/cmm with differential significant for reactive lymphocytosis 19% and bandemia 8%. Liver function tests were abnormal with elevated total bilirubin 3.8 mg/dL, AST 366 U/L, ALT 460 U/L, ALP 562 U/L. Synthetic function was intact. Hepatic ultrasound was unrevealing. Extensive infectious workup revealed acute EBV infection with serologies showing positive VCA IgM Ab 74.3 U/mL, negative VCA IgG Ab 11.9 U/mL, negative EA Ab < 5 U/mL, negative EBNA Ab < 3 U/mL. Patient was managed supportively with improved symptoms. She was instructed to avoid physical contact sports for one month upon discharge. Discussion: Clinically significant EBV induced hepatitis is a rare entity seen in < 5% of cases. Nevertheless, it is important to consider EBV as a causative pathogen of acute hepatitis. Heterophile antibody or Monospot test is the diagnostic test of choice with a sensitivity of 85% and a specificity of 100%;however, false negatives can occur especially early in the disease course. EBV serology has an improved sensitivity of 97% with a comparable specificity of 94%. As such, follow-up serology is necessary especially if clinical suspicion is high. While no specific EBV targeted therapies exist, it is important to identify it given the potential complications, including splenic rupture, airway obstruction, malignancies, lymphoproliferative disorders, among others.

Febrile palpebral edema

Febrile palpebral edema

Jaundice as a Rare Manifestation of Epstein-Barr Virus Primary Infection

Epstein-Barr virus (EBV) primary infection usually presents with classic symptoms of infectious mononucleosis (IM) like fever, lymphadenopathies and tonsillopharyngitis. Liver damage is frequently mild and self-limited and there are only a few cases of severe EBV-induced cholestatic hepatitis and jaundice reported in the literature. The authors present the case of a 22-year-old woman who was admitted with acute fever and jaundice. Physical examination revealed posterior cervical lymphadenopathies and painful hepatosplenomegaly. Laboratorial findings suggested an obstructive cause for jaundice but ultrasound and magnetic resonance cholangiopancreatography excluded biliary duct pathology. Heterophile antibodies were negative but EBV-specific antibodies revealed isolated positive viral capsid antigen (VCA) immunoglobin (Ig) M suggesting the diagnosis of early phase of EBV primary infection. The diagnosis of EBV-induced cholestatic hepatitis was confirmed after identification of EBV deoxyribonucleic acid (DNA) in blood and by liver biopsy. Supportive management was provided and, despite an initial clinical deterioration, the patient had a favorable outcome. EBV is a virus with a high prevalence worldwide, mainly subclinical, and jaundice is a rare manifestation of the infection. Although the majority of the patients recover without sequelae, progression to liver failure has been described and a careful assessment for complications is mandatory. Therefore, EBV infection should be included in the comprehensive differential diagnosis of jaundice in all age groups.

A case of heterophile antibody interference causing a falsely positive thyroglobulin in a patient with non-relapsing thyroid carcinoma

A case of heterophile antibody interference causing a falsely positive thyroglobulin in a patient with non-relapsing thyroid carcinoma

Diagnostic Dilemma: A Case of Undetectable TSH

Introduction: Under steady-state conditions, measurement of TSH is accepted as the best assessment of thyroid function. The widely used TSH chemiluminometric assays have very low limits of detection and can help distinguish between the various causes of subnormal TSH. However, when evaluating a patient with abnormal thyroid tests but without thyroid symptoms, an appraisal of the test should be considered. Clinical Case: A 63-year-old South Asian man was referred to endocrinology for evaluation of a non-detectable TSH (<0.01 µIU/mL) that was reproduced on repeat testing, both using Siemens ADVIA Centaur TSH3-UL immunoassay. The patient was clinically euthyroid and denied taking biotin supplements. Testing of thyroid hormone showed normal values for free T3, total T3, free T4, and total T4. Additional labs included normal studies for free thyroxine by equilibrium dialysis, thyroid stimulating immunoglobulin, and heterophilic antibodies. Thyroid uptake and scan showed uniform uptake of 5.1% and 15.1% at 2-hours and 24-hours, respectively, with no dominant nodules. Hypothalamic-pituitary hormonal testing and MRI pituitary were both normal as well. When TSH testing was repeated on a separate platform, Roche’s eCLIA immunoassay, detectable values were obtained (TSH 6.48 µIU/mL). Conclusions: Testing of serum TSH by commercially available immunoassays is based on the sandwich method in which one antibody binds to the β-subunit of TSH and the other to the α-β interface. Most assays use monoclonal antibody pairs to achieve high selectivity. Immunoassay tests are prone to interferences, particularly by way of altering the measurable concentration of the analyte or by altering antibody binding (1). In this case, the presence of detectable TSH depended on the platform by which it was measured. This finding suggests a TSH-β variant with impaired immunoreactivity but functionally normal bioactivity. Such a mutation has been previously reported to occur five times more frequently among South Asian individuals than the general population (2). Genetic testing was offered to the patient to confirm this suspicion but was declined.It is incumbent on the clinician to reconcile a test result that is discordant with the clinical presentation. Having a fundamental understanding of the principles of the testing platform can assist in identifying potential sources of error. Failing to recognize a possible interference can lead to unnecessary healthcare expenditures, misdiagnosis and inappropriate management, potentially at a cost to the patient’s wellbeing. When faced with an undetectable TSH with otherwise normal thyroid hormones and unremarkable clinical picture, it is best to repeat the TSH test using a different available platform.

Thyrotropin-Producing Pituitary Adenomas

Abstract Thyrotropin-producing pituitary adenomas are rare cause of hyperthyroidism and it compose about 0.5-3% of all functioning pituitary tumors. Diagnosis of thyrotropin-producing pituitary adenomas can be challenging because TSH concentrations can be normal with only elevated T4. As a result, patient would be simply treated as primary hyperthyroidism. The latency between onset of hyperthyroidism and diagnosis of pituitary adenoma was reported to be 4-6 years. Many patients had radioactive iodine treatment or thyroidectomy treatment for primary hyperthyroidism at the time of diagnosis. A 35-year-old male with history of intermittent FT4 elevation for the past 3 years presented at endocrine clinic for evaluation. Patient also had recent headache and dizziness. TSH was only marginally elevated once in the past 3 years. Alpha-subunit was found to be 2.6 ng/mL with negative heterophile antibody. MRI showed a 13.7 mm x 20.4mm x16.1mm sellar and suprasellar mass without cavernous sinus invasion but with chiasmal compression. Other pituitary hormone co-secretion was not found in this patient. Patient was treated with octreotide 20mg monthly for 3 month with normalization of T4 and size of the tumor also decreased on the medication. Patients was prepared for transsphenoidal surgery. Treatment for thyrotropin-producing pituitary adenomas is mainly surgery. However, medical therapy with somatostatin analogs does play an important part in terms of inducing euthyroid prior to surgery. There are also articles describing shrinkage of the tumor prior to surgery while on somatostatin analogs. There were also rare case reports of thyroid storm from thyrotropin-producing pituitary adenomas when patients were not treated with somatostatin analogs prior to surgery. The surgical outcome was determined by the size of the tumor. Transient hypothyroidism or hypopituitarism can happen after the surgery. However, it is more common in external beam radiotherapy or radiosurgery treatment. For thyrotropin-producing pituitary microadenomas, transsphenoidal surgery is the treatment of choice with high remission rate. In some difficult cases where octreotide was not controlling the hyperthyroidism, methimazole use in combination with octreotide after surgery was also documented in the literature. The idea of using somatostatin analogs as primary treatment of thyrotropin-producing pituitary adenomas due to the risk of hypopituitarism with transsphenoidal surgery was explored in some literature. But, no strong evidence of better outcome with medication treatment alone was found.

Atypical transmission of Epstein-Barr virus to a medical practitioner—a case report

: We present a case of a 26-year-old medical practitioner who was diagnosed with Epstein-Barr virus, pre-COVID-19, following exposure to respiratory droplets from an infected patient. The medical practitioner presented to his general practitioner with a 5-day history of bilateral upper-palpebral swelling (Hoagland’s Sign) and coryzal symptoms and was initially diagnosed with allergic rhinitis. The diagnosis was revised 2 weeks later, following the development of classical symptoms and serological evidence of Epstein-Barr virus infection. The Epstein-Barr virus specific antibody should be measured if suspicion for infectious mononucleosis is high with a negative monospot test. These specific antibody tests are superior in ruling out Epstein-Barr virus infection when compared to the heterophile antibody test for a negative outcome. There is a dearth of literature regarding Epstein-Barr virus transmission via respiratory droplets and our case appears to be the first reported incident of Epstein-Barr virus transmission in an immunocompetent healthcare worker after exposure to respiratory droplets from a patient’s sternutation. As such, we strongly advocate the use of masks and practising appropriate hand hygiene in all patients suspected or confirmed to have an acute Epstein-Barr virus infection and also seek to highlight the atypical nature of symptom manifestations and transmission seen in Epstein-Barr virus infections.

Dysphagia and Epigastric Pain in an Adolescent Boy.

1. Senthil Velan Bhoopalan, MBBS, PhD* 2. Rabea Alhosh, MD† 1. *St. Jude Children’s Research Hospital, Memphis, TN 2. †University of Nevada Las Vegas, Las Vegas, NV A 17-year-old previously healthy boy presents with a history of epigastric abdominal pain associated with some difficulty in swallowing for the past 3 days. He denies any emesis but reports nausea. The abdominal pain is localized to the epigastric area without any radiation. Pain is reported at 7 on a scale of 1 to 10. He denies any diarrhea but had noticed a few episodes of black tarry stool for the past 2 days. His sexual history is significant for oral sex with a single female partner, but he denies any genital or oral lesions. He was seen by his pediatrician 2 days ago. His pediatrician suspected a gastric ulcer and prescribed him pantoprazole, which the patient never obtained. On presentation he has a temperature of 103°F (39.4°C) and appears mildly dehydrated. His vital signs are otherwise within normal limits. On physical examination the patient has dry lips and mucosa, but no oral lesions are noted. Mild epigastric tenderness without any rigidity or rebound tenderness is noted. Examination findings are otherwise normal. Initial laboratory evaluation shows a white blood cell count of 12,900/μL (12.9×109/L), and the remainder of the blood cell count and metabolic panel are normal. The results of the antigen test for influenza, the heterophile antibody test for infectious mononucleosis, and the rapid streptococcal antigen test are negative. His CRP level is elevated to 12 mg/dL (120 mg/L). A computed tomographic scan …

Potential false-positive reasons for SARS-CoV-2 antibody testing and its solution.

Coronavirus disease 2019 (COVID‐19) has brought a huge impact on global health and the economy. Early diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is essential for epidemic prevention and control. The detection of SARS‐CoV‐2 antibodies is an important criterion for diagnosing COVID‐19. However, SARS‐CoV‐2 antibody testing also has certain false positives causing confusion in clinical diagnosis. This article summarizes the causes of false‐positive detection of SARS‐CoV‐2 antibodies in clinical practice. The results indicate that the most common endogenous interferences include rheumatoid factor, heterophile antibodies, human anti‐animal antibodies, lysozyme, complement, and cross‐antigens. The exogenous interference is mainly incomplete coagulation of the specimen, contamination of the specimen, and insufficient optimization of the diagnostic kit's reaction system.

Prevalence of heterophilic antibodies in serum samples from horses in an equine hospital, and elimination of interference using chicken IgY

BackgroundHeterophilic antibodies in serum and plasma can interfere with mammalian antibodies in immunoassays and result in false test results, usually false positive. Although studies screening for heterophilic antibodies as well as elimination studies have been conducted in dogs and cats, knowledge of the presence of heterophilic antibodies in other species in veterinary medicine is limited. In this study, a 2-site sandwich-type interference assay that detects anti-mouse antibodies was used to detect heterophilic antibodies in a population of horses treated in an animal hospital.ResultsA total of 194 serum samples from 127 individual horses were analyzed. There were 11/127 (8.7%) interference-positive horses, and these were analyzed in an assay exchanging the capture mouse IgG with chicken IgY. The positive samples were negative in the chicken IgY assay, indicating elimination of a possible interference, with the chicken-based assay. Four interference-positive samples were from geldings, and anti-Müllerian hormone (AMH) was analyzed from these samples. AMH concentrations were negative in these samples as expected in geldings, indicating that the heterophilic antibodies did not cause interference in the AMH assay.ConclusionThe present study shows that there are heterophilic antibodies in horse serum samples like in samples from humans, dogs, and cats. The use of chicken-based reagents, such as chicken IgY, which do not cross-react with mammalian IgG, eliminates the effects of interfering antibodies in the samples. Equine heterophilic antibodies do not necessarily cause interference in commercial immunoassays.

False Positives in Thyroglobulin Determinations Due to the Presence of Heterophile Antibodies: An Underrecognized and Consequential Clinical Problem

ObjectiveTo report a case series of thyroid cancer patients in whom false positive results in immunometric assays for thyroglobulin (TgIMA) were caused by heterophilic antibody interference, describe the clinical scenario in which this interference should be suspected, and recommend methods to demonstrate the interference. MethodsThree patients with unexpectedly elevated thyroglobulin results (range, 1.6-75 ng/mL) were studied. In the first patient, thyroglobulin was elevated despite the presence of Tg antibody. In the second patient, suppressed thyroglobulin was higher than a recent stimulated thyroglobulin. In the third patient, thyroglobulin became detectable years after treatment and did not change after thyroid-stimulating hormone stimulation. TgIMA concentration determination was compared to determination by a mass spectrometry method (TgMS). Thyroglobulin was also remeasured after preabsorption with heterophile antibody blocking reagents and after serial dilutions. ResultsIn all cases, thyroglobulin was undetectable by TgMS. In 2 of 3 patients, dilutions provided nonlinear thyroglobulin results. After blocking agent preabsorption, thyroglobulin dropped by 35%, 45%, and 91% in the 3 samples. ConclusionFalse positive thyroglobulin concentrations from heterophilic antibody interference have significant impact on the management of thyroid cancer. Here we show that TgMS assays can be used to rule out heterophilic antibody interference. This interference should be suspected when a detectable thyroglobulin by TgIMA does not respond to thyroid-stimulating hormone or is discordant from the clinical assessment.

Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests

IntroductionDiscordant thyroid function tests are routinely encountered in clinical practice. Differential diagnoses include acute thyroxine (T4) ingestion, laboratory interference from heterophilic antibodies, thyroid hormone resistance, thyroid-stimulating hormone (TSH)-secreting pituitary adenomas, and T4 protein binding abnormalities. The impact of abnormal binding proteins may be less recognized since widespread use of free T4 (FT4) assays compared to older total T4 assays.Case reportA 69-year-old female was referred for assessment of discordant thyroid function tests. Biochemistry since July 2015 showed persistently elevated FT4 levels by immunoassay ranging between 25 to 34 pmol/L with normal or slightly decreased TSH ranging between 0.05 to 2.74 mU/L. The patient was clinically euthyroid on 100 mcg daily of levothyroxine for Hashimoto’s thyroiditis. FT4 measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was 19.5 pmol/L. Exome sequencing (confirmed by Sanger sequencing) detected a guanine to adenine substitution at residue 725 of the ALB gene previously associated with dysalbuminemic hyperthyroxinemia. The patient’s daughter had similar thyroid function tests and the same genetic variant. FT4 results from 3 different automated immunoassays showed the Roche Cobas and Siemens Centaur platforms to be most affected by the variant, and Abbott Architect had the best agreement with LC-MS/MS.ConclusionFamilial dysalbuminemic hyperthyroxinemia is a potential cause of discordant thyroid function tests. Clinicians suspecting protein-binding abnormalities may further investigate using reference methods such as LC-MS/MS and equilibrium dialysis if available. The increasing accessibility of exome sequencing offers a cost-effective method of diagnosing genetic variants that cause discordant thyroid function tests.

The underestimated issue of non-reproducible cardiac troponin I and T results: case series and systematic review of the literature.

Cardiac troponins (cTn) are the preferred biomarkers for the evaluation of myocardial injury and play a key role in the diagnosis of acute myocardial infarction (MI). Pre-analytical or analytical issues and interferences affecting troponin T and I assays are therefore of major concern given the risk of misdiagnosis. False positive troponin results have been related to various interferences including anti-troponin antibodies, heterophilic antibodies, or elevated alkaline phosphatase level. On the other hand, false negative results have been reported in the case of a large biotin intake. These interferences are characterized with erroneous but reproducible troponin results. Of interest, non-reproducible results have also been reported in the literature. In other words, if the sample is reanalyzed a second time, a significant difference in troponin results will be observed. These interferences have been named "fliers" or "outliers". Compared to the biotin interference that received major attention in the literature, troponin outliers are also able to induce harmful clinical consequences for the patient. Moreover, the prevalence of outliers in recent studies was found to be higher (0.28-0.57%) compared to the biotin interference. The aim of this systematic review is to warn clinicians about these non-reproducible results that may alter their clinical judgment. Four case reports that occurred in the Clinique of Saint-Luc Bouge are presented to attest this point. Moreover, we aimed at identifying the nature of these non-reproducible troponin results, determining their occurrence, and describing the best way for their identification.