Hypeprolactinemia: still an insidious diagnosis

Abstract

Hyperprolactinemia can have different causes: physiological, pharmacological, and pathological. When investigating the etiology of hyperprolactinemia, clinicians need to be aware of several conditions leading to misdiagnosis. The most popular pitfalls are: acute physical and psychological stress, macroprolactin, hook effect, even though antibodies interferences and biotine use have to be considered. A 52-year-old woman was referred to Endocrinology clinic for oligomenorrhoea and headache. She worked as a butcher. Hormonal evaluation showed very high PRL (305 ng/ml, reference interval: <24 ng/ml) measured with the ECLIA immunoassay analyzer Elecsys 170. The patient’s pituitary MRI was normal and macroprolactin was normal. Hormonal workup showed LH: 71.5 mU/ml (2–10.9 mU/ml), FSH: 111.4 mU/ml (3.9–8.8 mU/ml), Estradiol: 110.7 pg/mL (27–122 pg/ml). Since an interference was suspected, the sample was sent to another laboratory using a different assay. After antibody blocking tubes treatment (Heterophilic Blocking Tube, Scantibodies) PRL was 28.8 ng/ml (reference interval < 29.2 ng/ml). Analytical interference should be suspected when assay results are not consistent with the clinical picture. Endogenous antibodies (EA) include heterophile, human anti-animal, autoimmune and other nonspecific antibodies, and rheumatoid factors, that have structural similarities and can cross-react with the antibodies employed by the immunoassay, causing hyperprolactinemia misdiagnosis. The patient’s job (butcher), led us to suspect the presence of anti-animal antibodies. Clinicians should also carefully investigate the use of supplements. Biotin can falsely increase hormone concentration in competitive assays. Many clinicians are still not informed about these pitfalls that are not mentioned in some recent reviews on PRL measurement.

Hormone Immunoassay Interference: A 2021 Update

“…However, heterophilic Abs are highly heterogeneous in nature, their concentrations vary largely between patients, and no blocking reagent/method is completely successful in preventing such interference. Although the frequency of heterophilic Ab interference may be declining, recent reports concerning erroneously elevated concentrations of PTH, FSH, LH, and prolactin demonstrate that this type of interference can still occur with any immunoassay [58][59][60].…”

The Importance Of Macroprolactin In The Diagnosis Of Hyperprolactinemia

“…Circulating PRL concentrations in normal men and women are 3-14 ug/L and 4-24 ug/L (PRL conversion units: 1 ug/L = 21.2 mU/L) [1]. In blood, PRL is a heterogeneous mixture of PRL of variable sizes: 65-85% monomeric PRL, 15-30% dimeric (40-60 kDa) "big" PRL, and < 10% >150 kDa macroprolactin (MPRL) [3][4][5]. MPRL is a complex formed by monomeric PRL and IgG anti-prolactin auto-antibodies although non-IgG variants do exist.…”

Iperprolattinemia: vecchie e nuove insidie diagnostiche

“…I recenti metodi di dosaggio sono meno sensibili a tale effetto perché contengono concentrazioni maggiori di anticorpi rilevatori ed effettuano una diluizione automatica 1:10 del campione [2]. Tuttavia, in alcuni macroprolattinomi, la diluizione 1:10 non è sufficiente, ed è consigliabile richiedere al laboratorio una diluizione manuale del campione 1:100 [2]; -la presenza di anticorpi endogeni -anticorpi eterofili, anticorpi anti antigeni animali (HAMA) e autoanticorpipuò interferire con i dosaggi che utilizzano anticorpi per il dosaggio degli antigeni [5,6]. La convivenza/lavoro con animali, la somministrazione di antisieri/immunoglobuline animali, vaccini o trasfusioni sono alcune fonti di anticorpi interferenti [5,6].…”

“…• Pseudociesi Fig. 1 Insidie laboratoristiche nel dosaggio della prolattina al sito dell'interferenza [5,6]. In caso di sospetto, è necessario effettuare un pretrattamento con reagenti bloccanti gli anticorpi interferenti o utilizzare un dosaggio che risenta poco della presenza di questi, come la spettrometria di massa.…”

“…L'utilizzo di alte concentrazioni di biotina (es. per caduta di capelli o per rinforzare le unghie) può interferire con questo dosaggio, determinando falsi positivi negli assay competitivi e falsi negativi negli assay a sandwich [5,6]. Anche se se l'uso di multivitaminici contenenti alte dosi di biotina è poco comune in Italia, andrebbe richiesto ai pazienti se assumono biotina prima di effettuare indagini di laboratorio.…”