Underappreciation of the “Hook Effect” leading to Mismanagement of a Patient, a Tale of Preventable Disaster

Abstract

Abstract Introduction: When evaluating pituitary adenomas, one needs to be cognizant of the “hook effect” - an assay artifact leading to under-reporting of extremely high prolactin levels. We report a case of a patient with a macroprolactinoma with an initial reported prolactin level of less than 1.0 ng/dl. Such an extreme case of the “hook effect” in a prolactinoma has not been reported yet. Case Presentation: A 53-year-old male with a medical history of type II DM initially presented in 2017 with blurred vision. Vital signs and labs, including pituitary hormone levels, were all within normal range. Prolactin level was reported as less than 1.0 ng/dl (normal 2-18 ng/dl). MRI brain showed a large pituitary mass and he was diagnosed with a non-secreting pituitary macroadenoma with mass effect. The patient subsequently underwent transsphenoidal resection of the pituitary adenoma. Prolactin level was noted to be elevated at 1608 ng/dl after the procedure. Unfortunately, the patient was lost to follow up. Two years later, the patient presented again with persistent headaches and worsening vision. MRI brain revealed a large suprasellar mass, measuring at 4.9 x 4 x 3 cm, with extension into the third ventricle and left cavernous sinus, indicating a recurrence of the pituitary adenoma. Prolactin levels measured were elevated 12,030 ng/dl. At this time, the patient was started on cabergoline with significant improvement in symptoms and reduction in prolactin levels to 1792 ng/dl within 4 weeks after initiation of therapy. He is currently still in remission with weekly cabergoline therapy. Conclusion: The most used prolactin assay typically reports the presence of detectable heterotrimeric immune complex formations made up of prolactin antigens sandwiched between ‘capture antibodies‘ at one end and ‘reported antibodies’ at the other end of the prolactin antigen. In prolactinomas, prolactin levels are usually present in relative excess to the two assay antibodies. This leads to the oversaturation of antibody sites with most of prolactin being complexed to only a single antibody instead of two antibodies, thus impairing adequate immune complex formation. Only a few remaining prolactin antigen are “sandwiched” to form the heterotrimeric complex and are therefore reported as “detectable.” As a result, true prolactin levels are substantially underreported, potentially leading to incorrect diagnosis, treatment delay, exposure to surgical risk and complications and increased economic burden to the patient and the healthcare system. The best method to avoid the “hook effect” and to correctly interpret prolactin values would be to obtain prolactin levels in appropriately diluted serum specimens (10-100-fold dilution of the sample). This will lead to appropriate immune complex formations and increase the sensitivity and specificity of the prolactin assay.