Cross-reactivity in assays for prolactin and optimum screening policy for macroprolactinaemia

Macroprolactin cross-reacts in immunoassays for prolactin causing apparent hyperprolactinaemia (macroprolactinaemia) and consequent misdiagnosis and mismanagement of patients.We determined the prevalence of macroprolactinaemia using prolactin immunoassays with reported "high" (Tosoh) or "low" cross-reactivity (Roche) with macroprolactin. We additionally modelled the effects of increasing the screening threshold on workload and sensitivity in the detection of macroprolactinaemia.A review of routine requests for prolactin received in a 12 month period identified 670 sera with hyperprolactinaemia (Tosoh assay). Treatment with polyethylene glycol (PEG) precipitation demonstrated normal levels of monomeric prolactin in 165 sera (24.6%) indicating macroprolactinaemia. In the macroprolactinaemic cohort, total prolactin levels were lower with the Roche assay (473 ± 132 mU/L; mean ± SD) compared to the Tosoh assay (683 ± 217 mU/L), p < 0.005. The prevalence of macroprolactinaemia was also lower with the Roche assay (6.2%). The number of samples that required screening for macroprolactinaemia fell by 14% when Roche gender specific total prolactin reference limits were applied. Use of a higher screening threshold (700 mU/L) reduced the screening workload considerably (Roche by 45%, Tosoh by 37%) however, the sensitivity of detection of macroprolactinaemia decreased markedly (Roche 90%, Tosoh 59%).Macroprolactin interferes in both Tosoh and Roche prolactin immunoassays. Use of an assay with a relatively low cross reactivity with macroprolactin, e.g. Roche, will lead to a modest reduction in the screening workload. Increasing the screening threshold above the upper limit of the assay reference interval will also reduce the screening workload but leads to disproportionate increases in the number of cases of macroprolactinaemia which are missed.