Etiology and bioactivity of macro TSH

Objective TSH is a sensitive indicator of thyroid function. In subclinical hypothyroidism, however, serum TSH concentrations are elevated despite normal thyroid hormone levels. Macro TSH is a large molecular sized TSH on gel filtration chromatography. We hypothesized that the bioactivity of macro TSH might be low like macro PRL and that macro TSH may be accumulated in the circulation. Thus, patients with macro TSH may show elevated TSH levels despite normal thyroid hormone levels, similar to subclinical hypothyroidism. This study aimed to characterize the nature of macro TSH. Patients We screened macro TSH in 1083 patients with subclinical hypothyroidism (634 women and 449 men, aged 64.6 ± 17.7 years) followed at our hospital, and in 54 serum samples that were sent to our laboratory from doctors in other hospitals, suspecting the presence of macro TSH. Measurements Macro TSH was screened by polyethylene glycol (PEG) method, in which macro TSH was precipitated with 12.5% PEG. The PEG-precipitable TSH (%), which may represent the amount of macro TSH, was calculated as (total TSH - free TSH) / total TSH × 100. Serum samples that exhibited PEG-precipitable TSH ratios greater than 75% (mean + 1.5 SD in controls) were subjected to gel filtration chromatography to confirm macro TSH. The biological activity of macro TSH was examined in the FRTL-5 rat thyroid cell line. Protein G column and HAMA (human anti-mouse antibodies) blockers were used to characterize macro TSH. Macro PRL was examined in patients with macro TSH using the same method as macro TSH. Results Among 1083 patients with subclinical hypothyroidism, 14 patients had macro TSH (1.3%). Among 54 serum samples that were requested to examine the presence of macro TSH, 5 serum samples were found to containe macro TSH. The nature of macro TSH in these 19 serum samples included 14 anti-TSH autoantibodies of IgG class, 2 non-IgG-associated, and 3 HAMA. Macro TSH showed low bioactivity compared to the immunoreactivity. Three patients with macro TSH also had macro PRL. Conclusions Macro TSH was heterogeneous, but it is mostly comprised of TSH and anti-TSH autoantibodies. Because 3 of 19 patients with macro TSH also had macro PRL, common mechanisms may be involved in the generation of macro TSH and macro PRL in some patients. When PEG-precipitable TSH exceeds 90% in serum samples with TSH above 10 mU/l, clinicians should strongly suspect the presence of macro TSH and confirm it by gel chromatography. Because macro TSH exhibited low bioactivity, thyroid hormone replacement therapy may not be required in patients with subclinical hypothyroidism due to macro TSH except for those with high serum free TSH levels.