Laura P B Elbers, Carla Moran, Victor E A Gerdes, Bregje van Zaane, Joost C M Meijers, Erik Endert, Greta Lyons, Krishna Chatterjee, Peter H Bisschop and Eric Fliers
Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor β (THRB or THRB) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in THRB-expressing tissues. We tested the hypothesis that the hypercoagulable state in hyperthyroidism is mediated via the THRB.
We conducted a cross-sectional study from November 2013 to January 2015 in 3 hospitals in the Netherlands and the United Kingdom.
Patients with RTH due to defective THRB (n=18), patients with hyperthyroidism (n=16) and euthyroid subjects (n=18) were included. TH concentrations and markers of coagulation and fibrinolysis were measured. Data are expressed as median (interquartile range).
Free thyroxine (FT4) levels were slightly higher in hyperthyroid patients than in RTH patients (53.9 (30.5–70.0) and 34.9 (28.4–42.2)pmol/L, respectively, P=0.042). Both groups had raised FT4 levels compared with euthyroid subjects (14.0 (13.0–15.8)pmol/L, P≤0.001). Levels of von Willebrand factor (VWF), factor (F) VIII, fibrinogen and d-dimer were significantly higher in hyperthyroid patients than in RTH patients (VWF 231 (195–296) vs 111 (82–140)%, FVIII 215 (192–228) vs 145 (97–158)%, fibrinogen 3.6 (3.0–4.4) vs 2.8 (2.5–3.2)g/L, d-dimer 0.41 (0.31–0.88) vs 0.20 (0.17–0.26)mg/L, respectively, P≤0.001), while there were no differences between RTH patients and euthyroid controls.
Parameters of coagulation and fibrinolysis were elevated in hyperthyroid patients compared with patients with RTH due to defective THRB, whereas these parameters were not different between euthyroid controls and RTH patients, despite elevated FT4 concentrations in RTH patients. This indicates that the procoagulant effects observed in hyperthyroidism are mediated via the THRB.
Serena Khoo, Greta Lyons, Anne McGowan, Mark Gurnell, Susan Oddy, W Edward Visser, Sjoerd van den Berg, David Halsall, Kevin Taylor, Krishna Chatterjee and Carla Moran
Familial dysalbuminaemic hyperthyroxinaemia (FDH), most commonly due to an Arginine to Histidine mutation at residue 218 (R218H) in the albumin gene, causes artefactual elevation of free thyroid hormones in euthyroid individuals. We have evaluated the susceptibility of most current free thyroid hormone immunoassay methods used in the United Kingdom, Europe and Far East to interference by R218H FDH.
Different, one- and two-step immunoassay methods were tested, measuring free T4 (FT4) and free T3 (FT3) in 37 individuals with genetically proven R218H FDH.
With the exception of Ortho VITROS, FT4 measurements were raised in all assays, with greatest to lowest susceptibility to interference being Beckman ACCESS > Roche ELECSYS > FUJIREBIO Lumipulse > Siemens CENTAUR > Abbott ARCHITECT > Perkin-Elmer DELFIA. Five different assays recorded high FT3 levels, with the Siemens CENTAUR method measuring high FT3 values in up to 30% of cases. However, depending on the assay method, FT4 measurements were unexpectedly normal in some, genetically confirmed, affected relatives of index FDH cases.
All FT4 immunoassays evaluated are prone to interference by R218H FDH, with their varying susceptibility not being related to assay architecture but likely due to differing assay conditions or buffer composition. Added susceptibility of many FT3 assays to measurement interference, resulting in high FT4 and FT3 with non-suppressed TSH levels, raises the possibility of R218H FDH being misdiagnosed as resistance to thyroid hormone beta or TSH-secreting pituitary tumour, potentially leading to unnecessary investigation and inappropriate treatment.