Narayanan Kandasamy, Laura Fugazzola, Mark Evans, Krishna Chatterjee and Fiona Karet
Pendred syndrome, a combination of sensorineural deafness, impaired organification of iodide in the thyroid and goitre, results from biallelic defects in pendrin (encoded by SLC26A4), which transports chloride and iodide in the inner ear and thyroid respectively. Recently, pendrin has also been identified in the kidneys, where it is found in the apical plasma membrane of non-α-type intercalated cells of the cortical collecting duct. Here, it functions as a chloride–bicarbonate exchanger, capable of secreting bicarbonate into the urine. Despite this function, patients with Pendred syndrome have not been reported to develop any significant acid–base disturbances, except a single previous reported case of metabolic alkalosis in the context of Pendred syndrome in a child started on a diuretic.
We describe a 46-year-old female with sensorineural deafness and hypothyroidism, who presented with severe hypokalaemic metabolic alkalosis during inter-current illnesses on two occasions, and who was found to be homozygous for a loss-of-function mutation (V138F) in SLC26A4. Her acid–base status and electrolytes were unremarkable when she was well.
This case illustrates that, although pendrin is not usually required to maintain acid–base homeostasis under ambient condition, loss of renal bicarbonate excretion by pendrin during a metabolic alkalotic challenge may contribute to life-threatening acid–base disturbances in patients with Pendred syndrome.
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.
Kristian Løvås, Clara G Gjesdal, Monika Christensen, Anette B Wolff, Bjørg Almås, Johan Svartberg, Kristian J Fougner, Unni Syversen, Jens Bollerslev, Jan A Falch, Penelope J Hunt, V Krishna K Chatterjee and Eystein S Husebye
Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone.
To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics.
Design, setting and participants
A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105).
Main outcome measures
Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity.
Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean −0.28 (95% confidence intervals (CI) −0.42, −0.16); UK and New Zealand: −0.21 (95% CI −0.36, −0.06)). Lumbar spine Z-scores were reduced (Norway: −0.17 (−0.36, +0.01); UK and New Zealand: −0.57 (−0.78, −0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine.
BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15–25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.
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.