We would like to comment on some of the points made by Wakeling et al. in their manuscript entitled ‘‘Subclinical Hyperthyroidism in Cats: A Spontaneous Model of Subclinical Toxic Nodular Goiter in Humans?’’ (1). The authors state: ‘‘The purpose of this study was to determine whether a relationship exists between TSH concentration and thyroid histopathology in biochemically euthyroid cats (as assessed by tT4 [serum total T4 concentration] thereby providing further evidence for the existence of subclinical hyperthyroidism in cats.’’ We certainly support the idea that the histopathological changes associated with spontaneous feline hyperthyroidism provide a model of toxic nodular goiter (Plummer’s disease), and have contributed to the literature in this regard (2–4). Undoubtedly, there is a prodromal period for this disease associated with clinically and biochemically undetectable hyperthyroidism. However, the authors of this manuscript have chosen a ‘‘healthy’’ population dominated by cats with chronic renal disease which we propose confounds the interpretation of their data. The concern rises from the observation in human patients with chronic kidney disease, both before as well as following kidney transplantation, that there is an increased frequency of goiter and thyroid adenomas (as well as hypothyroidism, probably due to increased serum iodine levels). In one study (5) of patients with chronic renal disease, the incidence of abnormal thyroid structures (nodules or abnormal echogenicity on ultrasound) in patients before or chronically after transplantation was 63=70% with 13=17% having goiter. The control group with normal renal function had 29%=16%, respectively. Despite the increased tendency for nodules, the thyroid volume was not significantly altered in the chronic kidney disease patients. A second concern is the reliance on the heterologous canine TSH assay to characterize thyroid hyperfunction in these cats. The commercially available canine TSH assay does detect gross elevations of TSH in the cat, such as during methimazole therapy. The assay has a sensitivity limit of 0.03 ng=mL that translates to about 0.1 ng=mL (very close to 1 mU=L) when corrected for 36% crossreactivity to recombinant feline TSH (6,7). Therefore, as was true for firstgeneration human TSH assays, on a case-by-case basis, a normal concentration cannot be reliably distinguished from an undetectable value. The authors quote from ‘‘unpublished data’’ (now published in reference 8) from 90 cats that the reference range for healthy senior cats is 7 years of age had detectable TSH. The authors note: ‘‘However, it is likely that not all cats with TSH <0.03 ng=mL have subclinical hyperthyroidism, particularly cats with severe concurrent illness and young cats.’’ Of the 59 cats for which there was histopathological data, 41 had chronic kidney disease and 13 were young cats. Therefore, 54=59 or 91.5% of the cases fit the categorization over which they raise concern. The authors continue: ‘‘In particular, it is known that kidney disease suppresses thyroid hormone production in cats and that the degree of suppression of tT4 is related to the severity of the concurrent disease (25).’’ As one of us was an author on this study (9), we would state that while the depression of serum total T4 concentration was observed, no measurement of thyroid hormone production per se was undertaken. The authors state that because creatinine was similar in the normal TSH and high TSH groups, and body weight and liver enzymes were similar, there were no differences in the populations. Aside from the effects of a chronic illness, uremia per se will be a major contributor to altering thyroid hormone metabolism, in part through alteration of serum T4 binding. No free T4 measurements were provided in the current study to evaluate this possibility, but the subsequent publication by the authors (8) supports this hypothesis in cats: the median free T4 concentration in the group with chronic kidney disease was only slightly higher than that of normal euthyroid population while the median total T4 concentration
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