Carmel T. Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS
University College Dublin Veterinary Hospital, UCD, Belfield, Dublin, Ireland
Hyperthyroidism is considered to be the most common endocrine disorder of cats and a disease frequently encountered in small animal practice. The diagnosis has always been considered relatively straightforward by demonstrating increased circulating concentrations of the active thyroid hormones triiodothyronine (T3) or, more commonly, thyroxine (T4). However, today, severe cases of hyperthyroidism are less commonly seen, as cats tend to be diagnosed earlier in the course of their disease. This impacts the efficacy of the diagnostic tests used to confirm or refute the diagnosis, because the abnormalities encountered become less obvious and the possibility of occult hyperthyroidism is greater. In addition, the confounding effects of non-thyroidal factors are likely to have a greater impact in early or mild cases of hyperthyroidism.
Routine Clinicopathological Features
There are no pathognomonic routine clinicopathological features for hyperthyroidism. Many haematological changes have been reported including erythrocytosis, macrocytosis and a stress leucogram. However, the changes are relatively mild and not clinically significant. Hyperphosphataemia and hyperglycaemia have been described and not surprisingly because of the age of affected cases, a proportion has azotaemia. However, mild to marked increases in liver enzyme activities (ALT, ALP, AST, LDH) are the most striking biochemical abnormalities associated with hyperthyroidism, occurring in approximately 90 % of cases. The degree of elevation correlates with the severity of hyperthyroidism. As a consequence, abnormalities may not be present in early hyperthyroidism and extreme elevations with only mildly increased thyroid hormone concentrations suggest concurrent hepatic disease. Nevertheless, hyperthyroidism is the most common cause of raised liver enzyme activities in older cats. Performing such routine tests helps support a diagnosis of hyperthyroidism, but probably is most useful in depicting any concurrent disorders that may potentially influence the accuracy of the thyroid function tests.
Thyroid Function Tests
To date, measurement of basal concentrations of total and free T4 and total T3 has been routinely used in the diagnosis of feline hyperthyroidism. There has been recent interest in evaluating circulating thyrotropin (thyroid stimulating hormone, TSH) concentrations in cats using the assay designed and validated for canine samples.
Circulating total T3 and total T4 values are often concurrently elevated in hyperthyroidism. However, total T3 values are within the reference interval in a significant proportion of over 30 % of hyperthyroid cats. In such cases, the clinical signs of hyperthyroidism are usually mild and the total T4 concentration only marginally elevated (< 100 nmol/l with a typical reference interval of 15–60 nmol/L) and it is likely that the serum total T3 concentration would increase into the thyrotoxic interval if the disorder were allowed to progress untreated. Severe concurrent non-thyroidal illness (NTI) may also play a role in suppressing T3 concentration by inhibiting peripheral conversion of T4 to T3, as it does in humans, although this appears to be a less common phenomenon in cats.
Serum total T4 concentration is elevated in the majority of hyperthyroid cats with values exceeding up to 20 times the upper limit of the reference interval. However, it is becoming increasingly recognised that serum total T4 concentration may also be within the mid to high end of the reference interval (> 30 nmol/l) in a significant percentage (approximately 10 % of all cases and 40 % of those classified as mildly affected) of hyperthyroid cats. Most cats with reference interval total T4 concentration have early or mild disease where nonspecific fluctuation of hormone concentration may play a role. However, the presence of concurrent NTI can also affect circulating total T4 concentration in hyperthyroid cats. From 22 to 79 % of reference interval total T4 values in hyperthyroidism have been attributed to concurrent NTI in different studies (McLoughlin et al. 1993; Peterson et al. 2001). The mechanisms remain unclear, but are more likely to involve changes in protein binding or metabolism rather than any effect on the hypothalamic-pituitary-thyroid axis. Reference interval values resulting from the suppressive effect of non-thyroidal disease are only expected in cats with early or mild hyperthyroidism, as the degree of suppression has little diagnostic significance in hyperthyroid cats with markedly elevated serum total T4 concentration. Despite the possibility of encountering mid to high reference interval values in mildly hyperthyroid cats with concurrent disease, they usually do not pose a diagnostic dilemma, because serum total T4 concentrations also decline in euthyroid individuals with similar illnesses. Low total T4 values are only expected in hyperthyroid cats with the most severe concurrent disorders, and in these cases, other criteria, particularly detection of a palpable thyroid nodule, may indicate the need to further investigate hyperthyroidism.
Many laboratories have recently decreased the upper limit of the total T4 reference interval to 40 and even 30 nmol/L, suggesting that this better reflects values found in healthy aged cats. However, whilst increasing the sensitivity of total T4 for diagnosing hyperthyroidism, it potentially adversely affects specificity and may give rise to a number of false positive diagnoses.
In human thyrotoxicosis, assessment of free T4 is considered a better diagnostic test for hyperthyroidism, because it is less affected by non-thyroidal factors and provides a more accurate reflection of thyroid status. Notably, when serum total T4 concentration is increased, the concentration of free T4 is disproportionately increased and this may be related in part to relative saturation of binding proteins by T4 and subnormal concentration of the principal binding proteins. In addition, serum free T4 concentration remains elevated in hyperthyroid patients with NTI when total T4 concentration is suppressed into the reference interval. Measurement of free T4 concentration has been evaluated in hyperthyroid cats and appears to be a useful diagnostic test, particularly in cats with reference interval serum total T4 concentration. In cats categorised as mildly hyperthyroid with or without a concurrent illness, serum free and total T4 concentration are elevated in > 90 and approximately 60 % cases, respectively. The increased diagnostic sensitivity of free T4 measurement is complicated by a loss of specificity because of the effect of NTI in increasing values in euthyroid cats. Circulating free T4 concentration should therefore be interpreted with caution if used as the sole diagnostic criterion for confirmation of hyperthyroidism. More reliable information is obtained when interpreted together with a serum total T4 concentration. A mid to high reference interval total T4 and elevated free T4 concentration is consistent with hyperthyroidism. By contrast, low total T4 and elevated free T4 values are usually associated with NTI.
In humans, measurement of circulating TSH concentration is usually used as a first-line discriminatory test of thyroid function because of its excellent diagnostic performance. Hyperthyroidism is associated with suppressed values, accurately measured by assays whose functional sensitivity can be up to 30 times lower than the lower end of the reference interval. More importantly is the log-linear negative feedback relationship between free T4 and TSH where a linear change in free T4 corresponds to a logarithmic change in TSH. Significant changes in TSH can therefore be readily picked up with only relatively small changes in free T4. A species-specific feline TSH assay has not yet been developed. However, assays for measuring canine TSH (cTSH) are widely available and it has been suggested that its measurement may provide some diagnostic information in cats. In one study of two separate groups of hyperthyroid and euthyroid cats both with mild chronic kidney disease, circulating cTSH concentrations were at or below the limit of detection of the assay (0.03 ng/mL) in all hyperthyroid, but only 10 % of the latter group. Euthyroid cats with undetectable cTSH concentrations were more likely to have histopathological evidence of thyroid nodular hyperplasia than euthyroid cats with detectable cTSH values. In addition, older cats with undetectable cTSH concentrations are more likely to develop hyperthyroidism within one year compared to cats with detectable concentrations. As a consequence, measurement of cTSH using the canine assay has been suggested to provide evidence for the existence of clinical and subclinical hyperthyroidism in cats.
Caution is advised in overinterpreting the value of cTSH measurements in cats. The current canine assays only detect a proportion of recombinant feline TSH. As a consequence, the limit of detection, already considered poor at 0.03 ng/mL, may be even higher for feline TSH. Such limits are inappropriate in distinguishing normal from the suppressed values expected in hyperthyroidism. In addition, a potential effect of NTI is suppression of TSH and large studies evaluating such an effect using an appropriate feline assay have not yet been carried out. Perhaps, the only use for such TSH measurement would be to exclude hyperthyroidism if a value exceeded the lower limit of detection of the assay.
Other Diagnostic Tests
In the majority of hyperthyroid cats with reference interval total T4 concentration, identification of concurrent disease, repeat total T4 analysis or simultaneous measurement of free T4 allows confirmation of the diagnosis. Further diagnostic tests are rarely required. However, dynamic thyroid function tests have been recommended in the past as helpful in confirming a diagnosis of hyperthyroidism, particularly when repeated total T4 concentrations remain within reference interval or free T4 analysis is unavailable or diagnostically unhelpful. Such tests include the T3 suppression test and both the TSH and thyrotropin releasing hormone (TRH) response tests. Like most diagnostic tests, they are not 100 % accurate and are capable of giving rise to false positive and negative results. Where these tests have been evaluated, the study groups comprised hyperthyroid, healthy or euthyroid cats with NTI. Few hyperthyroid cats with concurrent disease have been specifically studied. In one such report, results of the TRH response test were largely indistinguishable between sick euthyroid and hyperthyroid cats with concurrent disease and total T4 concentrations within or below the reference interval.
NTI likely exerts less effect on the results of quantitative thyroidal radioisotope uptake than basal total T4 concentration, and potentially could exclude hyperthyroidism in those few euthyroid cats with elevated free T4 concentration. It has also been suggested that 99mTc04-scans are a more sensitive means of diagnosing hyperthyroidism than basal thyroid hormone analyses or TRH response test results, but further studies are required in hyperthyroid cats with concurrent NTI. Care should be taken in interpreting uptake results in cats recently treated with antithyroid drugs as thyroidal radioisotope uptake is increased after methimazole withdrawal.
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