Diagnosis
The diagnosis of hyperthyroidism is often obscured in cats with azotaemic CKD, even when this is relatively mild. It is very common in our clinic to see cats that have been diagnosed with CKD that lose weight in spite of a continued good appetite, they have a palpable goitre, their creatinine concentration may actually decline and although there is a strong clinical suspicion that the cat is hyperthyroid measurements of total thyroxine (T4) are within the laboratory reference range. One of the simplest ways to diagnose hyperthyroidism in cats with CKD if the total T4 measurements are not initially elevated is simply to repeat the test. This approach is particularly useful when a correctable cause of 'sick euthyroid syndrome' is also present.
Since free T4 is the biologically active hormone available for entry into cells, and it is the concentration of this that is tightly regulated, it has been proposed that this should be a better test of thyroid function than total T4. However, when free T4 measurement is used in isolation for the diagnosis of hyperthyroidism false-positive test results do occur; the test is sensitive but not as specific as total T4 measurement.1 Measurement of free T4 can be used to confirm the diagnosis of hyperthyroidism when used in combination with other diagnostic tests.2 The combination of a high-normal total T4 value (>30 nmol/l) and elevated free T4 measurement is relatively sensitive and specific for diagnosis of hyperthyroidism.
In people, the most often employed screening test for hyperthyroidism is suppression of endogenous TSH levels. Only if TSH is low will total or free T4 be measured to confirm the diagnosis of hyperthyroidism and quantify its severity. Unfortunately, the assays developed for use with human serum do not perform well in other species. An assay is available for measurement of TSH in canine serum and this assay can be used with feline samples although it lacks sensitivity; almost all hyperthyroid cats will have undetectable (<0.03 ng/ml) TSH concentration but unfortunately so will some normal cats.2,3 Whilst the assay undoubtedly has limitations measurement of TSH in cats can occasionally be useful: for example, if TSH is detectable (i.e., has any value ≥0.03 ng/ml) then a diagnosis of hyperthyroidism is excluded. Additionally, the combination of elevated total or free T4 and undetectable TSH concentration is strongly supportive of the diagnosis of hyperthyroidism.2 Interestingly, it seems that at least some of the cats with undetectable TSH concentrations are sub-clinically hyperthyroid and over time will go on to develop clinical signs of the disease.4
An alternative approach to the diagnosis of occult hyperthyroidism is to perform a T3 suppression test. The predictive value of this test in cats with CKD has not been objectively evaluated but it is generally held to be a good, if somewhat arduous, way of testing thyroid function. In the specialist clinic then scintigraphy can also aid in the diagnosis.
Trial medical therapy, or even thyroidectomy, is sometimes advocated in cats with suspected but unproven hyperthyroidism. Although this pragmatic approach is attractive in some cases, especially when the clinical suspicion of hyperthyroidism is very strong, it can be problematic in cats with CKD, because it is then unclear whether a poor response is due to deteriorating renal function or an incorrect initial diagnosis.
Treatment
Treatment of hyperthyroidism results in a decline in glomerular filtration rate (GFR) with a concomitant increase in urea and creatinine concentrations. This decline in GFR is associated with resolution of the hyperthyroid state, rather than adverse effects of any particular treatment modality. It has been demonstrated in cats treated with radioiodine, by surgery or with medical therapy, with about a third of all treated cats developing mild, stable azotaemic CKD. In addition to the effects on GFR, expansion of the extracellular fluid volume and muscle wasting in cats with hyperthyroidism serve to lower serum creatinine concentration, masking the presence of renal disease. When evaluating cat's renal function prior to treatment of hyperthyroidism emphasis is given to the creatinine measurements rather than urea. It has been observed that urea is almost always elevated in hyperthyroid cats and decreases with treatment in most instances, it does not indicate a patient that is likely to develop azotaemic CKD once euthyroid.
Does this apparently detrimental effect of treatment on GFR mean that we should not treat cats for hyperthyroidism? In the majority of cats the decrease in renal function is without immediate clinical consequences, outweighed in significance by the deleterious effects of continued hyperthyroidism. It is also possible (see below) that untreated hyperthyroidism is actually damaging to the feline kidney. In cats that are azotaemic prior to treatment for hyperthyroidism it is generally recommended that they be treated medically initially (and with a gradually escalating dose), so that if their condition deteriorates the anti-thyroid medications can be discontinued and the cat will return to a hyperthyroid state. If the biochemical deterioration is mild following treatment, and the well-being of the cat is improved, then permanent treatment for hyperthyroidism (surgery/radioiodine therapy) can be considered. However, in general the survival of cats that have azotaemic CKD prior to treatment of hyperthyroidism is poor; in our studies performed in first-opinion practices the median survival time was only 178 days [range 0–1,505 days].5
Could Hyperthyroidism Actually Be Damaging to the Feline Kidney?
Hyperthyroidism could be damaging to the feline kidney by several mechanisms. In the hyperthyroid state volume expansion occurs primarily due to stimulation of the renin-angiotensin aldosterone system. There is also a concurrent increase in heart rate. These changes could result in glomerular hypertension, resulting in an accelerated decline in functional nephron mass. Hyperthyroid cats are also hyperphosphatemic and have elevated parathyroid hormone (PTH),6 effects that could result in mineralisation of soft tissues and worsening of renal function as well as contributing to patient morbidity through the loss of bone mineral density.
Hyperthyroid cats have proteinuria which usually decreases with treatment. Proteinuria has been associated with shorter survival times in cats with CKD and in those with hypertension. Studies of cats with hyperthyroidism indicate that proteinuria is (weakly) associated with overall survival time but is not associated with the development of azotaemia following treatment.5
An alternative theory to explain the co-incident occurrence of hyperthyroidism and CKD is that cats with poor renal function have decreased excretion of goitrogens and this predisposes them to the development of hyperthyroidism.
Predicting Cats That Will Develop Azotaemia With Treatment of Hyperthyroidism
Several studies have attempted to predict the cats that will develop azotaemia following treatment for hyperthyroidism. In some studies measurement of GFR has been found to predict azotaemia following treatment;7 however, this is not very practical for day-to-day use in the clinic. Not surprisingly higher pre-treatment creatinine concentrations have been associated with the development of azotaemia once cats are euthyroid, however, the association is relatively weak and so it is difficult to predict outcome on an individual basis.5 Urine specific gravity does not seem to predict the development of azotaemia with treatment.5,8
Currently, although there may be clinical suspicion for the presence of underlying CKD, for example in a very old patient with palpably small kidneys, or in a patient with a relatively high pre-treatment creatinine concentration and very severe hyperthyroidism, there does not seem to be one diagnostic test that performs well in predicting renal outcome. As a result the best approach seems to be to treat the patient and monitor renal function, rechecking the creatinine concentration once the patient is euthyroid. Even once total T4 has normalised creatinine concentrations may continue to increase for a few months following the control of hyperthyroidism before stabilizing.9 It is worth noting that it is often difficult to predict whether the patient has become azotaemic simply on the basis of how the cat is doing clinically. Most cats that develop azotaemia following treatment for hyperthyroidism show almost no clinical signs (with a careful history an increase in water intake can often be documented although the owners frequently do not perceive this as a problem). In fact, most cats that develop azotaemia following treatment of hyperthyroidism gain weight and show an improvement in demeanour and so CKD will only be documented if biochemical testing is performed.
Prognostic Significance of Azotaemia in Cats Treated for Hyperthyroidism
Azotaemic CKD is a frequent problem in geriatric cats but is relatively slow to progress. In fact, in general, cats treated for hyperthyroidism that develop azotaemia do not have any difference in survival time when compared with cats that remain non-azotaemic. The situation may be different in patients that develop hypothyroidism following treatment; a recent study of cats treated for hyperthyroidism found the proportion of cats with azotaemia was significantly greater (57%) in the cats developing hypothyroidism than in those that remained euthyroid (30%). When the survival of these cats was studied it was found that hypothyroid cats that developed azotaemia within the follow-up period had significantly (p=0.018) shorter survival times (median survival time 456 days, range 231–1589 days) than those that remained non-azotaemic (median survival time 905 days, range 316–1869 days). Subsequently it has also been demonstrated that treating the hypothyroidism ameliorates the azotaemia.10
What implications does this study have for clinical practice? It now seems prudent to not over-treat cats for hyperthyroidism but to aim for a total T4 concentration that is in the range of 15–35 nmol/l (1.2–2.7 µg/dl).
Although cats that have total T4 concentrations lower than this do not tend to demonstrate overt signs of hypothyroidism they will tend to gain weight, have higher creatinine concentration and lower PCV. In those cats that develop azotaemia survival times may actually be reduced. It is not clear that this is due to the effect of the azotaemia per se, it is the combination of problems that appears to contribute to patient morbidity.
References
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2. Wakeling J, Moore K, Elliott J, Syme H. Diagnosis of hyperthyroidism in cats with mild chronic kidney disease. J Small Anim Pract. 2008;49(6):287–294.
3. Peterson ME. Feline focus: diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet. 2013;35(8):E1–6.
4. Wakeling J, Elliott J, Syme HM. Evaluation of predictors for the diagnosis of hyperthyroidism in cats. J Vet Intern Med. 2011;25(6):1057–1065.
5. Williams TL, Peak KJ, Brodbelt D, Elliott J, Syme HM. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med. 2010;24(4):863–869.
6. Barber PJ, Elliott J. Study of calcium homeostasis in feline hyperthyroidism. J Small Anim Pract. 1996;37(12):575–582.
7. Adams WH, Daniel GB, Legendre AM, Gompf RE, Gove CA. Changes in renal function in cats following treatment of hyperthyroidism using I-131. Vet Radiol Ultrasound. 1997;38(3):231–238.
8. Riensche MR, Graves TK, Schaeffer DJ. An investigation of predictors of renal insufficiency following treatment of hyperthyroidism in cats. J Feline Med Surg. 2008;10(2):160–166.
9. Boag AK, Neiger R, Slater L, Stevens KB, Haller M, Church DB. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Vet Rec. 2007;161(21):711–715.
10. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med. 2014;28(4):1251–1255.