Hyperthyroidism: A view from the urinary tract (Proceedings)

Hyperthyroidism is one of the most commonly diagnosed diseases of the older cat. Geriatric cats with hyperthyroidism may also have concurrent chronic kidney disease (CKD). Systemic hypertension, proteinuria, and urinary tract infection (UTI) can be consequences of either hyperthyroidism or CKD. Hyperthyroidism can increase glomerular filtration rate (GFR) in cats with CKD which can attenuate or resolve mild to moderate azotemia. In addition, serum creatinine may be decreased in cats with weight loss and decreased muscle mass. In both cases, reductions in BUN and serum creatinine concentrations make it more difficult to detect concurrent CKD. Conversely, the CKD may depress thyroid hormone concentrations (euthyroid sick syndrome) making it more difficult to diagnose hyperthyroidism. Initial treatment of cats with suspected or confirmed CKD should ideally be accomplished with a reversible anti-thyroid medication in order to assess any adverse effects on renal function. Systolic blood pressure and urine protein creatinine ratio (UP/C) should be evaluated prior to and after treatment. Urine cultures should be obtained as part of the workup of both hyperthyroidism and CKD. In either case, a concurrent UTI should be managed as a complicated UTI with long-term antibiotic treatment based on culture and sensitivity results.

Clinical Signs/Physical Examination

Classic clinical signs of hyperthyroidism include weight loss, polyuria/polydipsia (PU/PD), and polyphagia in an older cat. Fewer than 5% of cats with hyperthyroidism are less than 8 years of age; the average age at diagnosis is 12-13 years. A thyroid enlargement (thyroid slip) can often be palpated in hyperthyroid cats, although some euthyroid cats will also have enlargement of one or both glands. In cats with concurrent CKD, kidneys may be small and/or irregular. Approximately 50% of cats with hyperthyroidism will exhibit PU/PD. A primary polyuria may occur as a result of thyrotoxicosis increasing cardiac output and GFR as well as increased renal medullary blood flow which has the potential to decrease renal medullary hypertonicity and urine concentrating ability. Some cats with hyperthyroidism may also have a primary polydipsia secondary to the effects of high thyroid hormone concentrations on the thirst center. Regardless of the mechanism, decreased urine specific gravity makes interpretation of azotemia problematic (is it pre-renal azotemia superimposed on decreased concentrating ability or renal azotemia?). Systemic hypertension is another common finding in hyperthyroid cats. High blood pressure may be caused by increased cardiac output, sympathetic tone, and arteriolar resistance and if sustained, can lead to intraglomerular hypertension, glomerular sclerosis, and proteinuria. No matter what the underlying cause, hypertension can damage the eyes, brain, heart, and kidney of affected cats. For example, tachycardia murmurs, and gallop rhythms may be associated with hypertrophic cardiomyopathy. Similarly, whether proteinuria arises from hypertension or CKD, progressive renal disease is a potential consequence.

Increased practitioner awareness of hyperthyroidism, an increasing population of geriatric cats, and increased diagnostic testing of older cats (wellness exams) has resulted in earlier diagnosis of hyperthyroidism in many cases. Clinical signs in these cases may be more subtle compared with an advanced case of hyperthyroidism. With earlier diagnosis, weight loss may be present but emaciation will be less likely and body condition scores will be higher. Similarly, PU/PD is less likely to be observed by owners and appetite and activity levels may be only slightly increased in cats with early hyperthyroidism.

Clinicopathologic findings associated with hyperthyroidism may include a slight erythrocytosis; perhaps secondary to increased tissue oxygen consumption. Serum ALT is increased in approximately 75-90% of cats with hyperthyroidism and is thought to be associated with malnutrition, hepatic hypoxia, and/or toxic effects for thyroid hormone on hepatocytes. Azotemia is observed in approximately 25% of hyperthyroid cats and may be due to dehydration, increased protein turnover (BUN), and/or CKD. Concurrently, urine specific gravity is often decreased as discussed previously.

Diagnosis

The best screening test for the diagnosis of hyperthyroidism is the total T4 (TT4) concentration. An increased TT4 is specific for hyperthyroidism however false negative results may occur with non-thyroidal illness (e.g., CKD). In cats with compatible clinical signs of hyperthyroidism that have a TT4 in the normal range, repeating the test in two weeks is usually the first recommendation. If results are still in the normal range on the second test, a free T4 (fT4) (measured by equilibrium dialysis) may be assessed. In comparison to the TT4, the fT4 is more sensitive but may result in more false positive results. A low normal TT4 with a high fT4 is moresuggestive of non-thyroidal illness, whereas and high normal TT4 with an increased fT4 suggest hyperthyroidism (especially with compatible clinical signs). Rarely a T3 suppression test may be employed to help confirm a diagnosis. Nuclear scintigraphy compares the uptake of technetium-99m by the thyroid to the salivary glands (a normal thyroid to salivary gland ratio is < 1.6:1.0). Nuclear scintigraphy is both sensitive and specific and it is considered the gold standard diagnostic test.

Pre-Treatment Evaluation

Several studies have demonstrated that GFR declines with treatment for hyperthyroidism; this decline is independent of the treatment modality (medical, surgical, radioactive iodine). This decrease in GFR should be considered a consequence of the resolution of the hyperthyroid state and not a side effect of the treatment itself. The potential for a decrease in GFR to adversely affect the patient's quality of life suggests that a thorough pre-treatment evaluation of the heart (potential pre-renal effects) and kidneys is important. The goal is to identify patients that may be harmed by permanent treatment of their hyperthyroidism.

Thoracic radiographs to asses the cardiac silhouette should be performed to rule out cardiomyopathy (especially in cases with a murmur or gallop rhythm). Any changes in the cardiac silhouette should be further evaluated with echocardiography. A baseline blood pressure should be determined and a complete minimum data base (CBC, serum biochemistry profile, UA) obtained. Although it is thought to be a better positive prognostic indicator than minimally concentrated urine, hypersthenuric urine specific gravity (>1.035-1.040) prior to treatment does not guarantee adequate renal function post treatment. Combining urine specific gravity and TT4 concentration was helpful in predicting post-treatment azotemia in one study (USG < 1.035 and TT4 > 7.8 µg/dL together were poor prognostic indicators). The urine dipstick and sulfosalicylic acid assays are unreliable screening tests for proteinuria in cats and therefore a feline specific albuminuria assay and/or a urine protein/creatinine ratio (UP/C) should be utilized to quantitate proteinuria/albuminuria. Persistent proteinuria of renal origin is a poor prognostic indicator for progression of CKD in cats; however pre-treatment proteinuria does not appear to be predictive of post-treatment azotemia in hyperthyroid cats. Urinary excretion of NAG was also not predictive of post-treatment azotemia in hyperthyroid cats. Urine cultures are recommended in all cases but are required in cats with pyuria and/or hematuria; UTI occurs in 12-22% of hyperthyroid cats and 13-30% of CKD cats and with both underlying diseases, the infection is often clinically silent. Pre-treatment GFR measurement may be a useful predictor of post-treatment renal function. Although exceptions exist, pre-treatment GFR values > 2.25-2.5 ml/min/kg body weight are thought to predict adequate post-treatment renal function. Finally in cats with suspected CKD, renal imaging with ultrasound and/or radiographs is recommended to further assess kidney tissue architecture and help rule out ascending infections, uroliths, and renal infiltrative disease. In cats that have obvious CKD and/or severe hypertension (> 180 mmHg), these issues should be addressed prior to treatment of the hyperthyroidism.

Methimazole Trial Treatment

Inasmuch as treatment of hyperthyroidism can result in a renal functional decline that can affect the cat's quality of life, a methimazole trial is often recommended prior to permanent treatment (surgery or I131 ). After obtaining baseline values (TT4, CBC biochemistry profile, UA, urine protein determination, and blood pressure), methimazole is administered orally at an initial dose of 2.5 mg/cat every 12-24 hrs (it's often recommended to use the once daily dose in cats with suspected CKD however a euthyroid state is achieved in a higher percentage of cats treated twice daily vs. once daily). If after one week the TT4 is not in the low normal range, the dose of methimazole should be increased (e.g., 2.5 mg/cat BID or 5.0 mg/cat in the AM and 2.5 mg/cat in the PM depending on the initial dose). Baseline kidney function and blood pressure values should be rechecked after the cat has been euthyroid for 4 weeks. If renal parameters or clinical signs of CKD worsen with methimazole, treatment should be discontinued or the dose reduced to a tolerable level for long-term treatment. The goal in this case would be to maximize renal function while controlling clinical signs of hyperthyroidism. Maintenance of a mild hyperthyroid state may be beneficial in some CKD cats. In all cats with CKD, avoidance of over-treatment resulting in hypothyroidism is important since GFR may be adversely reduced. If there are only slight or no changes in the renal data base after 4 weeks of maintaining a low normal TT4, permanent treatment can be considered.

Adverse side effects of methimazole can include gastrointestinal signs (vomiting is common), facial and neck excoriations (uncommon), blood dyscrasias (e.g., immune-mediated thrombocytopenia which is rare), and hepatoxicity (rare). Transdermal administration of methimazole can be effective but may take up to 2-3 weeks longer to achieve a euthyroid state. Gastrointestinal signs are less common with transdermal application, but other adverse effects may still be observed.

Summary

In most cases, treatment of hyperthyroidism in cats with concurrent CKD results in overall improvement, however management of cats with both conditions remains a "balancing act". In a recent retrospective study, hyperthyroid cats with concurrent CKD had significantly shorter survival time (median survival of approximately 2.5 years) compared with hyperthyroid cats with normal renal function (median survival time of approximately 4 years). Additionally, survival time in hyperthyroid cats treated with methimazole alone was shorter (median survival of 2 years) compared with cats treated either with I131 alone (median survival of 4 years) or cats treated with methimazole followed by I131 (median survival of 5.3 years).