Friday, October 14, 2011

Does Iodine Deficiency Cause Thyroid Disease in Cats?

Although only first described in cats in the last 1970s (1), today hyperthyroidism is clearly the most common endocrine disorder of cats, being detected at rates as high as 2% of all cats examined (2). Cats certainly live longer today than they did 35 years ago when we first described the disease, but it is highly unlikely that this epidemic of hyperthyroidism is solely the result of the aging cat population.

Other factors must be involved: the most likely candidates include deficiencies or excesses in the cat's diet or the chronic exposure to one or more "thyroid-disrupting" chemicals present in the environment, drinking water, or diet (2).

Is Diet the Cause of Feline Hyperthyroidism?

All epidemiologic studies of cats with hyperthyroidism reported to date have identified commercial cat food diets as a risk factor for developing the disease (3-10). One of these studies suggested that particular flavors of canned food (fish, liver, and giblets) may be involved (5), and another incriminated cans with plastic linings in easy-open (pop-top) lids (8), which may contain the thyroid disruptor chemical bisphenol-A (BPA).

Soy isoflavones, a well-known goitrogen that inhibits thyroid hormone synthesis (11,12), are also known to be present in many dry cat foods (13). Finally, most recently, iodine deficiency has "resurfaced" as a candidate for development of goiter and subsequent hyperthyroidism in cats (6,14).

Dietary Iodine Excess or Deficiency

Because of the clear association between diet and hyperthyroidism, several studies have attempted to implicate iodine in the cause or progression of the disease. The iodine content of cat food has always been extremely variable. However, a definite trend for adding lower amounts of iodine to cat food has occurred over the last 30 years as the recommended dietary iodine requirements for cats has changed (14).

In the mid-1980s, shortly after hyperthyroidism was first reported, most commercial cat food diets were found to contain very high amounts of iodine, often up to 10 times the recommended level (15). Subsequently, the recommendations for iodine supplementation to cat food diets were lowered (16).

By the early 1990’s, another study reported that only 10% of the cat food tested had iodine concentrations that exceeded the upper limit of recommended iodine concentrations, whereas about 25% of the foods had iodine concentrations that were below the level of detection (17). In that study, the widest variation in iodine content was in canned food, whereas dry food diets were less variable.

Similar findings in the variation of iodine levels between cat foods were reported in another study of commercial foods in 2002, in which the iodine content between foods varied by a factor of 30-fold (18). Again, however, the average iodine content of commercial cat foods was lower than they had been in the 1980s.

Thus, between the 1980s and early 2000s, iodine concentrations appeared to range between non-detectable and extremely high levels in a variety of canned foods. Large variations in iodine concentration among cat foods may reflect the widely different iodine concentrations of ingredients used (e.g., glandular tissue, fish), as well as the amounts of iodine added to the foods by the different manufacturers.

The role that iodine plays in the development of hyperthyroidism remains unclear, but it can be postulated that wide swings in iodine intake over time may contribute to the development of thyroid disease in cats (19-21). It also possible that some cats will be consistently fed a low iodine diet, which would also predispose a cat to thyroid hyperplasia and goiter (22,23).

Could Iodine Deficiency Now Be Contributing to the Disease?

Iodine deficiency is a known cause of thyroid hyperplasia and goiter in man and all animals, including cats (22-25). Iodine is a key element needed in the synthesis of thyroid hormones. As a consequence, inadequate iodine intake leads to low circulating thyroid hormone concentrations, which spurs the pituitary gland to increase its secretion of TSH (Figure 1). Persistently high circulating TSH concentrations will lead to thyroid hyperplasia and possibly goiter (22,23).  It's possible that with enough time and continued stimulation, the hyperplastic thyrocytes may become autonomous, leading to adenomatous hyperplasia and then to thyroid adenoma. As these tumors continue to grow and function independent of TSH control, hyperthyroidism would ensue leading to suppression of pituitary TSH secretion. In some cats, transformation of adenomatous hyperplasia/adenoma to thyroid carcinoma will occur (26).

Fig. 1: Pathogenesis of thyroid hyperplasia & goiter in chronic iodine deficiency.  Although simple goiter caused by iodine deficiency is well-documented, it is not known for certain if iodine deficiency, at least by itself, can lead to the development of true thyroid tumors and hyperthyroidism.
So, based on the trend to lower iodine levels in cat food over the last two decades, could iodine deficiency be contributing to the explosion in hyperthyroid cases that we are seeing today? In support of that reasoning, a recent case-control study reported that cats consuming commercial foods which were relatively deficient in iodine were more than 4 times as likely to develop hyperthyroidism compared with cats that ate iodine-supplemented foods (6,14).

In another study supporting the possible role of iodine deficiency in the pathogenesis of this disease, hyperthyroid cats had lower-than-normal urinary iodine excretion. Following successful treatment for hyperthyroidism, urinary iodine excretion in these cats increased into the normal range (27). The investigators hypothesized that the hyperthyroid cats may have had a pool of stored iodine that was excreted in the weeks following treatment. They suggested that if the urinary iodine concentrations of their hyperthyroid cats reflected iodine intake while the disease was developing, inadequate iodine intake may be a risk factor for hyperthyroidism.

Does Iodine Deficiency Act Synergically with Other Goitrogens or Thyroid Disruptors?

It is difficult to envision how iodine deficiency, excess, or wide fluctuations in iodine intake would be solely responsible for the thyroid adenomatous changes and the development of hyperthyroidism in cats. However, we must remember that most, if not all, hyperthyroid cats are also exposed to other goitrogens or thyroid disruptors in the water, diet, or the environment (e.g., BPA and PBDE) throughout their lifetime (2,8,28). Thus, iodine deficiency may act together with these other goitrogens in a synergistic or cooperative manner to effect multiple sites of thyroid hormone metabolism or action; over time, this may lead to the adenomatous thyroid changes characteristic of hyperthyroidism.

In support of this reasoning, studies in rats demonstrate that soy isoflavones are not highly goitrogenic when added to the diet alone, but soy will consistently induce thyroid hyperplastic and adenomatous changes in the presence of iodine deficiency (29,30). In other words, soy can cause goiter, but only in animals or humans consuming diets that are only marginally adequate in iodine, or in those who are otherwise predisposed to developing goiter because of other factors.

Could Hill's Prescription y/d Diet Make this Situation Worse?

Hill's y/d diet (31), clearly being an ultra-low, iodine deficient diet is effective in lowering serum T4 values in hyperthyroid cats. Since these cats already have developed the thyroid adenomatous hyperplasia and thyroid adenoma(s) responsible for hyperthyroidism, we do not have to worry about inducing thyroid disease in these cats — they already have it!

But, will lowering T4 and T3 secretion in these hyperthyroid cats lead to increases in circulating TSH and continued stimulation of thyroid growth and proliferation in some cats? Will this TSH stimulation cause transformation of benign adenomatous thyroid tissue to carcinoma, as has been documented to occur in some hyperthyroid cats (26)?

The short answer is this: we simply do not know.  The long-term safety studies needed to answer this question have not yet been done. Because Hill's y/d is not a drug (although it's certainly being marketed as a replacement for methimazole), the company is not required to do the these safety studies, and it's fairly clear that they have no intension of paying to have them done.

Nevertheless, it would definitively be prudent NOT to feed y/d to clinically normal cats, since even mild decreases in thyroid hormone secretion could stimulate TSH secretion (22,23). Again, this could lead to thyroid hyperplasia, goiter, and would definitely predispose the cat to developing hyperthyroidism in the future (Figure 1).

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