Abstract
Hyperthyroidism is recognised not only as the commonest endocrine disease of domestic cats but as one of the most frequently diagnosed disorders in small animal practice. Prior to its first definitive diagnosis in 1979, there were few reports of pathological abnormalities in feline thyroid glands and only anecdotal reference to clinical signs that may have been caused by hyperthyroidism. Since that time, there has been a marked increase in the frequency of diagnosis of feline hyperthyroidism. It is unlikely that increased awareness and improved diagnostic capabilities alone account for such a dramatic increase in the prevalence of this disease and it has been suggested that hyperthyroidism is truly a new disease of cats. However, this is complicated by a growing cat population, an increased longevity for cats and possibly, a greater propensity to seek veterinary advice.
Thyrotoxicosis arises because of the excess production of the active thyroid hormones, triiodothyronine (T3) and/or thyroxine (T4) from an abnormally functioning thyroid gland. To date, much research has been carried out culminating in a wealth of data on clinical manifestations, diagnostic tests and therapeutic options. Histopathologically, functional adenomatous hyperplasia (adenoma) of one (approximately 30% of cases) or more commonly, both (70% of cases) thyroid lobes is known to be the most common abnormality associated with hyperthyroidism while thyroid carcinoma is rare, accounting for less than 2% of cases. However, the cause and pathogenesis of the condition remain unclear.
Epidemiological risk factors
Hyperthyroidism is a disease exclusively of older cats and unlike the situation in humans, there is no sex predisposition. Two separate epidemiological studies have reported that two genetically related breeds, the Siamese and Himalayan, are at decreased risk of developing hyperthyroidism (Kass et al 1999, Scarlett et al 1988). There is also an increased risk of developing hyperthyroidism in cats fed almost entirely canned food and in those using cat litter (Kass et al 1999, Scarlett et al 1988). In addition, cats that prefer to eat certain flavours of canned cat food (fish or liver and giblet flavour) have a significantly increased risk of developing hyperthyroidism (Martin et al 2000). Because of this dietary association, several studies have attempted to implicate iodine in the cause or progression of the disease. The iodine content of cat food is extremely variable and often up to 10 times the recommended level (Johnson et al 1992, Mumma et al 1986) and it has been postulated that wide swings in daily iodine intake may somehow contribute to the development of thyroid disease. However, although serum free T4 concentrations are acutely affected by varying iodine intake, more prolonged ingestion has no apparent statistical effect (Kyle et al 1994, Tarttelin et al 1992).
There are many other goitrogenic compounds (eg, phthalates etc) that cats may be exposed to that could contribute to the development of adenomatous lesions. These may be of particular importance because most are metabolised by glucuronidation, a metabolic pathway particularly slow in the cat.
Thyroid autoimmunity
Initial studies in hyperthyroid cats suggested that autoantibodies (thyroid microsomal and antinuclear) were not uncommon and could be involved in the pathogenesis of the condition (Kennedy & Thoday 1998). Graves' disease, an important cause of thyrotoxicosis in humans, is an autoimmune disorder in which circulating antibodies (thyroid stimulating immunoglobulins (TSIs)) bind to TSH receptors and mimic thryotropin (thyroid stimulating hormone, TSH), thereby promoting thyroid hormone production and secretion. However, three separate studies, using two different techniques have failed to demonstrate such TSIs in hyperthyroid cats (Brown et al 1992, Kennedy et al 1989, Peterson et al 1987). Increased titres of thyroid growth stimulating immunoglobulins (TGIs) have been demonstrated in hyperthyroid cats (Brown et al 1992). These are also found in a wide variety of human thyroid disorders. In cats, there is no correlation between thyroid function and TGI activity in vitro and their role in the pathogenesis of hyperthyroidism remains unclear.
Toxic nodular goitre
Adenomatous thyroid tissue from hyperthyroid cats retains its histopathological appearance and continues to grow and function when transplanted into nude mice, confirming its autonomous nature (Peter et al 1987). In addition, thyroid cells from hyperthyroid cats, cultured in TSH-free media also continue to grow and function (Peter et al 1991). As such feline hyperthyroidism more closely resembles human toxic nodular goitre than Graves' disease. Somatic mutations of the TSH receptor gene are an important cause of toxic adenoma in humans. However, one research group, investigating the possibility of such a cause in cats, did not find any corresponding mutations between codons 480 and 640 of the feline TSH receptor gene, the area corresponding to the majority of human disease (Pearce et al 1997). Another study demonstrated decreased expression of a G-protein (specifically Gi2) that is normally involved in inhibition of a wide range of G-protein-dependent intracellular signalling processes, amongst them the signal to secrete thyroid hormones (Hammer et al 2000, Ward et al 2001). The genetic basis of this finding and its role in the pathogenesis of the disorder is unclear but it is likely that altered G-protein expression is somehow involved.
Thyroid tissue from hyperthyroid cats has also been examined immunohistochemically to identify expression of the oncogenes c-ras, bc12 and the tumour suppressor gene p53. Overexpression of the product of c-ras was demonstrated but there was no detectable staining for either bc12 or p53 in any cats. Gain-of-function mutations in this oncogene may therefore play a role in the aetiopathogenesis of the feline disease (Merryman 1999).