Wednesday, July 17, 2013

Top 10 Clinical Endocrinology ACVIM Abstracts, Part 3

Today’s post completes our look at some of the interesting research that was presented at the annual American College of Veterinary Internal Medicine Forum last month in Seattle, Washington.

I'm ending with 4 abstracts on thyroid disease, two of which I'm a coauthor. I apologize in advance for including my own work in this top list, but I'm biased! As always, if you disagree with any of my picks or my reviews, I welcome your comments.

Finally, if you can count, you will realize that I've reviewed 11 abstracts in my last 3 posts, rather than the "Top 10" as my title indicated.  To be honest, I couldn't decide which abstract to exclude from my list and the "Top 10" title sounded better!

Broome MR, Peterson ME. Use of L-thyroxine supplementation after radioiodine therapy helps blunt the worsening of azotemia in hyperthyroid cats with pre-existing kidney disease. J Vet Intern Med 2013;27:685-686.

Hyperthyroidism develops in cats secondary to 1 or more autonomously functional thyroid adenomas. The progressive thyrotoxicosis that ensues causes the chronic suppression of endogenous TSH release and ultimately the atrophy of normal thyroid tissue in these cats. This thyroid atrophy can lead to a period of transient hypothyroidism following curative radioiodine therapy. Once T4 values fall, circulating TSH levels increase, leading to reactivation of the previously suppressed and atrophied thyroid tissue in the large majority of these cats. Between 30-40% of cats with hyperthyroidism have preexisting chronic kidney disease (CKD). Iatrogenic hypothyroidism has been shown to contribute to worsening of azotemia and shortened life expectancy in cats with preexisting CKD (Williams et al, J Vet Intern Med. 2010;24:1086). In hyperthyroid cats with concurrent azotemia, the transient hypothyroidism that follows radioiodine therapy may contribute to additional renal function decline and worsening of the cats’ CKD stage. The purpose of this study was to evaluate if prevention of this transient hypothyroidism would blunt the progression of azotemia commonly seen following the resolution of thyrotoxicosis in these cats with preexisting CKD. In this study, 195 hyperthyroid cats with concurrent CKD (IRIS stage 2 to 3) were treated with radioiodine (range, 1-10 mCi, median, 3 mCi). Of the 195 CKD cats, 85 cats were discharged on L-T4 (0.1 mg, PO q24 h), whereas the remaining 110 cats served as controls (no L-T4 supplementation). In both groups, total T4, BUN, and creatinine levels were recorded before treatment and then again at 1, 3 and 12 months following radioiodine therapy. Following successful radioiodine therapy, both groups of cats with preexisting CKD demonstrated increases in serum BUN and creatinine levels that gradually progressed over the 12-month period (Table 1). However, the percent rise in median creatinine concentrations in the 85 cats treated with L-T4 was significantly less than the rise in the 110 cats not supplemented with L-T4 (12.5% vs 33.3%; P < 0.05). These results suggest that L-T4 supplementation of radioiodine-treated cats with CKD may help limit progression of azotemia, presumably by avoiding the transient hypothyroidism that commonly develops after radioiodine therapy. 

Comments—Untreated hyperthyroidism can lead to the development of chronic kidney disease (CKD) by many mechanisms (1-3). Between 30-40% of cats with hyperthyroidism have pre-existing CKD at time of diagnosis of the thyroid condition (3,4).

Treatment of the hyperthyroid state can worsen azotemia, but this worsening may be related to degree of lowering in circulating T4 and T3 concentrations. Iatrogenic hypothyroidism has been shown to contribute to worsening of azotemia and shorten the life expectancy in cats with pre-existing CKD (5). In hyperthyroid cats with concurrent azotemia, the transient hypothyroidism that follows radioiodine therapy may contribute to additional renal function decline and worsening of the cats’ CKD stage (6).

The Bottom Line— The results of this study suggest that L-T4 supplementation of radioiodine-treated cats with concurrent CKD may help limit progression of azotemia by avoiding the transient hypothyroidism that commonly develops after radioiodine therapy.  In agreement with our feline studies, recent reports also show that thyroid hormone replacement can help attenuates the decline of renal function in CKD patients with subclinical or overt hypothyroidism (7-9).

Further research is in progress, but short-term L-T4 supplementation has become an integral part of the protocol for treating hyperthyroid cats with renal disease at our practice.

  1. Basu G, Mohapatra A. Interactions between thyroid disorders and kidney disease. Indian J Endocrinol Metab 2012;16:204-213. 
  2. Mariani LH, Berns JS. The renal manifestations of thyroid disease. J Am Soc Nephrol 2012;23:22-26. 
  3. Williams TL. Is hyperthyroidism damaging to the feline kidney? PhD thesis, Department of Veterinary Clinical Sciences: Royal Veterinary College,  University of London, 2013.
  4. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743.
  5. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092. 
  6. Peterson ME, Broome MR. Radioiodine for feline hyperthyroidism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013;in press.
  7. Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2012;97:2732-2740. 
  8. Hataya Y, Igarashi S, Yamashita T, et al. Thyroid hormone replacement therapy for primary hypothyroidism leads to significant improvement of renal function in chronic kidney disease patients. Clin Exp Nephrol 2012. 
  9. Shin DH, Lee MJ, Lee HS, et al. Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism. Thyroid  2013;23:654-661. 

              Chciuk K, Behrend EN, Martin L, et al. Evaluation of thyroid-stimulating hormone, total thyroxine,and free thyroxine concentrations in 65 hyperthyroid cats receiving methimazole therapy. J Vet Intern Med 2013;27:691-692.

              Iatrogenic hypothyroidism following treatment of feline hyperthyroidism can have deleterious effects on renal function. Serum total thyroxine concentration (T4) is commonly used to evaluate therapy, but no study has examined the use of both serum free thyroxine by equilibrium dialysis (FT4ed) and thyroid-stimulating hormone (TSH) concentrations. The purpose of this study was to compare the ability of T4, FT4ed, and TSH concentrations to diagnose treatment-induced hypothyroidism in hyperthyroid cats receiving methimazole. We hypothesized that FT4ed would identify more cats with iatrogenic hypothyroidism as compared to T4. A total of 65 samples from previously-diagnosed hyperthyroid cats receiving methimazole therapy and with T4 concentrations <48 nmol/L were included. Samples had been submitted to the diagnostic laboratories at Auburn University (n = 22) and Michigan State University (n = 43). T4, FT4ed and TSH concentrations were measured via assays previously validated for use in cats. Correlation was tested via a Spearman Rank Order test. Significance was set at the p < 0.05 level. The median (range) T4, FT4ed, and TSH concentrations were 20 (3-48) nmol/L, 20 (3-57) pmol/L, and 0.1 (.08-9.1) ng/ml, respectively. Overall, 23 cats (35%) had an elevated TSH concentration (>0.30 ng/ml). For cats with elevated TSH concentrations, median T4 and FT4ed concentrations were 11 (3-40) nmol/L and 12 (3-35) pmol/L, respectively. Cats with normal TSH concentrations (<0.30 ng/ml) had median T4 and FT4ed concentrations of 23.5 (5-48) nmol/L and 27.0 (6-57) pmol/L, respectively. The percentage of cats with an elevated TSH concentration in combination with a low T4 (<10 nmol/L), FT4ed (<10 pmol/L), or both T4 and FT4ed concentration were 17%, 12% and 11%, respectively. Eleven cats (17%) had an elevated TSH despite normal T4 and FT4ed concentrations. One cat (1.5%) had a normal TSH despite low T4 and FT4ed concentrations. Of 24 cats with T4 concentrations between 10-25 nmol/L (low end of the reference range 10 nmol/L), 7 (29%) had an elevated TSH. Of 26 cats with FT4ed concentrations between 10-25 pmol/L (low end of the reference range 10 pmol/L), 11 (42%) had an elevated TSH. A significant positive correlation was found between T4 and FT4ed concentrations (p < 0.001). A significant negative correlation was found between both T4 and TSH concentrations (p < 0.001) and between FT4ed and TSH concentrations (p < 0.0001). The data suggest that FT4ed does not identify more cats with iatrogenic hypothyroidism as compared to T4. As some cats had an elevated TSH concentration despite having a normal T4 or FT4ed, further investigation may be warranted.

              Comments—Iatrogenic hypothyroidism can develop during therapy with antithyroid drugs (1-3), after thyroidectomy (1,3,4), or following radioiodine therapy (1,5-8). Although early reports suggested that clinical signs associated with severe iatrogenic hypothyroidism in cats were uncommon and that most cats did not require treatment, it is now realized that milder degrees of iatrogenic hypothyroidism are relatively common and that these cats may benefit from thyroid replacement therapy (especially if concurrent CKD is present) (3).

              Many cats with iatrogenic hypothyroidism will develop high serum TSH concentration as measured by the cTSH assay (1,3,9). In a cat suspected of hypothyroidism, the finding of a high serum TSH value in combination with low serum concentrations of total or free T4 can generally be considered diagnostic for hypothyroidism.

              As reported in this study, high serum TSH values are common (over a third) in hyperthyroid cats treated with methimazole. However, 17% of these cats had a high TSH value despite completely normal T4 and free T4 concentrations.

              The Bottom Line— As reported in this study, it is not uncommon for high serum TSH to develop in cats treated for hyperthyroidism despite maintenance of completely normal concentrations of T4, free T4, or both (9). This brings up a number of questions that still remain unanswered.

              Do these cats really have mild degrees of hypothyroidism? Is this a form of subclincal hypothyroidism, as reported in man (10-11)? Should the methimazole dosage be reduced or should they be treated with levothyroxine despite their normal circulating thyroid hormone values? Or are these serum TSH values falsely high, simply representing a TSH laboratory artifact? At this time, the answers to these questions remain unknown.

              1. Graham P. Measurement of feline thyrotropin using a commercial canine-specific immunoradiometric assay. J Vet Intern Med 2000;14:342.
              2. Fischetti AJ, Drost WT, DiBartola SP, et al. Effects of methimazole on thyroid gland uptake of 99mTC-pertechnetate in 19 hyperthyroid cats. Vet Radiol Ultrasound 2005;46:267-272.
              3. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092.
              4. Welches CD, Scavelli TD, Matthieson DT, et al. Occurrence of problems after three techniques of bilateral thyroidectomy in cats. Vet Surg 1989;18:392-396.
              5. Meric SM, Rubin SI. Serum thyroxine concentrations following fixed-dose radioactive iodine treatment in hyperthyroid cats: 62 cases (1986-1989). J Am Vet Med Assoc 1990;197:621-623.
              6. Jones BR, Cayzer J, Dillon EA, et al. Radio-iodine treatment of hyperthyroid cats. N Z Vet J 1991;39:71-74.
              7. Peterson ME, Becker DV. Radioiodine treatment of 524 cats with hyperthyroidism. J Am Vet Med Assoc 1995;207:1422-1430.
              8. Nykamp SG, Dykes NL, Zarfoss MK, et al. Association of the risk of development of hypothyroidism after iodine 131 treatment with the pretreatment pattern of sodium pertechnetate Tc-99m uptake in the thyroid gland in cats with hyperthyroidism: 165 cases (1990-2002). J Am Vet Med Assoc 2005;226:1671-1675.
              9. Peterson ME. Diagnostic testing for feline thyroid disease: hypothyroidism. Compend 2013; 35: E1-E6.
              10. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76-131.
              11. Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat and how. Drugs 2012;72:17-33. 

              Gallagher B, Mooney CT. Prevalence and risk factors for hyperthyroidism in Irish cats from the greater Dublin area. J Vet Intern Med 2013;27:689.

              Hyperthyroidism is a common feline endocrinopathy. However, prevalence varies widely with geographical location. Anecdotal reports suggest this disorder is rare within the Irish feline population. The aim of this study was to document the prevalence of hyperthyroidism in geriatric cats in the greater Dublin area of Ireland and to assess risk factors for development of the disease. Practitioners within the study area were requested to select cats presenting to their clinic aged 10 years or older, in which blood sampling was being performed for geriatric health screening or clinical investigation purposes, independent of suspected thyroid status. Serum samples were submitted to University College Dublin Diagnostic Endocrine Laboratory for total thyroxine (T4) measurement by a chemiluminescent method (Canine Total T4, Immulite 1000, Siemens). Cats were classified as hyperthyroid, equivocal or euthyroid based on a total T4 concentration of > 60 nmol/L, 30–60 nmol/L or <30 nmol/L, respectively. Repeat measurement of total T4 after 4-6 weeks, or free T4 by equilibrium dialysis was recommended in all equivocal cases. Animals receiving treatment for hyperthyroidism were excluded. In order to fulfill the study criteria a questionnaire completed by the client and veterinarian detailing historical and physical information was requested with each submission. Associations between different categorical variables were analysed by Chi- square or Fisher’s exact test. Total T4 concentrations in hyperthyroid animals reported to have palpable or non-palpable goitre were compared using the Mann-Whitney U test. A P-value of < 0.05 was considered statistically significant. A response rate of 77% from 45 targeted practices was achieved. Samples were submitted from 508 cats; 181 male, 238 female and 89 unreported. Thyroid hormone analysis identified 107 (21%) hyperthyroid, 53 (10%) equivocal and 348 (69%) euthyroid cases. Weight loss (P < 0.0001), polyphagia (P < 0.0006) and dyspnoea (P = 0.0370) were significantly associated with a diagnosis of hyperthyroidism. Vomiting or diarrhoea was not (P = 0.684 and P = 0.2758 respectively). Cats with goitre were more likely to be diagnosed as hyperthyroid (odds ratio (OR) = 2.958, 95% CI = 1.778 – 4.920) compared to those without. Tachycardia (P = 0.0018), but not the presence of a cardiac murmur (P = 0.1892) had a significant association with hyperthyroidism. Increasing age was the only significant risk factor (P = 0.0015). A relationship between sex, breed, vaccination status, parasite control, environment or preferred food flavour was not established. There was no significant difference between the total T4 concentration of hyperthyroid cats with or without reportedly palpable goitre (P = 0.3316). Hyperthyroidism is not uncommon in Irish cats. Historical and physical examination findings including weight loss, polyphagia, dyspnoea, goitre and tachycardia are significantly associated with hyperthyroidism. Surprisingly age was the only recognised risk factor for the development of the disease. The identified but unexplained inability of the study practitioners to palpate goitre in hyperthyroid animals over a range of total T4 concentrations may explain the previously perceived low prevalence of this condition in Ireland.

              Comments—In this study, a large population of Irish geriatric cats were screened for hyperthyroidism. Although it has been thought that feline hyperthyroidism was a rare condition in Ireland (1), this study found that that 107 (21%) of the 508 screened cats were definitely hyperthyroid and another 52 cats (10%) were borderline hyperthyroid.

              The Bottom Line— Hyperthyroidism is an extremely common condition in older cats, occurring in about 10% of cats older than 9 years of age (1-3).  Even in a country, such as Ireland, where hyperthyroidism has traditionally been considered to be a rare condition, this study proves that this is not the case.

              Since all hyperthyroid cats develop a thyroid tumor as part of their disease, thyroid palpation should be incorporated into the routine physical examination for all cats, especially for geriatric cats (2,4). Even if a thyroid nodule cannot be palpated, annual thyroid screening is recommended for all cats older than 10-years of age to help in earlier detection of this condition.

              1. Caney S. Advances in our understanding of feline hyperthyroidism. Vet Ireland J 2012;2:450-454.
              2. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
              3. Peterson M. Hyperthyroidism in cats: What's causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 2012;14:804-818. 
              4. Peterson ME. Diagnostic testing for hyperthyroidism in cats: more than just T4. J Fel Med Surg 2013: in press. 

              Broome MR, Peterson ME. Ectopic sublingual thyroid neoplasia in the dog: 25 cases (1995-2012). J Vet Intern Med 2013;27:685-686. 

              Thyroid embryology defines the normal migration of thyroid tissue from its origin as an epithelial proliferation in the floor of the pharynx at the base of the tongue (ie, the foramen caecum) along the path of the thyroglossal tract. The embryologic path of the thyroid gland includes the tongue and hyoid apparatus. Failure to associate fully with the embryologic aortic sac leads to the incomplete descent of the thyroid and the presence of sublingual ectopic thyroid tissue. Ectopic thyroid tissue in this location can occasionally become neoplastic. Two previous reports describe a total of 9 cases of sublingual thyroid carcinoma in dogs (JAVMA 1989;195:1606; ASVS Veterinary Symposium 2011;217). No reports of benign thyroid neoplasia developing in this location have been identified. Medical records reviewed between 1995-2012 revealed 519 dogs with thyroid carcinoma, confirmed by thyroid scintigraphy. During that period, 25 dogs with ectopic sublingual thyroid neoplasia were identified (5% of all thyroid carcinoma cases). The dogs ranged in age from 4-15 years (median, 9 yrs), with 13 neutered males and 12 spayed females. Breeds included mix (6 dogs), Golden Retriever (4), American Staffordshire Terrier (2), and Labrador Retrievers (2). Eight dogs (32%) had high serum T4 levels, consistent with hyperthyroidism. Twelve dogs had normal total T4 levels, 4 dogs had low values, and 1 dog’s T4 value was not available. Four dogs had pulmonary metastases confirmed by scintigraphy and 4 had concurrent cervical disease, and 1 dog had both concurrent cervical disease and pulmonary metastasis. Seventeen dogs had histopathologic confirmation and 7 dogs had cytologic confirmation of thyroid malignancy. Fourteen dogs were treated with surgery; of these, 9 had excision of the basihyoid bone. All tolerated surgical intervention, including hyoid bone resection. Gross surgical excision of thyroid disease was confirmed scintigraphically in 7 dogs, 5 of which required hyoid bone resection. Thirteen dogs were treated with high-dose radioiodine (dose range, 40-130 mCi; mean, 95 mCi). No lasting complications following radioiodine were identified. Radioiodine therapy resulted in a marked response, as measured by percent decreased radionuclide uptake (range 42-100%, mean, 80%) in 8 dogs with gross disease. Radioiodine was also successful in ablating normal thyroid tissue in 3 dogs without persistent gross disease. Nine dogs were treated with both surgery and radioiodine. Surgery was performed prior to radioiodine therapy in all 9 dogs. One dog with a thyroid tumor deemed initially surgically unresectable had a successful surgical excision following radioiodine therapy. Conclusions: In dogs, ectopic sublingual thyroid carcinoma is not uncommon. Surgical excision of the basihyoid bone is often indicated for gross resection of laryngeal thyroid carcinoma and is well tolerated. Adjunctive high dose radioiodine therapy is indicated for cases of incomplete surgical excision of local disease or when metastatic disease is confirmed scintigraphically.

               Comments—Numerous cases of ectopic cranial mediastinal and heart base thyroid carcinomas in the dog have been reported (1-3). Ectopic thyroid tissue higher up in the sublingual area is also not rare, and this tissue may also become neoplastic. Until this report, however, only 9 cases of sublingual thyroid carcinoma have been reported in the dog (4,5).

              The Bottom Line— In dogs, ectopic sublingual thyroid carcinoma is not uncommon, diagnosed at a rate of 5% of all thyroid carcinomas in our practice. These results reveal that partial surgical excision of the hyoid apparatus is generally indicated for gross resection of sublingual thyroid carcinoma, which is well tolerated.

              High dose radioiodine therapy may be helpful in treating those dogs with overt hyperthyroidism (about 30% of the dogs of this report were hyperthyroid.cases).  Adjunctive high dose radioiodine or chemotherapy therapy may also be useful with incomplete surgical excision and/or with metastatic or multicentric disease.

              1. Birchard SJ, Roesel OF. Neoplasia of the thyroid gland in the dog—a retrospective study of 16 cases. J Am Anim Hosp Assoc 1981;17:369–372. 
              2. Liptak JM, Kamstock DA, Dernell WS, et al. Cranial mediastinal carcinomas in nine dogs. Vet Comp Oncol 2008;6:19-30.  
              3. Stassen QE, Voorhout G, Teske E, et al. Hyperthyroidism due to an intrathoracic tumour in a dog with test results suggesting hyperadrenocorticism. J Small Anim Pract 2007;48:283-287. 
              4. Donner G.S. Common head/neck tumors in uncommon locations —hyoid apparatus, nasal septum. In: Conference Proceedings American College of Veterinary Surgeons. Chicago, Ill, 2011;217-220.
              5. Lantz GC, Salisbury SK. Surgical excision of ectopic thyroid carcinoma involving the base of the tongue in dogs: three cases (1980-1987). J Am Vet Med Assoc 1989;195:1606-1608. 

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