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Hair thinning in a hypothyroid dog. Dermatological abnormalities occur in around 80 per cent of cases

Recent developments in the diagnosis RICHARD DIXON of canine hypothyroidism

HYPOTHYROIDISM is a relatively common endocrine disorder of dogs, with a reported prevalence of between 0.2 and 064 per cent compared with estimates of 0*0005 to 1.5 per cent for canine diabetes mellitus. However, accurate confirmation of the diagnosis of this disease is difficult as the clinical signs vary in terms of severity, type and number and often mimic other common conditions. In addition, numerous diagnostic tests are available with a wide range of recommendations for their use and interpretation. This article summarises the current understanding of canine hypothyroidism and outlines a practical clinical approach to its diagnosis.
Richard Dixon graduated from Glasgow in 1993. After a spell in small animal practice in Hull, he returned to Glasgow University as a small animal house physician. During this time he was awarded the RCVS certificate in veterinary radiology and developed his interests in small animal clinical biochemistry and endocrinology. He was recently awarded a PhD for investigations into the diagnosis of canine hypothyroidism. He is currently working as a veterinary clinical pathologist in Devon, specialising in endocrinology.

AETIOLOGY Hypothyroidism is a clinical syndrome that results from inadequate circulating thyroid hormone concentrations. The most commonly recognised underlying cause of hypothyroidism is lymphocytic thyroiditis in which the thyroid gland becomes progressively infiltrated with lymphocytes, macrophages and plasma cells. Thyroid tissue is slowly destroyed, progressively reducing the capacity for hormone production. Although the under-

lying cause of thyroiditis is not fully understood, a breed predisposition has been demonstrated (Nachreiner and others 2000) and, in one series of borzois studied, an autosomal recessive mode of inheritance was proposed (Conaway and others 1985). Another common thyroidal pathology in canine hypothyroidism is idiopathic atrophy in which the thyroid becomes infiltrated with adipose and fibrous connective tissue. Hypothyroid dogs with thyroiditis tend to be younger than those without thyroiditis and it has

The principal product of the thyroid gland is thyroxine (T4) although a small amount of tri-iodothyronine CT3) is also produced. The secretion of T4 and T3 is stimulated by the release of the pituitary glycoprotein thyrotropin (thyroid stimulating hormone, cTSH). Thyrotropin secretion is stimulated by hypothalamic thyrotropin-releasing hormone (TRH) secretion. Both T4 and T3 exert a negative feedback effect on cTSH and TRH synthesis and secretion. Thyroxine exists in the circulation as both proteinbound (99.9 per cent) and free hormone (0.1 per cent). In peripheral tissues, T4 is converted to the more metabolically active T3. Circulating total T4 concentrations fluctuate throughout the day, and 'subnormal' total T4 concentrations are in fact
a common finding in perfectly healthy dogs. However, there is no circadian rhythm to canine T4

secretion.
328

Normal regulation of canine thyroid function

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been suggested that idiopathic atrophy may be the end stage of lymphocytic thyroiditis. Furthermore, euthyroid dogs with thyroiditis tend to be younger than both these groups. This is consistent with a theory of progression from 'thyroiditis but euthyroid', through 'thyroiditis and hypothyroidism' to 'hypothyroidism without thyroiditis' (Nachreiner and others 2000). Clinical hypothyroidism only develops after approximately 75 per cent of the tissue is destroyed. Thyroid pathology can therefore be present for months or years before clinical signs of hypothyroidism become apparent.

SIGNALMENT

Spontaneous hypothyroidism is most frequently recognised in medium to large breeds, particularly labrador retrievers, spaniels, dobermanns, Shetland sheepdogs and setters. It typically affects middle-aged dogs but tends to present at a younger age in the predisposed breeds. It is rare in dogs less than two years of age although the underlying pathology obviously starts before clinical signs become apparent. Both entire and neutered males and females are affected.
CLINICAL SIGNS Thyroid hormones perform myriad functions involving multiple tissues and organ systems. Deficiency of thyroid hormones can therefore result in a variety of presenting signs (see table below). Contrary to popular belief, polyuria and polydipsia are rarely (if ever) due to hypothyroidism, and their presence should generally direct the investigation elsewhere. Metabolic abnormalities occur in over 80 per cent of cases. These include lethargy, weight gain or obesity and exercise intolerance. Dermatological abnormalities occur in around 80 per cent of cases and include hair thinning, particularly affecting the flanks, tail and thighs, dry or poor coat quality, skin hyperpigmentation, seborrhoea and superficial pyoderma. Metabolic and dermatological signs occur concurrently in approximately 70 per cent of cases. Less common signs include neuromuscular, reproductive, ocular, gastrointestinal and cardiovascular abnormalities. Laryngeal paralysis, megaoesophagus, peripheral vestibular disease, cranial nerve disorders,

Lymphocytic thyroiditis -

behavioural abnormalities and seizures have all previously been attributed to hypothyroidism in the literature. However, the variation in assessment of thyroidal status in many of these reports and the universally erratic response to thyroid hormone replacement therapy leaves the role, if any, of thyroid dysfunction in these conditions to be clarified. It is probable that thyroid disease is associated with a small percentage of such cases, but hypothyroidism is certainly an uncommon cause of each. Similarly, while a small number of cases of female infertility may be associated with hypothyroidism, it is an uncommon cause of this problem. Recently, diarrhoea secondary to small intestinal bacterial overgrowth has also been reported as a feature of hypothyroidism.
DIAGNOSIS The diagnosis of hypothyroidism is undeniably problematic. First, none of the individual clinical signs of hypothyroidism are pathognomonic for the disease and are often associated with other diseases. Secondly, while there are a number of characteristic laboratory abnormalities, none are specific and many parameters are affected by non-thyroidal illness (NTI) and a variety of medica-

the most common cause of canine hypothyroidism

Extensive hair loss caused by hypothyroidism

wl

Category
Metabolic

Clinical sign Lethargy Weight gain Exercise intolerance Weakness Cold intolerance

Frequency
Very common Very common Very common Common Occasional

Dermatological Hair thinning Poor quality coat Hyperpigmentation Pyoderma Seborrhoea

Otitis Skin thickening

Very common Common Common Common Occasional Occasional Occasional

Other

Neuropathies Poor fertility

Diarrhoea

Occasional Occasional Occasional

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tions that have often been used prior to diagnostic testing. As a result of the diagnostic difficulties, and the ease and apparent advantages of trial therapy, the 'presumptive diagnosis' of hypothyroidism and the use of thyroid hormone supplementation is widespread. However, this approach causes a number of long-term difficulties (see later) and, while trial therapy has a role to play in the confirmation of hypothyroidism in a few rare cases, its widespread use should be discouraged. Despite the absence of a 'perfect' test, a number of practical steps can be taken to maximise the clinician's accuracy and limit the use of the therapeutic trial, and these are discussed below.

ENDOCRINE TESTS
Total thyroxine Circulating total T4 concentration is invariably decreased in dogs with hypothyroidism. However, many nonthyroidal factors will also decrease total T4 and fluctuations below the reference range regularly occur in healthy dogs. In addition, a decreased total T4 concentration is common in NTI and is associated with certain drug therapies. Consequently, a subnormal total T4 concentration does not confirm hypothyroidism. However, total T4 measurement is a useful method for ruling out hypothyroidism as very few hypothyroid dogs have reference range values.

PRE-EVALUATION
The first step in confirming hypothyroidism is not the investigation of thyroidal status but, rather, the evaluation of non-thyroidal factors, including recent drug therapies and the investigation of NTIs that are most commonly associated with the presenting signs. Various drugs widely used in veterinary practice interfere with thyroid function tests. Specifically, steroids decrease thyroid hormone concentrations and may also decrease cTSH secretion; sulphonamide-containing drugs directly inhibit thyroid hormone synthesis and may even cause a temporary reversible state of hypothyroidism; and barbiturate anticonvulsants decrease both total and free T4 concentrations. Thyroid hormone test results should therefore be interpreted cautiously in dogs that have received these medications. If possible, assessment of thyroid function should be postponed for around six weeks after such medication has been stopped (or as long as is practical, bearing in mind the duration and dose of the therapies that have been used). Many NTIs have been shown to cause a reduction in circulating thyroid hormone concentration, and the recovery phase of NTI has been associated with a temporary increase in circulating cTSH values. Spontaneous hyperadrenocorticism is of particular concern as many of the clinical features of this disease are similar to hypothyroidism, and profound (but reversible) suppression of thyroid function frequently occurs. The exclusion of NTI and assessment of recent drug usage at the outset may completely eliminate the need for subsequent evaluation of thyroid status. If pre-evaluation excludes the most likely alternative diagnoses, then investigation of hypothyroidism should be performed. In such cases where thyroid testing is required, adequate pre-evaluation allows a much more confident interpretation of the results.

andsenitive Marker for

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ROUTINE ABNORMALITIES
There are a number of well recognised routine clinicopathological abnormalities associated with hypothyroidism. Hypercholesterolaemia and hypertriglyceridaemia are reported in approximately 75 to 80 per cent of cases and a mild non-regenerative anaemia is also common. Unfortunately, these abnormalities are equally, if not more, common in dogs with NTI. Recently, studies comparing the routine biochemical and haematological results from hypothyroid dogs and those with clinically similar illnesses demonstrated that the most reliable abnormalities that specifically helped identify hypothyroidism were decreased red cell count, increased y-glutamyl transferase, hypercholesterolaemia and neutropenia (Dixon and others

Endogenous thyrotropin (cTSH) Decreased circulating thyroid hormone concentrations result in reduced negative feedback on the pituitary gland. Circulating cTSH concentration is therefore theoretically increased in primary hypothyroidism. The combination of reduced T4 and increased cTSH values is highly specific for hypothyroidism. However, approximately 20 per cent of hypothyroid dogs have reference range cTSH values. Dogs with this combination of test results pose the greatest diagnostic dilemma as subnormal total T4 but reference range cTSH values are typical of NTI. In this situation, if the index of suspicion for hypothyroidism remains high, the tests outlined below are appropriate next steps. Abnormally high cTSH values can occur in euthyroid dogs receiving sulphonamide therapy or during recovery from NTI, although total T4 values are usually normal. The use of the T4 to cTSH ratio has also been employed but assessment of the individual values is of principal importance. On balance, therefore, combined total T4 and cTSH measurement is an economic and fairly reliable approach, especially if pre-evaluation has been performed.

1999).
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Free T4 Free T4 is the metabolically active fraction of T4 and its measurement is widely acknowledged to more closely reflect tissue thyroidal status than total hormone determination. Free hormone is less affected by NTI and various drug therapies than total T4, although barbiturate anticonvulsant therapy has recently been shown to decrease free T4 concentrations in dogs (Muller and others 2000) and severe NTI can decrease free T4 concentrations in humans. Free hormone is'potentially of particular value in those dogs with subnormal total T4 and reference range cTSH results because it helps distinguish genuine hypothyroidism from NTI. However, measurement of free T4 has been complicated by the various assay methodologies available, some of which are unreliable when used in patients with NTI. The recommended 'dialysis' method for free T4 measurement is now commercially available from several UK diagnostic laboratories. The use of traditional 'analogue' assays for free T4 estimation offers no additional diagnostic information over total T4 measurement and is not recommended.

surement of TgAb confirms the presence of thyroid pathology but does not provide an assessment of thyroidal function. However, the principal limitation of TgAb measurement is that not all dogs with hypothyroidism have lymphocytic thyroiditis and, therefore, while a positive TgAb result provides strong evidence of thyroid disease, a negative result cannot rule it out. Epidemiological analysis of the prevalence of TgAb has shown a peak in dogs of up to four to six years of age, which subsequently declines, presumably as the thyroid tissue becomes ablated and the antigenic stimulus decreases.
TSH stimulation

The bovine TSH response test is widely acknowledged to be the single best test for the assessment of thyroidal status. The test provides an indication of thyroidal function but, more importantly, functional reserve capacity. Approximately 10 per cent of cases give equivocal results with this test and in these dogs it is usually appropriate to wait and reassess after a period of several months. However, bovine TSH is no longer widely available in practice and its use is largely restricted to research institutions. The use of recombinant human TSH has recently been evaluated (Sauve and Paradis 2000) and may also prove to be useful, but at this time further studies are required.
TRH stimulation

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Thyroglobulin antibodies Thyroglobulin antibodies (TgAb) are produced during the development of lymphocytic thyroiditis. Until 1997, the commercially available methods for TgAb estimation were based on human methods; they were unreliable and false positive results were common. However, a more specific assay for canine TgAb is now commercially available and has recently been evaluated (Nachreiner and others 1998, Dixon and Mooney 1999). The mea-

Due to the limited availability of bovine TSH, the TRH response test has been used as an alternative method of assessing thyroidal reserve. Dogs with hypothyroidism fail to demonstrate a response to TRH administration, and a 'normal' response excludes hypothyroidism. However, with the recent availability of a reliable free T4 assay, both of these conclusions can now usually be reached using the tests outlined above. In addition, failure to respond to TRH does not confirm hypothyroidism, and is a frequent finding in both healthy dogs and, more commonly, those affected by NTI. The TRH response test therefore offers few, if any, advantages over the basal tests now available, and is no longer recommended by the author.
cTSH response to TRH In humans with primary hypothyroidism, the TSH response to TRH administration is increased, presumably as a consequence of thyrotroph up-regulation. In contrast, NTI typically blunts the TSH response to TRH. However, in dogs this test offers no advantages over the routine basal tests outlined above.

THERAPEUTIC TRIAL
PPRIPW
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The use of a therapeutic trial to confirm hypothyroidism is, initially at least, an appealing proposition. It avoids the diagnostic problems outlined above and adequately treated hypothyroid dogs invariably respond excellently. However, exogenous thyroid hormone suppresses cTSH and therefore endogenous thyroid function. Hence, once thyroid hormone replacement therapy has been instituted, assessment of thyroidal status at a later date becomes profoundly confusing. Furthermore, the administration of thyroid hormone to dogs with 'normal' thyroid function is known to have physiological effects that are easily interpreted as a clinical response. For example, increased hair growth has been proven to occur in euthyroid dogs receiving thyroid hormone. Nevertheless, it is
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",
i

(right) 'Rat tail' appearance in a hypothyroid dog before thyroxine treatment. (far right) The same tail after treatment

cleari th'at adeqUately treated hypotiioild dlogs deimlonlstrate a marked clinical improx ement anid tailuIrC to completely respond caLin thelcfor-c bc consider-ed Lsetul cV idence ol' a misdilatiosis. On balance, the use of triall thel`apy shouldC bc reserxed foi cases in wxhich thiere aLre nio diagnlostic .alternatixves. Oxneirs oft' thiese animals Should he made axwarec
o' the

to

elnsLIrIe adleqUate hloodl hoit none cotienitriations. B31hi(1

Samples tIo tIioniitorinig peak totaLl T4 aud cTSH coiicc\IoLIIS p1oSt- pill andI thCI-CtratiotiS mu1LSt he collecctcl SiX toteC iii1OriiiIg tlet .laps iS LuSual>1 tIlh imost coixeniciIt. Fli
peak circulating total I coticetit tioH ShoUld bc abox e (i) to 70) i p ImIate1 the tiormI 1al ralIge. \ aIeIS Of appt nniillo/litle alre LILIallV assoliated xw ithi excellct clili cll cotiti-ol peak total T4 'oneeitrtitis (i less than11 *1

limitations that

may

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ike

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patient man iemieit more difficuilt, patticularlVn if the ciinical rCslpon1se is, as is often tIle CaSC, equixocVal. If triial theriapy is used as a diagllostic tool, it is recolinmiienided thait, it there is a good clinical iesponse. thera-1py should be temlporari-Ix stopped. If thele is a- el meacal contraindication to stopping treatment (eg. thc prcscnce of

tiiol/litre itidicate the iedlot alti ivi ilcase

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conCuIrr1elIt panicreatitis). the othlt conIditionI shou0ld be ic replacemenit therapy IMt1eACted and thy roid lioriioe stopped xhen appropriate. If clinical signs ot IwpothyroidisIII teeiL. thenl treaCtm11enIt should he Ie instituted: it the clinicatl aIbn-orm.alities do 1not Ietuilrn thell thele is obh iouIslN nio nieed to e -n1stitteC thlCI aplry
TREATMENT AND THERAPEUTIC MONITORING

sglit ltiV lo0Iget -ternill thelCIapeuLtic colltrol. I iipr-oxe xx ithill a niltter Metabolic sitgs t'l-CIreLqCltit' of dla s otf stat tilLt ti attimilt tIlathe CS1pou1Se is Li-all \ d-;ilamtic. DcrmiatoloLical abuotrmalItics take lottLcc to imiiproxve, bit Milost dooS .ic CsSciitaillx> clilocallx' 1t0iltiiA xx ithilt 2 wc!ck,s ()f statiitigL, thieLt ap>. A less thiall Citt11
atio pleCtC ICeSpOtisc s1i0oildl protlipt CotAisldrlt

of ci liici

iMaCleCteIL thict irap

PROGNOSIS

(i a

Ivni scliagiiosis

pirogilosis tf cxcelleiit. Thict-c

The

H>pothy roidism is ulidoLihtedly otie of the imiost satisfyeildocrinlie dliseaLses to tielat. Otice daily thier apy I-CsLilts in a good clinical responise in x irtUally all eases. xw ithi very fexw animials requinl-gll tw ice daily medication. A startinm dose of 0)02 m,/ko tlhioxine (Soloxine: ima.niltflCturedl in the USA by Daniels andcldistributed in the UK bNy Aniiolds) should be Lsed. Approxinmately hallf of allI Lst ImIen t t ea.ses wx il reqire a suhsequLenit dose adCtju aehiexe optimal thetrapeltie coneentirations. ThelLpuCtiC mon0itoulill shoctld bc peftor-niiet xwithin o afitcr chanigLe i 0a ill dosagc twx o xxeeks of statrtino thcrl-.lNr
ing
334

xx elI ti catecl Ii>p(ot1vl-olch c(logs is oV cx luce to suIggest that life cX\pCCtalie>\ iS alteletcl. aticl tIlh ClLal it> Oi lite should be
iis

cri CLoocl. Re1gu1lar rulot1itoltimtl. at vIi less thall Si\ moutith>vi tittcrsals is ceomiitleclICICI. ITrcatcdl dioeLs maI.lx be proie to titetl ittetit sceclacr xhactcrt ail ilifecoti'S I >'lk aticl cpisodes of pv> o(cltv1ia ill pat ticuLlatl. A\lth1oLiLg f (itch clos ate a! so potetltially at riisk ctICe01iiiti01c. Ii> pot Old of d1cx clopilig othlct iiiiLHiC-mctliediatd ciuclocriniopatlhiics. I s ticSi "I sec (lil ies ii0st c0111111011a glaticl; at k> ogn pit1CilI iII tLOL's .1'C ( IV I-CCoLIIIiSCCI j)1VoLn1;Ll(tlCl A'l1V1ClO11C01tS 1lN loth>tI oitchisili ill associatiou xx ithi diabctes iilillttlts oi

pi>ilac1 icl1octil ticisili.

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References CONAWAY, D. H., PADGETr, G. A. & NACHREINER, R. F. (1985) The familial occurrence of lymphocytic thyroiditis in borzoi dogs. American Journal of Medical Genetics 22, 409-414 DIXON, R. M. & MOONEY, C. T. (1999) Canine serum thyroglobulin autoantibodies in health, hypothyroidism and non-thyroidal illness. Research in Veterinary Science 66, 243-246 DIXON, R. M., REID, S. W. J. & MOONEY, C. T. (1999) Epidemiological, clinical, haematological and biochemical characteristics of canine hypothyroidism. Veterinary Record 145, 481-487 MULLER, P. B., WOLFSHEIMER, K. J., TABOADA, J., HOSGOOD, G., PARTINGTON, B. P. & GASCHEN, F. P. (2000) Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. Journal of Veterinary Internal Medicine 14, 157-164 NACHREINER, R. F., BOWMAN, M. M., GRAHAM, P. A., REFSAL, K. R. & PROVENCHER-BOLLIGER, A. (2000) The prevalence of thyroglobulin antibody is strongly influenced by breed: a retrospective study of 45,131 canine thyroid diagnostic test results. Journal of Veterinary Internal Medicine 14, 232 NACHREINER, R. F., REFSAL, K. R., GRAHAM, P. A., HAUPTMAN, J. & WATSON, G. L. (1998) Prevalence of autoantibodies to thyroglobulin in dogs with nonthyroidal illness. American Journal of Veterinary Research 59, 951-955 SAUVE, F. & PARADIS, M. (2000) Use of recombinant human thyroid-stimulating hormone for thyrotropin stimulation test in euthyroid dogs. Canadian Veterinary Journal 41, 215-219

Further reading DIXON, R. M. & MOONEY, C. T. (1999) Evaluation of serum free thyroxine and thyrotropin concentrations in the diagnosis of canine hypothyroidism. Journal of Small Animal Practice 40, 72-78 FRANK, L. A. (1996) Comparison of thyrotropin-releasing hormone (TRH) to thyrotropin (TSH) stimulation for evaluating thyroid function in dogs. Journal of the American Animal Hospital Association 32, 481-487 LOTHROP, C. D., TAMAS, P. M. & FADOK, V. A. (1984) Canine and feline thyroid function assessment with the thyrotropinreleasing hormone response test. American Journal of Veterinary Research 45, 2310-2313 PETERSON, M. E., MELIAN, C. & NICHOLS, R. (1997) Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thyrotropin concentrations for the diagnosis of hypothyroidism in dogs. Journal of the American Veterinary Medical Association 211, 1396-1402 SCOTT-MONCRIEFF, J. C. & NELSON, R. W. (1998) Change in serum thyroid-stimulating hormone concentration in response to administration of thyrotropin-releasing hormone to healthy dogs, hypothyroid dogs and euthyroid dogs with concurrent disease. Journal of the American Veterinary Medical Association 213, 1435-1438 SCOTT-MONCRIEFF, J. C., NELSON, R. W., BRUNER, J. M. & WILLIAMS, D. A. (1998) Comparison of serum concentrations of thyroid-stimulating hormone in healthy dogs, hypothyroid dogs, and euthyroid dogs with concurrent disease. Journal of the American Veterinary Medical Association 212, 387-391 SPARKES, A. H., GRUFFYDD-JONES, T. J., WOTTON, P. R., GLEADHILL, A., EVANS, H. & WALKER, M. J. (1995) Assessment of dose and time responses to TRH and thyrotropin in healthy dogs. Journal of Small Animal Practice 36, 245-251

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Recent developments in the diagnosis of canine hypothyroidism

Richard Dixon In Practice 2001 23: 328-335

doi: 10.1136/inpract.23.6.328

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