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  1. 1. Department of Veterinary Medicine College of Veterinary & Animal science, Bikaner Rajasthan University of Veterinary & Animal Science , Bikaner Submtited By Kavita Jaidiya PHD Scholar
  2. 2. Introduction  Hypothyroidism (HpoT) is a multisystemic disease that results from deficiency of thyroid hormones (TH), thyroxine (T4) and triiodothyronine (T3)( Cooper and Ladenson 2013) .  Hypothyroidism is of primary origin in about 95% of cases, affecting mainly middle-aged dogs ( Feldman and Nelson 2015) .  It is a single endocrinological disease suspected most commonly in canine suffering from alopecia (Doering and Jensen, 1973).
  3. 3. Anatomy of Thyroid Gland  Located lateral to the trachea, in the region of the proximal tracheal rings (evans et al , 2013).  Functional unit is the thyroid follicle, which comprises the follicular cells (thyrocytes) and colloid, each gland containing both large (resting) follicles and small (active) follicles. 1: Resting follicles (larger and with numerous vacuoles) 2: Active follicles (smaller in size).
  4. 4. Thyroid Hormone  It is a Iodine-containing amino acids.  100 % of T4, but only 20% of T3 is derived from the thyroid gland. Rest of T3 is derived from extrathyroidal enzymatic deiodination of T4 (Catharine, 2010).  In the dog T4 is bound to: TBG (thyroid hormone-binding globulin) 60 %, TBPA (transthyretin)17%, Albumin 12% and HDL2 (apolipoprotiens)11% (Victor, 2011).  Only 0.1% is free T4 fraction (FT4), which is the bioavailable hormone (Wang et al., 2000) and determines the thyroid condition of the individual.  In contrast to the protein-bound T4 fraction, FT4 concentration remains constant regardless of fluctuations in plasma transporter proteins (Morreale et al.,2002).
  5. 5. Function of thyroid hormone  Thyroid hormones increase the metabolic rate and oxygen consumption of most tissues, (with the exception of the adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary).  Thyroid hormones have positive inotropic and chronotropic effects on the heart. They increase the number and affinity of beta- adrenergic receptors and enhance the response to catecholamines.  Thyroid hormones have catabolic effects on muscle and adipose tissue, stimulate erythropoiesis, and regulate both cholesterol synthesis and degradation.  Thyroid hormones are also essential for the normal growth and development of the neurologic and skeletal systems.
  6. 6. Classification based on etiology  Primary hypothyroidism accounts for more than 95 percent of the cases and is usually caused by lymphocytic thyroiditis or idiopathic thyroid atrophy (Carmel, 2003).  Secondary Hypothyroidism (thyroid stimulating hormone, TSH) deficiency due to congenital malformation, pituitary destruction (tumors, trauma, autoimmune hypophysitis) or even its suppression, normally caused by hormones or drugs such as glucocorticoids ( Feldman and Nelson 2015)  Tertiary hypothyroidism, caused by a thyrotropin releasing hormone (TRH) deficiency due to pituitary adenoma. (Robert et al., 2007)  Not reported in dogs.
  7. 7. Primary hypothyroidism A- Lymphocytic thyroiditis Lymphocytic thyroiditis is a common canine condition that can lead to functional hypothyroidism. It is associated with more than 50% of cases of canine hypothyroidism.(Peter A. Graham et al., 2001) heritable in beagles and borzois(Patty, 2012) Characterized by infiltration of the thyroid gland by lymphocytes, plasma cells, and macrophages. Lastly fibrous connective tissue replaces parenchyma. Clinical hypothyroidism develops only when greater than 75% of the functioning thyroid tissue has been destroyed by the infiltrative process.
  8. 8. B. Idiopathic atrophy  45 -50 % of cases  Degenerative disorder ,no inflammatory infiltrate  although initially the disease is characterized by goiter (slight to significant increase in gland volume) (Feldman and Nelson, 1996), in last parenchyma replaced by adipose tissue.  Fibrosis and inflammation are minimal.  Idiopathic thyroid atrophy may be the result of thyroiditis.  As with thyroiditis, hypothyroidism develops slowly over time .
  9. 9. C- Thyroid neoplasia Does not develop until at least 75% of the thyroid has been destroyed (Patty, 2012). Most are euthyroid , 7 % hyperthyroid , 40 % hypothyroid D- Other congenital or acquired forms of primary hypothyroidism (thyroid gland dysgenesis, dyshormonogenesis, iodine deficiency) are rare. -Many affected puppies die early in life and are categorized as ‘fading puppy’ syndrome. -Also due to deficient dietary iodine intake. - Causes disproportionate dwarfism. -Ruled out in dogs being evaluated for pituitary dwarfism.
  10. 10. Central Hypothyroidism (secondary and tertiary)  Naturally-occurring secondary hypothyroidism is rare and is usually congenital but if acquired is most likely the result of a pituitary tumour.  Central hypothyroidism is most commonly associated with congenital disorders affecting the pituitary gland (Kooistra et al., 2000) in association with neoplasia (Mooney and Anderson , 1993).
  11. 11. Congenital hypothyroidism Congenital hypothyroidism (CH) is one of the most common neonatal endocrine disorders, presenting with abnormal growth and intellectual impairment.(shiguo liu et al,2018)  Congenital hypothyroidism is caused by thyroid dysgenesis, dyshormonogenesi, defects in the transport of thyroid hormones, TSH receptor-blocking antibodies, maternal medications, or a deficiency (endemic goitre) or excess of iodine (LaFranchi 2007).  Congenital hypothyroidism causes impaired development of the central nervous system (CNS) and skeleton (Beaver and Haug , 2003 ).  Congenital hypothyroidism is an inherited autosomal recessive trait in rat terriers, toy fox terriers, and giant schnauzers (Patty,2012).
  12. 12. Sings of Congenital hypothyroidism  Congenital hypothyroidism results in mental retardation and stunted disproportionate growth due to epiphyseal dysgenesis and delayed skeletal maturation (Cathrine, 2010).  Affected dogs are mentally dull and have large, broad heads, short thick necks, short limbs, macroglossia, hypothermia, delayed dental eruption, ataxia, and abdominal distention.  Dermatologic findings are similar to those seen in the adult hypothyroid dog.  Other clinical signs may include gait abnormalities, stenotic ear canals, sealed eyelids, and constipation.  Affected puppies are often the largest in the litter at birth but start to lag behind their littermates within three to eight weeks of age.
  13. 13. Subclinical hypothyroidism  Subclinical hypothyroidism is the first phase of the disease, representing approximately 25% of all cases (Snyder,2000).  Subclinical hypothyroidism is defined as an elevated serum TSH level associated with normal total or free T4 and T3 values(Michael et al .,2001)  Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.(rodondi et al.,2010)  The system responds with increased thyrotropic cell sensitivity to TRH stimulation (Castillo et al., 2001).  The first changes are seen in lipid metabolism (increase in the LDL-cholesterol fraction), the reproductive and immune systems, and the skin (with recurrent infections) (Victor, 2011) .
  14. 14. Clinical hypothyroidism  At this stage the daily secretion of T4 is severely affected.  Clinical signs vary greatly because thyroid hormone impacts myriad of systems .  Clinical are not always the typical obesity, lethargy and poor hair cover as described in many textbooks (Victor, 2011) . 1- Dermatological sign  Dermatologic abnormalities are the most common presenting complaints (Beale, 1993). But they appear in later stages of the disease.  Dermatologic changes occur in 60-80 percent of hypothyroid dogs (Catharine, 2010).
  15. 15.  Dry scaly or greasy skin (Seborrhea sicca or oleosa), change in coloration, strong smelling of skin , hyperkeratosis, hyperpigmentation. Poor hair coat quality, fading of hair color, failure of hair re-growth.  The hair is often brittle and easily epilated, and loss of undercoat or primary guard hairs may result in a coarse appearance or a puppy hair coat (short, softer under coat).  Most dogs with hypothyroidism do not show generalized hair loss but “rat tail” is common (Victor, 2011), which spares head and extremities.  Hypothyroid dogs are predisposed to recurrent bacterial infections of the skin like Malassezia spp. infections and demodicosis.  Myxedema (cutaneous mucinosis) is a rare dermatologic manifestation of hypothyroidism characterized by puffy but nonpitting thickening of the skin, especially of the eyelids, cheeks, and forehead and is classically referred to as ‘tragic face’ (Doering and Jensen, 1973). Dermatological sign--- ----
  16. 16.  Appearance is due to drooping of the eyelids and thickening of the lips and of the skin over the forehead, leading to more skin folds .  It is caused by deposition of hyaluronic acid and glycosaminoglycan in the dermis.  Satish et al. (2007) found skin abnormality – 94%, Generalized hair loss - 88%, Typical rat tail - 83%, Skin lesions, pigmentation and pruritus - 27%, Brittle, dry and lusterless coat - 83% . Puppy – like coat - 22% , Myxedema - 16%.  Other changes include ceruminous otitis, poor wound healing and increased bruising.  A variety of other ‘atypical’ and secondary dermatological abnormalities are also possible. The alopecia may be patchy and asymmetric or may only affect one area (e.g., the bridge of the nose) (Carmel, 2003).  Retarded turnover of hair (carpet coat) or hypertrichosis can occur particularly in Irish setters and boxers (Carmel,2003). Dermatological sign--- ----
  17. 17. Tragic facial expression
  18. 18. BMR related Signs  Common clinical signs attributable to decreased metabolic rate include lethargy, mental dullness, weight gain, unwillingness to exercise, and cold intolerance.  Obesity occurs in approximately 40% of hypothyroid dogs, but most obese dogs suffer from over-nutrition rather than hypothyroidism (Catharine, 2010). Many dogs may present with normal body weight or even weight loss. This is due to poor digestion and nutrient assimilation, as a result of altered motility of the small bowel and less bile secretion (Gebhard et al., 1992).  The decrease in glucose consumption leads to lethargy and increased sleepiness, though some dogs may become aggressive (Beaver and Haug , 2003).  Satish et al. (2007) recorded obesity - 88%, generalized weakness, lethargic, dull and listless, exercise intolerance, dyspnoea, gasping, bradycardia, cyanotic tongue - 55%
  19. 19. Myxedema/tragic face
  20. 20. Obesity
  21. 21. Rat tail appearance
  22. 22. Corneal lipidosis
  23. 23. Head tilt
  24. 24. Short, soft under coat – Puppy Coat
  25. 25. Excess callus formation.
  26. 26. Alopecia with Hyperpigmentation
  27. 27. 3- Neurologic dysfunction A-Peripheral neuropathy  About 2-4% dogs exhibit some behavioral changes and neurological signs such as, head tilt, seizures, ataxia, circling and facial nerve paralysis (Nesbit et al.,1980 and Baker, 1997).  Peripheral neuropathy caused by hypothyroidism affects primarily middle-aged and older individuals (Jaggy et al., 1994), especially of middle- to large-sized breeds.  Neurological symptoms of hypothyroidism can originate from the central and peripheral nervous systems (Rudas et al.,2005 and Nunez et al., 2008) as well as from the muscles.  Specific presentations and their incidence that would be included under behavioral signs include aggression, cold intolerance (15%), decreased libido, exercise intolerance, lethargy or mental dullness (20% to 70%), prolonged anestrus (4% to 40%), and weight gain or obesity (41% to 60%).(Bonnie V. Beaver et al,2013)
  28. 28.  In neurological manifestations of hypothyroidism, the dog may not show any of the classical symptoms such as lethargy and dermatological changes (Srivastava et al., 2013 and Budsberg et al.,1993).  However, (Indrieri et al., 1987) reported dermatological changes, weight gain and hypercholesterolaemia (Cuddon, 2002) in dogs with peripheral neuropathies.  Symptoms from the peripheral nervous system are exercise intolerance, general weakness, ataxia, paraparesis, tetraparesis, deficits of conscious proprioception, and decreased spinal reflexes (Catharine, 2010) and symptoms of the cranial nerves such as facial paralysis (McKeown, 2002) vestibular syndrome, trigeminal nerve (Fors, 2006), reduced spinal reflexes and muscle atrophy (Bischel et al.,1988).  Proprioceptive positioning deficits and decreased spinal reflexes are generally more evident in the hind limbs, however(jaggy et al., 1994).  The clinical signs of generalised peripheral neuropathy reduced spinal reflexes in all four limbs can occur caused by hypothyroidism are usually reversible after two to three months treatment using thyroid hormone supplements (Cizinauskas et al.,2000). Intermittent, as well as constant, forelimb lameness is described in dogs with hypothyroidism (Budsberg et al.,1993).
  29. 29. Cardiovascular system:  Sinus bradycardia, weak apex beat, low QRS voltages, and inverted T waves occur in hypothyroid dogs.  Reduced left ventricular pump function but rarely myocardial failure in dogs.  Dilated cardiomyopathy and hypothyroidism may occur concurrently with dramatic long-term improvement in cardiac function after treatment with l-thyroxine.  Canine hypothyroidism may occur in association with other immune-mediated endocrine disorders such as hypoadrenocorticism and diabetes mellitus.  Hypothyroidism causes insulin resistance and may mask the classic electrolyte changes of hypoadrenocorticism. Polyendocrinopathies
  30. 30. Ocular changes:  Corneal lipidosis, corneal ulceration, uveitis, lipid effusion into the aqueous humor, secondary glaucoma, lipemia retinalis, retinal detachment, and keratoconjunctivitis sicca may occurs in hypothyroidism. Hemostasis • Decreased plasma von Willebrand factor concentration has been reported in hypothyroid dogs but canine hypothyroidism is rarely associated with clinical bleeding, and platelet function.
  31. 31. Epidemiology:  Hypothyroidism is the most common hormone imbalance of dogs with the incidence rate at about 1: 150 to 1: 500 (Chastain and Panaciera, 1995).  Dogs beyond 8 yrs are more susceptible (Panaciera, 1994).  Most cases are seen in dogs over one year of age middle-aged dogs and is rarely diagnosed in dogs less than two years of age (Carmel, 2003) although perhaps 10% may be in younger animals.  A small number (approx. 3%) of cases are congenital, while the rest relate to pathology acquired during growth (Victor, 2011).  Hypothyroidism can affect any age or breed of dog (Dixon et al., 1999).
  32. 32.  Hypothyroidism secondary to lymphocytic thyroiditis appears to develop at a younger age than idiopathic thyroid atrophy (Patty, 2012).  Labrador, Doberman, Golden Retriever, German shepherd, Spaniels, Great Dane, Dachshund have great risk (Patty, 2012 and Nesbitt et al., 1980).  More common in mid to large pure-bred dogs (Carmel, 2003).
  33. 33.  In india Spitz was showing high incidence (56%) followed by Labrador (28%) and German shepherd (17%) (Satish et al., 2007).  This variation could probably be due to the habitation of different breeds in different regions. Spayed females and castrated males are at greater risk (Panaciera, 1994). Males and females, either neutered or entire, appear to be affected equally (Carmel, 2003).
  34. 34. Diagnosis and Treatment
  35. 35. Total triiodothyronine (T3)  T3 is three to five times more potent than T4 (pro-hormone).  Measurement of T3 therefore reflects metabolic status more accurately, but it plays no role in the diagnosis of hypothyroidism (Carmel, 2003), as circulating concentrations are often maintained in the reference range in hypothyroid dogs (Peterson et al., 1997).  This is because of compensatory mechanisms both within the thyroid gland (increasing secretion of T3), and possibly in extra- thyroidal tissue (up-regulating peripheral T4 conversion).  TT3 concentrations fluctuate out of reference ranges even more than TT4 concentrations in euthyroid dogs (Catharine,2010).
  36. 36. Total Thyroxin (T4)  Circulating total T4 concentration is invariably low in hypothyroid dogs (Peterson et al., 1997; Dixon and Mooney, 1999).  Extremely valuable screening test to rule out hypothyroidism unless anti-T4 antibodies cause a spurious increase, which are produced in 2% of dogs with hypothyroidism (Graham et al., 2001).  Basal T4 has a 95% positive predictive value, the 5% lacking are due to the presence of T4 antibodies (Cauzinille, 2005), but it is poorly specific due to numerous nonthyroidal factors like non- specific hormone fluctuation in healthy dogs, breed, any non- thyroidal illness and numerous drug therapies including glucocorticoids, potentiated sulphonamides and anticonvulsants (Muller et al., 2000; Kantrowitz et al., 2001).  Thus, a low total T4 concentration alone does not confirm hypothyroidism. Total T4 concentrations do not differ significantly between males and females but are higher in small dogs than in medium and large-breed dogs
  37. 37. Differential diagnosis for Thyroid hormone
  38. 38. Free thyroxin (FT4)  Free T4 is the active fraction of total T4 and is more closely reflect metabolic status at the tissue level than total T4.  It is less affected by the myriad factors (drug therapies, non- thyroidal illness, breed) and T4 autoantibodies etc. capable of lowering total T4 and is thus a more specific diagnostic test for hypothyroidism.  Overall, it is considered to be the best single diagnostic test for hypothyroidism but it is not without problems (Peterson et al., 1997; Dixon and Mooney, 1999), as free T4 is only accurately measured by equilibrium dialysis or ultrafiltration techniques and these are not widely available and are relatively expensive.
  39. 39.  Certain drugs, particularly anticonvulsants and glucocorticoids, are capable of lowering both total and free T4 concentrations (Muller et al., 2000) and severe nonthyroidal illness has also been associated with decreased free T4 concentration in a few cases (Kantrowitz et al., 2001).  With regard to THs, FT4 is the fraction that best reflects the peripheral thyroid condition and is the first to become affected (Wang et al., 2000).  A decrease in FT4 is indicative of hypothyroidism in all dogs diagnosed for clinical hypothyroidism, 30% presented with protein-bound T4 levels close to the lower limit, with diminished FT4 and increased TSH levels, together with morphological alterations of the gland and clinical signs (Victor, 2011).
  40. 40. Endogenous thyroid-stimulating hormone (TSH)  Decreased circulating thyroid hormone concentrations reduce the negative feedback effect on the pituitary gland and consequently, in primary hypothyroidism, TSH concentrations rise.  Approximately 20 to 30% (Kooistra et al., 2000), 13% to 38% (Catharine,2010) of hypothyroid dogs have a TSH concentration within the reference range, which might be due to suppressive effects of concurrent non-thyroidal illnesses or from drug therapies, non-specific fluctuation, existence of secondary hypothyroidism or production of unrecognizable TSH isomers
  41. 41.  TSH concentrations increase above the reference range in 7% to 18% of euthyroid dogs, however, limiting the specificity of measuring TSH alone for diagnosis of hypothyroidism (Catharine,2010).  TSH is the best estimator of the thyroid gland axis, and is the most sensitive marker for evaluating thyroid function. TSH elevation is diagnostic of hypothyroidism, independently of the T4 values (Snyder, 2000).  Despite the low specificity of TSH alone for diagnosis of hypothyroidism, in dogs with concurrent low TT4 or fT4 concentration, specificity of an increased TSH concentration for diagnosis of hypothyroidism approaches 100%.
  42. 42. Effect of Drugs on Thyroid Hormone Concentrations  Glucocorticoids influence peripheral metabolism of thyroid hormones and inhibit TSH secretion. The effect of glucocorticoids is dependent on the dose and specific preparation.  In most studies oral administration of glucocorticoids at immunosuppressive doses (1 to 2 mg/kg q12h) resulted in rapid decreases in TT4, fT4, and T3, but little change in serum TSH.
  43. 43. Evaluation of the lipid profile  30-40% of all dogs with hypothyroidism present with total cholesterol elevation (Xenoulis and Steiner ,2010).  It is important to measure LDL-cholesterol, since an increase in relation to HDL-cholesterol can indicate thyroid deficiency (Xenoulis and Steiner , 2010).
  44. 44. Diagnostic Tests for Hypothyroidism in Dogs
  45. 45. Therapeutic response  Therapeutic response has also been suggested as a method of confirming hypothyroidism in dogs with inconclusive total T4 and cTSH concentrations. However, caution is advised. Thyroid hormone supplementation suppresses TSH production and endogenous thyroid function. Hypofunction invariably occurs once supplementation is withdrawn and can lead to confusing clinical signs for up to eight weeks later (Panciera et al., 1989).  Thyroid hormone supplementation is known to have several physiological effects that can easily be misinterpreted as a successful response to therapy in euthyroid dogs.
  46. 46. Thyroid Ultrasound thyroid gland in many hypothyroid dogs has a smaller volume and s-sectional area and tends to be less echogenic (Catharine, 2010).  Ultrasound is a useful imaging tool for assessment of thyroid glands and measurement of thyroid size.(Lyshchik et al,2004)  Three-dimensional ultrasound is a useful and precise image method in the measurement of thyroid volume as compared with 2D ultrasonography, and this method enables to exactly detect the alteration of the thyroid lobe volume in a relatively short time.(Alireza Vajhi et al,2010)
  47. 47. How are hypothyroid dogs treated?  Synthetic T4 products have greater standardization and potency and a longer shelf life compared with crude preparations. T4 itself is considered to be a physiological pro-hormone, serves to normalize both circulating T4 and T3 concentrations and pituitary cTSH production, and can effectively be administered once daily.  The recommended dose in clinical hypothyroidism is 11-22 μg/kg, starting with the lower dose and gradually increasing the dosage until the desired concentration has been reached. (Dixon et al., 2002).
  48. 48.  In adequately treated dogs, there is usually a dramatic improvement in metabolic signs within days. Dermatological abnormalities can take several months to improve and, frequently, there is worsening of alopecia before new hair re-growth commences.  There is wide inter-individual variation in gastrointestinal absorption and response to T4 replacement therapy. As a consequence, it is important to monitor dogs after commencing therapy.
  49. 49.  Administration of lower doses (3-10 μg/kg) in subclinical hypothyroidism.  Administration of lower doses in elderly animals.  Presence of heart failure or kidney disease: administration of lower doses in order not to overburden the affected organs.  Gestation or proximity to mating: administration of higher doses (between 25-50%) in order to secure good ovulation or spermatogenesis and avoid embryonic and fetal deaths/reabsorptions.  Dogs with oncological diseases or chronic infections, where metabolic rest is indicated: administration of lower doses. Recommendation for treatment (Victor, 2011)
  50. 50.  Dixon and Mooney (1999) advise initially administering levothyroxine every 12h, progressing to once daily dosing).  Reassessment can then be performed every 6-12 months (Dixon et al.,2002).  In the case of congenital hypothyroidism, treatment should start as soon as possible in order to avoid irreparable damage to the central nervous system. The dosage in puppies with congenital hypothyroidism or juvenile hypothyroidism is 5-20 μg/kg.  Adequately treated animals have a normal life expectancy and quality of life.  Regular monitoring is required and consideration needs to be given to the development of other immune mediated endocrinopathies (polyglandular syndromes). In such cases, hypothyroidism most commonly occurs in association with hypoadrenocorticism or diabetes mellitus.
  51. 51.  Improvement in activity - first 1 to 2 weeks of treatment.  Weight loss - within 8 weeks.  Normal hair coat- several months and the coat may initially appear worse as telogen hairs are shed.  Improvement in myocardial function - 8 weeks but may be delayed for as long as 12 months.  Neurologic deficits - 8 to 12 weeks.  Vestibular symptoms - two to four months (Jaggy et al., 1994 and Bischel et al., 1988 ). Time of Clinical Improvement