Canine Hypothyroidism – part 1
Victor Castillo PhD
Hypothyroidism is the most common canine endocrine disorder; most cases are seen in dogs over one year of age although perhaps 10% may be in younger animals. A small number (~ 3%) of cases are congenital, while the rest relate to pathology acquired during growth. The canine thyroid gland is located lateral to the trachea, in the region of the proximal tracheal rings (1). Histologically, the 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 (Figure 1). The embryogenesis and maturation of the foetal thyroid axis can be divided into three periods:
The first period corresponds to embryogenesis of the gland; the thyroid forms in the third and fourth pharyngeal pouches, beneath what will become the tongue. Migration of the thyroid towards the trachea and the start of its physiological function are regulated by transcription factors. TSH-R (thyroid stimulating hormone (TSH) receptor) is expressed at the end of embryonic development of the gland, with the initiation of iodine uptake in the foetal thyroid gland (2). During this stage 100% of the thyroxin (T4) originates from the mother, and is essential for correct development of the nervous system and other embryonic tissues.
The second period corresponds to maturation of the foetal thyroid axis and commences when the thyroid reaches its anatomical location. At this point the hypothalamus begins to release thyrotrophin-releasing hormone (TRH), and consecutively TSH synthesis and release, iodine uptake by the foetal thyroid gland, and T4 synthesis is observed. Note that a large proportion of T4 undergoes deionization in the foetus to the reverse form of triiodothyronine (rT3). During this period 50% of T4 is maternally derived, but this gradually decreases to 20% at the end of the gestational period. This maternal contribution is essential for foetal growth and the maintenance of euthyroid status in the newborn puppy during the first 24h of life.
The third period corresponds to the interval after birth, and culminates with anatomical maturation of the thyroid gland (2). In the newborn puppy the thyroid follicles are not yet fully developed; at 48-72h postpartum the first mature follicles are observed, and after one week the thyroid gland is histologically and anatomically mature. This maturation in turn correlates with the action of TSH and T4 in the newborn animal; at 48h postpartum TSH increases while T4 decreases – thus allowing follicle maturation and a subsequent increase in T4 levels (Figure 2).
Synthesis and function of the thyroid hormones
An understanding of the various thyroid hormones (THs) is essential for the clinician. The thyroid gland produces mainly T4, with lesser amounts of T3 (1). In the gland TSH binds to receptors, activating a series of events culminating in the release of T3 and T4 into the bloodstream. These hormones are extensively bound to plasma transporter proteins (99.9%), which serve as a TH reservoir. Only 0.1% corresponds to the free T4 fraction (FT4), which is the bioavailable hormone (1,3). This fraction determines the thyroid condition of the individual, since it is the form of the hormone that is available for uptake by the body cells. In contrast to the protein-bound T4 fraction, FT4 concentration remains constant (even in the puppy) regardless of fluctuations in plasma transporter proteins. Protein levels can vary due to physiological causes (increasing in heat and pregnancy) or disease (increasing in obesity and decreasing in liver disease, digestive disorders and kidney disease) (2). In the dog, the half-life of circulating T4 is 12h, although this is prolonged to 24h in the case of the intracellular hormone (1,3). The transformation of T4 into T3 is regulated by the enzyme deiodinase. Deiodinase isomers are found in the bloodstream and within the cells, where tissue requirements determine how much T4 is converted to T3. Note that T3 and T4 levels vary according to the tissue involved (2,4). The differences in tissue requirements lead to the concept that some tissues may show hypothyroidism earlier than others, despite adequate TH levels in the bloodstream (4) which in turn may explain why clinically manifested hypothyroidism can be observed despite normal TH levels in blood. The hypophyseal thyrotropic cells are considered to be the first cells to become hypothyrotic; their ability to detect early decreases in daily T4 levels results in increased TSH secretion (4,5).
Regulation of the thyroid axis
Regulation of the thyroid axis depends on the daily synthesis and secretion of T4. In the hypothalamus and hypophysis, T4 inhibits respectively the synthesis of TRH and TSH. If synthesis of T4 is reduced, neither the hypothalamus nor the thyrotropic cells are inhibited, and both TRH and TSH increase. Conversely, when T4 synthesis is increased, a greater conversion from T4 to T3 takes place, with the inhibition of TRH and TSH (4,5). In contrast to the human situation, euthyroid dogs show no marked diurnal variations in either TSH or T4 (6).
Hypothyroidism is defined as deficient thyroid hormone action upon its target organs, secondary to T4 and T3 secretory failure, nuclear receptor defects (resistance to the hormone), or TSH secretory or molecular defects (2). The adult and juvenile forms of the disease are clinically and etiologically different.
Hypothyroidism in adult dogs
The main cause of hypothyroidism in the adult dog is an autoimmune disorder (60% of all cases), leading over time to thyroid gland atrophy – although initially the disease is characterized by goitre (slight to significant increase in gland volume) (1). Depending on the course and clinical expression of the disorder, hypothyroidism can be subclinical or clinical. Note the term “subclinical” does not imply the absence of clinical manifestations but rather refers to the presence of mild to moderate signs not characteristic of the disease but which suggest the existence of hypothyroidism (5). Depending on the endocrine biochemical findings (alteration of TSH and THs), the disorder is classified into four stages (Table 1) (5,7).
Subclinical hypothyroidism... is the first phase of the disease, representing approximately 25% of all cases (5,7). Subclinical hypothyroidism is characterised by an increase in TSH concentration with T4 levels (total or free fraction) within the reference range. As the thyroid gland becomes affected, the daily secretion of T4 decreases but the blood concentrations remain within the normal reference range – though close to the lower limit. At this point different tissues begin to suffer a lack of T4. These variations in T4 levels are detected within the hypophysis and hypothalamus, resulting in less conversion of T4 into T3. The system responds with increased thyrotropic cell sensitivity to TRH stimulation. As the disease advances and T4 secretion is increasingly impaired, the hypophysis responds with an increase in TSH to force T4 production and thus maintain euthyroid conditions (5,7). 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), and the clinical or biochemical expression of these altered functions will provide clues to the existence of subclinical hypothyroidism.
Clinical hypothyroidism... is characterized by obvious clinical signs that can be characteristic of hypothyroidism. At this point the daily secretion of T4 is severely affected.
• The dermatological presentations of hypothyroidism are often overemphasized. They appear in later stages of the disease. Most dogs with hypothyroidism do not show generalized hair loss (20%). In contrast, it is common to observe dry or oily seborrhoea and/or the so-called “rat tail” (Figure 3).
• Excess body weight and obesity are often observed (30%), but 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 (5,8).
• Given the importance of TH in the function of the nervous system, alterations are observed at both peripheral and central levels (9,10). The decrease in glucose consumption leads to lethargy and increased sleepiness, though some dogs may become aggressive (Figure 4) (11).
• Reproductive function is severely affected (anoestrus in females and oligo- or azoospermia or lack of libido in males). Rarely galactorrhoea may be seen, even in males (1,2). It is therefore important not to assume that Ho is obligatorily characterized by obesity, lethargy and bilateral seborrhoeic alopecia. It is necessary to take a variety of signs into account, including those that are less obvious or which may suggest the existence of some other disorder.
Congenital and juvenile hypothyroidism
Hypothyroidism in the puppy can be congenital or juvenile, i.e. acquired during growth period (Figures 5 and 6). Congenital hypothyroidism is attributable to defects in thyroid gland development (failure to migrate or undergo cell growth), or to thyroid peroxidase enzyme deficits (1,2). A TSH secretory defect (e.g. due to hypopituitarism), is a less common cause. In contrast to foetal hypothyroidism caused by maternal hypothyroxinaemia (which affects all foetuses) congenital hypothyroidism is only found in puppies that carry the mutation giving rise to the gland disorder. During the growth phase the puppy can develop hypothyroidism in the same way as the adult animal (2,5). In congenital hypothyroidism, thyroid hormone deficiency in both the fetus and newborn animal gives rise to impaired development of the central nervous system (CNS) and skeleton (1,9,11,12). Congenital hypothyroidism and juvenile hypothyroidism should be differentiated from other disorders that cause growth retardation, such as growth hormone deficiency, rickets, malnutrition, congenital heart diseases, portocaval shunts and megaesoephagus.
COME BACK NEXT WEEK FOR THE SECOND HALF OF THIS ARTICLE... DIAGNOSIS & TREATMENT!
This article was kindly provided by Royal Canin, makers of a range of veterinary diets for dogs and cats. For the full range please visit www.RoyalCanin.co.uk or speak to your Veterinary Business Manager:
1. Feldman EC, Nelson RW. The thyroid gland. Canine and feline endocrinology and reproduction. 2nd ed. Philadelphia: WB Saunders, 1996; 67-185.
2. Morreale de Escobar G, de Vijlder J, Butz S, et al. The thyroid and brain, European Thyroid Symposium. NY: Schattauer, 2002; 33-233.
3. Wang R, Nelson JC, Weiss RM, et al. Accuracy of free thyroxine measurements across natural ranges of thyroxine binding to serum proteins. Thyroid 2000; 10: 31-9
4. Duncan Basset JH, Harvey CB, Williams GR. Mechanism of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol 2003; 213: 1-11.
5. Snyder PJ. The pituitary in hypothyroidism. In: Braverman LE, Utiger RD, eds. The Thyroid. A Fundamental and Clinical Text. 8th ed. Philadelphia: Lippincott, Willians & Wilkins A, Wolter Kluwer Company, 2000; 811-814.
6. Kooistra HS, Dias-Espineira M, Mol JA, et al. Secretion pattern of thyroidstimulating hormone in dogs during euthyroidism and hypothyroidism. Domest Anim Endocrinol 2000; 18:19-29.
7. Castillo V, Rodriguez MS, Lalia J. Estimulación con TRH y evaluación de la respuesta de la TSH en perros. Su importancia en el diagnóstico de la enfermedad tiroidea subclínica (hipotiroidismo subclínico y tiroiditis autoinmune eutiroidea). Revista Científica 2001; 11: 35-40.
8. Gebhard R, Stone B, Andreini J, et al. Thyroid hormone differentially augments biliary sterol secretion in the rat. I. The isolated perfused liver model. J Lipid Res 1992; 33:1459-1466.
9. Nunez J, Celi S, Ng L, et al. Multigenic control of thyroid hormone functions in the nervous system. Mol Cell Endocrinol 2008; 287:1-12.
10. Rudas P, Rónai ZS, Bartha T. Thyroid hormone metabolism in the brain of domestic animals. Domest Anim Endocrinol 2005; 29: 88-96.
11. Beaver BV, Haug LI. Canine behaviors associated with hypothyroidism. J Am Anim Hosp Assoc 2003; 39: 431-437.
12. Glinoer D. Potential consequences of maternal hypothyroidism on the offspring: evidence and implications. Horm Res 2001; 55: 109-114.
13. Rezzonico J, Guntsche Z, Bossa N. Determinación ecográfica de volume tiroideo normal en niños y adolescentes en Mendoza-Argentina. Revista Argentina Endocrinología Metabolismo 1994; 31: 72-78.
14. Xenoulis PG, Steiner JM. Lipid metabolism and hyperlipidemia in dogs. Vet J 2010; 183: 12-21.
15. Sparkes AH, Gruffydd-Jones TJ, Wotton PR et al. Assesment of dose and time responses to TRH and thyrotropin in healthy dogs. J Small Anim Pract 1995; 36: 245-251.
16. Dixon RM, Mooney CT. Evaluation of serum free thyroxine and thyrotropin concentrations in the diagnosis of canine hypothyroidism. J Small Anim Pract 1999; 40: 72-78.
17. Ramírez Benavides GF, Osorio JH. Niveles séricos de tetrayodotironina libre (T4L), mediante el método de electroquimioluminiscencia en caninos. Revista Científica 2009; 19: 238-241.
18. Castillo V, Rodriguez MS, Lalia J, et al. Parámetros bioquímicos-endócrinos de utilidad en la etapa de crecimiento del ovejero alemán, doberman y gran danés. Archivos Medicina Veterinaria 1997; 29: 105-111.
19. Skopek E, Martina Patzl M, Nachreiner R. Detection of autoantibodies against thyroid peroxidase in serum samples of hypothyroid dogs. Am J Vet Res 2006; 7: 809-814.
20. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002; 43: 334-344.
This article was previously published in 2011.