JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM  
February 2019
E-N13

HISTORY:  This calf presented with a swelling of the ventral neck region.

HISTOPATHOLOGIC DESCRIPTION:  Thyroid gland:  Diffusely, there are increased numbers of follicular epithelial cells in single or multiple layers of columnar epithelium forming variably sized, tortuous follicular structures and occasionally forming papillary projections (hyperplasia).  Follicular cells have indistinct cell borders, a basally located oval nucleus containing clumped chromatin and 1-2 indistinct nucleoli, and a moderate amount of deeply eosinophilic cytoplasm (hypertrophy).  Occasionally, follicular lumina are either collapsed or contain a scant amount of eosinophilic, vacuolated secretory material (colloid) admixed with low numbers of foamy macrophages.  Multifocally, within the subcapsular connective tissue, there is hemorrhage, a few scattered macrophages, lymphocytes, and plasma cells, fewer nondegenerate neutrophils, and few reactive fibroblasts embedded within a brightly eosinophilic, fibrillar to homogeneous material (fibrin).

MORPHOLOGIC DIAGNOSIS:  Thyroid gland, follicular epithelium:  Hyperplasia and diffuse, marked, Holstein, bovine.

CONDITION:  Diffuse hyperplastic goiter

GENERAL DISCUSSION:

• Goiter is a clinical term for non-neoplastic, non-inflammatory, and non-nodular enlargement of the thyroid gland which occurs in all domestic animals and birds
• Goiter is the result of hyperplasia of thyroid follicular cells from increased stimulation by TSH, due to inadequate thyroxine (T4) synthesis and blood concentrations of thyroxine and triiodothyronine (T3)
• Types of goiter: diffuse hyperplastic, colloid goiter & congenital dyshormonogenetic
• Primarily a disease of newborns; young from dams with iodine deficient diets are more likely to develop thyroid hyperplasia and have clinical signs of hypothyroidism

PATHOGENESIS:

• Normal thyroid function: Low levels of free (active) T4 (thyroxine, tetra-iodothyronine)  > stimulation of the hypothalamus to secrete TRH (thyroid releasing hormone) > stimulation of the anterior pituitary thyrotroph basophils to secrete TSH (thyrotrophin, thyroid stimulating hormone) > binding to basal aspect of thyroid follicular cells > biosynthesis and secretion of T4 and T3
• Four major causes/mechanisms of hyperplastic goiter (inadequate thyroxine synthesis):
  • Iodine deficient diets
  • Goitrogenic compounds: Interfere with thyroid hormone synthesis
    • Thiouracil and sulfonamides; prolonged low level exposure to thiocyanates produced by ruminal degradation of cyanogenetic glucosides from plants such as white clover (Trifolium), couch grass (Cynoden), linseed meal, and Brassicaceae family (white clover, rape, kale, brocolli) cause congenital goiter in ruminants
    • goitrin (from Brassica ) inhibits organification of iodine
    • mimosine (legume)- not directly goitrogenic; converted in rumen to 3-hydroxy-4(1H)-pyridone> prevents binding of iodine to thyroid
  • Excess dietary iodine caused thyroid hyperplasia (dry seaweed containing excess iodine, mineral supplements): Inhibits the uptake of iodine by (1) blocking the peroxidation of iodide to iodine by thyroid peroxidase (2) interferes with the conversion of monoiodotyrosine to diiodotyrosine (conjugation step), and (3) blocks the release of hormone from the follicle by interfering with proteolysis of colloid
  • Inherited dyshormonogenic goiter: Autosomal recessive genetic enzyme defects involved in the synthesis of thyroid hormone; documented in sheep (Corriedale, Dorset Horn, Merino, Romney breeds), Afrikander cattle, Saaneen dwarf goats, toy fox terriers and a French bulldog
    • Inability to synthesize and secrete adequate amounts of thyroid hormones
    • Bilateral diffuse hyperplastic goiter with hyperplasia and hypertrophy of follicular cells
    • Low circulating T3 and T4
    • Defect in thyroglobulin mRNA may be the cause of low level of thyroglobulin
  • Congenital hypothyroidism with hyperplastic goiter (from impaired thyroid hormone production of any cause)
    • Prolonged gestation
    • Newborns (pigs, goats, lambs, calves) show myxedema and alopecia, swollen tongue, weakness, among other signs
    • Dam may be normal
    • Uncommon in carnivores
  • Mechanism of goitrogenesis: All of these factors result in decreased blood levels of T3 and T4 >> feedback to hypothalamus to increase thyrotropin releasing hormone (TRH)>> stimulation of pituitary to increase thyroid stimulating hormone (TSH) secretion >> hypertrophy and hyperplasia of follicular cells
    • Abbreviated pathogenesis (i.e. for goiterogenic compound): Dam eats Brassica> inhibits generation of T4/T3> decreased serum T4/T3> release of TRH (from hypothalamus)> inc. TSH (from pituitary gland)> thyroid follicular hyperplasia
  • Colloid goiter:
  • Involutionary phase of hyperplastic goiter (cause of hyperplasia resolved, i.e. iodine added to diet, etc.)
  • Continued production of colloid from hyperplastic follicles, with decreased endocytosis (decreased demand) because of decreased circulating levels of TSH following return to normal T3/T4
  • Diffuse change that affect the entire lobe
  • Decreased vascularity and macrofollicle development due to colloid distension
  • Older animals have reduced colloid endocytosis and follicular distention secondary to lower thyrotropin secretion and T4 requirements
  • Follicular cells become flattened and atrophic and follicles are distended by abundant bright eosinophilic colloid

TYPICAL CLINICAL FINDINGS:

• Dam: Prolonged gestation; larger goiters may cause dystocia; increased incidence of retained placenta; typically no evidence of thyroid dysfunction
• Foals: extreme weakness, die within a few days; +/- slightly enlarged thyroids
• Calves: usually more resistant than foals, most survive; few calves are born partially or completely hairless- these are either born dead or die shortly post birth
• Lambs/kids/piglets: Myxedema & alopecia; born dead or die shortly post birth; palpable, enlarged thyroid glands in lamb/kid but not piglet (short neck & myxedema); swollen tongue/edematous larynx may be contributing factors to the death of the animal
• Domestic carnivores: Hyperplastic goiter & hypothyroidism is not a prominent feature; puppies: less severe forms are more common, often recover spontaneously; dry, coarse, and sparse hair coat; narrow palpebral fissures; broad skulls and legs, which are relatively thicker and heavier than normal; less often, other congenital defects such as vascular anomalies may be present

TYPICAL GROSS FINDINGS:

• Hyperplastic goiter: Firm, dark red, enlarged thyroid gland lobes; usually bilateral
• Colloid goiter: Bilaterally enlarged, lighter, and more translucent thyroid gland lobes
• Neonate: Alopecia, rough haircoat, myxedema, swollen tongue and/or larynx, musculoskeletal deformities (lambs and foals)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Hyperplastic goiter: Numerous irregularly shaped follicles lined by hypertrophied and hyperplastic follicular epithelium, with minimal colloid; well vascularized perifollicular interstitium
• Colloid goiter: Macrofollicles lined by attenuated to atrophic epithelium and that are distended with eosinophilic, vacuolated colloid
• Neonate: Hypoplastic hair follicles; delayed osseous maturation with absence of ossification centers (lambs)

DIFFERENTIAL DIAGNOSIS: Mass in the neck area:

• Nodular/adenomatous (cat) thyroid hyperplasia: Multiple, well-demarcated, unencapsulated hyperplastic foci that may be bilateral with minimal compression of adjacent thyroid with variable amounts of colloid; incidental in dog/horse; causes hyperthyroidism in cat
• Thyroid follicular adenoma: Usually single, encapsulated; incidental in dogs/horses, more common in cats; compresses adjacent thyroid
• Thyroid follicular carcinoma: Invades through capsule; metastasis to lung; can cause hyperthyroidism in dogs (boxers predisposed)
• Thyroid C-cell (parafollicular cells) adenomas: Discrete, single/multiple gray to tan nodules
• Thyroid C-cell (parafollicular cells) carcinoma: firm; usually large, hemorrhagic, with areas of necrosis; occur frequently in old to aged bulls
• Parathyroid (chief cell) tumors:
  • Adenomas: Single, well demarcated, encapsulated white to red-brown, with atrophy of remaining parathyroid; closely packed chief cells divided into small groups by fine fibrovascular septa; +/- oxyphil cells
  • Carcinomas: Larger; infiltrate capsule and adjacent thyroid
  • Functional tumors may cause hypercalcemia and osteodystrophia fibrosa

COMPARATIVE PATHOLOGY:

• Lambs, Goats: Extensive alopecia, palpable to visible enlarged thyroid gland, weak (ingestion of goitrogenic compounds by dam)
• Foals: Congenital goiter from inadequate or excess dietary iodine in the mare
• Pigs: Hairless, stillborn or weak with myxedema around the neck
• Ruminants:
• Congenital dyshormonogenetic goiter in sheep (Corriedale, Dorset Horn, Merino, Romney breeds), Afrikander cattle and Saanen dwarf goats; autosomal recessive; defect in thyroglobulin biosynthesis
• Rat Terriers: Autosomal recessive defect; nonsense mutation in the thyroid peroxidase gene; hypomyelination of corpus callosum; to a lesser degree corona radiata, longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord; low serum T4 and fT4 (by ED) and markedly elevated levels of TSH
• Toy Fox Terriers: Congenital hypothyroidism with goiter; autosomal recessive; nonsense mutation in the thyroid peroxidase gene; abnormal haircoat, stenotic ear canals and delayed eye opening; microscopic lesions similar to hyperplastic goiter
• Tenterfield Terriers: Homozygous missense mutation of the thyroid peroxidase (TPO) protein; autosomal recessive defect; growth failure with shortened legs and delayed eye opening, abnormal haircoat, inability to nurse; hyperplastic thyroid lesions
• Psittacines: Hyperplastic goiter common because of iodine deficiency, respiratory distress, starvation
• Great Cormorants: Hyperplastic / hypertrophic follicles with loss / deficiency of colloid with a possible association with dioxin accumulation
• Reptiles: Colloid goiter reported in giant tortoises eating goitrogenic plants; one report in an eastern diamondback rattlesnake
• Fish: Secondary to iodine deficient diet
• Bottlenose dolphins: Congenital diffuse hyperplastic goiter; microscopic lesions similar to hyperplastic goiter
• Humans:
  • Iodine deficiency: Severe hypothyroidism and cretinism in children (myxedema, lethargy, obesity, and retardation of growth, sexual, and mental development); +/- respiratory distress due to inadequate surfactant
  • Grave"s disease: Autoantibodies to thyrotropin receptors; hyperthyroidism, exophthalmos, focal infiltrative dermopathy; thyroid hyperplasia with lymphocytic infiltrate

 

REFERENCES:

1. Bojanic K, Acke E, Jones BR. Congenital hypothyroidism of dogs and cats: a review. N Z Vet J. 2011;59(3):115-122.
2. Campbell AJ, Croser EL, Milne ME, Hodge PJ, Webb Ware JK. An outbreak of severe iodine-deficiency goiter in a sheep flock in north-east Victoria. Aust Vet J. 2012;90(6):235-239.
3. Chiba A, Oguma K, Hatakeyama H, Inomata K, Honma R. Thyroid leions in the Great Cormorant (Phalacrocorax carbo) of Nigata, Central Japan: A possible association with dioxin accumulation. J Wildl Dis. 2009;45(1):242-247.
4. Dodgson SE, Day R, Fyfe JC. Congenital hypothyroidism with goiter in tenterfield terriers. J Vet Intern Med. 2012;26(6):1350-1357.
5. Fyfe JC, Kampschmidt K, Dang V, Poteet BA, He Q, Lowrie C, Graham PA, Fetro VM. Congenital hypothyroidism with goiter in toy fox terriers. J Vet Intern Med. 2003;17:50-57.
6. Galgano M, Spalla I, Callegari C, et al. Primary hypothyroidism and thyroid goiter in an adult cat. J Vet Intern Med. 2014;28:682–686.
7. Garner MM, Shwetz C, Ramer JC, Rasmussen JM, Petrini K, Cowan DF, Raymond JT, Bossart GD, Levine GA. Congenital diffuse hyperplastic goiter associated with perinatal mortality in 11 captive-born bottlenose dolphins (Tursiops truncatus). J Zoo Wildl Med. 2002;33(4):350-355.
8. Kuczynski LA, Schwartz P, Peddle G, Huang S, Mai W, Giger U. Goiter with vascular anomalies in a litter of Polish Lowland sheepdogs. J Am Anim Hosp Assoc. 2012;48(4):278-283.
9. Loukopoulos P, Bautista AC, Puschner B, et al. An outbreak of thyroid hyperplasia (goiter) with high mortality in budgerigars (Melopsittacus undulatus). J Vet Diagn Invest. 2015;27(1):18-24.
10. Major S, Pettigrew RW, Fyfe JC. Molecular genetic characterization of thyroid dyshormogenesis in a French bulldog. J Vet Intern Med. 2015;29:1534-1540.
11. Miller MA. Endocrine System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:699-701.
12. Ong CB, Herdt TH, Fitzgerald SD. Hyperplastic goiter in two adult dairy cows. J Vet Diagn Invest. 2014;26(6):810-814.
13. Pettigrew R, Fyfe JC, Gregory BL, Lipsitz D, DeLahunta A, Summers BA, Shelton GD. CNS hypomyelination in rat terrier dogs with congenital goiter and a mutation in the thyroid peroxidase gene. Vet Pathol. 2007;44:50-56.
14. Rosol TJ, Grone A. Endocrine system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier Limited; 2016:320-326.
15. Seelig DM, Whittemore JC, Lappin MR, Myers AM, Avery PR. Goitrous hypothyroidism associated with trimethoprim-sulfamethoxazole in a young dog. 2008;232:1181-1185
16. Taeymans O, O"Marra SK. Imaging diagnosis--acquired goitrous hypothyroidism following treatment with trimethoprim sulfamethoxazole. Vet Radiol Ultrasound. 2009;50(4):442-444.

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