JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M22 (NP)

Signalment (JPC 21474-26): Middle-aged, breed unspecified dog

HISTORY: Skin biopsy from an increasingly lethargic dog that had haircoat thinning and loss over the trunk.

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Diffusely, there is moderate epidermal and follicular orthokeratotic hyperkeratosis. Multifocally, there is melanin pigment in all layers of the epidermis (hyperpigmentation). Follicular infundibula are distended up to 0.2mm by concentric layers of keratin admixed with cellular debris and melanin, and lined by attenuated external root sheath epithelium (follicular keratosis). Nearly 100% of follicles are in telogen phase, some of which lack hair shafts (hairless telogen/kenogen). Telogen follicles have hypocellular bulbs (follicular atrophy), have thickened external root sheaths, lack internal root sheaths, and contain irregular lamellations of brightly eosinophilic trichilemmal keratin (flame follicles). Dermal collagen fibers are shrunken and separated by abundant clear space (edema). Occasionally, arrector pili muscles have pale vacuolated sarcoplasm (degeneration). Multifocally, apocrine glands are mildly ectatic and lined by attenuated epithelium. 

MORPHOLOGIC DIAGNOSIS:  Haired skin:  Atrophy, follicular, diffuse, moderate, with follicular and epidermal orthokeratotic hyperkeratosis, flame follicles, and follicular ectasia, breed unspecified, canine

CONDITION:  Hypothyroidism

GENERAL DISCUSSION:

• Most common endocrine dermatopathy of dogs
• Most common in middle-aged or older dogs, with no sex predilection; more common in castrated males and ovariohysterectomized females
• Causes are either primary (>90%) or secondary (due to decreased TSH secretion):
  • Primary: Lymphocytic thyroiditis (E-M01), thyroid follicular atrophy, thyroid neoplasia, developmental defects of the thyroid gland
  • Secondary: Pituitary neoplasia (hypopituitarism), iodine deficiency or excess, hypothalamic defects, iatrogenic via surgery or drugs, lesions that infiltrate or destroy the adenohypophysis
• Predisposition in many breeds: Doberman pinscher, golden and Labrador retriever, laboratory beagles, Chow Chow, Great Dane, Irish wolfhound, boxer, English bulldog, dachshund, Afghan hound, Newfoundland, Alaskan malamute, Brittany spaniel, poodle, Irish setter, and miniature schnauzer
  • Familial hypothyroidism in giant schnauzers
• Congenital hypothyroidism with goiter reported in Tenterfield Terriers, as well as Toy Fox and Rat Terriers – due to dyshormonogenesis, caused by thyroid gland failure to produce sufficient hormone to inhibit pituitary release of TSH

PATHOGENESIS:

• Primary hypothyroidism is divided into two main categories: (1) Lymphocytic thyroiditis, and (2) Idiopathic follicular atrophy
  • Lymphocytic thyroiditis (autoimmune disease): multifocal to diffuse interstitial infiltration with lymphocytes, plasma cells, and macrophages with increase in fibrous tissue; production of autoantibodies directed against thyroglobulin, thyroperoxidase, the TSH receptor and other thyroid follicular cell antigens
    • Lymphocytic thyroiditis progression: thyroglobulin autoantibody-positive sub-clinicalà thyroglobulin autoantibody-positive hypothyroidism (75% of the gland must be destroyed before clinical hypothyroidism) à thyroglobulin autoantibody-negative hypothyroidism
  • Idiopathic follicular atrophy: follicular epithelium is lost or replaced by adipose tissue with minimal inflammatory response
    • May be end stage lymphocytic thyroiditis with subsided lymphocytic inflammation
  • Congenital hypothyroidism (rare)
    • Maternal diet is iodine deficient or contains goitrogens → insufficient synthesis of thyroxine → reduced blood T3 and T4 → hypothalamus and pituitary gland secrete thyrotropin →hyperplasia of thyroid follicular cells
    • Maternal diet high in iodine → high blood iodine → interferes with thyroid hormone production →low blood T4 →hypothalamic and pituitary stimulation → secretion of thyrotropin
    • Iodine deficient regions of North America: Great Lakes basin, Rocky Mountains, northern Great Plains, upper Mississippi River valley, and the Pacific Coast region
  • The autoimmune mechanism responsible for primary hypothyroidism is unknown
  • In the skin, receptors for thyroid hormones are on sebocytes and cells of the outer root sheath and dermal papilla
  • Thyroid hormones influence serum and cutaneous fatty acid concentrations and sebaceous gland function resulting in seborrhea; seborrhea predisposes the dog to secondary staphylococcal or Malassezia infections
  • Secondary dermatitis is also due to alterations in the cutaneous barrier and immune dysfunction; pruritus may be present when secondary infection is present
  • Myxedema occurs in some hypothyroid dogs; thyroid hormones help regulate production of dermal glycosaminoglycans; hyaluronic acid accumulates in the dermis with lack of these hormones

 

TYPICAL CLINICAL FINDINGS:

• Cutaneous signs in dogs:
  • Alopecia develops in areas of friction (elbows, hips, neck, bridge of nose) and on the entire length of the tail (“rat tail”)
  • Bilaterally symmetric truncal alopecia less common than previously thought
  • Seborrhea; dry, coarse, brittle, easily epilated haircoat that fails to regrow after clipping
  • Hyperpigmentation and hypotrichosis with fine retained hairs that give appearance of a “puppy coat”
  • Myxedema (mucin accumulation) occurs in severe cases and may result in “tragic facial expression”
• Non-cutaneous signs in dogs:
  • Weakness, stiffness, decreased exercise tolerance, muscle wasting (type 2 fibers preferentially affected), and obesity are classic clinical signs that may or may not be present
• Clinical pathology:
  • Normocytic-normochromic nonregenerative anemia
  • Hypercholesterolemia due to decreased lipid metabolism and intestinal excretion can lead to atherosclerotic changes in vessels of the heart, kidney, and GI tract (C-M05)
  • Lymphocytic thyroiditis: thyroglobulin autoantibodies

 

TYPICAL GROSS FINDINGS: 

• Alopecia of tail (“rat tail”) and in areas of friction
• Secondary seborrheic skin disease, pyoderma, pododermatitis, and/or otitis externa
• Myxedema, if present, is most pronounced on the face (forehead, eyelids, around the lips); no characteristic pitting as with other types of edema
• Hyperpigmentation, lichenification, and comedones (not specific)

• Atherosclerotic changes in vessels of the heart, kidney, and GI tract
• Thyroid gland may be smaller and lighter in color
• Other associated lesions: Reduced sperm production with marked spermatogenic epithelial atrophy, decreased joint function with pain and effusion, hepatocellular steatosis, hepatomegaly, pulmonary thromboembolism , xanthogranulomas, glomerular lipidosis, corneal lipidosis (often unilateral)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Non-specific: Predominantly telogen follicles; epidermal and follicular infundibular hyperplasia, and empty hair follicles (kenogen)
• Marked orthokeratotic hyperkeratosis, follicular keratosis, increased melanocytes, epidermis and sebaceous glands may be atrophic, normal, or hyperplastic
• Mucin accumulation in the dermis and subcutis (myxedema)
• Other possible histologic changes: Thickened dermis, flame follicles, vacuolation of hypertrophied arrector pili muscles, and secondary staphylococcal and/or malassezial dermatitis
• Idiopathic follicular atrophy (“collapse”) thyroid changes: degeneration of individual follicular cells (characterized by poorly defined plasma membranes and irregularly shrunken nucleus) → lack of normal thyroid follicles; presence of microfollicles in cytoplasm of individual follicular cells; remaining hypertrophic follicular cells form small nests close to capillaries +/- thickened basement membrane
• Lymphocytic thyroiditis thyroid changes: multifocal to diffuse infiltrates of lymphocytes, plasma cells, and macrophages → replacement of the thyroid gland by mature fibrosis connective tissue and few remaining scattered foci of inflammatory cells

ADDITIONAL DIAGNOSTIC TESTS:

• Total T4 (TT4) is sensitive, but not specific; if TT4 is decreased then thyroid stimulating hormone (TSH) and/or free T4 by dialysis (fT4D) should be measured
• Decreased fT4D is highly specific for hypothyroidism in non-sighthound dogs
  • Greyhounds and other sight hounds normally have lower total T4 and free T4 concentrations than other dogs

• Serum T3 correlates poorly with clinical disease; TT4 may be decreased in non-thyroidal illnesses (euthyroid sick syndrome)
• Thyroid aspirates:
  • Lymphocytic thyroiditis: Lymphocytes, plasma cells, macrophages, and thyroid epithelial cells +/- colloid
  • Follicular atrophy: Well-differentiated thyroid epithelial cells +/- adipose connective tissue cells or colloid

 

DIFFERENTIAL DIAGNOSIS:

• Other endocrine dermatoses may have similar gross and microscopic findings thus clinical differentiation is required
  • Hyperadrenocorticism/hyperglucocorticoidism (I-M23): Dystrophic mineralization involving dermal collagen, dermal thinning, epidermal and sebaceous atrophy
  • Telogen effluvium: Very uncommon, increased numbers of hair follicles in telogen phase
  • Alopecia X: Specific affected breeds (plush coated dogs such as Pomeranians); diffuse, prominent formation of flame follicles
  • Hyperestrogenism (I-M23): Consider other clinical signs; in males, may be due to canine Sertoli cell tumor (often associated with cryptorchidism)
  • Estrogen-responsive and testosterone-responsive dermatoses
• Follicular dysplasia

 

COMPARATIVE PATHOLOGY:

• Hypothyroidism in other animals occurs less frequently and is usually in association with iodine deficiency and goiter
• Sheep and cattle: Hereditary in Merino sheep and Afrikaner cattle - defect in biosynthesis of thyroid hormone produces symmetrical hypotrichosis and thick, myxedematous, wrinkled skin
• Goats: Saanen and dwarf goat strains - hereditary congenital thyroglobulin deficiency produces symmetrical hypotrichosis and thick, myxedematous, scaly skin
• Cats: Naturally occurring disease has only rarely been reported; hypothyroidism in cats is almost always iatrogenic following treatment for hyperthyroidism
• Birds: Generalized loss of feathers and a failure to regrow; no skin lesions; generalized follicular inactivity and atrophy associated with epidermal thinning and atrophy of dermal collagen; excessive mucin deposition in dermis
• Horses: Congenital hypothyroidism; associated with angular limb deformities due to delayed ossification
• Lymphocytic thyroiditis occurs in an obese strain of chickens, NHP, Buffalo rats and resembles Hashimoto’s disease in humans
• Pigs: Familial form of neonatal respiratory distress; cause may be hypothyroidism; alveolar damage with hyaline membranes and bronchiolar necrosis; additional signs include mildly prolonged gestation, fine hair coat, generalized edema, and follicular hyperplasia with lack of colloid
• Rhinoceros: Hypothyroidism has been linked to skin lesions in domestic species

 

REFERENCES:

1. Caswell JL, Williams KJ. Respiratory System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals Volume 2. 5th ed. Philadelphia, Pennsylvania: Elsevier; 2016:516.
2. Choi U, Arndt T. Endocrine and Neuroendocrine Systems. In: Raskin RE, Meyer DJ, Boes KM, ed. Canine and Feline Cytopathology. 4th ed. Elsevier; 2023:599.
3. Duncan M. Perissodactyls. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals. Academic Press; 2018:440.
4. Gal A, Castillo-Alcala F. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:659, 681-682.
5. Lopez A, Martinson SA. Respiratory System, Thoracic Cavities, Mediastinum, and Pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:578.
6. Mauldin EA, Peters-Kennedy J. Integument System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals Volume 1. 5th ed. Philadelphia, Pennsylvania: Elsevier; 2016:587-588.
7. Miller MA. Endocrine System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:785, 802-803, 806.
8. Rosol TJ, Gröne A. Endocrine Glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals Volume 3. 5th ed. Philadelphia, Pennsylvania: Elsevier; 2016:315-316, 318-321.
9. Schmidt RE, Reavill DR, Phalen DN. Integument. In: Pathology of Pet and Aviary Birds. 2nd ed. John Wiley & Sons, Inc; 2015:252.
10. Stockham SL, Scott MA. Thyroid function. In: Fundamentals of Veterinary Clinical Pathology. 2nd ed. Blackwell Publishing; 2008.
11. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:742.
12. Valentine BA. Skeletal Muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:1002.
13. Van Wettere AJ, Brown DL. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:511.
14. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:1250-1251.

Click the slide to view.

---