Pathology in Practice

Jason Pieper Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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Suzette LeClerc Department of Veterinary Diagnostic Laboratory, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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Adam Stern Department of Veterinary Diagnostic Laboratory, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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History

A 6-year-old spayed female Akita was evaluated for continued management of flea bite hypersensitivity, pyoderma, and suspected atopic dermatitis.

Clinical and Gross Findings

At the time of the examination, the dog was being treated with 1,750 mg of cephalexin orally every 12 hours; 100 mg of diphenhydraminea orally every 12 hours; 34.5 mg of milbemycin oxime and 690 mg of lufenuronb orally once monthly; 1,760 mg of spinosadc orally every 3 weeks; weekly baths with 2% chlorhexidine gluconate, 2% miconazole nitrate, tromethamine, disodium EDTA dihydrate, and ceramides shampood; gentamicin sulfate and betamethasone valerate spraye applied topically to the caudal portion of the dorsum as needed; and 3% chlorhexidine and 0.5% climbazole moussef applied topically to the entire body once daily. The dog weighed 58.6 kg (128.9 lb) at this examination. According to the owner, the current treatment had resulted in moderate improvement in the level of the pruritus during the preceding month but no improvement in the overall appearance of the dog's coat.

Abnormal physical examination findings were limited to the integumentary system. There was a bilaterally symmetric partial alopecia (Figure 1) with a mild amount of scale over the trunk, flanks, dorsal and ventral portions of the neck, and dorsal aspect of the head. Hair shafts were dry and brittle on palpation, had follicular casting, and were easily epilated. Cytologic examination of affected areas revealed no abnormal findings. Skin biopsy specimens were obtained from multiple locations on the dorsum and flanks and submitted to the University of Illinois Veterinary Diagnostic Laboratory for diagnostic examination.

Figure 1—
Figure 1—

Photograph of the dorsal aspect of the neck of a 6-year-old spayed female Akita with partial alopecia and mild scale that was adhered to the skin. The hair shafts were also dry and brittle.

Citation: Journal of the American Veterinary Medical Association 250, 3; 10.2460/javma.250.3.287

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Histopathologic Findings

The skin biopsy specimens were immersion fixed in neutral-buffered 10% formalin. Tissues were routinely processed for histologic evaluation and stained with H&E stain. On histologic examination, the epidermis was mildly hyperplastic to normal in thickness and moderately hyperpigmented; there was mild to moderate, predominately basketweave-type orthokeratotic hyperkeratosis. Follicular infundibula were dilated and hyperkeratotic with follicular plugging of several ostia. In 1 section, adnexal units appeared decreased in density and widely spaced within a thickened fibrous dermis. In 2 other sections, individual dermal collagen bundles were separated by clear to lightly eosinophilic material, which was suspected to be either edema or mucin. Lymphatic vessels were mildly ectatic. With regard to growth phases of hair, follicles were in anagen, haired and nonhaired telogen, and catagen arrest. Secondary follicles were generally atrophied to narrow cords (Figure 2). Sebaceous glands were identifiable in most adnexal units but were severely to moderately atrophied. A single adnexal unit appeared to lack sebaceous glands. There was a mild interstitial and perivascular accumulation of eosinophils, lymphocytes, and plasma cells. Alcian blue staining (pH, 2.5) of skin biopsy sections was performed, and the material within the dermis stained blue, which was consistent with mucin (Figure 3).

Figure 2—
Figure 2—

Photomicrograph of a section of a skin biopsy specimen obtained from the dog in Figure 1. Notice the atrophied secondary hair follicles (arrow) and clear space between collagen bundles (arrowheads). H&E stain; bar = 200 μm.

Citation: Journal of the American Veterinary Medical Association 250, 3; 10.2460/javma.250.3.287

Figure 3—
Figure 3—

Photomicrograph of another section of a skin biopsy specimen obtained from the dog in Figure 1. The use of Alcian blue stain reveals the presence of mucin, which is identifiable by the blue coloration between collagen bundles (arrows). Alcian blue stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 250, 3; 10.2460/javma.250.3.287

Additional Clinicopathologic Findings

On the basis of the clinical and microscopic examination findings, hypothyroidism was highly suspected. A thyroid hormone panel revealed low total thyroxine (T4) concentration (6 nmol/L; reference range, 11 to 60 nmol/L), low free T4 concentration (2 pmol/L; reference range, 6 to 23 pmol/L), and high thyroid-stimulating hormone (TSH) concentration (91 mU/L; reference range, 0 to 30 mU/L). These findings were consistent with primary hypothyroidism.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: mild eosinophil-rich interstitial and perivascular dermatitis of haired skin with atrophy of secondary hair follicles and sebaceous glands, orthokeratotic hyperkeratosis, epidermal hyperpigmentation, and dermal mucinosis.

Case summary: skin changes induced by hypothyroidism in a 6-year-old Akita.

Comments

Numerous diseases can cause partial alopecia with scaling in dogs. Some of the more common diseases include hypersensitivity disorders (eg, flea bite hypersensitivity and atopic dermatitis), endocrine diseases (eg, hypothyroidism, hyperadrenocorticism, and sex hormone dermatoses), sebaceous adenitis (to which Akitas are genetically predisposed), keratinization disorders (eg, primary or secondary seborrhea, vitamin A-responsive dermatosis, sebaceous gland dysplasia, and exfoliative dermatoses), epitheliotropic cutaneous lymphoma, systemic lupus erythematosus, demodicosis, dermatophytosis, and nutritional disorders (eg, fatty acid deficiencies).1

On the basis of the clinical and microscopic examination findings, hypothyroidism was highly suspected in the case described in the present report. A thyroid hormone panel revealed findings consistent with primary hypothyroidism. In dogs, primary hypothyroidism is the most common form of hypothyroidism (> 95% of cases), typically with destruction of the thyroid gland.2 Thyroid gland destruction typically is a result of lymphocytic thyroiditis or idiopathic atrophy. Secondary hypothyroidism is a deficiency of TSH and rarely occurs in dogs. Secondary hypothyroidism is a result of congenital malformation of the pituitary gland, neoplastic destruction of the pituitary gland, or suppression of thyrotroph function by hormones or drugs.2 Tertiary hypothyroidism, which is a result of a deficiency in thyrotropin-releasing hormone secretion, in dogs has not been reported to our knowledge. Congenital defects in thyroid hormone synthesis in dogs have rarely been reported.2,3

Lymphocytic thyroiditis is characterized by diffuse infiltration of the thyroid gland by lymphocytes, plasma cells, and macrophages with subsequent destruction of the follicles and secondary fibrosis. This is a progressive disease process that sometimes requires 1 to 3 years to develop, and clinical signs are not evident until 75% of the gland is destroyed. There are several stages of the disease process; stage 1 is characterized by the presence of serum thyroglobulin and thyroid hormone autoantibodies, whereas stage IV involves overt clinical signs and low serum T4 concentration.2 Vaccine administration was originally hypothesized to be a contributing factor, but a more recent study4 revealed a lack of association between repeated vaccination and postmortem evidence of thyroiditis in Beagles.

Canine hypothyroidism has a reported prevalence of 0.2% to 0.8%. Clinical signs of primary hypothyroidism are usually present during middle age, with a mean age at diagnosis of 7 years. No sex predilection has been reported.3 Many breeds, including Golden Retrievers and Doberman Pinschers, are reported to be at a higher risk of developing hypothyroidism.3 Thyroiditis has been shown to be heritable in Beagles and Borzois.5,6 In Doberman Pinschers, English Setters, and Rhodesian Ridgebacks, an association of hypothyroidism with DLA class II haplotype DQA1*00101 (a major histocompatibility complex-encoded gene) has been reported.3

There are numerous clinical signs associated with hypothyroidism, which make diagnosis difficult in general, although some signs are more characteristic for specific dog breeds. More common metabolic clinical signs include lethargy, mental dullness, weight gain, inactivity, and weakness.7 Dermatologic clinical signs develop in 60% to 80% of hypothyroid dogs.8,9 Dermatologic abnormalities may include alopecia on the bridge of the nose, elbows, entire length of the tail, and trunk; a dull, brittle coat; thick, puffy, nonpitting skin; variable hyperpigmentation; seborrhea; recurrent skin infections; and lack of pruritus.10 Thyroxine is responsible for stimulating the anagen phase of the hair cycle; alopecia develops because of a lack of progression of the normal hair cycle.11 A variable amount of hyperpigmentation is most likely attributable to inflammation.

It is important to have a high index of suspicion for hypothyroidism prior to performing diagnostic testing. Dogs with no clinical signs of hypothyroidism have a greater chance of a false-positive test result than do dogs with signs of hypothyroidism.2 Basal thyroid hormone concentrations commonly measured for diagnosis of hypothyroidism include serum concentrations of total T4, free T4, and TSH. In combination, these assessments can increase the specificity for a correct diagnosis of hypothyroidism, but sensitivity can decrease. Serum total T4 concentrations can be decreased as a result of nonthyroidal illness or drug administration and increased as a result of the presence of total T4 autoantibodies. Commonly administered medications that are known to falsely decrease serum total T4 concentration include glucocorticoids, phenobarbital, and sulfonamides. Sighthounds and performance dogs (eg, sled dogs) are known to also have lower serum total T4 concentrations than other groups of dogs.2 Serum free T4 concentration is best measured by equilibrium dialysis and can be the most accurate single hormone measurement for diagnosis of hypothyroidism in dogs.3 Low serum total T4, low free T4, and high TSH concentrations are diagnostic for hypothyroidism. Results of microscopic examination of skin biopsy specimens are usually not diagnostic in canine cases of hypothyroidism.12 Nonspecific abnormalities suggestive of an endocrinopathy include hyperkeratosis, follicular keratosis, follicular dilatation, follicular atrophy, predominance of telogen hair follicles, empty hair follicles, epidermal melanosis, and sebaceous gland atrophy. Abnormalities supportive of hypothyroidism include vacuolated arrector pili muscles, hypertrophied arrector pili muscles, excessive dermal mucin content, and thickened dermis.13 Mucin can be identified as blue or blue-green material in skin sections stained with Alcian blue stain.12

For initial treatment of dogs with primary hypothyroidism, synthetic sodium levothyroxine is administered orally at a dosage of 0.02 mg/kg (0.009 mg/lb) every 12 hours. Adequate treatment effect should be confirmed with monitoring 4 to 8 weeks after initiation of levothyroxine administration. Treatment is considered adequate if serum total T4 concentration is high, normal, or slightly greater than the upper reference limit 4 to 6 hours after levothyroxine administration. Improvement in activity level should be evident in 1 to 2 weeks with weight loss in 8 weeks after initiation of treatment; however, dermatologic improvement may take several months.3

Although hypothyroidism is a commonly diagnosed disease in dogs, it is rare to make the diagnosis on the basis of histopathologic findings alone. Microscopic examination of skin biopsy specimens from dogs with hypothyroidism usually reveals nonspecific abnormalities suggestive of an endocrinopathy, which then requires further evaluation of serum thyroid hormone concentrations. Even though the diagnosis for the dog of the present report was made following histologic examination of skin biopsy specimens, it was verified by assessment of serum thyroid hormone concentrations.

For the dog of the present report, the dermatologic signs resolved within 2 months after initiation of levothyroxine administration. At that time, a thick undercoat was evident and the hair was soft to the touch. This dog had a combination of disease processes concurrently affecting the skin (flea bite hypersensitivity and hypothyroidism). This case is a good illustration of the need to perform additional diagnostic testing when evaluating a patient with partial post-treatment improvement of its dermatologic disease.

Footnotes

a.

Benadryl, McNeil-PPC, Fort Washington, Pa.

b.

Sentinel, Novartis, Lincoln, Neb.

c.

Comfortis, Elanco, Indianapolis, Ind.

d.

MiconaHex + Triz Shampoo, Dechra, Overland Park, Kan.

e.

GentaCalm, Dechra, Overland Park, Kan.

f.

Douxo Chlorhexidine Mousse, Sogeval, Irving, Tex.

References

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