JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M18

Signalment (JPC# 2367492):  Pig

 

HISTORY:  This pig had been on an experimental zinc deficient diet since weaning.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin:  Diffusely, the stratum corneum is expanded up to 200 µm by lamellations of keratin with retained nuclei (parakeratotic hyperkeratosis). There is marked epidermal hyperplasia with anastomosing rete ridges, projections of stratum spinosum and granulosum that interdigitate with the stratum corneum (papillated hyperplasia), and thickening of the stratum spinosum (acanthosis).  The stratum spinosum has intercellular edema characterized by prominent intercellular bridges (spongiosis).  Multifocally, hair follicular epithelium exhibits similar changes including epithelial hyperplasia and parakeratotic hyperkeratosis.  Follicular ostia and infundibula are often mildly ectatic and variably filled with lamellations of keratin admixed with moderate numbers of viable and necrotic neutrophils, fragmented hair shafts, and necrotic cellular debris (luminal folliculitis).  Within the superficial dermis, there are low numbers of predominantly perivascular lymphocytes, plasma cells, and macrophages with fewer eosinophils and neutrophils.  There is a mild increase in periadnexal and perivascular clear space (dermal edema) and ectatic apocrine glands.

 

MORPHOLOGIC DIAGNOSIS:  Haired skin, epidermis and follicular epithelium:  Hyperkeratosis, parakeratotic, diffuse, severe, with hyperplasia, mild lymphoplasmacytic dermatitis and neutrophilic luminal folliculitis, breed unspecified, porcine.

 

ETIOLOGIC DIAGNOSIS:  Zinc-responsive parakeratosis or dermatosis

 

CAUSE:  Zinc deficient diet, impaired zinc absorption / metabolism

 

CONDITION:  Zinc deficiency

 

GENERAL DISCUSSION: 

• Zinc (Zn) is required in many biophysiologic processes:
  • Zn is a component of >70 metalloenzymes and is a cofactor for other enzymes that regulate RNA and DNA metabolism
  • Zn is needed for bone and muscle growth, reproductive function, feed utilization, vitamin A absorption, normal leukocyte function, keratogenesis, and wound healing
• Zn deficiency can occur in any domestic species, but most often manifests as parakeratosis in pigs and dogs
  • Diffuse parakeratosis can also be seen in many chronic dermatoses as well as zinc-responsive dermatosis, dermatophilosis, superficial necrolytic dermatitis, and thallotoxicosis

 

PATHOGENESIS: 

• Zn is important in skin protection against free radical-induced oxidative damage
• Hereditary Zn deficiency:
• Possible deficiency of Zn ligands necessary for intestinal transport of Zn
• Two biochemical pathways exist for absorption of Zn:
  • Passive diffusion of Zn into enterocytes (nonsaturable)
  • Transporter-dependent (saturable) - impaired in cattle
• Nutritional Zn deficiency:
  • Low concentrations of dietary Zn
  • Alterations of intestinal flora or enteric bacterial or viral infections can result in malabsorption of Zn and other nutrients
  • Excess phytates bind Zn (i.e. soybean phytic acid or high cereal diets)
  • Excess calcium, metals (i.e. iron), or vitamins chelate Zn, impairing its absorption
  • Low concentration of dietary free fatty acids

 

TYPICAL CLINICAL FINDINGS:

• Growing pigs (2-4 months of age) can exhibit parakeratosis
• Decreased appetite, decreased growth rate, listlessness, shivering, stiff or swollen joints, increased susceptibility to infections, inflamed nasal and/or oral mucosa

 

TYPICAL GROSS FINDINGS:

• Initial cutaneous lesions are usually symmetrical, erythematous macules on the lower limbs (particularly over joints), face (ears, eyes, snout), scrotum, tail
• Cutaneous lesions may develop into papules covered with a dry brown crust up to 2-3 mm thick that may be penetrated by deep fissures
• Tongue may appear "furred"
• Esophageal mucosa appears dull and white, not glistening and smooth

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Diffuse epidermal and follicular parakeratotic hyperkeratosis is the hallmark of Zn-responsive dermatoses, but is not present in all cases
• Hyperplastic superficial perivascular dermatitis; often eosinophilic and lymphocytic
• Hypergranulosis, acanthosis
• Intraepidermal pustular dermatitis and folliculitis with secondary bacterial infection

 

ADDITIONAL DIAGNOSTIC TESTS: 

• History, examination, skin biopsy, and response to Zn therapy add to final diagnosis
• Plasma or serum Zn levels are usually low, but results may not be accurate due to sampling, physiologic, and environmental factors

 

DIFFERENTIAL DIAGNOSIS: 

Gross differentials in the pig:

• Sarcoptic mange (I-P06): Usually intensely pruritic; skin scrape for mites
• Exudative epidermitis, Staphylococcus hyicus: Usually younger age group, predominately greasy crust
• Dermatosis vegetans: Hereditary disease of Landrace pigs with foot lesions including rings parallel to coronary grove
• Porcine juvenile pustular psoriasiform dermatitis (I-M14, pityriasis rosea): Lesions on ventral abdomen are symmetrical, forming mosaic or serpiginous pattern

 

COMPARATIVE PATHOLOGY:

Primates: Alopecia and thickening of the skin, particularly the tail; retarded skeletal growth; teratogenesis and prolonged parturition

Dogs

• Zinc-responsive dermatosis (presents as one of two clinical syndromes):
• Syndrome I:
• Primarily Siberian huskies and Alaskan malamutes, also Great Danes and Boston Terriers (Lee, Vet Dermatol 2016)
• Inherited defect of Zn absorption or metabolism
• Crusting, scaling, alopecia of periorbital skin, face, pressure points, footpads
• Parakeratosis extends into hyperplastic follicular infundibula; +/- dyskeratosis, spongiosis, dermatitis, hypogranulosis
• Hyperpigmentation with chronicity
• Hyperkeratotic footpads (DDx: canine distemper virus)
• Lifelong Zn supplementation required

• Syndrome II:
  • Occurs in rapidly growing, large breed dogs fed zinc deficient diet, or over-supplemented with chelating agents (calcium, phytates)
  • Considered rare due to balanced commercial dog foods
  • Similar lesions but more severe lesions than syndrome I
    • Only transient Zn supplementation required
  • Hereditary nasal hyperkeratosis of the Labrador retrievers
    • Autosomal recessive inheritance

Gross differentials of diffuse hyperkeratosis in the dog:

• Dermatophytosis, pemphigus foliaceus, and pyoderma

Histological differentials of diffuse hyperkeratosis in the dog:

• Lethal acrodermatitis of bull terriers: Autosomal recessive inheritance;  not responsive to oral Zn supplementation; pathogenesis of low plasma Zn disease is unknown, copper deficiency (presumed); causes growth retardation, progressive dermatopathy, paronychia, diarrhea, bronchopneumonia, and death by 18 months of age; thymic and lymph node hypoplasia and giant cell bronchopneumonia seen postmortem
• Superficial necrolytic dermatitis (I-M16): Distinct band of hydropic, pale keratinocytes within the stratum spinosum (red, white and blue)
• Vitamin A responsive dermatosis: Predominantly marked follicular keratosis on chest and abdomen; histologically there is
• Generic dog food dermatosis: Rapid onset; systemic illness is common
• Thallium toxicosis (I-T01, very rare, thallium banned in the U.S.): brick red mucous membranes; epithelial necrosis is common
• Canine distemper virus (I-V12): Hyperkeratotic foot pads 
• Sarcoptic mange (I-P06) and flea-hypersensitivity dermatitis: Diffuse parakeratosis with increased lymphocytes, eosinophils, plasma cells, and mast cells
• Perivascular dermatitis with hyperkeratosis: various degrees of orthokeratosis and/or parakeratosis
• Congenital follicular parakeratosis: cornification disorder of Rottweilers and Labrador retrievers; X-linked dominant inheritance; epidermis is acanthotic, hair follicles have marked papillated parakeratotic hyperkeratosis that forms conically shaped projections

Ruminants (goats, sheep, cattle, New World camelids):

• Dietary deficiency or diets with Zn high chelating agents (calcium, iron, phytates)
• Alopecia, scaling, crusting of skin on face, neck, distal extremities, and mucocutaneous junctions
• Histopathologic: Papillated epidermal hyperplasia, spongiosis, superficial perivascular lymphoeosinophilic dermatitis, with parakeratotic hyperkeratosis
• Parakeratosis also affects forestomachs
• Sheep:
• Wool-eating and drooling
• Orthokeratotic hyperkeratosis predominates
• Thin wool that loses its crimp and epilates easily; entire fleece can shed
• Normal ringed structure of the horns is lost; horns can shed
• New World camelids (Agnew, Camelidae 2018):
• Alopecia, dermal thickening, scaling, hyperpigmentation
• Lesions on the face, ventral abdomen, lateral thorax, and inguinal area.
• Those with darker fleeces are more susceptible to zinc-responsive dermatosis
• Cattle:
• Hereditary zinc deficiency (HZD)
  • Also called: lethal trait A46, hereditary parakeratosis, hereditary thymic aplasia, and edema disease
  • Commonly affected are young Fresian and black pied Danish calves of Friesian descent in Europe and shorthorn cattle in the U.S.
  • Crusting and alopecia on muzzle, eye, base of ears, ventral mandible
  • Lesions eventually spread to neck and skin over joints
  • Resolves with Zn supplementation
  • Defects in SLC39A4 gene causes intestinal malabsorption of zinc
  • Calves may develop conjunctivitis, rhinitis, bronchopneumonia, or diarrhea
  • Thymic hypoplasia with depletion of other lymphoid organs
  • Ddx: Phospholipase D4 Deficiency in Fleckvieh calves (Langenmayer, VetPath 22)

Equine:

• Reported in foals with a Zn deficient diet
• Alopecia and scaling of the limbs, ventral abdomen, and thorax

 

REFERENCES: 

1. Agnew D. Camelidae. In: Terio KA, McAloose D, St. Leger JA, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:189.
2. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Diseases of the dermis. In: Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Publishing Professional; 2005:188-191.
3. Langenmayer MC, Jung S, Fux R, Wittlinger C, Tschoner T, Majzoub-Altweck M, Knubben-Schweizer G, Fries R, Hermanns W, Trefz FM. Macrophages in dermal disease progression of phospholipase D4-deficient Fleckvieh calves. Vet Path. 2022 Mar; 59(2):319-327.
4. Lee FF, Bradley II CW, Cain CL, et al. Localized parakeratotic hyperkeratosis in sixteen Boston Terrier dogs. Vet Dermatol. 2016(27):384-396.
5. Maudlin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th Philadelphia, PA: Elsevier Saunders; 2016: 532-533, 584-586. 
6. Miller WH, Griffin CE, Campbell GA. Muller & Kirk’s Small Animal Dermatology. 7th ed. Philadelphia, PA: WB Saunders Co.; 2013: 583, 689-692.
7. Pritzker KPH, Kessler MJ. Arthritis, muscle, adipose tissue, and bone diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research Volume 2: Diseases. 2nd ed. London, UK: Academic Press; 2012:663.
8. Welle MM, Linder KE. The integument. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 1200-1201.

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