JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M20

Signalment (JPC #86N264D):  A 6-year-old Shire gelding

 

HISTORY:  This horse had a 1-month history of lameness and reluctance to move.

 

HISTOPATHOLOGIC DESCRIPTION:  Hoof and 3rd phalanx (P3): Diffusely the dermal-epidermal lamellar margin is highly irregular and the normal architecture of the hoof wall is obscured by degeneration, necrosis, and marked irregular hyperplasia of the epidermal laminae. Diffusely, the primary epidermal laminae are markedly elongated and expanded up to four times normal by parakeratotic and orthokeratotic hyperkeratosis and occasionally contain accumulations of lamellated keratin or dyskeratotic keratinocytes.  Secondary epidermal laminae are disorganized, blunted, clubbed, thickened, or elongated; occasionally form anastomoses; and are multifocally lost in groups or individually. Remaining epidermal laminar keratinocytes are often swollen with abundant pale, microvacuolated cytoplasm (intracellular edema) or are separated by clear space (intercellular edema). In all layers of the epidermis, there are occasional scattered keratinocytes that have intensely eosinophilic cytoplasm and a pyknotic nucleus (necrosis). Multifocally, there are longitudinal clefts separating the epidermal laminae and basement membrane from the adjacent dermal laminae; clefts rarely contain a small amount of cellular debris and few erythrocytes. There are increased clear spaces separating fibrous connective tissue in both primary and secondary dermal laminae, and lymphatics within the laminar corium are frequently dilated (edema). Multifocally, the P3 exhibits bony remodeling characterized by moderate numbers of osteoclasts within Howship’s lacunae, scalloped bony trabecular margins lined by numerous osteoblasts, and thin basophilic reversal lines that roughly parallel the surface. P3 is multifocally capped by irregular proliferations of woven bone and the medullary cavity is filled with loose, myxomatous fibrous connective tissue (medullary fibromyxoid proliferation). Palmar/plantar to P3 there is a nodular accumulation of degenerate neutrophils, macrophages, hemorrhage, fine fibrillar and beaded eosinophilic material (fibrin), and eosinophilic cellular and karyorrhectic debris (necrosis).  

 

MORPHOLOGIC DIAGNOSIS:  Hoof and 3^rd phalanx:  Epidermal laminar degeneration and necrosis, chronic, diffuse, severe, with epidermal hyperplasia, hyperkeratosis, multifocal basement membrane retraction, edema, and bony remodeling of P3, Shire, equine.

 

CONDITION:  Laminitis

 

SYNONYM:  Founder

 

GENERAL DISCUSSION:

• Laminitis is a common, painful condition of horses resulting in the separation of the epidermal laminae from the underlying basement membrane of the dermal laminae of the hoof
• Occurs in any hoofed species, especially horses & cattle
• Obese ponies are at increased risk
• Three histologic grades, which correspond to degree of lameness

 

PATHOGENESIS: 

• The pathogenesis of laminitis is not completely understood, and is likely multifactorial;
• Severe clinical signs are due to the separation of the distal phalanx (P3/coffin bone) from the inner hoof wall (rather than primary inflammation)
• Current proposed mechanisms for the onset of laminitis: Inflammatory cytokines à increase in matrix metalloproteinases-2 and -9 (MMP-2, MMP-9) à breakdown of epidermal laminae (elongation and disorganization of basal and parabasal keratinocytes, attenuation of tips of SEL) and detachment of basement membrane (BM) à loss of BM à separation of dermal and epidermal laminae (key in loss of structural integrity of P3/hoof wall attachment) à collapse of secondary laminae à loss of capillaries à increased resistance to blood flow, arteriovenous shunting, and eventual ischemic damage
• 4 Distinct forms of laminitis (not mutually exclusive):
  1. Inflammatory laminitis: Release of inflammatory toxins/cytokines (inflammatory theory, due to e.g. carbohydrate overload, black walnut-induced, sepsis, systemic inflammation caused by GI disease, pneumonia, and septic metritis) à degradation of BM and dyshesion of epithelial cells from BM, Matrix Metalloproteinase (MMP) activation (enzymatic theory), leukocyte infiltration, hemodynamic changes (vascular theory)
  2. Endocrinopathic laminitis/laminopathy: Insulin resistance, obesity, pituitary pars intermedia dysfunction, hyperinsulinemia, +/- corticosteroid-induced; little if any inflammation, stretching of the secondary laminae (rather than early separation from BM) leading to eventual separation at the tips of the secondary epidermal laminae
  3. Contralateral limb laminitis/laminopathy: Initiated by poor blood flow/ischemia à enzyme activation and BM degradation + effects of increased load bearing (tension and stretch on lamellar tissues)
  4. Traumatic laminitis (“road founder”): Secondary to intense training and excessive contusion of repeated foot trauma
• Commonalities to all forms: Dermal-epidermal separation at the interface of the lamellar basal epithelial cells and the underlying BM and dermis
• 3 phases of laminitis
  1. Developmental: Prodromal, pre-clinical
  2. Acute: Increased hoof wall temperature, bounding digital pulse, severe pain, little gross alteration (no hoof deformity) but may have congestion/hemorrhage of laminar dermis and swelling above coronary band; may have acute separation/displacement of P3 (“sinker”)
  3. Subacute: If no radiographic changes after 72hrs of acute onset, subacute phase begins and can last 8-12 weeks.
  4. Chronic laminitis (founder): Associated with rotational or vertical displacement of P3 relative to the hoof wall due to loss of interlocking force of epidermal laminae; if severely affected, P3 may penetrate the sole; the space between P3 and the hoof wall is filled with firm white tissue (proliferative epidermis), toe turns up, and cranial aspect of hoof has divergent horizontal ridges

 

TYPICAL CLINICAL FINDINGS:

• Pain, lameness, abnormal stance, reluctance to move
• Pounding digital pulses, increased temperature of hoof wall

 

TYPICAL GROSS FINDINGS: 

• Acute: Swelling of coronary band
• Chronic: Circumferential divergent hoof rings, altered hoof growth, flattened sole, rotation +/- penetration of third phalanx through sole, depressed coronary band

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Acute:

• Secondary lamina lose their normal “club” shape and become elongated, tapered, and disorganized with swelling, vacuolization, and degeneration of secondary laminar epithelial cells
• Separation of secondary laminar epithelial cells from basement membrane, first in the region of parabasal cell attachment and later at basal cells (confirm with PAS), clumping of secondary laminar epithelial cells, loose aggregates of BM free within dermis
• Congestion, hemorrhage, and edema

Chronic:

• Marked irregular hyperplasia and hyperkeratosis of the epidermal laminae
• Regenerated secondary laminae may have disrupted architecture and may form anastomosing and irregular epidermal cords
• Remodeling of P3, including osteoclastic resorption, bony remodeling, and medullary fibromyxoid proliferation

 

ULTRASTRUCTURAL FINDINGS:

• Shrinkage and loss of hemidesmosomes in basal epithelial cells
• Separation of basement membrane from epithelial cells
• Basal epithelial cell degeneration: collapse of cytoskeleton tonofilaments, rounding of basal cell nuclei

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Radiography to determine rotation of P3, characterized by a lack of parallelism on the lateral projection between the hoof wall and cranial face of P3
• Digital venograms and perfusion casts; decreased perfusion indicates a worse prognosis
• Magnetic resonance imaging

 

DIFFERENTIAL DIAGNOSIS:

• Gross: Selenium toxicity results in hoof deformation and sloughing

 

COMPARATIVE PATHOLOGY:

• Laminitis can occur in all ungulates
• Pigs and ruminants: Laminar epidermis consists of primary laminae only, no secondary laminae
• Cattle:
  • Pathogenesis: Several causes in cattle including carbohydrate overload, metritis, ketosis, mastitis, and a heritable form in Jersey cattle
  • Microscopic findings: Chronic cases may exhibit arteriosclerosis (unlike horses), chronic dermal granulation tissue, thrombosis, perineural fibrosis, perivascular accumulations of macrophages with hemosiderin, parakeratotic and orthokeratotic hyperkeratosis
  • Gross findings: Characteristic “slipper foot” with chronic recurrent bouts of subclinical laminitis.
• Cattle, Sheep, Pigs: Foot rot or hoof damage and secondary infection can result in laminitis; acute cases can also exhibit perineural edema and swelling of endothelial and smooth muscle cells of vessels; common causes of foot rot are:
  • Cattle and sheep: Bacteroides nodosus, Fusobacterium necrophorum
  • Pigs: Fusobacterium necrophorum, Trueperella pyogenes, Borrelia suilla
• Sheep:
• The use of dirty, contaminated plunge baths leads to infection of skin abrasions, resulting in cellulitis and eventually laminitis; Erysipelothrix rhusiopathiae (I-B08) is most common, Bluetongue virus (D-V16, M-V01, N-V02) can also lead to degeneration and inflammatory changes

 

References:

1. Mauldin EA, Peters-Kennedy J. Integumentary system. In: In: Maxie MG Jubb, Kennedy,and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Ltd. 2016:702-703.
2. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 1203-1209.

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