JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
March 2022
M-M07

Signalment (JPC #2314370):  A young guinea pig

 

HISTORY:  This guinea pig was fed autoclaved commercial rabbit food for a period of 6 weeks prior to death.

 

HISTOPATHOLOGIC DESCRIPTION:  Stifle joint (femur, tibia, and patella):  The femoral and tibial physeal cartilage is diffusely irregular and thinned, characterized by shortening, loss, and disorganization of chondrocyte columns within the zone of proliferation, a poorly discernible zone of hypertrophy, and a thin resting zone. There is a marked paucity of primary and secondary spongiosa. Remaining primary spongiosa consist of spicules of cartilage lacking osteoid seams (scorbutic lattice) that are lined by few osteoblasts and that extend into the metaphyses.  Multifocally there are coalescing microfractures of the scorbutic lattice often surrounded by hemorrhage, fibrin, and edema. Diffusely the medullary cavity of the femur and tibia contain reduced amounts of epiphyseal and metaphyseal trabecular bone, as well as thinning of the cortical bone (osteopenia).  Multifocally within the tibial metaphyseal medullary cavity, hematopoietic elements are replaced by loosely arranged mesenchymal cells (myelofibrosis) and hemorrhage, fibrin, and edema.  Hemorrhage, fibrin, and edema frequently separates and elevates the periosteum from the cortex and extends into the adjacent periarticular connective tissue and skeletal muscle.

 

MORPHOLOGIC DIAGNOSIS:  Tibia and femur, physes and periarticular tissue:  Failure of endochondral ossification, with scorbutic lattice formation, osteopenia, microfractures, and subperiosteal and periarticular hemorrhage, guinea pig (Cavia poricellus), rodent.

 

ETIOLOGIC DIAGNOSIS:  Scorbutic osteoarthropathy

 

CAUSE:  Hypovitaminosis C / Ascorbic acid deficiency

 

CONDITION:  Scurvy

 

GENERAL DISCUSSION:

• Most mammals synthesize ascorbic acid (Vitamin C) from glucose via glucuronic & gulonic acid via the enzyme L-gulonolactone oxidase
• Animals that lack the enzyme L-gulonolactone oxidase and therefore cannot synthesize L-ascorbic acid and so require sufficient dietary vitamin C include: Humans, nonhuman primates (except some prosimians), guinea pigs, capybaras, Indian fruit bats, several species of birds (red-vented bulbul bird, northern shrike, Indian pistrel), cetaceans and fish (channel catfish, trout, salmon, most aquarium fish)
• Ascorbic acid is required by fibroblasts, odontoblasts, and osteoblasts for the formation of collagen, dentin, and osteoid
• Hallmarks of scurvy are capillary hemorrhage and lack of bone deposition
• Disease is most severe in young, growing animals
• Guinea pigs with prenatal vitamin C deficiency serve as a model of human Lissencephaly type II
• Severity of changes depends on degree of dietary insufficiency

 

PATHOGENESIS:

• Ascorbic acid (vitamin C) is required for hydroxylation of proline and lysine, essential in the formation of collagen's helical structure, rigidity, and strength
• Lack L-gulonolactone oxidase AND decreased dietary vitamin C> decreased hydroxylation of proline/lysine> decreased deposition of collagen and decreased cross linking of fibrillar collagen (types 1-5)> decreased amounts of collagen and weak cartilage; decreased osteoid (microfractures); increased blood vessel fragility with hemorrhage (usually periarticular because most collagen turnover & blood vessels are epiphyseal/metaphyseal); loose attachment of periosteum to bone/tooth loss
• Anemia results from a combination of hemorrhage and interference with folate metabolism and iron absorption
• Focal myocardial necrosis sometimes occurs, resulting in sudden death
• Other functions of ascorbic acid:
  • Catabolism of cholesterol to bile acids
  • Macrophage migration and granulocyte phagocytosis
  • Cofactor of dopamine beta-oxidase, which converts dopamine to noradrenaline
  • Antioxidant
  • Folate metabolism
  • Iron absorption

 

TYPICAL CLINICAL FINDINGS:

• Joint pain, reluctance to move, lameness, muscle wasting, scruffy haircoat, anorexia, delayed healing of skin wounds, +/- anemia
• Subclinical form in guinea pigs:
  • Anorexia, weight loss, diarrhea, and death
  • Bone lesions only evident histologically

 

TYPICAL GROSS FINDINGS:

• Periarticular hemorrhage; gingival swelling, hemorrhage, erosion, ulceration, tooth loss
• Swollen joints/enlarged costochondral junctions (“scorbutic rosary”)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Initially, dilation of metaphyseal vessels
• Thin physis with irregular columnization; primary spongiosa remain cartilaginous without replacement by bone
• Most characteristic lesions are in metaphysis- naked (lacking osteoid deposition) spicules of calcified cartilage (“scorbutic lattice”) derived from zone of provisional calcification in the growth plate; reduced or absent deposition of osteoid on this cartilage framework
• Decreased numbers of osteoblasts
• Microfractures of the trabeculae and metaphyseal hemorrhage
• Proliferation of mesenchymal cells in the medullary cavity (displacing hematopoietic cells) loosely arranged with interspersed aggregates of eosinophilic material
• Decreased osteoclasts, with reduced matrix remodeling
• Resorption of dentin, derangement of odontoblasts, and fibrosis of the pulp during the early stages of the disease
• Cortices of long bones may be thin
• Periosteal and subperiosteal hemorrhages may be present

 

ADDITIONAL DIAGNOSTIC TESTS:

• Radiographic lesions:
  • Dense metaphyseal line (collapsed fragile spicules of mineralized cartilage)
  • Submetaphyseal translucent zone
  • Epiphyseal fractures

 

DIFFERENTIAL DIAGNOSIS:

• Rickets: Abnormal endochondral ossification from inadequate mineral deposition; soft and pliable bones with enlarged costochondral junctions; thickened and disordered zone of hypertrophied cartilage cells in the physis, defective calcification, failure of normal cartilage degeneration, and deposition of excess osteoid in the metaphysis
• Osteoporosis/Osteopenia: Reduced bone mass with thin, porous cortices; reduced number, size, and connectivity of bony trabeculae
• Osteogenesis imperfecta: Defect in type 1 collagen synthesis resulting in decreased bone production; lack of cortical bone and thin, loosely spaced trabeculae of unmodelled bone with retention of cartilage cores; multiple fractures

 

COMPARATIVE PATHOLOGY:

• Humans, most nonhuman primates (except some prosimians), capybaras, Indian fruit bats, several bird species (e.g. red-vented bulbul bird, northern shrike, Indian pipstrels) and fish species (channel catfish, trout, salmon, most aquarium fish) lack the enzyme L-gulonolactone oxidase and cannot synthesize ascorbic acid
• Squirrel monkeys
  • Pericranial hemorrhage resulting in large hematomas that become surrounded by a thin rim of bone (cephalohematoma) in affected young animals (predominant lesion)
  • Long bones: Metaphyseal fibrosis, premature epiphyseal closure, and reduced cartilage cellularity
  • Oral lesions have not been seen in this species
• Rhesus macaques: Metaphyseal fractures with periosteal hemorrhage within long bones
• Pigs: Autosomal recessive mutation involving L-gulonolactone oxidase; normal until 2-3 weeks post-weaning (milk is high in ascorbic acid); classic scorbutic lesions, though more severe than other species; subperiosteal accumulations of clotted blood around shafts of affected bones
• ODS rats (Osteogenic Disorder Shionogi): od/od homozygotes lack L-gulonolactone oxidase and develop scurvy
• Fish: Develop lordosis, scoliosis, hemorrhage, and depigmentation; branchial arch and gill filament deformations
• Reports of suspected hypovitaminosis C in hand-reared frugivorous bats (Pteropus pumilus) and sanguinivorous bats (Desmodus rotundus); wing hematomas and gingival bleeding with resolution following dietary supplementation

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016: 239-241.
2. Capo I, Hinic N, Lalosevic D, et al. Vitamin C depletion in prenatal guinea pigs as a model of lissencephaly type II. Vet Pathol. 2015;52(6):1263-1271.
3. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:83-84.
4. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 499, 501.
5. Farina LL, Lankton JS. Chiroptera. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 610.
6. Frasca Jr. S, Wolf JC, Kinsel MJ, Camus AC, Lombardini ED. Osteichthyes. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 955.
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8. Lowenstine LJ, McManamon R, Terio KA. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 375.
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10. Miller MA, Zachary JF. Mechanisms and morphology of cellular injury, adaptation, and death. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Inc; 2017:59,122,347.
11. Pritzker KPH, Kessler MJ. Arthritis, Muscle, Adipose Tissue, and Bone Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2, 2^nd San Diego, CA: Elsevier Inc; 2012:660-661.

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