JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

November 2023

U-M02 (NP)

 

Signalment (JPC# 86-950): A 4-month-old calf

 

HISTORY: Tissue from a calf euthanized because of necrotizing glossitis and abscessation of the mandible

 

HISTOPATHOLOGIC DESCRIPTION: Kidney, periodic acid-Schiff stain (PAS) stain: Diffusely, cortical tubular epithelial cells contain single to multiple, irregularly round, intracytoplasmic, variably PAS-positive (bright pink to red) bodies that measure up to 15um in diameter. Multifocally, medullary tubular epithelial cells occasionally contain similar intracytoplasmic, PAS-positive material. There is mild diffuse subcapsular tubular ectasia. Focally, the interstitium is minimally expanded by few lymphocytes and plasma cells.

 

MORPHOLOGIC DIAGNOSIS: Kidney, tubular epithelium: Intracytoplasmic PAS-positive bodies, diffuse, moderate, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS: Hereditary renal tubule hypergranulation

 

CAUSE: Hereditary mutation in LYST or Beige gene

 

CONDITION: Chédiak-Higashi Syndrome (CHS)

 

GENERAL DISCUSSION:

• Autosomal recessive disorder of Aleutian mink; Hereford, Japanese Black, and Brangus cattle; blue smoke Persian cats; beige rats and mice; killer whales; blue and silver foxes; white tigers; bison; and man
• Results in the accumulation of abnormally large granules in a variety of cell types including leukocytes, platelets, hepatocytes, renal tubular epithelium, neurons, endothelial cells, and melanocytes
• Granules are:

• Melanosomes (melanocytes)
• Lysosomes (many cell types)
• Cytoplasmic granules (e.g. fused primary and secondary granules of neutrophils) 

• Affected animals have an increased susceptibility to infection (a common cause of death of animals with CHS), partial oculocutaneous hypopigmentation (partial albinism), photophobia, and bleeding tendencies

 

PATHOGENESIS:  

• Autosomal recessive genetic defect (LYST [CHS-1] or Beige gene) which codes for a membrane-associated lysosomal trafficking regulator

• Results in reduced or absent lysosome formation, migration, and exocytosis; abnormal (usually excessively large) granule formation in many cells (e.g. lysosomes, cytolytic granules, platelet granules, and melanosomes)

• The fusion of pre-existing normal granules results in the formation of giant granules within the cytoplasm of neutrophils, eosinophils, basophils, monocytes, lymphocytes, thrombocytes, melanocytes and other cell types, including hepatocytes, renal tubule epithelial cells, neurons, and endothelial cells 
• Immune dysfunction:

• Leukocytes exhibit defective motility and chemotactic response
• Impaired fusion of lysosomes with phagosomes results in decreased bactericidal activity with normal neutrophil counts; phagocytosis is unaffected. Neutrophil enlarged granules are azurophilic granules
• Loss of CD8 T-cell and natural killer cell cytotoxic activity, resulting in increased susceptibility to neoplasia (especially lymphoproliferative tumors) and viral infection

• Hypopigmentation: Partial albinism (color dilute effect) abnormally large melanosomes are difficult to pass from melanocytes to  keratinocytes
• Bleeding tendencies: Platelet dense (delta) granules are either absent or indistinct with defective storage of ADP (ADP normally promotes platelet adherence and aggregation), resulting in deficient platelet clumping especially in response to exposed collagen

• Dense granules contain serotonin, histamine, epinephrine, Mg⁺⁺, ATP/ADP, Ca⁺⁺, GTP/GDP
• Coagulation is normal in Japanese black cattle and cats with CHS

 

TYPICAL CLINICAL FINDINGS:

• Skin: Hypopigmentation 
• Eyes: Photophobia, lacrimation, cataract (cats) 
• Bleeding disorders: Platelet counts are normal but have reduced dense granules; impaired aggregation resulting in prolonged hemorrhage from minor wounds (prolonged buccal mucosal bleeding time test)
• Leukocyte dysfunction: Reduced innate immunity; recurrent infections. Neutrophil counts are normal to low (in cats). 
  1. Aleutian mink are more susceptible to parvovirus than normal mink 
  2. Beige rats are more likely to get ulcerative dermatitis syndrome (S. aureus)
  3. Blood smear: granulocytes with large cytoplasmic granules

 

TYPICAL GROSS FINDINGS:  

• Skin: Hypopigmentation
• Eyes: Abnormal ocular pigmentation (pseudoalbinism); cataracts (cats)
• Occasionally cutaneous abscesses, oral ulcers, and subcutaneous hematomas secondary to leukocyte and platelet defects

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Hallmark of the disease is the presence of enlarged granules within melanocytes, neutrophils, eosinophils, and monocytes
• Haired skin: Irregular clumping of melanin within hair shafts, decreased number of melanin granules within the pigmented layer of the epidermis
• Eyes: Hypopigmentation of the iris and fundus
• Kidney: Variably sized, irregular, PAS-positive granules within the tubule epithelial cells

 

ULTRASTRUCTURAL FINDINGS:

• Giant granules in all granule-containing cells
• Marked decrease of osmiophilic dense bodies and cytoplasmic vesicles

 

ADDITIONAL DIAGNOSTIC TESTS:  

 

DIFFERENTIAL DIAGNOSIS:

• Eosinophilic granules in renal tubular epithelial cells: Histiocytic sarcoma in rodents
• Periocular albinism and platelet disfunction: Hermansky-Pudlak syndrome in man
• Periocular color dilution: Copper deficiency in ruminants (especially sheep)
• Enlarged intracytoplasmic granules in leukocytes: Mucopolysaccharidosis VI/VII

 

COMPARATIVE PATHOLOGY:  

• Cats: CHS is the cause of the blue-smoke color of certain Persian cats; it is frequently associated with cataracts and increased susceptibility to respiratory infections and neonatal septicemia
• Mink: CHS is the cause of the blue-grey fur color of Aleutian mink; although all mink are susceptible to Aleutian mink disease parvovirus, mink with the Aleutian trait are particularly susceptible to severe and fatal disease (U-V05, P-V14)

 

REFERENCES:  

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016:143. 
2. Durham AC, Boes KM. Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:831.e1.
3. Mauldin EA, Peters-Kennedy J.  Integumentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:556.
4. Miller MA, Lyle LT, Zachary JF. Mechanisms and Morphology of Cellular Injury, Adaptation, and Death. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:50. 
5. Snyder PW. Diseases of Immunity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:337-338. 
6. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 99.
7. Tizard IR. Veterinary Immunology, an Introduction. 8th ed. St. Louis, MO:  Saunders Elsevier; 2009:449.
8. Valli VEO, Kiupel M, Bienzle D.  Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:110,259.
9. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1201.
10. Zablotsky SM, Walker DB. Peripheral Blood Smears. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:481.

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