JPC SYSTEMIC PATHOLOGY

ENDOCRINE SYSTEM

January 2025

E-M05 (NP)

 

Signalment (JPC #2677977): 4-year-old castrated male German shorthair pointer dog 

 

HISTORY: Tissue from a dog with chronic weight loss, azotemia, and hyperkalemia. 

 

HISTOPATHOLOGIC DESCRIPTION: Adrenal gland: Diffusely, the cortex is reduced to a thin rim of tissue with loss of the distinct radial arrangement of cells within all zones, and retention of remnants of stromal elements including thin strands of supporting fibrous connective tissue and blood vessels. The capsule is thickened up to 2-3x normal by fibrous connective tissue that is accentuated by subjacent cortical stromal collapse. The cortex is infiltrated by moderate numbers of lymphocytes, plasma cells, macrophages, and fewer eosinophils admixed with hemorrhage, fibrin, and edema. Macrophages often have microvacuolated cytoplasm and intracytoplasmic golden brown, granular pigment (hemosiderin). There are multifocal clusters of remaining zona reticularis cells with foamy, vacuolated cytoplasm (lipoidal degeneration).

 

MORPHOLOGIC DIAGNOSIS: Adrenal gland, cortex: Atrophy and loss, pancortical, diffuse, severe, with lymphoplasmacytic and histiocytic adrenalitis, German shorthair pointer, canine.

 

CONDITION: Primary (idiopathic) hypoadrenocorticism (Addison’s disease)

 

GENERAL DISCUSSION:

• Idiopathic adrenocortical atrophy is the most frequently observed lesion in dogs with hypoadrenocortism; typically bilateral and affecting all 3 layers of cortex
• Thus, typically deficient production of all classes of corticosteroids:
  • Zona glomerulosa: Secretes mineralocorticoids (aldosterone); secretion independent of ACTH
  • Zona fasciculata: Secretes glucocorticoids (cortisol) and small amounts of androgens; secretion controlled by hypothalamic-pituitary axis
  • Zona reticularis: Secretes androgens and glucocorticoids
• Can occur in any breed, sex, or age, but most frequent in young adult dogs 
• Loss of 85-90% of adrenocortical cells must occur before clinical signs are obvious

 

PATHOGENESIS:

• Primary hypoadrenocorticism (adrenal-dependent hypoadrenocorticism/Addison’s disease)
  • Idiopathic: Unknown pathogenesis; likely immune mediated destruction of cortex – generation of autoantibodies against cortical cells with progressive degeneration and lymphoplasmacytic adrenalitis 
  • Granulomatous disease: Destruction of adrenal cortex with histoplasmosis, blastomycosis, coccidiomycosis, or tuberculosis
  • Systemic viral disease: ovine herpes virus 2 (malignant catarrhal fever) can cause lymphocytic adrenalitis in cattle. 
  • Other: Amyloidosis; infarction secondary to coagulopathy; cancer metastasis and subsequent destruction of adrenal cortex; hemorrhage and necrosis with replacement by fibrous connective tissue
• Reduced secretion of mineralocorticoids (primarily aldosterone) = marked alterations in serum potassium, sodium, and chloride levels due to decreased activity of Na-K-ATP pumps in renal collecting tubules
  • Kidney excretes less potassium, leading to severe hyperkalemia and marked cardiovascular disturbances 
  • Kidney resorbs less sodium/chloride in renal tubules, leading to various degrees of hypernatriuria and hyperchloruria and corresponding decreases in the serum; water follows the sodium excretion, resulting in dehydration 
• Reduced secretion of glucocorticoids results in:
  • Failure of gluconeogenesis and increased insulin sensitivity = moderate hypoglycemia 
  • Lack of negative feedback on the pituitary gland, increased release of ACTH that binds to melanocyte-stimulating hormone (MSH) in skin = hyperpigmentation 
  • Lack of inhibition of lymphocyte production or distribution = lymphocytosis 
• Hypercalcemia occurs in 30% of dogs; unknown mechanism, though possibly due to decreased renal excretion and increased calcium binding to protein or citrate 

 

TYPICAL CLINICAL FINDINGS:

• Chronic, insidious illness; initially episodic (waxing-waning) and only manifested in times of stress
  • Recurrent episodes of gastroenteritis – vomiting, diarrhea, anorexia 
  • Slowly progressive loss of body condition
  • Failure to respond appropriately in stressful situations – hypotension, weakness
  • Hyperpigmentation 
• Often present in acute circulatory collapse (shock-like coma) and renal failure 

 

CLINICAL PATHOLOGY:

• Hyponatremia and hyperkalemia 
  • Sodium/potassium ratio less than 27:1 is highly suggestive of adrenal insufficiency (normal range 27:1 to 40:1)
• ACTH stimulation (test of choice) 
  • No cortisol response following ACTH administration
  • The zones of adrenal cortex appear to become damaged at the same rate, so ACTH stimulation is used to directly assess cortisol synthesis and indirectly assess aldosterone synthesis
  • Does not distinguish primary from secondary adrenocortical insufficiency
• Hypochloridemia
• Hypoglycemia 
• Hypercalcemia – 30% of Addison’s patients 
• Hemoconcentration, azotemia 
• Classic leukogram = neutropenia, lymphocytosis, eosinophilia, and normal monocyte numbers; AKA absence of a stress leukogram in stressful situations
• Baseline plasma cortisol may be within reference interval or decreased

 

TYPICAL GROSS FINDINGS:

• Bilateral adrenal cortical atrophy
• Compensatory pituitary hyperplasia 
• Microcardia (due to hypotension)
• Dehydration
• Hyperpigmentation
• Enlarged lymph nodes (lymphoid hyperplasia)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Adrenal cortex is reduced to 1/10 or less of its normal thickness with marked atrophy of all three zones
• Adrenal medulla and capsule become relatively more prominent
• Multiple foci of lymphocytes and plasma cells early in disease giving way to atrophy and fibrosis and condition progresses
• Thickened capsule from collapse of cortex and fibroblast proliferation

 

DIFFERENTIAL DIAGNOSIS:

For hypoadrenocortisim:

• Secondary hypoadrenocorticism
  • Naturally occurring disease (pituitary dependent hypoadrenocorticism); reduced secretion of ACTH by pituitary (i.e. due to neoplasia) resulting in decreased synthesis of adrenocortical hormones 
  • Iatrogenic (E-M04): Acute discontinuation of chronic corticosteroid administration, or overdosage with o,p'-DDD (mitotane) for treatment of hyperadrenocorticism

 

For hyperkalemia:

• Acute renal failure: Important differential diagnosis for clinical signs and clinical pathology of Addison's disease in general
• Urinary outflow obstruction
• Severe metabolic acidosis
• Chylous pleural effusion
• Pseudohyperkalemia: Akita (large concentration of potassium in RBCs); hemolyzed blood sample

 

COMPARATIVE PATHOLOGY:

• Feline: Rare; may be primary (idiopathic) or secondary (administration of 
• Hoffmann’s two-toed sloth and giant ant eater: similar clinically to that in dogs

 

REFERENCES:

1. Agnew D, Nofs S, Delaney MA, et al. Xenartha, Erinacoemorpha, Some Afrotheria, and Phloidota. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:521.
2. Capen CC. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol 3. 6^th ed. Philadelphia, PA: Elsevier; 2016: 341-342.
3. Miller MA. Endocrine System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:792-793.
4. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2^nd Ed. Ames, IA: Blackwell Publishing; 2008:83, 451, 515, 519, 601-602.

 

 

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