JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
January 2022
E-M01

Signalment (JPC #1939231):  BB/Wistar rat

HISTORY:  None

SLIDE A: HISTOPATHOLOGIC DESCRIPTION:  Pancreas:  There is a diffuse decrease in number of the islets of Langerhans.  The few remaining islets are infiltrated by moderate numbers of lymphocytes, plasma cells, and fewer histiocytes which occasionally extend into the surrounding pancreatic acini.  Multifocally the periductal connective tissue is moderately expanded by a similar inflammatory infiltrate. 

MORPHOLOGIC DIAGNOSIS:  Pancreas, islets of Langerhans:  Loss, diffuse, moderate, with lymphocytic insulitis, BB/Wistar rat, rodent.

ETIOLOGIC DIAGNOSIS:  Immune-mediated insulitis and atrophy

SLIDE B: HISTOPATHOLOGIC DESCRIPTION:  Thyroid gland:  There is diffuse infiltration of thyroid architecture by numerous lymphocytes, plasma cells, and fewer histiocytes that replace 80% of thyroid follicles and separate, surround, and compress remaining follicles that are either small and irregular, collapsed with little colloid, or are enlarged up to 200 um in diameter and contain luminal eosinophilic cellular and karyorrhectic debris (necrosis), sloughed epithelial cells, and few macrophages and neutrophils admixed with variable amounts of colloid.  Multifocally, the adjacent fibroadipose tissue and brown fat is expanded by few lymphocytes and neutrophils and a mild amount of clear space separates the connective tissue (edema).

Parathyroid gland: Essentially normal.

MORPHOLOGIC DIAGNOSIS:  Thyroid gland:  Thyroiditis, lymphoplasmacytic, diffuse, severe, with mild periglandular steatitis, BB/Wistar rat, rodent.

ETIOLOGIC DIAGNOSIS:  Immune-mediated thyroiditis

GENERAL DISCUSSION:

• > 80% of diabetes-prone BioBreeding (BBDP) rats develop spontaneous insulin-dependent diabetes mellitus, characterized by autoimmune mediated destruction of insulin secreting beta-cells in islets of Langerhans with concurrent T-cell deficiency
• Also seen in Wor-BB rats which become diabetic but have normal numbers of T-cells
• Up to 50% of diabetic BB rats also develop lymphocytic thyroiditis

PATHOGENESIS:

• Mutation in IAN-5 > deficiency in RT6+ T-cells (immunoregulatory CD4+ and CD8+ T-cells) > development of autoimmunity directed against islet cells of the pancreas
• Islet cells constitutively express eotaxin, which, in the face of a lack of appropriate immunoregulation, signals accumulation of eosinophils, mast cells, and macrophages; these cells express IFN-gamma, IL-6, IL-1β, and TNF-α, which results in a lymphoplasmacytic inflammatory reaction
• Molecular mechanism of pancreatic beta-cell destruction predominantly involves necrosis, with apoptosis playing only a minor role
• Variability in insulitis and thyroiditis due to differences in interactions between MHC II genes and organ specific autoantibodies
• Two additional genes contributing to disease have been identified: RT1u and Gimap5
• Type I diabetes in domestic animals is characterized as immune mediated damage to β cells with the primary effector being CD8+ T cells; the precise trigger is unclear but viral agents may trigger damage in some cases

TYPICAL CLINICAL FINDINGS:

• Abrupt onset of clinical signs at 60-120 days of age
• Weight loss, hyperglycemia, glucosuria, polyuria, and hypoinsulinemia followed by ketoacidosis, dehydration, and a moribund state
• Lymphocytic thyroiditis in rats does not usually result in hypothyroidism

TYPICAL GROSS FINDINGS:  No gross lesions

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Variable severity of both lesions
• Pancreas
• Acute: Lymphocytic infiltration of islets; beta cell degranulation; necrosis
• Chronic: Reduction in size and number of islets; lack of inflammation
• Thyroid: Irregular size and shape of thyroid follicles, separated primarily by lymphocytes

COMPARATIVE PATHOLOGY:

• BB rat is an animal model for Type-1 (juvenile-onset insulin-dependent) diabetes mellitus and Hashimoto's disease (autoimmune lymphocytic thyroiditis) in man
• Cattle: Immune-mediated islet (β cell) destruction with resulting Type-1 diabetes; DM in cattle may be associated with viral disease such as Foot and Mouth disease or Bovine viral diarrhea
• Dogs: Hypothyroidism is usually the result of primary lesions in the thyroid gland that include idiopathic follicular atrophy (“collapse”) and  lymphocytic thyroiditis; less common causes include bilateral nonfunctional thyroid tumors or severe iodine-deficient hyperplastic goiter
• Idiopathic follicular atrophy (“collapse”)
• Primary degenerative disease (vs. trophic atrophy of follicular cells secondary to decreased TSH secretion)
• Progressive loss of follicular epithelium and replacement by adipose tissue, with minimal inflammatory response
• Gross: Thyroid gland usually smaller and lighter in color
• Initial histologic lesion characterized by individualized follicular cell degeneration; progression to loss of normal follicles, with remaining follicular cells that contain microfollicles within cytoplasm +/- thickening of basement membrane
• Lymphocytic thyroiditis
• Production of autoantibodies directed against thyroglobulin, thyroperoxidase (a microsomal antigen), the TSH receptor, or other thyroid follicular cell antigens
• Gross: Thyroid gland enlarged, normal, or shrunken; pale-white
• Multifocal to diffuse infiltrates of lymphocytes, plasma cells, and macrophages with occasional lymphoid nodules (migration of inflammatory cells separates follicular cells from their basement membraneàfollicular degeneration); progresses to replacement of thyroid gland with mature fibrous connective tissue and scattered inflammatory cells; oncocytes seen in long standing disease; C cells appear prominent due to loss of follicles
• Basement membrane of thyroid follicles thickened by electron-dense deposits that represent immune complexes
• Extra-thyroidal lesions: Gain in body weight, lesions in skin and hair coat hyperkeratosis, hyperpigmentation, and myxedema common; I-M22), reproductive abnormalities (lack of libido and decreased sperm count in males; abnormal or absent estrous cycles in females), normocytic, normochromic, nonregenerative anemia, and hypercholesterolemia (results in secondary extrathyroidal lesions to include hepatomegaly, atherosclerosis, renal glomerular and corneal lipidosis)
• Serum free T4 (fT4) has the highest single-test diagnostic sensitivity, specificity, and accuracy in detecting thyroid disease in dogs
• Type I diabetes is seen in dogs and there are breed predispositions; there is evidence for immune mediate destruction of β cells in some cases but lymphocytic inflammation is not a consistent finding
• Horses: Lymphocytic thyroiditis with fibrosis has been reported in horses imported for slaughter in Italy, resembling Hashimoto’s thyroiditis
• Camels: Autoimmune thyroiditis reported in dromedary camels has been associated with hypothyroidism, TSH autoantibodies, Trypanosoma evansi infection, and lowered male fertility

REFERENCES:

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4. Fehsel K, Kolb-Bachofen V, Kroncke K-D. Necrosis is the predominant type of islet cell death during development of insulin-dependent diabetes mellitus in BB rats. Lab Invest 2003;83:549-559.
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