AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

ENDOCRINE SYSTEM

January 2019

E-M01

 

Signalment (JPC #1939231): BB/Wistar rat

 

HISTORY: None

 

MICROSCOPIC DIAGNOSIS (Slide a): 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: Atrophy, diffuse, moderate, with lymphocytic insulitis, BB/Wistar rat, rodent.

 

ETIOLOGIC DIAGNOSIS: Immune-mediated insulitis and atrophy

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

 

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, glycosuria, 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 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 idodine-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), 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

 

 

REFERENCES:

1.    Awata T, Guberski D, Like A. Genetics of the BB rat: Association of autoimmune disorders (diabetes, insulitis, and thyroiditis) with lymphopenia and major histocompatibility complex class II. Endocrinology 1995;136:5731-5734.

2.    Doukas J, Mordes J, Swymer C, Niedzwiecki D, Mason R, Rozing J, Rossini A, Greiner D. Thymic epithelial defects and predisposition to autoimmune disease in BB rats. Amer J Pathol 1994;145:1517-1524.

3.    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.

4.    Ferguson DC and Hoenig M. Endocrine system. In Latimer KS, ed. Duncan and Prasse’s Veterinary Laboratory Medicine. 5th ed. Ames, IA: Iowa State University press; 2011: 304-313.

5.    Hessner MJ, Wang X, Meyer L, Geoffrey R, Jia S, Fuller J, Lernmark A, Ghosh S. Involvement of eotaxin, eosinophils, and pancreatic predisposition in development of type I diabetes mellitus in the BioBreeding rat. J Immunol 2004;173:6993-7002.

6.    Jennings V, Dillehay D. Immunology. In: Suckow MA, Weisbroth SH, Franklin CL, eds. The Laboratory Rat. London, UK: Elsevier Academic Press; 2006:853-854.

7.    Jubb KA, Stent AW. Pancreas. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier; 2016:368-373.

8.    Miller MA. Endocrine system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:701, 718.

9.    Rosol TJ, Grone A. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier; 2016:310-320.


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