JPC SYSTEMIC PATHOLOGY

ENDOCRINE SYSTEM

January 2025

  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 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 µm 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, plasma cells 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 lymphoplasmacytic steatitis, BB/Wistar rat, rodent.

 

ETIOLOGIC DIAGNOSIS: Immune-mediated thyroiditis

 

GENERAL DISCUSSION:

• Autoimmune thyroid disease, with infiltration of the gland by thyroid-reactive lymphocytes, is thought to be triggered by the interaction of genetic and environmental factors (e.g., excessive iodine, infections, pregnancy)
• > 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
• 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 
• Variability in insulitis and thyroiditis due to differences in interactions between MHC II genes and organ specific autoantibodies
• Molecular mechanism of pancreatic beta-cell destruction predominantly involves necrosis, with apoptosis playing only a minor role
• 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
• Other non-immune pathogeneses are possible depending on species such as idiopathic/dietary triggered pancreatitis, streptozocin administration, pancreatic islet amyloidosis, encephalomyocarditis virus, or pancreatectomy causing insulin-dependent diabetes

 

TYPICAL CLINICAL FINDINGS:

• Diabetes mellitus: 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
• Hypothyroidism: Screen with serum T4 test, thyroglobulin/T3/T4 autoantibody titer with circulating T3/T4/TSH to confirm
• Clinical signs of lymphocytic thyroiditis (hypothyroidism) are typically only present after thyroid atrophy at which time inflammatory cells are no longer present

 

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 
• Cytology, thyroid: Poorly exfoliative. Varying numbers of lymphocytes, plasma cells, macrophages, and thyroid epithelial cells with or without colloid; in atrophic thyroid lesions, small numbers of thyroid epithelial cells and spindle cells may be found in the smears +/- colloid

 

COMPARATIVE PATHOLOGY:

Autoimmune type 1/”insulin-dependent” diabetes (T1DM):

• 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: T1DM 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
• Birds: Marked macrovesicular vacuolation of beta cells, +/- lymphocytic infiltrate, chronic lymphocytic pancreatitis, or islet cell carcinoma found in cases of diabetes mellitus in psittacines, red-tailed hawks, and emperor penguins.
• Human: Absolute deficiency of insulin due to autoimmune destruction of the pancreatic beta cells
• NHP: Streptozocin mediated beta cell necrosis is a laboratory model of human T1DM. Macaques get spontaneous low-frequency T1DM; lymphocytic islet inflammation followed by reduced insulin staining on IHC
• Mice: NOD mice develop lymphocytic islet inflammation prior to development of T1DM

 

Lymphocytic thyroiditis:

• 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
• 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
• Chickens: “Obese strain” chickens develop autoimmune thyroiditis, Fayoumi chickens develop feather amelanosis due to spontaneous lymphocytic thyroiditis

 

REFERENCES:

 

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