Signalment:  

23-year-old, male rhesus macaque (Macaca mulatta).The animal was part of a long term visual-based cognition study. Cephalic implants and circumferential scleral search coils had been surgically placed. Euthanasia was performed due to a history of chronic weight loss and failure to thrive.

Gross Description:  

Overall, the animal was in fair body condition with petechiae on the skin of the inguinal region bilaterally, as well as multifocally on the abdomen. The liver and spleen were both enlarged with diffuse pallor. There was a 3 mm deep, focal surface depression of the cortex of the left kidney, and on cut section the cortex also contained a focal, 1 cm diameter cyst. Marked degenerative changes were also seen in both stifles, with the left medial condyle in particular being irregular and roughened.

Histopathologic Description:

Splenic architecture is diffusely effaced by marked deposits of amorphous, smudgy to finely fibrillar, extracellular eosinophilic substance (amyloid). This material fills and expands the parenchyma, and especially replaces the microanatomic regions of white pulp and also imparts a nodular pattern to its deposition. There is associated compression of the adjacent red pulp regions, although many of the blood vessels are distended and congested. Foci of hemorrhage are also seen within the nodular amyloid deposits.

Morphologic Diagnosis:  

Diffuse splenic amyloidosis.

Condition:  

Amyoidosis

Contributor Comment:  

Amyloidosis is a disease caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded, normally soluble, protein. The name amyloid originates from results of early crude iodine-staining techniques that led to the mistaken identification of the protein material as starch. Serum amyloid A (SAA) proteins comprise a family of vertebrate proteins that associate predominantly with high density lipoproteins (HDL). All amyloid fibrils share a common cross-β-pleated sheet core structure, with the polypeptide chains running perpendicular to the fibril long axis, regardless of the particular protein from which they are formed. Fibrils are usually about 10 nm in diameter, and are straight, rigid, and nonbranching. Numerous biochemically distinct amyloid proteins have been characterized in humans and animals, but the three most common types are as follows: 1) AA (amyloid-associated) (a unique non-immunoglobulin protein synthesized by the liver); 2) AL (derived from plasma cells and contains immunoglobulin light chains); and 3) Aβ (β-amyloid protein found in cerebral lesions of Alzheimer disease).

Amyloidosis may be primary or secondary. Primary amyloidosis arises due to overproduction of the immunoglobulin light chain and may be neoplastic or genetic in origin. Secondary, or reactive systemic amyloidosis is a complication of chronic infections and inflammatory conditions and is characterized by a sustained acute phase response. Although the pathogenesis of reactive systemic amyloidosis is poorly understood, it is associated with persistently increased production of SAA (thus making SAA a major acute phase reactant). Although its major physiological function remains unclear, SAA is produced under the control of numerous cytokines, including interleukin-1, interleukin-6 and tumor necrosis factor-α released during inflammation. Increased levels of SAA are common in chronic inflammation, but amyloid deposition usually does not occur. In individuals that do develop amyloidosis, there is limited or defective SAA proteolysis with formation and deposition of insoluble AA protein. Proposed underlying mechanisms include failure of degradation due to excess levels of SAA relative to enzyme; an intrinsic proteolytic enzyme defect; or a structural defect in the SAA molecule that makes it resistant to degradation. The end result, however, is that accumulated amyloid deposits cause pressure atrophy of surrounding tissues, thus impairing normal body function and resulting in organ failure and ultimately death.

Reactive systemic amyloidosis is not uncommon in rhesus macaques, and has additionally been reported in other nonhuman primates (including common marmosets, squirrel monkeys, pigtail macaques, Celebes macaques, cynomolgus macaques, a stumptailed macaque, baboons, a mangabey and chimpanzees). The condition has been associated with chronic vascular catheterization, as well as underlying conditions such as rheumatoid arthritis, retroviral infection, parasitism, and enterocolitis. Amyloid deposition is most frequently seen in the space of Disse in the liver, the lamina propria of the gastrointestinal tract, the corticomedullary junction of the adrenal gland, either the red or white pulp of the spleen, and the renal medullary interstitium. The small intestine is the region of the gastrointestinal tract most often and most severely affected. Renal glomerular involvement is rare, except in marmosets.

Clinical signs are related to the affected site as well as the amount of amyloid deposited, but include weight loss, diarrhea, and hepatosplenomegaly. Protein losing enteropathy may accompany enteric amyloidosis. Laboratory findings may include elevated levels of SAA, hypoproteinemia, hypoalbuminemia, hypergammaglobulinemia, and elevated liver enzymes with hepatic involvement. There is, however, no reliable diagnostic assay, preventive measure or treatment for secondary amyloidosis. Although gross postmortem lesions are often absent, the liver and/ or spleen may be massively enlarged, pale, waxy and firm. Prominent splenic nodules may be seen cut section, and the intestinal mucosa may be thickened. With the light microscope and hematoxylin and eosin staining, amyloid appears as an amorphous, eosinophilic, extracellular substance. Its differentiation from other similar appearing materials, like fibrin and collagen, depends on the pathognomonic, red-green birefringence observed when preparations correctly stained with Congo red are viewed in intense unidirectional polarized light. This optical effect is produced by alignment of the dye molecules along the protein fibrils.

JPC Diagnosis:  

Spleen, white pulp: Amyloidosis, nodular, diffuse, marked, with lymphoid depletion and loss.

Conference Comment:  

The contributor provides an exemplary review of amyloidosis, and the fairly classic example provided herein features the typical pattern of amyloid deposition in the spleen, with the white pulp being primarily affected and compressing the adjacent red pulp. The following table, adapted from Snyder summarizes the most commonly encountered amyloidoses in veterinary medicine:(10)

Amyloidosis
Category	Associated Diseases	Major Fibril Protein	Precursor Protein
Systemic
Primary amyloidosis (immunocyte dyscrasias)	Multiple myeloma Monoclonal B cell proliferations	AL	Immunoglobulin light chains
Secondary amyloidosis (reactive systemic amyloidosis)	Chronic inflammation	AA	SAA
Familial amyloidosis (may be systemic and/or localized)	Amyloidosis in Shar-Pei dogs (renal medullary interstitium), Abyssinian cats (renal glomeruli), and Siamese cats (liver)	AA	SAA
Localized
Amyloid of aging	Senile plaques Cerebral amyloid angiopathy Neurodegenerative disease	Aβ	APP
Endocrine tumors	Thyroid C cell tumors	A Cal	Calcitonin, polypeptide hormones and/or prohormones
Islets of Langerhans	Diabetes mellitus	IAPP	IAPP
Isolated amyloid of pulmonary vasculature		Apolipoprotein A-1	Apolipoprotein A-1
Prion diseases	Transmissible spongiform encephalopathies	Misfolded prion protein (PrPsc)	Normal prion protein (PrP)
AL = amyloid light chain; AA = amyloid associated; SAA = serum amyloid A; APP = amyloid precursor protein; A Cal = amyloid of hormone origin; IAPP = islet amyloid polypeptide

References:

1. Abbas AK: Diseases of immunity: amyloidosis. In: Robbins and Cotran Pathologic Basis of Disease, eds. Kumar V, Abbas AK, Fausto N, 7th ed., pp. 258-264. Elsevier, Philadelphia, PA, 2005
2. Blanchard JL: Generalized amyloidosis, nonhuman primates. In: Monographs on Pathology of Laboratory Animals: Nonhuman Primates I, eds. Jones TC, Mohr U, Hunt RD, pp. 194-197. Springer-Verlag, Berlin Heidelberg, Germany, 1994
3. Cohen AS: General introduction and a brief history of the amyloid fibril. In: Amyloidosis, eds. Marrink J, Van Rijswijk MH, pp. 3-19. Nijhoff, Dordrecht, The Netherlands, 1986
4. Hukkanen RR, Liggitt HD, Anderson DM, Kelley ST: Detection of systemic amyloidosis in the pig-tailed macaque (Macaca nemestrina). Comp Med 56:119-127, 2006
5. Jakob W: Spontaneous amyloidosis of mammals. Vet Pathol 8:292-306, 1971
6. Ludlage E, Murphy CL, Davern SM, Solomon A, Weiss DT, Glenn-Smith D, Dworkin S, Mansfield KG: Systemic AA amyloidosis in the common marmoset. Vet Pathol 42:117-124, 2005
7. MacGuire JG, Christe KL, Yee JL, Kalman-Bowlus AL, Lerche NW: Serologic evaluation of clinical and subclinical secondary hepatic amyloidosis in rhesus macaques (Macaca mulatta). Comp Med 59:168-172, 2009
8. Pepys MB: Amyloidosis. Ann Rev Med 57:223-241, 2006
9. Puchtler H, Sweat F, Levine M: On the binding of Congo red by amyloid. J Histochem Cytochem 10:35564, 1962
10. Snyder PW: Diseases of immunity. In: Pathologic Basis of Veterinary Disease, eds. McGavin MD, Zachary JF, 4th ed., p. 248. Mosby Elsevier, St. Louis, MO, 2007

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4-1 . Spleen

4-2. Spleen

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