JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #1741589): Dog of unknown age and gender.
HISTORY: This dog had proteinuria, hypoproteinemia, and had lost more than 2 grams of protein in the urine in a 24-hour period.
HISTOPATHOLOGIC DESCRIPTION: A (H&E): Kidney: Diffusely, glomerular tufts are globally expanded by variable amounts of amorphous, extracellular, hyaline to finely fibrillar waxy material (amyloid) that compresses capillaries and obscures glomerular architecture. Glomerular tufts are hypocellular with pyknosis and rare karyorrhectic debris (necrosis), and frequently fill Bowman’s space and adhere to Bowman’s capsule (synechia). Multifocally, tubular epithelium contains one or more of the following changes: swollen and vacuolated with vesiculate nuclei (degeneration); shrunken, hypereosinophilic with pyknosis (necrosis); increased basophilia, occasional mitoses and irregularly spaced hyperchromatic nuclei (regeneration); or contain brown cytoplasmic globular pigment (hemosiderin). Multifocally, tubules are ectatic, lined by attenuated epithelium, and contain abundant eosinophilic homogenous proteinaceous material (proteinosis) or tubular lumina contain necrotic cellular debris, granular deeply basophilic material (mineral) or round birefringent crystals with radiating lines (calcium carbonate). Multifocally within the interstitium, there are small amounts of amyloid, mild congestion, minimal hemorrhage, and few lymphocytes and plasma cells.
B (Congo red): Diffusely, glomerular tufts are expanded by abundant congophilic material that displays bright green birefringence under polarized light (amyloid).
MORPHOLOGIC DIAGNOSIS: Kidney: Amyloidosis, glomerular, global, diffuse, severe with multifocal tubular epithelial degeneration, necrosis, and rare regeneration, breed unspecified, canine.
CONDITION: Glomerular amyloidosis
- Pathologic proteinaceous material that produces many clinical syndromes
- Characterized by the deposition of an amorphous, hyaline substance, that can interfere with normal tissue function and eventually may produce pressure atrophy of adjacent cells
- All forms have a characteristic b-pleated sheet protein structure and congophilia
- Over 15 biochemically distinct forms of amyloid proteins
- Composed of about 95% fibril proteins; 5% P component and other glycoproteins
- There are two general categories of proteins that form amyloid:
- Normal proteins that have an inherent tendency to fold improperly, associate, and form fibrils, and do so when they are produced in increased amounts (e. immunoglobulin light chains, SAA)
- Mutant proteins that are structurally unstable and prone to misfolding and subsequent aggregation
- Classification of amyloidosis/Major Fibril Protein/Precursor Protein:
- Primary (Immunoglobulin-derived)
- Immunocyte dyscrasia with amyloidosis
- AL (amyloid light chain): Composed of immunoglobulin light chains (mostly lambda light chains) produced by plasma cells; associated with monoclonal B cell proliferation (multiple myeloma, extramedullary plasmacytoma)
- Secondary (reactive systemic)
- Most common form in domestic animals
- Reactive systemic amyloidosis (chronic inflammation or infection)
- AA (amyloid-associated): Derived from serum amyloid associated (SAA) protein - an apolipoprotein produced in the liver in response to IL-1, IL-6 and TNF-a; SAA easily detectable in plasma during the acute phase of inflammation
- AF (amyloid-familial): Hereditary autosomal recessive (some may be autosomal dominant with incomplete penetrance) condition in Abyssinian and Siamese cats and Chinese Shar Pei, beagle, gray Collies, English Foxhound dogs; likely associated with SAA and not a separate type of amyloid protein; can be localized to just kidney
- IAPP (amyloid of endocrine organs): Derived from islet amyloid polypeptide (IAPP) – normally secreted by β cells of pancreas; deposition of amyloid in pancreas of cats, macaques, baboons, raccoons and humans leading to type 2 diabetes mellitus
- Aβ (senile/old age amyloidosis): Neurodegenerative disease, senile plaques, cerebral amyloid angiopathy (rare in animals)
- Apolipoprotein AI (Apo AI): Deposition of amyloid in pulmonary vasculature of aged dogs
- Non-endocrine tumors: Amyloid-producing odontogenic tumor (APOT) of cat and dog; ameloblastomas; amyloid of ameloblastic lineage (positive for ameloblastin, amelogenin, sheathlinlaminin)
- PrPsc: Prion diseases (Chronic Wasting Disease) forming amyloid plaques in brain in addition to intraneuronal vacuolation
- Gastrointestinal: Age-related; unknown precursor protein (NOT AA)
- Uterine (caruncular) SAA3 amyloidosis in goats
- General: structural misfolding of precursor proteins into a cross-β-pleated sheets à deposition into tissues à disruption of normal function or pressure atrophy, degeneration, necrosis.
- Renal lesions: Long-standing glomerular amyloidosis > reduced renal vascular perfusion > tubular epithelial degeneration, necrosis and atrophy; interstitial fibrosis; and severe cases can have renal papillary necrosis
- Some studies indicating AA amyloidosis may be transmitted between animals and between species via seeding nucleation process (similar to prion diseases); studies involving cows, birds, cheetahs, mice,Japanese quail
- Linked to infection with Hepatozoon americanum, Ehrlichia canis in dogs and excess vitamin A in cats
- The mechanism whereby soluble circulating SAA results in deposition of insoluble amyloid fibrils is unknown, several mechanisms have been proposed; seeding of AA amyloidosis has been demonstrated experimentally in various animal models
TYPICAL CLINICAL FINDINGS:
- Vague clinical signs initially: Lethargy, anorexia, vomiting, weight loss, and polyuria/polydipsia
- Dependent on the magnitude of the deposits and organs affected
- Kidney: Most common site of deposition in dogs and cats
- Clinical pathology:
- Complete blood counts, serum biochemistry, and urinalysis suggestive of acute or chronic kidney disease
- Nephrotic syndrome (proteinuria, hypoalbuminemia, generalized edema, and hypercholesterolemia); proteinuria may be severe and occur in the absence of nephrotic syndromeDogs with amyloidosis usually have higher UP/UC ratios (>18) than with glomerulonephritis (5-15); [WNL<0.5)]
- Bence Jones proteinuria with multiple myeloma
TYPICAL GROSS FINDINGS:
- Enlarged, firm, pale gray to yellowish orange, and waxy organs (referred to as “lardaceous” due to resemblance to lard); edema
- Kidney has finely stippled appearance with fine yellow spots representing glomeruli
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Amyloid is an acellular, finely fibrillar to waxy, pale eosinophilic, homogenous,extracellular material
- Deposits primarily in the mesangial area (expanding the mesangial zone) and in the subendothelium of glomerular capillaries; eventually extending into the interstitium (less frequently) separating and surrounding tubules and arteries and within the tubular basement membrane
- Other findings: Interstitial fibrosis and lymphoplasmacytic infiltration, tubular atrophy, tubular dilation, mineralization, intratubular oxalate crystals, glomerular atrophy, and glomerulosclerosis
- Shar Pei: AA amyloid is somewhat preferentially deposited in renal interstitium but also present in glomeruli; renal medullary amyloidosis more common in Shar Pei than Non-Shar Pei, as is extra renal amyloid deposition
- Amyloidosis secondary to chronic inflammation most commonly involves kidney, liver, spleen, lymph nodes, CNS, testicles, lungs and adrenal and thyroid glands
- Primary plasma cell-associated amyloidosis often involves heart, GI tract, peripheral nerves, skin, and tongue
- The degree of effacement of capillary lumina is the basis for determining severity
- Non-branching fibrils of indefinite length and 0.7-1 mm diameter that form single to laterally aggregated bundles or interlocking mesh-like ribbons (b-pleated sheet only seen on x-ray crystallography) lacking periodicity; collaged fibers have periodicity
- TEM: Distinct fibrillar 9-11 nm (diameter) material in mesangium and GBM
ADDITIONAL DIAGNOSTIC TESTS:
- Congophilic: Congo red staining of amyloid “apple green” birefringence of Congo red-stained amyloid due to regularity and parallelism of dye molecules bound to aggregated fibrils
- According to WSAVA renal standardization study group: Definitive diagnosis requires the presence of green bifringent material in congo red stained sections with polarized light
- Material may also be present in medullary interstitium or artery walls
- If tissue pre-treated with potassium permanganate congophilic material goes away with AA amyloid
- H & E alone is unreliable due to overlap in eosinophilia between amyloid and sclerotic collagen
- Crystal violet: Amyloid will stain purple-violet
- Thioflavin T (fluorescent stain): Brilliant orange fluorescence - may be needed in cats as their amyloid may stain poorly with Congo red
- Strasburg method: Confirms the nature of the amyloid deposits
- Masson’s Trichrome: Amyloid is pale blue to orange
- Jones Methenamine Silver (JMS): Amyloid does not take up silver, but sclerotic collagen does
- PASH: Amyloid is pale pink
- Iodine: Glomeruli stain red-brown with iodine solution and turn purple when subsequently exposed to acetic acid/vinegar
- Direct fast scarlet stain
- Mass spectrometry
- Dogs: Shar-peis have glomerular amyloid deposition (78.6%) but also will have medullary deposition (100%).
- Medullary interstitium is more commonly affected with papillary necrosis (minimal glomerular involvement); kidneys are firm, shrunken, and coarsely nodular
- Type 2 diabetes [Beta cells produce Islet amyloid polypeptide (IAPP) also referred to as amylin ; IAPP-derived amyloid deposited within islets]; one study found that islet amyloidosis in diabetic cats was not more frequent than in control cats; also seen in raccoons, prevosts squirrels, NHPs
- Abyssinians: Hereditary: AA amyloid deposited in medullary interstitium
- Siamese: Hereditary; AA amyloid deposited in liver, kidney, other
- Amyloid-producing odontogenic tumors have been reported in the facial skin in 3 cats
- Black-footed cats: AA amyloidosis and resultant renal failure is the most common cause of death; most severe in the renal medullary interstitium and glomeruli; other affected sites include splenic follicular germinal centers, gastric lamina propria, and intestinal lamina propria
- Siberian tigers and cheetahs - high prevalence of systemic AA amyloidosis; renal medullary interstitial amyloid; all had chronic inflammation, especially gastritis; results in increased mortality of captive cheetahs
- Horses: Systemic AA amyloidosis or localized AL amyloidosis in skin and upper respiratory system (nasal); also AA amyloid in eyes of horses with recurrent uveitis
- Glomerular and medullary amyloidosis almost always secondary to chronic inflammation
- Cattle with mastitis, metritis, arthritis and pododermatitis have a high prevalence of systemic AA amyloidosis in response to inflammation
- Sheep and goats: Infrequent AA amyloidosis
- Pigs: RARE
- Birds: Most common in waterfowl secondary to conditions such as ulcerative pododermatitis (bumble foot); amyloid often stains more basophilic to purplish; ducks, swans, geese (liver, spleen, kidney); chickens can develop amyloid arthropathy, often associated with Entereoccus faecalis
- Common marmoset: Systemic (liver, adrenal glands, kidneys and intestines) AA amyloidosis
- Mice (have two types)
- Reactive systemic form (AA): Spleen, liver intestines, kidney; CBA, B6, C3H/HE, BLAB/c, SWR; A/J resistant
- Senile form: Apo AII; A/J, SJL
- IL-1 receptor antagonist knockout mice used as model to study AA amyloidogenesis
- amyloidosis associated with cardiac atrial thrombosis and left or right side congestive heart failure
- amyloid-like material occasionally found in the nasal mucosa, particularly above the vomeronasal organs
- Hamster: Females >males; identified a “hamster female protein” that is functionally similar to amyloid P; liver, kidney and adrenals affected; atrial thrombosis secondary to antithrombin III loss due to renal amyloidosis; also see amyloidosis associate with Girardia infection
- Gerbil: Secondary to chronic renal disease; liver, spleen, lymph nodes
- Rabbit: Deposited in the renal interstitium
- NHP: Common sites include the spleen, lymph nodes, kidney, liver, pancreatic islets and lamina propria or submucosa of the small intestine; especially in aged macaques, often due to chronic enterocolitis or other inflammatory conditions; cerebral plaques composed of amyloid-β have been described in macaques
- Island foxes (urocyon littoralis): AA prevelant, risk to species survivial; medullary interstitium; captivity is a risk factor; can be found in most/all organs but the brain
- African tiger snake (case report): suspected to be AA secondary to chronic inflammation
- Japanese Quail (Coturnix japonica):May develop intestinal amyloidosis with age; one animal in a natural setting developed AA amyloidosis associated with peritonitis
- Goats: Uterine (caruncular) SAA3 amyloidosis within the placentome of goats may be associated with abortion
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