JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #1796768): Adult baboon (Papio sp.)
HISTORY: Tissues from an adult baboon that was housed in an old, poorly-maintained facility. The animal lost condition and developed convulsions shortly before dying. A dark line was seen on the gums and mucous membranes were pale.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally, proximal tubule epithelial cell nuclei are enlarged 2 to 3 times normal size with marginated chromatin and contain 1 to 2, round to oval, 2 to 5 um in diameter, bright eosinophilic intranuclear inclusions. Multifocally, few lymphocytes and plasma cells infiltrate the interstitium.
Liver: Rarely, hepatic nuclei are enlarged 2 to 3 times normal size with marginated chromatin and contain 1 to 2, round to oval, 2 to 5 um in diameter, bright eosinophilic intranuclear inclusions. Multifocally, few lymphocytes and plasma cells infiltrate the periportal connective tissue.
MORPHOLOGIC DIAGNOSIS: Kidney, proximal convoluted tubules: Intranuclear inclusions, eosinophilic, few, baboon, nonhuman primate.
Liver, hepatocytes: Intranuclear inclusions, eosinophilic, rare.
Signalment (89-197-3): Hawai’i ‘amakihi (Hawaiian honeycreeper) (Hemignathus virens)
HISTORY: Tissue from an Hawai’i ‘amakihi, which was off feed and had slowed responses to stimuli. The animal eventually became lethargic, developed labored breathing, fell from its perch and was found dead.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally, proximal tubule epithelial cell nuclei are enlarged 2 times normal size by an amphophilic to light brown, irregular intranuclear inclusion, measuring up to 10 µm in diameter. Multifocally, proximal tubule epithelial cells are swollen and have vacuolated cytoplasm (degeneration).
Ovary; uterus: No significant findings.
MORPHOLOGIC DIAGNOSIS: Kidney, proximal convoluted tubules: Intranuclear inclusions, amphophilic to light brown, few, with multifocal tubular degeneration, Hawai’i ‘amakihi (Hemignathus virens), avian.
ETIOLOGIC DIAGNOSIS: Renal lead toxicosis (renal plumbism)
CAUSE: Lead intoxication
- Most common cause of heavy metal poisoning in cattle; young animals are most susceptible due to curiosity and licking of foreign objects
- Potentially fatal disease that occurs in cattle, sheep, horses, dogs, cats and waterfowl; rare in swine
- Lead is ubiquitous in the environment; sources include discarded car batteries, paint, oil field sites, machinery oil/grease, plumber’s putty, solder in tin cans and soldered joints, linoleum, pesticides and exposure to mining and reclaiming operations
- Poisoning can be peracute (no gross or microscopic lesions), acute, subacute or chronic depending on quantity absorbed; poisoning tends to be acute in ruminants and more chronic in horses; there is species variation in susceptibility to the poison
- Many tissues are affected and include the central and peripheral nervous systems, kidneys, liver, gastrointestinal system, bone marrow, vasculature and reproductive and endocrine systems
- The most common route of exposure is through the alimentary tract; less common routes include inhalation in which particles are absorbed or cleared by ciliary action and swallowed, absorption through the skin, and transplacentally (sheep)
- Common sources of lead:
- Cattle: paint and metallic lead in storage batteries
- Wild birds and mammals: ingestion of lead-containing ammunition, fishing tackle (including ingestion of carrion/prey containing these objects); contaminated sediments
- Dogs, zoo animals: lead-based paints
- Nonruminant animals absorb approximately 10% of ingested lead; ruminants less than 3%; young animals can absorb up to 90%
- High fat, low mineral (especially calcium) diets increase lead absorption
- Lead is transported in association with erythrocyte membranes and albumin, with small amounts unbound in the blood
- Lead is widely distributed in the body and is stored in soft tissues including bone, kidney and liver; excreted in bile, urine and milk or exfoliated in skin; lead has a relative neurotropism, causing the most deleterious effects in the CNS
- Lead inhibits the enzymes gamma-aminolevulinic acid dehydratase and ferrochelatase that are involved in hemoglobin synthesis and incorporation of iron which results in microcytic hypochromic anemia
- Inhibition of nucleotidase causes increased erythrocyte fragility and decreased survival time which contributes to anemia; random hydrolysis of nucleic acids; induction of RNA catalysis
- Lead can substitute for calcium ions in cationic transporters
- Lead exhibits direct toxic effects through disruption of metabolic pathways in neurons, astrocytes and cerebral endothelial cells (blood-brain barrier); disrupts calcium hemostasis and calcium’s role in biochemical reactions and neurotransmitter action; binding to calcium and zinc binding proteins
- Laminar necrosis in ruminants may be secondary to ischemia and not due to direct neurotoxicity; capillary alterations may be important in pathogenesis
TYPICAL CLINICAL FINDINGS:
- Abdominal pain, diarrhea and vomiting
- Neurologic signs, including severe depression, cortical blindness, gait incoordination, aimless walking, head pressing, trembling, grinding of teeth and seizures
- Important hemogram features include microcytic hypochromic anemia, basophilic stippling and the presence of nucleated erythrocytes in numbers disproportionate to the anemia (basophilic stippling in cattle can be normal)
- Disease is paralytic, chiefly affecting the cranial nerves; horses may show signs of laryngeal paralysis and “roaring,” or less commonly limb paralysis
- Can see generalized peripheral neuropathy resulting in muscle atrophy and weakness mimicking equine motor neuron disease
- Increased blood levels of lead, free erythrocyte protoporphyrin and decreased levels of aminolevulinic acid dehydrogenase
TYPICAL GROSS FINDINGS:
- Gross renal lesions are usually absent
- Cerebral edema, malacia and laminar cortical necrosis (polioencephalomalacia) in some subacute cases in ruminants
- A blue lead line can be seen on the gingiva adjacent to the teeth from precipitation of lead sulfide
- Characteristic band of sclerosis (lead line) is visible radiographically and grossly in the metaphysis of developing bones; caused by persistence of mineralized cartilage trabeculae in the metaphysis because of impaired osteoclastic resorption
- Gastric ulceration; erosion and ulceration of the ventriculus (birds)
- Presence of lead-containing material in gastrointestinal tract (e.g. paint chips)
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Acute lesions:
- Predominately affects the proximal convoluted tubules
- Nuclei may be enlarged and contain amorphous, eosinophilic, acid fast intranuclear inclusions that peripheralize the chromatin and appear large and vesicular
- Epithelial cells may be swollen or undergo necrosis and slough into the tubular lumen
- Increased apoptotic necrosis and proximal tubular cell replication
- Chronic lesions: (i.e. chronic plumbs)
- Chronic nephropathy has been reported in rats, gerbils and rabbits
- Characterized by tubular ectasia and interstitial fibrosis
- Lead intranuclear inclusions occur in other cells including hepatocytes, Schwann cells, endothelial cells and osteoclasts
- Intranuclear inclusions are composed of high concentrations of lead bound to certain proteins (other than nucleoprotein)
- Bone marrow will be hypocellular, with a marked decrease in mature erythrocytes and an increase in erythroblasts; mitotic figures will be common
- +/- Hepatocyte necrosis and Kupffer cell hemosiderosis or lipofuscinosis
- +/- Demyelination of peripheral nerves
- +/- Focal areas of vascular damage in the cerebrum and cerebellum
- Inclusions have a discrete electron dense central core surrounded by fibrillar structures (“star burst” or “fuzzy” appearance)
- Osteoclasts have abundant mineralized cartilage in the cytoplasm, indicating a possible defect in intracellular process of matrix
ADDITIONAL DIAGNOSTIC TESTS:
- Ziehl-Neelsen acid fast stain: inclusions are acid fast
- Tissue lead levels from liver and kidney are most helpful
- Intranuclear inclusion bodies in kidney and liver:
- Acidophilic, brick-shaped intranuclear inclusions (ACIN inclusions) are commonly seen in the kidney (proximal tubules) and liver of old dogs
- Herpesvirus or adenovirus inclusions
- Polyomavirus in birds
- Bismuth administration chronically in rhesus macaque may cause intranuclear inclusions in proximal tubule epithelial cells in kidneys
- Gerbils: Prone to accumulation of lead and chronic lead toxicity due to their urine-concentrating ability and gnawing behavior; often used for this purpose experimentally
- Dogs: CNS lesions include edema of the whtie matter of brain and spinal cord; degenerative changes in myelin sheaths; regional spongy degeneration and neuron lossRabbits: Lead toxicity is common among “free-ranging” pet rabbits due to their propensity to chew foreign objects
- Rat: Lead has carcinogenic potential; karyomegaly is a sensitive morphologic indication of lead toxicity
- At higher risk from metallic lead because the material is retained in the ventriculus, ground down, and slowly absorbed
- Lead toxicity is the leading cause of death in juvenile and adult free-flying condors; well-documented risk of disease in waterfowl, upland game birds and scavangers
- Chicken are more resistant than waterfowl
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