JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

October 2024

D-T09

 

Signalment (JPC# 2548860): 5-year-old male American Eider duck (Someteria mollisima dresseri)

 

HISTORY: This duck was depressed. A radiograph revealed a penny in the ventriculus. The duck was treated with itraconazole, fluids, enrofloxacin, and calcium versonate. There was no improvement over the next 10 days. The penny was surgically removed, but the duck died 24 hours later.

 

HISTOPATHOLOGIC DESCRIPTION: Pancreas and small intestine: Affecting 70% of the pancreatic tissue are coalescing regions of acinar cell atrophy and loss. Atrophied acinar cells are shrunken and angular with decreased intensity of zymogen granule staining and loss of zymogen granules. Surrounding, widely separating, compressing, and distorting remaining islands of acini are broad bands of loose fibrous connective tissue and a marked increase in variably mature, variably sized pancreatic ducts (tubular complexes). Ductal cells are individualized or forming ductal lumina and have round to oval, vesiculate nuclei. There is mild to moderate, multifocal expansion of the small intestinal serosa and peripancreatic and peri-intestinal adipose tissue by heterophils, lymphocytes, and macrophages admixed with hemorrhage, fibrin, edema, and scattered intra- and extrahistiocytic 1x3 µm bacilli. There is multifocal mild to moderate atrophy of peripancreatic adipose tissue. 

 

MORPHOLOGIC DIAGNOSIS: 1. Pancreas, exocrine: Acinar atrophy and loss, diffuse, marked, with extensive fibrosis and tubular complexes, American Eider duck (Someteria mollisima dresseri), avian.

2. Small intestine and adipose tissue: Serositis, fibrinous and heterophilic, diffuse, subacute, moderate, with intra- and extrahistiocytic bacilli. 

ETIOLOGIC DIAGNOSIS: Pancreatic zinc toxicosis

 

CAUSE: Zinc intoxication

 

CONDITION SYNONYM: New wire disease

 

GENERAL DISCUSSION:

• The pancreas is the main organ for zinc excretion/homeostasis
  • The pancreas accumulates zinc absorbed from the diet and secretes it as a component of exocrine pancreatic secretions, which is mediated by metallothionein
• Natural toxicosis is described in birds, cats, dogs, sheep, calves, horses, piglets receiving total parenteral nutrition, and humans
• Experimentally produced in cats, sheep, chickens, ducklings, rats, and ferrets
• Most commonly recognized scenario is ingestion of pennies, typically by diving ducks that mistake the currency as food; zinc presence can be chronic as pennies are too large to pass out of ventriculus
• Zinc is the fourth most commonly used metal; therefore there are numerous sources of exposure: pennies minted after 1982, shot pellets, nuts, bolts, galvanized cage wire mesh, paint, jewelry, topical creams containing zinc oxide/zinc salts, or inhalation (smelter fumes); other sources include pesticides and herbicides
• Zinc is an essential trace mineral and a component of ~200 metaloenzymes 

 

PATHOGENESIS:

• Pathogenesis of pancreatic lesions is not understood
• Toxicosis occurs through complex combination of inhibition of selenium, copper, iron, or calcium absorption and/or metabolism
• Ingestion (or inhalation) > Zn released in low pH of stomach > absorption in small intestine > bound to plasma albumin and macroglobulins > extracted by the liver and returned to bloodstream > concentrates in exocrine pancreas, hepatocytes, spleen, and renal tubular epithelium 

• Piglets: Acinar cells are targeted and undergo necrosis > atrophy > interstitial fibrosis
• Ducklings: Acinar cells also targeted and undergo apoptosis
• Sheep and cattle: Ductal epithelium is initial target and undergoes necrosis; acinar degeneration, necrosis, and interstitial fibrosis centers on damaged ducts

• Hypothesized pathogenesis for Zn-induced hemolysis: Inhibition of glutathione reductase and enzymes of hexose-monophosphate-shunt pathway > increased RBC susceptibility to oxidative damage > marked RBC fragility and decreased lifespan > extra- and/or intravascular hemolysis > spherocytosis and Heinz body anemia > regenerative anemia

 

TYPICAL CLINICAL FINDINGS:

• Nonspecific: Vomiting, lethargy, inappetence, weight loss, weakness, incoordination
• Pigmenturia (mostly hemoglobinuria), polyuria, polydipsia
• Mild elevations in AST, ALP, amylase, phosphorus, and uric acid
• Mild decreases in calcium (Zn competes with calcium for intestinal absorption), glucose, and total protein
• Heinz body hemolytic anemia

 

TYPICAL GROSS FINDINGS:

• Pancreas: May appear mottled due to necrosis
  • Acute phase: Pale and enlarged with edematous interlobular connective tissue that separates and widens lobules 
  • Chronic phase: Shrunken with fibrosis replacing the edema
• GI: Ulcers; brittle, discolored koilin layer in ventriculus
• Liver: Shrunken with dark sunken areas of necrosis and collapse; transitioning to later phase of disease appearing as postnecrotic scarring
• Mild to severe typhlitis
• Pericardial mineralization
• Kidneys: May appear pale and swollen

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Pancreatic acini:

• Acute: Microvesicular degeneration and necrosis of acinar cells characterized by loss of zymogen granules, decreased basophilia, cytoplasmic vacuolization, cellular atrophy, and necrosis of individual acinar cells
• Chronic: Atrophy, loss, and fibrosis of acinar cells
• Tubular complexes separated by abundant fibrous connective tissue (duct-like structures with low cuboidal or flattened cells which lack zymogen granules and surround a large lumen; they are thought to be a response to pancreatic injury)
• Inflammation generally minimal or absent; islets are spared

• Liver: Centrilobular hepatocyte vacuolation and necrosis, with hemosiderosis and hemophagocytosis
• Kidney: Renal tubular necrosis
• Ventriculus: Necrotizing or erosive ventriculitis
  • Disrupted koilin layer, ulceration of mucosa, and dysplasia of ventricular glands
• Brain: Neuronal degeneration possible (histologically similar to infectious spongiform encephalopathy)

 

ADDITIONAL DIAGNOSTIC TESTS:

• Radiographic evidence of metallic objects within GI tract
• High tissue or serum Zn concentrations
• Obtain samples with all-plastic syringes and store in glass vials with a royal blue stoppers (rubber contains Zn and can invalidate analyses)

 

DIFFERENTIAL DIAGNOSIS: 

• Pancreatic lesions in mammals:

• Duct obstruction by calculi or parasites: Causes interstitial edema and ischemic damage to acinar cells; may resemble lesions of Zn toxicosis, particularly in ruminants, because in ruminants lesions center on damaged pancreatic ducts; however, Zn toxicity lesions progress more slowly and have less uniform distribution than in duct obstruction
• Direct damage to acinar cells: Zinc (dogs, calves, and sheep); Cassia occidentalis; T-2 toxin, a trichothecene mycotoxin produced by Fusarium sp. (pigs and sheep); drugs including sulfonamides and potassium bromide-phenobarbital combinations (dogs +/- other species); systemic viral and bacterial infections, and ischemia due to a variety of causes
• Corticosteroids: Induction of P450 enzyme pathway within pancreatic exocrine tissue and oxidative damage
• Disturbed cytoplasmic enzyme trafficking in acinar cells: acute pancreatic necrosis

• Pancreatic necrosis in avian species:

• Hydropericardium syndrome (group I avian adenovirus): Intranuclear inclusion bodies; inflammatory cells should be present
• Highly pathogenic avian influenza: Heterophils and macrophages should be present
• West Nile Virus: American crows, necrosis in multiple organs

 

COMPARATIVE PATHOLOGY:

• Domestic mammals: Generally show GI distress, anemia, and hypoproteinemia
• Dogs: 

• Ingestion of pennies (and less commonly other zinc-containing objects/substances) can cause intestinal obstruction as well as systemic effects
• Often present with vomiting, diarrhea, anorexia, icterus, and severe Heinz body hemolytic anemia with hemoglobinuria and hematuria
• May also develop acute renal failure with hyperphosphatemia and granular casts
• Gross lesions: Splenomegaly and diffusely red kidneys

• Cats: Zinc associated with Heinz body hemolytic anemia
• Ruminants: Zinc toxicity may result from ingestion of zinc-containing objects/substances (including products used to treat dermatologic conditions in cattle and sheep)
  •  May develop necrotizing abomasitis and duodenitis with congestion and edema, and grossly green discoloration; ductular elements of the pancreas most vulnerable to damage
    • Subacute abomasal lesions may include exfoliation of glandular epithelium and proliferation of mucous neck cells
• Pigs: 
  • Chronic pancreatitis in pigs fed excessive zinc oxide (ZnO); ZnO used as a feed additive to increase growth and reduce enteric bacterial disease in weaners (Komatsu, J Vet Diagn Invest. 2020)
• Horses: 
  • Hair testing not useful to evaluate heavy metal (including zinc) exposure (van der Merwe, J Vet Diagn Invest. 2022)
  • Reference interval for Zn in horses in the Netherlands calculated to be 123-411 mg/kg dry weight (van der Merwe, J Vet Diagn Invest. 2023)
• Foals: Excess dietary zinc (or large dose from ingested paint or other source) can induce copper deficiency, resulting in lysis of cartilage 
• Avian (experimental): Direct injection into testes produces testicular teratomas
• Hyena: Described in a captive striped hyena following penny ingestion; severe, nonregenerative anemia, jaundice, and gallbladder edema; centrilobular hemosiderosis, cholestasis, Kupffer cell hyperplasia and single-cell necrosis 
• Ferrets: Acute pancreatitis, acute renal tubular injury, and anemia has been linked to zinc toxicosis (> 3000 ppm) (Sulkosky, Vet Pathol 2024)
• Gyrfalcons: Reference interval 11.3-35.0 µmol/L and other falcon species 12.5-33.5 µmol/L in the United Arab Emirates (Pappalardo, J Vet Diagn Invest 2021)

 

REFERENCES:

1. Abdul-Aziz T, Fletcher OJ. Chapter 9: Urinary System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 425
2. Abdul-Aziz T, Fletcher OJ. Chapter 12: Endocrine System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 546
3. Barnes HJ, Fletcher OJ, Abdul-Aziz T. Chapter 13: Reproductive System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 583.
4. Church, ME, Terio KA, Keel MK. Procyonidae, viverridae, hyenidae, herpestidae, eupleridae, and prionodontidae. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:307. 
5. Durham AC, Boes KM. Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:831.
6. Fenton H, McManamon R, Howerth EW. Anseriforms, ciconiiformes, charadriiforms, and gruiformes. In: Terio KA, McAloose D, St. Leger J eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier Inc. 2018:699.
7. Jubb KV, Stent AW. Pancreas. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Ltd; 2016:354-357.
8. Komatsu T, Sugie K, Inukai N, et al. Chronic pancreatitis in farmed pigs fed excessive zinc oxide. J Vet Diagn Invest. 2020;32(5):689-694.
9. Olson EJ, Dykstra JA, Armstrong AR, Carlson CS. Bones, Joints, Tendons, and Ligaments. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1060.
10. Pappalardo L, Silvanose C, Beaufrere H, Binoy A, Asmanis P. Reference intervals for Cu, Mg, and Zn in captive gyrfalcons and other falcon species in the United Arab Emirates. J Vet Diagn Invest. 2021;33(4):797-800.
11. Reavill DR, Dorrestein G. Psittacines, coliiformes, musophagiformes, cuculiformes. In: Terio KA, McAloose D, St. Leger J eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier Inc. 2018:773. 
12. Schmidt R, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015: 73, 88, 89, 119, 140, 229-230, 
13. Spagnoli ST, Gelberg HB. Alimentary System and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:441. 
14. Sulkosky SB, Garner MM, Burgess M, Williams BH, LaDouceur EEB. Review of spontaneous lesions in the exocrine pancreas of domestic ferrets (Mustela furo). Vet Pathol. 2024; doi: 10.1177/03009858241266943. Epub ahead of print.
15. Valli VEOT, Kiupel M, Bienzle D, Wood RD. Hematopoietic System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:123. 
16. Van der Merwe D, van den Wollenberg L, van Hees-Valkenborg J, de Haan T, van der Drift S, Vandendriessche V. Evaluation of hair analysis for determination of trace mineral status and exposure to toxic heavy metals in horses in the Netherlands. J Vet Diagn Invest. 2022;34(6)1000-1005.
17. Van der Merwe D, van den Wollenberg L, van Hees-Valkenborg J, de Haan T, van der Drift S, Vandendriessche V. Reference intervals for trace mineral and heavy metal concentrations in horse livers in the Netherlands. J Vet Diagn Invest. 2022;34(6)1000-1005.
18. Van Wettere AJ, Brown DL. Hepatobiliary System and Exocrine. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:541,543. 
19. Uzal FA, Plattner BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:52. 

 

 

 

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