JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

September 2024

D-M15

 

Signalment (JPC #2760643): 3-year-old military working dog

 

HISTORY: This dog presented with vomiting and abdominal pain. 

 

HISTOPATHOLOGIC DESCRIPTION: Pancreas: Replacing approximately 50% of the pancreatic parenchyma and extending into the peripancreatic adipose tissue are multifocal to coalescing areas of lytic necrosis, characterized by loss of cellular architecture and replacement with eosinophilic cellular and karyorrhectic debris, fibrin, hemorrhage, and edema which are rimmed by necrotic neutrophils and macrophages. Within the adjacent parenchyma, acinar cells are often either swollen with pale, vacuolated eosinophilic cytoplasm (degeneration), or are shrunken with hypereosinophilic cytoplasm, pyknotic nuclei, and loss of zymogen granules (single cell death). Within necrotic foci, blood vessel vascular tunics are expanded transmurally by scant necrotic cellular debris, fibrin, hemorrhage, and edema (vasculitis); few vessels contain fibrin thrombi. Foci of necrosis, inflammation, and hemorrhage multifocally extend into the peripancreatic adipose tissue, where adipocytes at the periphery exhibit loss of cellular detail (fat necrosis) and are replaced by basophilic, finely granular mineral and acicular cholesterol clefts (fat saponification).

 

Lymph node: Within the subcapsular and medullary sinuses, there is moderate draining hemorrhage, and macrophages often contain golden-brown, granular to globular, intracytoplasmic material (hemosiderin).

 

MORPHOLOGIC DIAGNOSIS: 

1. Pancreas: Pancreatitis, necrotizing, acute, multifocal, moderate, with peripancreatic fat necrosis and saponification, breed not specified, canine.
2. Lymph node: Draining hemorrhage, chronic-active, moderate.

 

ETIOLOGY: Unknown

 

CONDITION: Acute pancreatic necrosis

 

SYNONYMS: Acute pancreatitis, pancreatitis

 

GENERAL DISCUSSION:

• Pancreatitis: Term used for acute pancreatic necrosis as well as diseases that are primarily inflammatory (i.e. acute and chronic pancreatitis); these disorders have different causes, pathogeneses, and histologic characteristics 
  • Acute pancreatic necrosis is a life-threatening condition that may become chronic or relapsing; the inciting cause is often unknown and initially includes mesenteric adipose tissue adjacent to the pancreas and acinar cells at the edge or margin of the pancreatic lobules
  • Acute pancreatitis may occur when there is inflammation within a centrilobular region or a periductal pattern, and may occur associated with reflux of digestive enzymes from the duodenum; when severe may include extensive hemorrhage and histologic lesion may overlap with severe acute pancreatic necrosis
    • Any acute cases may become chronic pancreatitis (especially duct obstruction), which is accompanied by fibrosis and atrophy
  • Chronic interstitial pancreatitis is a pattern more commonly observed in cats and arises secondary to a process originating in the ducts; 
    • Only chronic pancreatitis and diabetes mellitus were correlated in recent studies in cats 
    • In cats, chronic pancreatitis almost always manifests as extensive fibrosis with little inflammation
    • Sporadic in horse associated with strongyle migration
• Acute pancreatic necrosis:
  • Most common pancreatic disease in dogs and occasionally occurs in cats, rare in other species
  • Acute and life-threatening syndrome or chronic relapsing syndrome that culminates in exocrine pancreatic insufficiency and diabetes mellitus (DM)
  • Cocker spaniels have increased incidence
  • Obese, sedentary bitches are predisposed

 

PATHOGENESIS:

• 3 major mechanisms of pancreatitis

• Obstruction of duct (calculi, parasites, neoplasia)
• Direct injury to acinar cells (T-2 mycotoxin, zinc, sulfa drugs, or ischemia)
• Disturbances of enzyme trafficking within acinar cells (aberrant transport of proenzymes as may occur with steroids)

• High fat meals in dogs is a common trigger with unclear specific pathogenesis

• Regardless of mechanism, all result in activated enzymes autodigesting the pancreas and peripancreatic fat
• Lysosomes and zymogen granules co-localize or fuse due to increased intracellular calcium concentration which activates trypsin 

• May represent the common pathway by which different mechanisms result in pancreatic necrosis

• Trypsin > activates enzymes (elastase and phospholipase A) > autodigestion, necrosis, vasculitis > vasoactive amine release > increased vascular permeability > edema, hemorrhage, thrombosis, ischemic necrosis
• Local activation of the complement cascade (activated prekallikrein) and cytokines (TNF-alpha, IL-1, IL-6, IL-8, and platelet activating factor) 
• Systemic consequences: Leukocytes generate reactive oxygen species (ROS) and more cytokines which consume protease inhibitors (e.g. alpha 1- protease inhibitor and macroglobulin), which trigger DIC, SIRS, etc.
• Hypoperfusion and possibly reperfusion may be important in the pathogenesis of necrosis (lesions are often at the periphery of the pancreatic lobule)
• Complete resolution of the pathologic process is unlikely

 

TYPICAL CLINICAL FINDINGS:

• Middle-aged to older dogs that are overweight or obese are at increased risk
• Severe acute abdominal pain with anorexia, vomiting, lethargy 
• Pancreatic lipase immunoreactivity (PLI): Most sensitive test
• Liver involvement: Increased ALT, AST, and/or ALP, hyperglycemia, glucosuria
• Secondary hyperlipidemia in dogs: Thought to be due to the release of inhibitors of lipoprotein lipase.
• Associated with mastocytemia, DIC, hypocalcemia (especially cats), hyperamylasemia (especially dogs), increased trypsin-like immunoreactivity (TLI), increased pancreatic lipase immunoreactivity (PLI), increased urine and plasma trypsinogen activation peptide (TAP), hypertriglyceridemia
• Increased lipase activity in peritoneal fluid of dogs with acute pancreatic necrosis

 

TYPICAL GROSS FINDINGS:

      pancreas

necrosis and saponification of adipocytes in the peripancreatic mesentery

      atrophied pancreatic tissue

• Pancreatic edema with gray-white areas and hemorrhage
• Peritonitis with fibrinous adhesions to affected areas on pancreas
• Peritoneal fluid may be hemorrhagic and contain fat droplets
• Repeated acute episodes may lead to chronic fibrosing pancreatitis
• Portal vein thrombosis (Rule outs: IMHA, pancreatitis, protein losing

nephropathy and enteropathy, peritonitis, corticosteroid administration, and neoplasia)

• Focal liver necrosis may be present

• A minority of dogs with pancreatic necrosis may develop multifocal necrotizing panniculitis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Coagulative or lytic necrosis of the peripancreatic adipose tissue and pancreatic parenchyma
• Edematous separation of the interstitium with mural necrosis
• Influx of leukocytes in varying degrees
• Focally extensive areas of hemorrhage and thrombosis of blood vessels
• Fibrinous exudates in the interlobular septa
• Saponification, necrosis, and inflammation of fat characterized by acidophilic, opaque, amorphous, or lacy intracytoplasmic substance, or basophilic fibrillar or granular mineralized substance 

 

ULTRASTRUCTURAL FINDINGS:

• Lysis of acinar cells
• Accumulation of large amounts of glycogen in a mononuclear cell

 

ADDITIONAL DIAGNOSTIC TESTS:

• Ultrasound: Enlarged, hypoechoic pancreas
• Radiography: Increased density in the right cranial quadrant (ground 

glass), left gastric displacement, right duodenal displacement, gas-filled duodenum/colon

 

DIFFERENTIAL DIAGNOSIS: 

• Gross: Nodular exocrine hyperplasia, zinc toxicosis 
• Histologic: Zinc toxicosis 
• Zinc toxicosis is a cause of pancreatic necrosis in dogs, calves, sheep, and waterfowl
• Exocrine pancreatic insufficiency (EPI): Low TLI

 

COMPARATIVE PATHOLOGY:

Causes of pancreatitis:

• Horses: Chronic interstitial pancreatitis due to migrating strongyles 
• Calves, sheep, dogs: Zinc toxicosis, pancreatic calculi
• Pigs: Cassia occidentalis (shrub in Southeastern US) intoxication; T-2 (trichothecene) mycotoxin toxicosis
• Non-human primates: Adenoviral pancreatitis has been reported in rhesus monkeys infected with simian immunodeficiency virus; other causes include Trichospirura leptostoma found in pancreatic ducts.
• Avian:
  • Turkeys: Pancreatitis has been reported with either highly pathogenic avian influenza (HPAI) or Turkey viral hepatitis; also copper toxicity causes pancreatic coagulative necrosis
  • Falcons: Hemorrhagic pancreatic necrosis was the most prominent finding in HPAI-infected falcons during outbreaks in the UAE
  • Owls: multifocal pancreatic necrosis was noted grossly in 3 great horned owls and histologically in numerous raptors with neurologic signs from HPAI (Wunschmann et al. 2024)
  • Seabirds: multifocal pancreatic necrosis was noted grossly in 4 herring gulls with HPAI; pancreatic and splenic necrosis was the most common pathological change in this group of gulls and skua (Lean et al. 2022)
  • Multiple avian species: Pancreatic necrosis is reported with birds affected by West Nile Virus
  • Guinea fowl: Pancreatic necrosis without liver lesions in Aviadenovirus infection
  • Pigeons: Lymphocytic pancreatic necrosis associated with pigeon paramyxovirus type 1
  • Quaker parrots: Have higher rates of acute pancreatic necrosis than other psitticines, that may be related to lipid dysmetabolism risk factors or other causes (obesity, increased abdominal adiposity, hypertriglyceridemia, dietary and metabolic factors); diffuse, severe coagulative necrosis
  • Psittacines: Herpesvirus (Pacheco’s disease), polyomavirus (budgerigar fledgling disease), poxvirus, and adenovirus may induce pancreatic necrosis and inflammation in systemic disease
  • Chickens: 
    • Picornavirus (avian encephalomyelitis) in chicks is associated with lymphoid infiltrate and reactive lymphoblast-like follicles in the pancreas
    • Aviadenovirus (inclusion body hepatitis) in chicks is associated with massive exocrine pancreatic necrosis and INIBs
• Cats (types of pancreatitis):
  • Associated with systemic toxoplasmosis in cats
  • Acute necrotizing pancreatitis: Similar to dogs, with or without fibrosis, abundant neutrophils
  • Acute suppurative pancreatitis (inflammation rather than necrosis) is likely due to ascending bacterial infection
  • Chronic pancreatitis: Fibrosis, lymphocytes, cystic dilation; most often affects cats without gastrointestinal disease
  • Both: Lobulation, amyloid, periductular inflammation, atypical nodules
  • Very little involvement of pancreatic ducts
• Ruminants
  • Foot and mouth disease virus (FMDV) is associated with pancreatic necrosis and pancreatitis in mountain gazelles (naturally and experimentally infected) and in pronghorn antelope (experimentally infected) 
• Fish
  • Infectious pancreatic necrosis (IPN, Birnaviridae family) is a viral disease of young salmonids; most commonly affects rainbow trout, brook trout, brown trout, Atlantic salmon, and a range of Pacific salmon species; causes severe pancreatic acinar cell necrosis
  • Cyprinid herpesvirus-2 causes pancreatitis with hematopoietic necrosis
• Invertebrates
  • Acute hepatopancreatic necrosis disease (AKA early mortality syndrome) of penaeid shrimp is caused by Vibrio parahaemolyticus; grossly the hepatopancreas (normally brown) appears white through the carapace; microscopic lesions include acute necrosis of the hepatopancreatic tubular epithelium, sloughing of degenerate cells to the lumen of tubules, and marked intratubular hemocytic inflammation
• NHPs
  • Macaque fatal fatty liver syndrome or uremia can both be accompanied by multifocal pancreatic necrosis

 

REFERENCES:

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2. Beaufrere H, Reavill D, Heatley J, Susta L. Lipid-related lesions in Quaker parrots (Myiopsitta monachus). Vet Pathol. 2019;56(2):282-288.
3. Brady AG, Carville Angela AL. Digestive System Diseases of Nonhuman Primates. In: Nonhuman Primates Biomedical Research: Diseases. Vol 2. 2nd ed. San Diego, CA: Academic Press; 2012:615.
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