SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
October 2021
D-T10 (NP)

Signalment (JPC# 2339016):  18-year-old quarter horse gelding

HISTORY:  This horse had mild to moderate colic for about 48 hours.  The veterinarian administered 500 mg flunixin meglumine; this same dose was administered three times over a ten hour period.  Despite supportive therapy, the horse died two days after admission.

HISTOPATHOLOGIC DESCRIPTION:  Colon:  Focally there is a well-demarcated, 1 cm wide ulcer characterized by loss of the mucosal epithelium, lamina propria, muscularis mucosa, and superficial submucosa with replacement by abundant necrotic debris, fibrin, numerous viable and degenerate neutrophils, fewer eosinophils, macrophages, and hemorrhage, fibrin, and edema.  The inflammatory infiltrate extends into and expands the adjacent submucosa where it is admixed with often hypertrophied fibroblasts and edema. Within several submucosal small vessels, there is loss of the endothelium, the tunica media is hypereosinophilic, and both the tunica media and tunica externa are infiltrated by low numbers of neutrophils and are expanded by variable amounts of fibrin, edema, and karyorrhectic debris (fibrinonecrotizing vasculitis).  The lumina of affected vessels often contain fibrin thrombi.  Remaining submucosal vessels are markedly congested. Focally within the central portion of the ulcer, there is a small portion of mucosa with retention of normal tissue architecture and loss of differential staining (coagulative necrosis).

MORPHOLOGIC DIAGNOSIS:  Colon:  Colitis, ulcerative, acute, focally extensive, severe, with fibrinonecrotizing vasculitis and thrombosis, quarter horse, equine.

ETIOLOGIC DIAGNOSIS:  Toxic colonic ulceration

CAUSE:  Non-steroidal anti-inflammatory drugs (NSAIDs)

GENERAL DISCUSSION: 

• Non-selective NSAIDs include salicylates (aspirin), propionic acids (ibuprofen, ketoprofen, fenoprofen, and naproxen), pyrazolones (phenylbutazone), anthranilic acids (meclofenamic acid), and aminonicotinic acids (flunixin meglumine)
• Phenylbutazone is the most common cause, but all have toxic potential in horses
• Predisposing factors such as dehydration, stress, renal disease, hepatic disease, or sepsis may exacerbate the development of NSAID toxicity
• Two well-recognized syndromes are attributed at least in part to NSAID toxicity:
  • Gastric and upper small intestine ulceration
  • Right dorsal ulcerative colitis (RDUC), aka right dorsal colitis (RDC)

PATHOGENESIS:

• NSAID administration > gastric hypermotility and a decrease in cyclooxygenase activity (COX1 and COX2) > decrease in prostaglandin E production > decreased mucosal blood flow, bicarbonate secretion and mucus production > decreased cell turnover and decreased migration of basal epithelium after injury > increased gastric acid (gastrin) production > erosions and ulcers
• Specific actions of NSAIDs which contribute to the formation of ulcers:
  • Directly cytotoxic to mucosal epithelial cells
  • Phenylbutazone (the NSAID most commonly associated with right dorsal colitis in horses) may also have a direct toxic effect on vascular endothelium
  • Block cyclooxygenase activity and the synthesis of mucosal protective prostaglandins
  • Directly reduce mucus and bicarbonate release independent of prostaglandin inhibition, interfering with protective effects of mucus and bicarbonate from endogenous acid (gastric acid)
  • Stimulate membrane bound sodium transport pumps, and increase proton loss
  • Reduce cytosolic ATP

TYPICAL CLINICAL FINDINGS:

• The most common clinical signs of NSAID toxicity in all species are due to gastric mucosal irritation and ulceration
• Anorexia, diarrhea, melena, abdominal pain or mild intermittent colic
• Protein losing enteroptahty (PLE) or stricture formation in horses with colonic mucosal damage
• Horses with hypoproteinemia from PLE may show secondary ventral edema
• Endotoxemia secondary to ulceration in horses
• Hyponatremia and hypochloremia
• Ulcerative stomatitis with difficult prehension and mastication
• Esophageal ulcers may cause excessive salivation or painful swallowing, groaning or extension of the neck
• Gastrointestinal ulcers lead to slow consumption of feed, inappetence (particularly for grain diets), or anorexia
• Horses with gastric outflow obstruction associated with gastroduodenal ulceration may exhibit reflux esophagitis or ptyalism

TYPICAL GROSS FINDINGS: 

• Ulcers can occur anywhere from the mouth to the rectum, and may be covered by a fibrinous exudate
• In chronic cases, stricture of the right colon can occur with subsequent impaction and colon rupture
• Mucosal edema
• Serosal petechiation
• Ulcerative stomatitis
• Abdominal effusion and ventral subcutaneous edema
• Renal papillary necrosis

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Gastrointestinal
  • Thrombosis and fibrinoid necrosis of submucosal veins; discrete mucosal ulcers with inflammatory cell infiltrates; submucosal edema or necrosis; lymphangiectasia; granulation tissue (with chronicity)
• Renal:
  • Fibrinoid necrosis of the veins of the renal crest; hemorrhage, edema, and inflammation; coagulative necrosis of the renal crest
• Hepatic:
  • Fibrinoid necrosis of portal veins; edema, hemorrhage, and inflammation; periportal hepatocellular necrosis

DIFFERENTIAL DIAGNOSIS:

• Salmonellosis: More diffuse and necrotizing; +/- intralesional bacilli
• Colitis X: Involves all four parts of the colon; severe edema and hemorrhage of the colonic wall
• Potomac horse fever (Neorickettsia risticii): Segmental to diffuse small and large intestinal hemorrhage, hyperemia, and congestion; occasional focal ulcers
• Clostridium perfringens type A enterotoxemia
• Purpura hemorrhagica (immune mediated): Necrotizing vasculitis and petechiae throughout the intestine, lung, muscle, and other tissues
• Equine viral arteritis (Togavirus, genus Arterivirus): Lesions in multiple organs
• Strongylus vulgaris endarteritis: Diffuse ischemia, not sharply delineated ulcers
• Castor oil toxicity

COMPARATIVE PATHOLOGY: 

• Virtually all animals can develop ulcerative lesions similar to those in the horse within the stomach and small intestine; however, the right dorsal colitis secondary NSAID administration is a lesion most commonly described in horses

REFERENCES:

1. Constable PD, Hinchcliff KW, Done SH, Grunberg W. Veterinary Medicine:  a Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats. 11th ed. St. Louis, MO: Elsevier; 2017:267-268.
2. D’Arcy-Moskwa E, Noble GK, Weston LA. Effects of meloxicam and phenylbutazone on equine gastric mucosal permeability. J Vet Intern Med. 2012; 26(6):1494-1499.
3. Geldberg HB. Alimentary system and the peritoneum, omentum, mesentery, and peritoneal cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:374.
4. Jones SL, Smith BP. Diseases of the alimentary tract. In: Smith BP, ed. Large Animal Internal Medicine. 4th ed. St. Louis, MO: Elsevier Mosby; 2015:693,732-734,874,1046.
5. Landolfi JA, Terrel SP. Proboscidae. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:418.
6. Uzal FA, Plattner BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier; 2016:55-57, 85.

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