JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-M08

 

SIGNALMENT (JPC #1898566):  12-year-old female Pomeranian dog

 

HISTORY:  This dog exhibited anorexia, lethargy, reluctance to move, dyspnea, and had areas of ulceration on the tongue.

 

HISTOPATHOLOGIC DESCRIPTION:  Stomach, fundus: Diffusely affecting the fundic superficial gastric glands and multifocally extending into the deep layers, there is chief and parietal cell necrosis characterized by shrunken, individualized cells with pyknotic nuclei admixed with cellular and karyorrhectic debris, degenerate neutrophils, fibrin, hemorrhage, edema, deposition of basophilic, finely granular mineral (mineral), and multifocal mineralization of necrotic cells. Multifocally gastric glands contain necrotic debris and neutrophils and are lined by attenuated epithelium. Multifocally the lamina propria and submucosa are expanded by neutrophils, macrophages, fewer lymphocytes, plasma cells, fibrosis, and edema.  Multifocally, vessels within the lamina propria and submucosa are variably occluded by eosinophilic, fibrillar to hyalinized fibrin with entrapped neutrophils, macrophages, and lymphocytes (fibrin thrombi), occasionally with recanalization.  Blood vessels multifocally exhibit loss or necrosis of the tunica intima and thickening of the tunica media by smooth muscle hypertrophy admixed with edema, fibrin, few neutrophils, karyorrhectic debris, and mineral (vasculitis). 

 

MORPHOLOGIC DIAGNOSIS:  Stomach, fundus: Parietal and chief cell necrosis, subacute, diffuse, moderate, with chronic-active gastritis, mucosal mineralization, fibrosis, vasculitis, and thrombosis, Pomeranian, canine.

 

ETIOLOGIC DIAGNOSIS:  Uremic gastritis, uremic gastropathy

 

GENERAL DISCUSSION:

• Uremia is a clinical syndrome of renal failure
• Ensues when GFR is
• Uremic gastritis is most common in carnivores; rare in ungulates and if present is usually due to obstructive (postrenal) kidney disease
• Severity of lesions depends on the duration of the uremic state
• Biochemical disturbances of uremia are due to impairment of the kidney’s regulation of fluid volume, regulation of electrolyte and acid-base balance, excretion of waste products, and metabolism of hormones

 

PATHOGENESIS:

• Lesions associated with uremia are secondary to:
  • Damage to endothelial cells > pulmonary edema, fibrinous pericarditis, atrial and aortic thrombosis, stomatitis, and gastritis
  • The precise pathogenesis of diffuse tissue mineralization in uremia is not well defined
    • May be dystrophic or metastatic
    • Local tissue characteristics (e.g. pH, etc.) likely play a role in mineral localization to specific tissues
  • Reduced glomerular filtration à retention of phosphate à reduction of ionized calcium; also deficiency of 1,25(OH)₂D₃ à increased synthesis and secretion of parathyroid hormone à secondary hyperparathyroidism à soft tissue mineralization, fibrous osteodystrophy, and parathyroid gland hyperplasia
    • Mineralization due to mass law (calcium x phosphorous > 70) – made more severe by reduced ability of kidneys to hydroxylate 25-hydroxycholecalciferol to calcitriol à decreased intestinal calcium absorption and increased parathyroid hormone (PTH) secretion (calcitriol suppresses PTH release)
  • Elevations in blood and salivary urea in combination with urease-producing bacteria (found in oral and gastric flora) generates ammonia which is caustic to oral mucosa
  • Decreased renal production of erythropoietin and increased erythrocyte fragility à anemia

 

TYPICAL CLINICAL FINDINGS:

• Anorexia, vomiting, diarrhea (+/- melena, hematemesis), weakness/malaise, severe halitosis
• Dehydration: secondary to reduced renal concentrating ability, vomiting, diarrhea
• Renal Azotemia: Increased serum creatinine and blood urea nitrogen; isosthenuria
• Hyperphosphatemia
• Increased PTH
• Nonregenerative anemia: Normocytic, normochromic
• Titrational metabolic acidosis (increased anion gap due to uremic acids)
• Normocalcemia to mild hypocalcemia; however, hypercalcemia may occasionally occur
• Hyperkalemia
• Red blood cell echinocytes (Burr cell)
• Increased BMBT (platelet function test) –indicates poor adherence of platelets to endothelium; unknown cause in uremia
• Hypoproteinemia/hypoalbuminemia
• Hypertension

 TYPICAL GROSS FINDINGS:

Nonrenal lesions of uremia

• Gastrointestinal:
  • Tongue: Oral lesions are due to either fibrinoid necrosis of arterioles or bacterial production of ammonia from urea in the saliva
    • Ulcerative, necrotic stomatitis/glossitis (underside of tongue, bilaterally symmetrical, secondary to urease positive oral microflora)
    • Infarction of tongue tip (secondary to vasculitis)

• Stomach:  Ulcerative and hemorrhagic gastritis – dogs/cats
  • Severity variable due to duration of uremia – no gross lesions or variable edema and thickening of rugal mucosa +/- focal ulceration
  • Severe congestion and hemorrhage of the body of the stomach
  • Mucosa thickened and deep red-black color
  • Mineralization of the middle and deep zones of gastric mucosa
  • Mucosal infarction may occur due to vascular lesions

• Colon: Ulcerative and hemorrhagic colitis – cattle/horses
  • Large areas of colonic mucosa edematous and dark red
  • GI contents hemorrhagic and smell like ammonia

• Small intestine: Intestinal lesions may occur simliar to stomach, but less common
• Cardiovascular:
  • Fibrinous pericarditis
  • Ulcerative atrial mural endocarditis (typically the left atrial endocardium) that can extend into the large arteries in close proximity to the valves
  • Atrial and aortic thrombosis
  • Left ventricular hypertrophy and dilation (chronic uremia)
  • Many systemic lesions occur secondary to systemic arterial lesions such as gastric infarction and myocardial necrosis
• Respiratory:
  • Subpleural intercostal mineralization – most constant lesion in dog
  • Solid, gritty, pale (pumice) lungs
  • Pulmonary edema (fibrin rich), hyperemia, and extensive mineralization especially the reticulin of alveolar walls – uremic pneumonitis
    • Note terminal pulmonary edema is common in animals dying of uremia
  • Vasculitis in alveolar capillaries
• Skeletal:
  • Fibrous osteodystrophy
• Endocrine:
  • Bilateral parathyroid hyperplasia (chief cells) – dogs and cats
• Brain:
  • White-matter spongiform degeneration +/- astrogliosis (uremic encephalopathy)

Renal lesions of uremia

• Variable
• If chronic, nephrocalcinosis (renal tubular epithelium damaged by increased intracellular calcium):
  • Fibrosed, mineralized kidney with sclerotic glomeruli, with multifocal atrophic and hypertrophic tubules – “end-stage kidney”

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Dogs: Stomach affected
  • Lamina propria between glands is edematous with increased mast cells
  • Severe mucosal congestion, edema, and necrosis
  • Mineralization of glands, vasculature, and lamina propria – mid to deep portions of mucosa
  • Atrophy of gastric glands with fibrosis and mineralization
  • Submucosal arteriopathy (myocyte necrosis, hypertrophy, mineralization, and  thrombosis); typically limited to the body and fundus
  • Shrunken, agranular, atrophic chief cells
  • Swollen and fragmented parietal cells

• Cats:
  • Gastric mucosal ulceration and erosions
    • Loss and necrosis of parietal
  • Mineralization of gastric mucosa
  • Tongue/oral mucosaà ulceration and erosions
• Cattle/horses: Colon affected
  • Coagulative necrosis, hemorrhage, and a neutrophilic infiltrate in mucosa

 

DIFFERENTIAL DIAGNOSIS:

For soft tissue mineralization:

• Vitamin D intoxication (excessive vitamin supplementation and ingestion of cholecalciferol containing rodenticides; ingestion of plants with vitamin D analogs: Cestrum diurnum, Solanum spp., Trisetum flavescens): metastatic calcification (phosphate salts) of large arteries, myocardium, gastric mucosa, lung, kidney

 

COMPARATIVE PATHOLOGY:

• Cats:
  • Pulmonary edema is the most frequent non-renal lesion of uremia
  • Gastric fibrosis
  • Hemorrhagic and ulcerative gastritis
  • Ulcerative glossitis and stomatitis
  • Hypokalemia common due to polyuric renal failure
• Cattle:
  • Ulcerative and hemorrhagic colitis
  • Edema of stomach and proximal intestine
  • Hyponatremia/hypochloridemia: Decreased tubular secretion and reabsorption
  • Hypocalcemia
• Horses:
  • Ulcerative and hemorrhagic colitis
  • Uremic gastritis occurs occasionally (DDX: cantharidin toxicosis)
  • Hypercalcemia (decreased renal excretion of calcium)
  • Hyponatremia/hypochloridemia: Decreased tubular secretion and reabsorption

 

REFERENCES: 

1. Ambrosio, MB, Hennig MM, Nascimento HL, Santos A, Flores MM, Fighera RA, Irigoyen LF, KommersGD. Non-Renal Lesions of Uraemia in Domestic Cats. Comp Path. 2020; 180:105-114
2. Breshears MA, Confer AW. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 640-641.
3. Cianciolo RE, Mohr FC. Urinary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 384-387.
4. Gelberg HB. Alimentary system and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: achary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 365
5. McLeland SM, Lunn KF, Duncan CG, Refsal KR, Quimby JM. Relationship among serum creatinine, serum gastrin, calcium-phosphorus product and uremic gastropathy in cats with chronic kidney disease. J Vet Intern Med. 2014; 28:827-837.
6. Tripathi NK, Gregory CR, Latimer KS. Urinary System. In: Latimer KS, ed. Duncan and Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Ames, IA: Wiley-Blackwell; 2011:280.
7. 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. St. Louis, MO: Elsevier; 2016: 16-17, 51.

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