JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

September 2024

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)
Teeth: Yellow tartar accumulation along the gum line (horses)

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 similar 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 (likely secondary to vascular changes/ischemia)
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 cells

Mineralization of gastric mucosa
Fibrosis
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 (Ambrosio et al, J Comp Pathol, 2020)
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

Wildlife:

Chronic renal disease occurs in captive rhinoceros similar to domestic animals; uremic mineralization of the lung and/or stomach is a potential sequelae

REFERENCES:

Ambrosio, MB, Hennig MM, Nascimento HL, Santos A, Flores MM, Fighera RA, Irigoyen LF, Kommers GD. Non-Renal Lesions of Uraemia in Domestic Cats. J Comp Pathol. 2020; 180:105-114
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.
Duncan M. Perissodactyls. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:439-440.
Machado M, Wilson TM, Sousa DER, Gonçalves AAB, Martins CS, Castro MB. Uraemic Encephalopathy in a Persian Cat with Chronic Kidney Disease. J Comp Pathol. 2020 Oct;180:100-104.
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: 427.
Stockham SL, Scott MA. Urinary System. In: Fundamentals of Veterinary Clinical Pathology. 2^nd ed. Ames, Iowa. Blackwell; 2008:425-433.
Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 707-709.
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; 2011:273,280.
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.