JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

September 2024

D-M10

 

Signalment (JPC #1322547): A young pig

 

HISTORY: None.

 

HISTOPATHOLOGIC DESCRIPTION: 

Liver: Multifocally and randomly, 40% of hepatic lobules are characterized by massive hepatocellular necrosis. Affected necrotic lobules are characterized by collapse of hepatic cords (stromal collapse). Hepatocytes within these necrotic lobules are shrunken with hypereosinophilic cytoplasm and pyknotic nuclei (necrosis or single cell death), admixed with hemorrhage, fibrin, and edema. Less affected hepatic lobules have segmental, often paracentral or central, foci of necrosis. Portal areas are moderately expanded by increased profiles of small bile ducts (biliary ductular reaction), lymphocytes, plasma cells, neutrophils, macrophages, hemosiderophages, reactive fibroblasts (periportal fibrosis), fibrin, hemorrhage, and edema. Periportal fibrosis occasionally bridges to adjacent portal areas (bridging fibrosis). Multifocally, the capsule is indented in association with areas of stromal collapse and periportal fibrosis. 

 

Lymph node: Multifocally the subcapsular, cortical, and medullary sinuses contain moderate amounts of hemorrhage, fibrin, and edema that expands the cortical sinuses (draining hemorrhage). The perinodal connective tissue is expanded by increased clear space (edema), and there are few fibrin thrombi within vessels. 

 

MORPHOLOGIC DIAGNOSES: 

1. Liver: Necrosis, massive, acute, multifocal, random, marked, with stromal collapse and hemorrhage, breed not specified, porcine.

2. Liver: Hepatitis, periportal to bridging, lymphoplasmacytic, histiocytic, and neutrophilic, subacute, moderate, with periportal fibrosis.

3. Lymph node: Draining hemorrhage, acute, multifocal, moderate, with edema and fibrin.

 

CAUSE: Vitamin E/selenium deficiency

 

CONDITION: Hepatosis dietetica, nutritional hepatic necrosis

 

GENERAL DISCUSSION:

• A now uncommon syndrome of young swine consisting of acute centrilobular to massive hepatic necrosis in association with one or more immediate or more chronic effects, such as “yellow-fat disease”, degeneration of skeletal and cardiac muscles, serous effusions, ulceration of the squamous mucosa of the stomach, and fibrinoid necrosis of arterioles (dietary microangiopathy, “mulberry heart disease”)
• Disease of young, rapidly growing pigs with inadequate dietary protein, vitamin E, and/or selenium
• Myocardial degeneration is the most common manifestation of vitamin E/selenium deficiency in growing/weaned pigs 6-20 weeks of age
• Striated muscle changes in some species are referred to as nutritional “muscular dystrophy”; some references consider “dystrophy” an inappropriate term for this condition

 

PATHOGENESIS:

• Nutritional origin with a complex pathogenesis; development of hepatic necrosis requires concurrent deficiencies of sulfur-containing amino acids, tocopherols (vitamin E), and trace amounts of selenium
• Selenium protects against hepatic necrosis and massive effusions, and tocopherols (vitamin E) are probably protective against other lesions of this syndrome
• Free radical generation with deficiency of free-radical scavengers such as vitamin E and selenium (protective through its role in glutathione peroxidase and other selenoproteins) à oxidative damage, loss of cell membrane integrity and stability

 

TYPICAL CLINICAL FINDINGS:

• Disease typically affects rapidly growing pigs in good condition that are fed diets largely of grain that contain protein supplements lacking in quantity or quality
• Some pigs may be nutritionally predisposed, and other predisposing factors may include a cold damp environment or other stress
• Death usually occurs acutely following a period of dullness without specific clinical signs, but melena, dyspnea, weakness, and trembling may be observed
• Jaundice is indicative of a relapsing clinical course
• Anemia may be present secondary to severe gastric ulceration

 

TYPICAL GROSS FINDINGS:

• Liver: Marked hepatic necrosis initially characterized by deep red, distended, and friable liver that later is characterized by parenchymal collapse and dense tracts of connective tissue (postnecrotic scarring); lesions are often most severe on the dorsal parts of the diaphragmatic surface; the right lobe may not have lesions and can undergo marked hypertrophy
• Gallbladder: Edema
• Stomach: Gastric ulceration (squamous portion), free and digested blood in stomach and intestine
• Heart: Extensive myocardial hemorrhage (intramural, subendocardial, epicardial) (see C-M06), with pulmonary edema, grey-white steaks/patches in the peri-, epi-, and/or myocardium; can see myofiber degeneration and mineralization 
• Adipose tissue: Often stained yellow (yellow-fat disease)
• Hemorrhagic diathesis may occur in relapsing cases, mainly manifest as articular/periarticular hemorrhage 
• Small volume, protein-rich effusion in body cavities, with fibrin strands in peritoneal cavity

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Liver: Centrilobular to massive coagulative necrosis and stromal collapse; usually not all lobes affected; acute and chronic lesions are found
• Heart: Foci of hyaline degeneration of cardiac myocytes
• Arterioles: In some cases, fibrinoid necrosis of small arterioles and veins occurs in many tissues (most commonly in mesentery, intestines, and cardiac muscle) and is an important diagnostic feature in cases of vitamin E-selenium deficiency
• Heart/Skeletal muscle: Selective, segmental, multifocal, polyphasic necrosis of myofibers +/- mineralization; myocyte degeneration (hyaline degeneration); hemorrhage, edema (nutritional muscular “dystrophy” and mulberry heart disease);

 

DIFFERENTIAL DIAGNOSIS:

Toxic hepatic necrosis:

• Gossypol toxicosis (cottonseed meal): Uniformly distributed centrilobular to submassive hepatocellular necrosis, also causes skeletal and cardiac muscle degeneration and necrosis and lung lesions
• Xanthium sp. (cocklebur) toxicosis: Similar to gossypol without cardiac lesions
• Cresol toxicosis (clay pigeons, asphalt shingles): Centrilobular to massive hepatic hemorrhage and necrosis without cardiac lesions
• Iron dextran toxicosis: Suckling pigs with marginal vitamin E/selenium levels; apparently due to iron-catalyzed lipid peroxidation in hepatocytes and skeletal muscle; cardiac toxicity from increased potassium released into the circulation

 

Fibrinoid necrosis of blood vessels:

• Edema disease (gastric submucosal vessels)
• Cerebrospinal angiopathy
• Porcine circovirus II vasculopathy
• Organic mercury toxicosis (meningeal vessels)

 

COMPARATIVE PATHOLOGY:

Conditions related to vitamin E/selenium deficiency in other species:

• Livestock (cattle, pigs, sheep are most commonly affected, also horses and goats): Nutritional myopathy, also known as white muscle disease (see M-M11) is often referred to as selenium/vitamin E deficiency, but often it is actually selenium deficiency that is the cause of myofiber degeneration; most common in neonatal animals; affects striated muscle (both cardiac and skeletal)
  • Adult horses: Temporal and masseter muscles are swollen and stiff leading to impaired mastication, inappropriately termed “maxillary/masseter myositis”
  • Vietnamese potbellied pigs: Distinctive clinical disorder thought to be related to vitamin E/selenium deficiency characterized by a short, stilted gait and tendency to walk on their toes, with multifocal polyphasic myofiber necrosis
• Dogs: Intestinal ceroidosis (AKA leiomyometaplasia or brown dog gut) can be induced by vitamin E deficiency in association with excess dietary lipids; grossly variable appearance from tan to dark brown intestinal serosal surfaces; histologically characterized by an accumulation of brown, granular, acid-fast, intracytoplasmic pigment (ceroid) in the perinuclear lysosomes of leiomyocytes
• Avian: 
  • Poultry, emus, psittacines: Vitamin E deficiency (+/- interaction with synthetic antioxidants, selenium, and sulfur-containing amino acids) causes 3 distinct syndromes:
    • Avian encephalomalacia (crazy chick disease, see N-M28): Swollen cerebellum with soft, dark, and/or hemorrhagic areas (cherry red cerebellum); malacia is most severe at the folial tips, but can involve the entire cerebellum; cerebellar surface hemorrhage is striking in turkey poults; fibrin thrombi in capillaries are considered a diagnostic feature of nutritional encephalomalacia caused by Vit E deficiency
      • Clinically, these birds will have tremors, incoordination, and recumbency 
      • In turkeys, lumbar spinal cord is most often affected (bilateral symmetrical necrosis of grey matter w/ vascular thrombosis and hemorrhage)
      • Note: primary selenium deficiency does not cause encephalomalacia directly, but can cause pancreatic lesions and a secondary Vit E deficiency via maldigestion and malabsorption
    • Exudative diathesis: Severe blood-stained edema of ventrum due to increased capillary permeability; pericardial effusion may cause sudden death
    • Muscular dystrophy: yellow/white/grey streaking or patches of cardiac muscle and skeletal muscle of the breast, legs, +/- gizzard; +/- mineralization; +/- hydropericardium; +/- depressed foci in chronic cases; can also see degeneration of ventricular musculature; LACKS INFLAMMATION 
    • Associated w/ lipofuscin accumulation in hepatocytes 
    • Can cause lymphoid depletion/bursal atrophy  
    • In fish-eating birds, associated w/ muscle disease secondary to a diet of improperly frozen/thawed fish (rancid PUFAs)
    • Can cause a spongiform encephalopathy in captive great-billed parrots (degeneration and loss of Purkinje cells and spongiform degeneration) – these birds will also have more characteristic myocardial and skeletal muscle lesions 
    • Associated w/ testicular degeneration 
    • Emu: Vitamin E deficiency associated with myopathy of pipping muscles (edema, hemorrhage, swelling), hepatosis dietetica (pale liver with hemorrhages and multifocal necrosis), cataracts (swollen, vacuolated lenticular fibers), noninternalized residual yolk sac, anasarca, and myocardial mineralization and necrosis in emu chicks
• Hamsters: Spontaneous hemorrhagic necrosis (SHN) of the CNS of fetal hamsters with necrohemorrhagic lesions most prominent in the prosencephalon, has been reproduced by feeding dams diets deficient in vitamin E
• Guinea pig: Nutritional myopathy is common and in some cases there is a clear relationship to selenium/vitamin E deficient diets; fetuses born to vitamin E-deficient sows may develop encephalomalacia
• Rabbits: Nutritional “muscular dystrophy”, neonatal mortality, infertility
• Carnivores, primates, camelids: Nutritional myopathy is unusual, although cats fed vitamin E-deficient diets develop steatitis (yellow fat disease)
• Wildlife, zoo animals: Multiple zoo animal species appear to be susceptible to nutritional myopathy, but evidence is circumstantial; the Rottnest quokka (a small nocturnal wallaby) and the nyala seem to be exquisitely susceptible
• Owl monkeys, marmosets, gelada baboons: Vitamin E responsive hemolytic anemia and necrotizing myopathy. Lesions accompanied by increased medullary and extramedullary hematopoiesis, erythroid hyperplasia, and binucleated rubricytes.
• Alligators: Farmed individuals with “double scale” disease were found to have multiple nutritional deficiencies, including hypovitaminosis E and zinc deficiency, that contributed to hepatic fibrosis and skin defects (Piras, Vet Pathol, 2024)

 

Selenium toxicity:

• Blind staggers in sheep and cattle (weakness and ataxia followed by death)
• Focal symmetrical polioencephalomalacia in pigs
• Alopecia, rough coat, emaciation in cattle and horses
• Lesions may develop at the coronary band in all species including grooves, cracks, corrugations; may lead to separation of hoof wall

 

REFERENCES:

1. Abdul-Aziz T, Fletcher OJ. Chapter 2: Lymphoid System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016:19.
2. Abdul-Aziz T, Fletcher OJ. Chapter 5: Cardiovascular System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016:147,188.
3. Barnes HJ, Abdul-Aziz T, Fletcher OJ. Chapter 4: Muscular System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016:121.
4. 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; 2016:582.
5. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing;2016:193,241,315.
6. Brown DL, Van Wettere AJV, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier;2022: 531-532.
7. Cantile C, Youssef, S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier;2016:308,472.
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9. Crespo R, Franca MS, Fenton H, Shivaprasad HL. Ch. 31 Galliformes and Columbiformes. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 748.
10. Cullen JM, Stalker MJ. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Saunders;2016:284-285.
11. Gelberg 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;2017:373.
12. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier;2016:571.
13. Miller LM, Gal A. Cardiovascular system and lymphatic vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier;2017:607-608.
14. Myers EA, Sander JE. Appendix. In: Boulianne M., ed. Avian Disease Manual. 8^th ed. Jacksonville, FL: American Association of Avian Pathologists;2019:189-191, 194.
15. Piras IM, Bezuidenhout A, Díaz-Delgado J, Slawski D, Kelly PA. Pathology of “double scale” skin defect in farmed American alligators (Alligator mississippiensis) and the possible association with hepatic fibrosis. Vet Pathol. 2024;0(0).
16. Rensing, KM, Lowenstine, LJ, et al. Ch. 14 New World and Old World Monkeys. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:345.
17. Schmidt R, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015; 9,10,74,116,201-202,230.
18. Shivaprasad HL. Nutritional diseases. In: Boulianne M., ed. Avian Disease Manual. 8^th ed. Jacksonville, FL: American Association of Avian Pathologists;2019:151-152.
19. Swayne DE, Barnes HJ, Abdul-Aziz T, Fletcher OJ. Chapter 10: Nervous System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016:470.
20. Valentine BA. Skeletal muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 1009, 1025-1029.

 

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