JPC SYSTEMIC PATHOLOGY

CARDIOVASCULAR SYSTEM

February 2025

C-M06 (NP)

 

SIGNALMENT (JPC #2077171): 3-month-old crossbred pig

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Heart: Affecting 30% of the myocardium, there are multifocal to coalescing, variably sized, intersecting bands of coagulative necrosis characterized by loss of differential staining and retention of architecture, admixed with less frequent foci of lytic necrosis characterized by stromal collapse and loss of myofibers with replacement by cellular debris, fibrin, edema, and infiltrates of macrophages, hemosiderophages, lymphocytes, plasma cells, and occasional eosinophils as well as scattered hemorrhage. Areas of lytic necrosis often surround areas of coagulative necrosis. Within areas of coagulative necrosis, necrotic cardiac myocytes have fragmented, hypereosinophilic sarcoplasm with loss of cross striations and pyknotic or karyorrhectic nuclei. Necrotic myofibers often contain basophilic, granular, sarcoplasmic mineral. Less commonly, myocytes are degenerate with swollen, vacuolated sarcoplasm. Multifocally there is vascular necrosis affecting the tunica media and tunica intima, characterized by disruption, vacuolation, and hypereosinophilia of the smooth muscle fibers with replacement by brightly eosinophilic, hyaline material (fibrinoid necrosis) and discontinuity of endothelium. Lesser affected, viable blood vessels are lined by hypertrophic/reactive endothelium and are surrounded by edema and low numbers of eosinophils and lymphocytes. 

 

MORPHOLOGIC DIAGNOSIS: Heart, myocardium: Degeneration and necrosis, monophasic, multifocal to coalescing, moderate, with multifocal fibrinoid vascular necrosis, mild lymphohistiocytic myocarditis, mineralization, and hemorrhage, crossbreed, porcine

 

ETIOLOGIC DIAGNOSIS: Nutritional cardiac degeneration and necrosis

 

CAUSE: Vitamin E/Selenium deficiency

 

CONDITION: Mulberry heart disease (MHD)

 

CONDITION SYNONYMS: Dietetic microangiopathy

 

GENERAL DISCUSSION:

• Vitamin E/selenium deficiency results in a broad spectrum of diseases in a variety of animal species, including myopathy (M-M11), steatitis, hepatic necrosis (D-M10), and/or encephalomalacia (N-M28) because of increased oxidative stress on cells 
• Any animal is susceptible but the syndrome is most frequently seen in cattle, sheep, pigs, and horses; young animals are most often affected, but all ages are susceptible and is infrequent in carnivores
• The most common nutritional deficiency leading to nutritional myopathy in most species is a deficiency in selenium; vitamin E deficiency without a deficiency in selenium is uncommon in mammals, but may be more common in reptiles and birds
• Nutritional myopathies tend to occur in either late winter or early spring, except in sheep in which they occur more in the fall
• Animals with high dietary polyunsaturated fatty acids require more vitamin E
• Rapid growth and diets deficient in selenium and vitamin E predispose to disease
• Morbidity is usually not high, but case mortality is virtually 100 percent

 

PATHOGENESIS:

• Feeding weanling piglets a vitamin E / selenium deficient diet will regularly reproduce the disease
• Vitamin E is an important antioxidant; it sequesters free radicals before they can initiate peroxidation of the polyunsaturated fatty acids of cell membranes
  • Diets that contain a large amount of polyunsaturated fats (e.g. fish oil) require greater amounts of dietary vitamin E
  • May be low in compounded rations due to storage and/or formulation
• Selenium is an essential constituent of the antioxidant enzyme glutathione peroxidase, which prevents peroxides from causing membrane damage
  • Organic selenium provides greater protection than inorganic selenium (selenite)
• Free radical generation with deficiency of free-radical scavengers such as vitamin E and selenium à oxidative damage, loss of cell membrane integrity and stability à calcium ions enter the damaged cell from the extracellular compartment à increased demand for energy to move calcium from cytosol into mitochondria away from calcium-sensitive myofilaments 
  • à mitochondria become overloaded with calcium à energy depletion
  • à excess calcium the cytosol à myofibril hypercontraction and degeneration
• Death is secondary to ventricular dysrhythmias and congestive heart failure
• Nutritional deficiency of vitamin E and/or selenium may result from:
  • Poor climate conditions/housing
  • Poor quality hay, grain, rancid food source (fish, cod liver oil)
  • Increased oxidative stress (e.g. iron injections in neonatal pigs) à increased consumption/depletion of antioxidants
  • Malabsorption of fat (e.g. cholestasis, cystic fibrosis, and small intestinal disease)
  • Competition from other elements (sulfur, zinc, silver, cadmium, tellurium)

 

TYPICAL CLINICAL FINDINGS:

• Affects young pigs in excellent condition, usually at 2-4 months of age, but may sporadically affect pigs of any age
• Sudden death without premonitory signs
  • Death is often due to development of ventricular dysrhythmias
• Irregular gait, stiffness, weakness, +/- paralysis, dyspnea, rapid or irregular heart rate, recumbency
• Normal temperature
• Clinical pathology:
  • AST, CPK, and LDH may be elevated (muscle and liver damage)
  • Tissue selenium levels may be normal
  • Tissue levels of vitamin E are equivocal

 

TYPICAL GROSS FINDINGS:

• If death occurred within 6 hours of onset, gross findings may be minimal and restricted to cyanosis of ears and ventral abdomen
• Extensive epicardial hemorrhages, chiefly on the right atrium and right ventricular free wall; in severe cases, hemorrhage may be more diffuse
• Pale streaks and patches of epicardial necrosis that extend into the myocardium (nutritional myopathy, M-M11)
• Hydrothorax and hydropericardium: Straw-colored fluid with fibrin that clots on exposure to air
• Pericardial edema, increased opacity
• +/- White chalky necrotic skeletal muscle (nutritional myopathy, M-M11) 
• +/- Centrilobular to submassive to massive hepatic necrosis (hepatosis dietetica, D-M10)
• +/- Leukoencephalomalacia (subacute cases): Bilaterally symmetrical softening of white matter and grey, translucent, depressed areas

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Dietary microangiopathy:

• Microscopic lesions are apparent 6-12 hours after onset of clinical signs; if animals die before 6 hours, microscopic evidence of myofiber degeneration may be minimal
• Acute findings:
  • Subserosal edema, plugging of lymphatics by fibrin, interstitial hemorrhage
  • Microthrombi may be present in capillaries of the myocardium
  • Variable arteriolar degeneration and necrosis in many organs may be a prominent feature: endothelial swelling +/- disruption, fibrinoid necrosis, formation of hyaline thrombi, and necrosis of smooth muscle cells of the tunica media
• Subacute findings:
  • Myofiber necrosis +/- mineralization, degeneration (hyalinized, fragmented myofibers), regeneration, fibrosis, and/or influx of macrophages
  • Panmyocardial congestion and hemorrhage

Lesions in other organs:

• Hepatosis dietetica (D-M10): Hepatic congestion with centrilobular to submassive necrosis
• Leukoencephalomalacia: Severe lysis of cerebral white matter, most severe in gyri of frontal lobes, in pigs surviving at least 24 hours 
• Steatitis (“yellow fat disease”
• Nutritional myopathy
• Serous effusions (“exudative diathesis”)
• Ulceration of the squamous mucosa of the stomach (pars esophagea)

 

DIFFERENTIAL DIAGNOSIS:

Causes of myocardial necrosis:

• Encephalomyocarditis virus (Picornaviridae, genus Cardiovirus): Acute death and myocardial necrosis
• Foot and mouth disease (Picornaviridae, genus Aphthovirus): Usually have typical vesiculoulcerative lesions; serology to differentiate from other vesicular diseases
• Swine vesicular disease (Picornaviridae, genus Enterovirus): Characteristic vesicles; serology to differentiate from other vesicular diseases
• Gossypol toxicosis
• Monensin toxicosis

 

COMPARATIVE PATHOLOGY:

• In order of susceptibility to vitamin E/selenium: cattle, sheep, pig > horse, goat > cat, dog
• Livestock (cattle, pigs, sheep are most commonly affected by nutritional myopathy, also horses and goats): 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, brown dog gut) can be induced by vitamin E deficiency in association with excess dietary lipids; grossly tan to dark brown intestinal serosal surfaces; histologically, accumulations of brown, granular, acid-fast, intracytoplasmic pigment (ceroid) in the perinuclear lysosomes of leiomyocytes
• Avian: 
  • Fowl: Vitamin E deficiency (+/- interaction with synthetic antioxidants, selenium, and sulfur-containing amino acids) causes 3 distinct syndromes:
    • Avian encephalomalacia (“crazy chick disease”, N-M28): swollen cerebellum with soft, dark, and/or hemorrhagic areas (cherry red cerebellum); cerebellar surface hemorrhage is striking in turkey poults
    • Exudative diathesis: Severe blood-stained edema of ventrum due to increased capillary permeability; pericardial effusion may cause sudden death
  • “Muscular dystrophy”: yellow-white skeletal muscle streaking of the breast, legs, +/- gizzard
  • Fish-eating birds (storks/herons): often seen in captivity with birds eating frozen whole fish with low vitamin E supplementation leading to fat necrosis/steatitis and skeletal and cardiac muscle degeneration and necrosis
• 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 and mink fed vitamin E-deficient (or rancid) diets develop steatitis (yellow fat disease)
• Primates (owl monkeys and marmosets): Vitamin E responsive hemolytic anemia and necrotizing myopathy 
• Wildlife, zoo animals: Many 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
• American pika: Myocardial necrosis causing death in 3 animals presumed to be due to stress or vitamin E/Selenium deficiency (Barrett et. al., J Vet Diagn Invest 2024)
• Wild Carnaby’s black cockatoos: Vitamin E/selenium deficiency is a differential for the cause of annual outbreaks of hindlimb paralysis syndrome observed in these endangered birds (Coiacetto et. al., J Comp Pathol 2024)
• Captive white-tailed deer: Selenium and/or vitamin E deficiency was one of the most common non-infectious post-mortem diagnoses in a retrospective study of records from the WVDL (Clarke, J Vet Diagn Invest 2023)

 

REFERENCES:

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2. Barrett A, Holder K, Knowles S, LaDouceur EEB. Retrospective of the pathology of American pikas. J Vet Diagn Invest. 2024;36(5):666-676.
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5. Clarke L. Postmortem diagnoses and factors influencing diagnoses in captive white-tailed deer in Wisconsin, 2009-2021. J Vet Diagn Invest. 2023;35(6):782-788.
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