JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
March 2022
M-M11

Signalment (JPC #2082440):  An adult male great blue heron (Ardea geriduas).

 

HISTORY:  This heron was unable to stand or fly.

 

HISTOPATHOLOGIC DESCRIPTION:  Skeletal muscle: Diffusely distributed throughout the section, 50% of myocytes are either swollen with vacuolated sarcoplasm (degeneration) or hypereosinophilic with loss of cross striations (hyalinization), pyknotic nuclei, fragmentation of myofibrils, and occasional contraction bands (necrosis). Degenerate and necrotic myocyte sarcoplasm frequently contains densely basophilic granular material (mineral). Necrotic myocytes are often surrounded and occasionally infiltrated by macrophages, heterophils, and hypertrophic and hyperplastic satellite cells. Occasionally, satellite cells are clumped together, and myocytes have internalized, linearly arranged ("rowing") nuclei with increased sarcoplasmic basophilia (regeneration).

 

Feathered skin: Diffusely the subcutaneous adipose tissue is characterized by loss of differential staining with retention of architecture (coagulative necrosis), often admixed with acicular cholesterol clefts. Multifocally, numerous macrophages and heterophils infiltrate necrotic fatty lobules. Abundant eosinophilic necrotic cellular debris multifocally surrounds necrotic adipocytes. There are occasional 3-10 um thick bands and globules of pale yellow to tan homogenous material (ceroid). Similar material is often within the cytoplasm of foamy macrophages. Few small arteries within the adipose tissue contain fibrin thrombi.

 

Heart: The epicardium is expanded 3-5 times normal with edema, fibrin, and low numbers of macrophages, lymphocytes, and plasma cells.

 

MORPHOLOGIC DIAGNOSES:  1.  Skeletal muscle, myocytes: Degeneration and necrosis, polyphasic, diffuse, moderate, with mineralization and rare regeneration, great blue heron (Ardea geriduas), avian.

2. Feathered skin, panniculus adiposus: Steatitis, necrotizing and histiocytic, diffuse, with extracellular and intrahistiocytic ceroid.
3. Heart, epicardium: Epicarditis, diffuse, subacute, minimal.

 

ETIOLOGIC DIAGNOSIS:  Nutritional myodegeneration and steatitis

 

ETIOLOGY:  Vitamin E/selenium deficiency

 

SYNONYMS:  Nutritional myopathy, white muscle disease, stiff lamb disease, nutritional panniculitis, yellow fat disease

 

GENERAL DISCUSSION:

• Vitamin E/selenium deficiency results in a broad spectrum of diseases in a variety of animal species, including myopathy, 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; it 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
• Striated muscle changes in some species are referred to as nutritional “muscular dystrophy”, which is an inappropriate term according to some references

 

PATHOGENESIS:

• 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
  • Selenium is more soluble in alkaline soils and is incorporated into growing plants; selenium content is diluted in lush forage; geographic regions of US have low selenium contents in soil
• 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, loss of ability to maintain ion gradients
  • 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
    • -> mitochondria become overloaded with calcium à energy depletion
    • -> excess calcium the cytosol à myofibril hypercontraction and degeneration
• Steatitis (yellow‑fat disease) may result from a combination of membrane damage and production of ceroid
  • Ceroid: similar to lipofuscin but is associated with a pathologic (oxidative) process often associated with vitamin E deficiency; ceroid is an acid fast, PAS-positive, yellow pigment; lectin binding immunohistochemistry may differentiate ceroid from lipofuscin but is a very laborious research tool and generally not used
• 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)

CLINICAL FINDINGS:

• Nutritional myopathy:
  • Bright, alert, but with muscle weakness or irregular gait
  • +/- intercostal muscle involvement à dyspnea
  • +/- myoglobinuria à coffee-colored urine
  • Possible acute death with no previous clinical signs
• Steatitis:
  • Pyrexia, malaise; pain or hyperesthesia on palpation
• Clinical pathology:
  • Elevated CK, LDH, AST, ALT (large animals)
  • Myoglobinuria is usually absent in young animals (less skeletal muscle)
  • Serum glutathione peroxidase is a good indicator of selenium levels

 

GROSS FINDINGS:

• Nutritional myopathy:
  • Bilaterally symmetrical lesions
  • Multifocal pale streaks parallel to fiber direction
  • Mineralization of skeletal/cardiac muscle
• Steatitis:
  • Yellow to yellow-brown subcutaneous and cavitary fat
  • Firm, lumpy, gritty fat
  • Subcutaneous edema
  • Fishy odor

 

LIGHT MICROSCOPIC FINDINGS:

• Nutritional myopathy:
  • Selective, segmental and polyphasic necrosis of myofibers +/- mineralization; myocyte degeneration (hyaline degeneration); basement membrane and satellite cells remain intact allowing for rapid myocyte regeneration
  • Preferentially, but not exclusively, involves type I muscle fibers
• Nutritional steatitis:
  • Edematous fat with areas of coagulative necrosis and infiltration by neutrophils, lymphocytes, macrophages, and multinucleate giant cells
  • Ceroid deposition between adipocytes; ceroid is positive for Sudan black, PAS positive, and acid-fast

 

DIFFERENTIAL DIAGNOSES:

• Myodegeneration:
  • Toxic myopathies (monensin [M-T01], Cassia [M-T02], Xanthium)
  • Inherited muscular dystrophy (M-M06)
  • Sarcocystosis (M-P04)
  • Exertional rhabdomyolysis (M-M14; typically monophasic pattern)
• Steatitis:
  • Fat necrosis: Trauma, pancreatic enzymatic necrosis
  • Cats: Sterile nodular panniculitis, lupus panniculitis

 

COMPARATIVE PATHOLOGY:

Vitamin E/selenium deficiency in other species:

• In order of susceptibility to vitamin E/selenium imbalance: cattle, sheep, pig > horse, goat > cat, dog
• Large domestic animals (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”; diets low in vitamin E can also cause equine degenerative myeloencephalopathy (N-M07) and equine motor neuron disease (N-M24)
  • Goats: selenium deficiency can lead to periorbital alopecia and generalized seborrhea
  • Pigs (see D-M10): Hepatosis dietetica (acute centrilobular to massive hepatic necrosis) in association with a combination of one or more of nutritional panniculitis (yellow fat disease), nutritional myopathy, serous effusions (“exudative diathesis”), ulceration of the squamous mucosa of the stomach (pars esophagea), and fibrinoid necrosis of arterioles (an important diagnostic feature of the disease; dietary angiopathy AKA “mulberry heart disease”, see C-M06)
    • 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
  • Carnivores, primates, camelids: Nutritional myopathy is unusual, although:
    • Cats and mink fed vitamin E-deficient diets develop steatitis (yellow fat disease)
    • 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, see 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
    • Captive great-billed parrots have high incidence of vitamin E deficiency-associated muscle degeneration, encephalomalacia, gliosis, and neuronal necrosis primarily of the cerebellum
  • 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
  • Wildlife, zoo animals: Multiple of zoo animal species appear to be susceptible to nutritional myopathy, but evidence is circumstantial; the Rottnest quokka (a small nocturnal wallaby) and the nyala are highly susceptible

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016: 193, 241, 315.
2. Brown DL, Van Wettere AJV, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:458-459, 464.
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