10-year-old male castrated Shetland Sheepdog (Canis familiars).This dog was diagnosed with dermatomyositis as a puppy; it had footpad lesions characterized by hyperkeratosis, erythema, scaling and crusting. The dog was treated first with novalexin and then prednisone; he did well for 10-12 days and then stopped eating. Most recently, the dog developed diarrhea, non-regenerative anemia and glucosuria. An abdominal ultrasound revealed a severe and diffuse mottled appearance of the liver with a honeycomb pattern. Liver aspirates were taken for cytology assessment and the footpads were biopsied. The animal continued to deteriorate and was euthanized at the owners request. The veterinarian obtained permission to perform a postmortem examination. The liver was diffusely nodular; the rest of the abdominal viscera were unremarkable. Samples of liver and skin were submitted for histopathology.
Two punch skin biopsies (0.7 cm in greatest diameter) with ulcerated surfaces and two fragments of liver (3.5 cm and 2.5 cm in their largest dimension) were submitted for histopathology. The liver samples had a nodular, irregular, capsular surface.
Two samples taken from the edges of the metatarsal pad and including the adjacent haired skin are examined. The epidermis is markedly, irregularly acanthotic and covered with many layers of parakeratotic keratin admixed with multifocal dense aggregates of necrotic cell debris and hemorrhage. There are foci of erosion with multiple foci of epidermal neutrophilic and lymphocytic infiltration. Keratinocytes in the stratum spinosum are markedly vacuolated, swollen and pale (intracellular edema) with plump nuclei. The stratum basale is markedly hyperplastic with numerous mitotic figures and increased nuclear to cytoplasmic ratio (in general, giving the epidermis a "red, white and blue" layered appearance). Occasional apoptotic bodies and migrating leukocytes are noted within the epidermis. Numerous bacterial colonies and 7 x 2 micron, PAS positive, budding yeast (consistent with Malassezia sp.) are present within the surface keratin (not present in all slides). Multiple hair follicles are dilated and filled with fragmented keratin. Perifollicular, periadnexal and perivascular infiltrates of lymphocytes, plasma cells, macrophages and neutrophils, often associated with fibrous tissue, are present within the dermis. In rare instances, the infiltrates appear to invade the dermoepidermal junction. Gram staining of bacterial colonies reveals gram positive cocci and gram negative rods.
The liver sections show extensive, interconnecting areas of parenchymal collapse and hepatocellular vacuolation, usually surrounding and isolating variably sized nodules of hepatocytes (nodular regeneration). The vacuolated hepatocytes are often markedly enlarged with large amounts of clear to occasionally granular cytoplasm and peripheralized dense nuclei. The areas of vacuolar change also contain multifocal clusters of bile ducts and scant bundles of fibrous tissue. Small collections of band and segmented neutrophils (consistent with extramedullary myelopoiesis) and small numbers of plasma cells and lipid-laden macrophages infiltrate the portal spaces in these areas. Small aggregates of pigment (ceroid and/or iron)-laden macrophages are often seen within the nodules of parenchymal cells (pigment granulomas); scant neutrophils and plasma cells also infiltrate these nodules.
1. Haired skin, bilateral, metatarsal areas: Laminar epidermal edema, degeneration and necrosis, severe, with marked basal cell hyperplasia, parakeratotic hyperkeratosis (ie. superficial necrolytic dermatitis), and pustules/neutrophilic crusts containing bacterial colonies and budding yeast (Malassezia sp.).
2. Liver: Hepatocellular vacuolar change (vacuolar hepatopathy), severe, diffuse, with parenchymal collapse, moderate bile duct proliferation and nodular regeneration.
|WBC||19.1 x 103/mm3||6.0-17.0|
|RBC||4.12 x 106/mm3||5.50-8.50|
Liver cytology performed approximately one week before euthanasia revealed cholestasis, low numbers of attenuated and rarefied hepatocytes and possible neutrophilic inflammation.
The histomorphologic appearance of the skin and liver samples are consistent with hepatocutaneous syndrome (also called superficial necrolytic dermatitis, metabolic epidermal necrosis, and necrolytic erythema) with secondary pyoderma and cutaneous yeast infection.
Hepatocutaneous syndrome is a rare necrotizing skin disorder of dogs that is most often associated with metabolic hepatic disease (often idiopathic vacuolar hepatopathy),(2,8) although it has also been described in diabetes mellitus, glucagon-secreting tumors (glucagonomas)(2-4,9) and prolonged phenobarbital administration.(5) It is thought that hepatic dysfunction may result in hypoaminoacidema, preventing essential amino acids from reaching the skin, leading to nutritional deprivation and subsequent necrosis. The proposed pathogenesis involves increased hepatic catabolism of amino acids (from increased gluconeogenesis),(2,7) elevated glucagon levels (due to decreased hepatic metabolism or glucagonsecreting tumors), or disturbance of zinc metabolism (possibly a result of malabsorption).(4,9) A report of superficial necrolytic dermatitis (SND) in dogs receiving phenobarbital suggested that drug induction of hepatic microsomal enzymes may result in excessive utilization of amino acids by the liver leading to deficiency.(5)
Affected animals typically develop alopecia, erythema, crusting, exudation, and ulceration of the skin. The lesions are generally distributed over the ventral aspect of the abdomen, mucocutaneous junctions, ears, periorbital region, and distal portions of the extremities. Probably the most common clinical dermatologic lesion is hyperkeratosis and deep fissuring of the footpads. Secondary skin infections with bacteria, yeasts, and dermatophytes are common. Pruritus and signs of pain are often apparent.(2-4,9) Anorexia, weight loss and lethargy may also be present.(3,4,9) Circulating liver enzyme activities are frequently high and plasma amino acid concentrations are severely low.(2,7) Results of a study of 36 dogs with histologically confirmed SND indicated that older small-breed dogs (including Shetland Sheepdogs) were primarily affected. The median age was 10 years, and 27 (75%) dogs were male.(7) Superficial necrolytic dermatitis has also been reported in cats(4) and captive black rhinoceroses.(6)
In skin sections, the histopathologic finding of parakeratosis with crusting, hydropic degeneration of keratinocytes in the stratum spinosum, and hyperplasia of the basal cell layer, imparts the characteristic red, white, and blue appearance (referred to by some as the French flag) that is diagnostic for the disease.(2) Livers of dogs with hepatocutaneous syndrome are grossly nodular. Histologically, there is severe vacuolation of hepatocytes, with parenchymal collapse and condensation of the reticulin fiber network accompanied by nodular regeneration.(8) This combination of liver features has been confused with hepatic cirrhosis by many authors. Ultrasonographic evaluation of the liver of affected dogs reveals an almost pathognomonic honeycomb pattern or Swiss cheese-like appearance consisting of a hyperechoic network surrounding hypoechoic areas of parenchyma.(2,3) The underlying cause of these hepatic changes is often undetermined; however, they have been suggested to support an underlying metabolic, hormonal, or toxic cause.(3) The cause for the hepatopathy in this dog was not determined.
Hepatocutaneous syndrome in dogs often has a poor prognosis, and survival times are often less than one year. Treatment generally includes parenteral and oral administration of amino acids, zinc, and essential fatty acids.(7) If the disease is caused by a glucagon-secreting pancreatic neoplasm, surgical removal of the neoplasm can lead to resolution of skin lesions.(2)
Differential diagnosis for canine SND includes other parakeratotic diseases such as zinc-responsive dermatosis and generic dog food-associated dermatosis. Clinical differential diagnoses include chronic erythema multiforme of older dogs, drug eruption, pemphigus foliaceous and systemic lupus erythematosus. Most of these can be ruled out by appropriate clinical history, physical examination, clinical laboratory, and histopathologic findings.(2)
1. Liver: Hepatocellular vacuolar degeneration, diffuse, marked with hepatocellular loss, nodular regeneration and ductular reaction.
2. Haired skin: Epidermal edema, degeneration, and necrosis, superficial, diffuse, marked, with basal cell hyperplasia, parakeratotic hyperkeratosis, and subacute dermatitis.
We thank the contributor for providing this excellent example and thorough analysis of the entity. Some conference participants reported difficulty in distinguishing regenerative hepatic nodules from islands of pre-existing, normal hepatic parenchyma. Following an animated discussion regarding hepatic histopathology, participants eventually agreed that hepatocytes within regenerative areas tend to be larger than those in the surrounding parenchyma and nodules are often delineated by variable amounts of fibrosis.(10) Additionally, while foci of hepatic regeneration may contain rudimentary portal tracts and terminal venules, hepatic cords are usually more than two cells thick with reduced sinusoidal space, resulting in a somewhat disorganized nodule that may compress adjacent tissue.(1,9)
The distinctive gross and histological appearance of nodular regeneration occurs as a result of its contrast with adjacent expanses of parenchymal atrophy and loss, which typically occur due to reduced blood flow and bile drainage. Macro/micronodular hepatic regeneration is classically associated with cirrhosis, where bridging fibrosis is also a characteristic lesion; however, the liver in this case is striking in its relative lack of fibrosis. Instead, foci of regeneration are bound by extensive areas of parenchymal collapse, hepatocellular vacuolation and bile ductular proliferation, which is a consistent finding in superficial necrolytic dermatitis.(9)
Participants further noted the prominent hepatocellular vacuolar degeneration within submitted sections of liver, which prompted a focused exploration of the distinction between hydropic, glycogen and lipid-type vacuolar degeneration. Hydropic degeneration often follows hypoxic incidents, toxic/metabolic insults or cholestasis, while intracellular accumulation of lipid is a response to physiologic or pathologic increases in lipid mobilization or derangements in lipid metabolism. Hepatocellular glycogen accumulation, otherwise known as steroid-induced hepatopathy or hepatic glycogenosis, is typically induced by exogenous or endogenous corticosteroids. Histologically, lipid-type vacuolar degeneration produces hepatocytes with discrete globules which may coalesce into a single large vacuole that peripheralizes the nucleus, while glycogen or hydropic-type vacuolar degeneration causes significant cell swelling with indistinct vacuolar boundaries and fine, feathery cytoplasm. In severe cases of glycogenosis, nuclei and organelles may be displaced to the periphery of the cell, which complicates differentiation from lipid-vacuoles.(9) In this situation, histochemical stains may be helpful; glycogen stains strongly with PAS, while lipid stains with oil-red-O.
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10. Wanless IR, Huang WY. Vascular disorders. In: Burt AD, Portmann BC, Ferrell LD, eds. MacSweens Pathology of the Liver. 6th ed. Philadelphia, PA: Elsevier Limited; 2012:627-629.