12-year-old male neutered Chihuahua, canine (Canis familiarisInitially, the animal was presented to the referring veterinarian (rDVM) for abdominal enlargement due to ascites. Exploratory laparotomy was performed and the liver was described as having numerous yellow nodules over the entire surface. Clinically, the rDVM was concerned about neoplasia. After the biopsies were reviewed, the rDVM was contacted and some additional information was obtained. The animal had crusty lesions on all four footpads and multifocally on all four limbs. The dogs owners had recently moved to a new residence and they thought the skin issues were due to flea infestation. The animal was euthanized three weeks after surgery and was submitted for necropsy. Samples submitted for the slide conference originated from the original surgical biopsy and necropsy tissue.

Gross Description:  

Footpads on all four limbs are covered by flaky golden-brown crusts. Crusts are either firmly adhered or easily peel away from the digital, metacarpal and metatarsal pads. The skin over the distal left lateral forelimb and left cubital region have similar areas of crusting and mild alopecia which measure 7 mm in diameter and 18 x 4 x 1 mm, respectively. Crusts are also present bilaterally over both hocks and measure 20 x 10 x 1 mm (left) and 22 x 12 x 1 mm on the (right). The subcutaneous tissues are expanded and ooze clear fluid (edema). The abdomen contains 1220 mL of golden serous fluid. The liver is 3.7% of total body weight (after removal of abdominal fluid). The liver contains innumerable widespread variably sized brown-red nodules separated by depressed tan areas (parenchymal collapse). The nodules range in size from 3 mm diameter up to 2.5 cm diameter.

Histopathologic Description:

Liver: At low power, there is multifocal to coalescing collapse and loss of hepatic parenchyma. The areas of collapse separate variably sized unencapsulated nodules of well diff-erentiated hepatocytes (regenerative hyperplasia). In areas of collapse, there are heavily vacuolated and swollen hepatocytes, increased bile duct profiles, plugs of golden material (bile) in canaliculi (canalicular cholestasis), and low numbers of lymphocytes, plasma cells, and neutrophils. Multifocally, within the areas of collapse, there are occasional areas containing mildly increased fibrous tissue (confirmed with trichrome). There are multifocal clusters of macrophages containing golden brown pigment.

There is some variation among slides because some samples were from the original biopsy while others were obtained during necropsy 3 weeks later.

Morphologic Diagnosis:  

Liver: Severe chronic multifocal to coalescing parenchymal loss and nodular regeneration with fatty change, biliary hyperplasia and canalicular cholestasis

Footpad: Marked chronic basal cell hyperplasia, intracellular edema (stratum spinosum), and parakeratotic hyperkeratosis (slide not included)

Lab Results:  

No laboratory diagnostic results were provided by referring veterinarian.


Hepatocutaneous syndrome

Contributor Comment:  

Gross and histologic changes in the liver and skin are consistent with hepatocutaneous syndrome. Most animals present clinically for the skin lesions; however, in this case the animal presented for the hepatic disease because the owners mistakenly associated the cutaneous lesions with fleas.


Hepatocutaneous syndrome has been reported in humans, dogs, cats, and the black rhinoceros.1,2,5-7 Older small breed dogs are primarily affected. The long-term prognosis for animals with hepatocutaneous syndrome is very poor. In cases of hepatocutaneous syndrome, the liver has a gross appearance resembling cirrhosis. Histologically, there are foci of regenerative nodular hyperplasia separated by areas of parenchymal collapse Text Box: Footpads, dog. Histologic examination of the footpad lesion should a superficial red zone of parakeratotic hyperkeratosis, a white zone of underlying intracellular edema of the cells within the stratum spinosum, and at bottom, a blue zone of basal cell hyperplasia (HE, 200X) Photo courtesy of: University of Tennessee College of Veterinary Medicine, Department of Pathobiology, 2407 River Drive, Room A201, Knoxville, TN 37996 heavily vacuolated hepatocytes. Hepatic changes are considered idiopathic, but have been suggested to be due to an underlying metabolic, hormonal, or toxic etiology. The pathogenesis of the associated skin lesions is unknown, but hepatic dysfunction with derangement of glucose and amino acid metabolism have been suggested.1,2,7


This disorder produces characteristic cutaneous changes that typically occur on the footpads, mucocutaneous junctions, and pressure points. Gross changes may include crusting, erosion/ulceration, erythema, alopecia, and exudation. The histologic appearance is often referred to as red, white and blue. (The red corresponds to superficial parakeratotic hyperkeratosis; white corresponds to pallor in the stratum spinosum which is due to intracellular edema; blue corresponds to basal cell hyperplasia.2 Depending on the duration of the disease, all of the classical components of the histologic lesion may or may not be seen and could also be obscured by secondary changes (e.g. erosion, ulceration, infection). Superficial necrolytic dermatitis (SNE), necrolytic migratory erythema (NME), and metabolic epidermal necrosis (MEN) have been terms used to refer to the cutaneous syndrome in humans.1 The majority of canine cases are associated with liver disease, whereas human cases are typically associated with a functional pancreatic glucagonomas. However, in animals, the cutaneous lesions have also been associated with glucagon secreting tumors, diabetes mellitus, pancreatic carcinoma, gastric carcinoma and thymic amyloidosis.5,7


Other differential diagnoses to consider for parakeratotic skin diseases include zinc-responsive dermatosis, generic dog food dermatosis, lethal acrodermatitis of bull terriers, irritant contact dermatitis, and thallium toxicosis.1,2 The signalment, clinical history, and ancillary diagnostic tests, in combination with histologic findings, should easily differentiate between these potential differentials.

Conference Comment:  

Hepatic lesions in canine hepatocutaneous syndrome tend to diffusely affect the liver and are non-inflammatory in nature. Lesions are often described as a degenerative hepatopathy with formation of cytoplasmic vacuoles, eventually leading to parenchymal collapse. Histologically, affected hepatocytes de-monstrate severe ballooning (both glycogen and/or lipid, micro- and macro-vesicular, vacuolar degeneration). Hepatic nodular regeneration is also an important component of the histologic lesions and the pattern is usually multifocal to coalescing and random. Bile duct proliferation may also be seen. A honeycomb appearance to the liver is described ultrasonographically.3 Common clinicopathologic abnormalities include elevated hepatic enzymes and non-regenerative anemia which may be microcytic. Other less common but reported abnormalities include hyperglycemia, thrombocytosis and elevated total bilirubin. Low plasma amino acid concentrations are also reported.3 Therapy is generally not effective and most dogs succumb to the disease within months of developing skin lesions.1,3 Although many dogs are pr-esented initially due to cutaneous lesions, some may only have hepatic lesions at the time of initial diagnosis and present with non-specific signs of lethargy and in appetence, have elevated hepatic enzymes and/or signs of hepatic encephalopathy.3


The moderator commented that this syndrome is very difficult to diagnose correctly based solely on the histologic hepatic lesions. The conference histologic description was very similar to the contributors description above. There is a sharp line of demarcation between de-generative and regenerative areas; sinusoids are compressed and largely obscured in the areas of vacuolar degeneration. Low numbers of binucleate hepatocytes, as well as rare mitoses within the foci of hepatocellular regeneration. 


The moderator commented on the atypical appearance of the regenerative nodules, noting that in regeneration, hepatic cords are most often arranged in double rows, while in this case they are singly arranged. The presence of one portal area per regenerative nodule is typical and is seen in some of the regenerative foci in this case. Conference participants also commented on the relative absence of fibrosis in the H&E stained section. The excellent gross image provided by the contributor was also discussed and the moderator noted that the gross cluster of grapes appearance imparted by the regenerative nodules is classic for this condition. 


Similar cutaneous lesions may be seen (without liver lesions), with glucagon-secreting pancreatic tumors. There is also a single case report of superficial necrolytic dermatitis associated with an insulin producing tumor in a dog.4


1. Byrne KP. Metabolic epidermal necrosis-hepatocutaneous syndrome. Vet Clin

North Am Sm Anim Pract. 1999; 29(6):1337-1355.


2. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat.

2nd ed. Ames, IA: Blackwell Publishing Professional; 2005:86-91.


3. Hall-Fonte DL, Center SA, McDonough SP, Peters-Kennedy J et al. Hepatocutaneous syndrome in Shih Tzus: 31 cases (1996-2014). J Am Vet Med Assoc. 2016; 248(7):802-813.


4. Isidoro-Ayza M, Lloret A, Bardagi M, Ferrer L, Martinez J. Superficial necrolytic dermatitis in a dog with an insulin-producing pancreatic islet cell carcinoma. Vet Pathol. 2014; 51(4):805-808.


5. Kimmel SE, Christiansen W, Byrne KP. Clinicopathological, ultrasonographic,

and histopathological findings of superficial necrolytic dermatitis with hepatopathy in a cat. J Am Anim Hosp Assoc. 2003; 39:23-27.


6. Munson L, Koehler JW, Wilkinson JE, Miller RE. Vesicular and ulcerative

dermatopathy resembling superficial necrolytic dermatitis in captive black

rhinoceroses (Diceros bicornis). Vet Pathol. 1998; 35:31-42.


7. Stalker MJ, Hayes MA. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. 5th ed. Philadelphia, PA: Elsevier Saunders; 2007:332.

Click the slide to view.

1-1. Liver, dog. 

1-2. Footpads, dog. 

1-3. Footpads, dog. 

1-4. Liver, dog. 

1-5. Liver, dog. 

1-6. Liver, dog. 

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