Hepatocutaneous syndrome is a rare, chronic, progressive, and usually fatal disorder. Although typically associated with diabetes mellitus, the liver lesion is a severe, degenerative, glycogen-like vacuolar hepatopathy (VH) that also can accompany pancreatic or neuroendocrine tumors and severe VH secondary to endogenous steroidogenic hormone release or chronic phenobarbital treatment.
In hepatocutaneous syndrome, bilaterally symmetric crusting and ulcerative lesions are found on mucocutaneous junctions and cutaneous regions susceptible to pressure injury (eg, footpads, ears, periorbital regions, and limb pressure points). Skin lesions are characterized by a marked parakeratotic epidermis. Edematous spaces between cells are filled with neutrophils, necrotic cells, and debris that create an eosinophilic layer. Mild neutrophilic perivascular inflammation is also seen.
Lesions are commonly referred to as “red, white, and blue” on H&E staining (red for parakeratosis, white for edema, and blue for hyperplasia). Skin lesions are present initially in most affected dogs, but liver lesions may precede cutaneous changes.
Clinical features include anorexia, weight loss, lethargy, polyuria/polydipsia (PU/PD), mild nonregenerative anemia, marked increases in alkaline phosphatase (ALP) and moderate increases in ALT and AST, hyperglycemia, decreased plasma amino acid concentrations (by 50% of normal), hypoalbuminemia, and increased total serum bile acid (TSBA) concentrations. High plasma glucagon levels are inconsistent.
Liver size is variable. On ultrasonography, multiple hypoechoic nodules surrounded by hyperechoic parenchyma are diffusely scattered throughout the liver, described as a “Swiss cheese” pattern. The association between the cutaneous and hepatic lesions is not understood but is speculated to involve hypoaminoacidemia or abnormal zinc metabolism. Liver lesions are not necroinflammatory and are not associated with fibrosis or cirrhosis. The prognosis for recovery from hepatocutaneous syndrome in dogs is poor.
Treatment focuses on correcting amino acid deficiencies and providing supportive care for cutaneous lesions and VH. In general, corticosteroids are contraindicated for the skin lesions. A commercial diet high in protein or formulated for dogs with hepatic insufficiency with an added “body-building” amino acid concentrate can be used.
Administration of IV amino acids requires delivery via a catheterized jugular vein. Aminosyn 10% crystalline amino acid solution (100 mL contains 10 g of amino acids) can be given IV, 500 mL/dog, over 8–12 hours. Symptoms from hyperammonemia may develop in susceptible dogs (previously demonstrating HE) but should resolve within 12 hours after completion of the infusion.
The IV amino acid infusion is repeated 7–10 days later if skin lesions persist; four cycles can be given. If no response occurs, further amino acid infusions are futile. Amino acid treatment results in regression of skin lesions and hepatopathy in some dogs.
Control of concurrent diabetes mellitus can be challenging, because insulin resistance suggests involvement of counter-regulatory hormones (glucagon, glucocorticoids, others). Supportive care requires use of appropriate broad-spectrum antifungals or other antimicrobials for superficial secondary bacterial and fungal invaders, zinc methionine supplementation (1.5–2 mg/kg, PO, every 24 hours), water-soluble vitamins (doubled daily dose), essential fatty acid supplements, and topical lesion cleansing.
Some dermatologists also recommend treatment with niacinamide (250–300 mg/dog, PO, every 12 hours). Ursodeoxycholic acid (daily dose of 15–20 mg/kg, divided and given every 12 hours with food) and antioxidants (vitamin E and SAMe) are recommended. Identification and treatment of underlying metabolic conditions is essential for control.
Chronic phenobarbital treatment has been an underlying cause in some dogs. Successful treatment with long-acting somatostatin (octreotide; prohibitively expensive) has been described in a single dog with hepatocutaneous syndrome secondary to metastatic glucagonoma.
