Overview

• Liver lesion-severe degenerative vacuolar hepatopathy (VH, macrovesicular lipid and glycogen), parenchymal collapse causing marked hepatic nodularity; associated with syndromic pressure point dermatosis and usually diabetes mellitus (DM).
• Liver lesions-may precede cutaneous lesions and DM.
• May develop in some dogs treated chronically with phenobarbital.

Signalment

• Middle-aged to older dogs
• Males may have greater predilection
• Syndrome in Shih Tzu dogs recognized

Signs

Causes & Risk Factors

• Etiology-associated with hypoaminoacidemia; causal role in cutaneous lesions and possibly liver lesions.
• Secondary causal role-suggested for ill-defined deficiencies: zinc, fatty acid, or niacin.
• Hyperglucagonemia-originally proposed causal mechanism but inconsistent (∼ 30%–40% of tested dogs demonstrate high plasma glucagon); poor correlation may reflect assay specificity or high hepatic glucagon extraction; pancreatic glucagon-producing tumor confirmed in <25% of dogs.
• Insulin resistant DM.
• Similar cutaneous lesions described with primary hepatopathies caused by: phenobarbital or rarely, with chronic mycotoxicosis.

Differential Diagnosis

• Cirrhosis-regenerative nodular hyperplasia with extensive connective tissue deposition and loss of architectural organization.
• Chronic hepatitis-inflammatory infiltrates; individual hepatocyte necrosis.
• Copper associated hepatopathy-high tissue copper associated initially with zone 3 necroinflammatory injury.
• Diffuse nodular hyperplasia-rare.
• Degenerative glycogen-type VH.

CBC/Biochemistry/Urinalysis

• CBC-mild to moderate non-regenerative to mild regenerative anemia; RBC microcytosis; neutrophilic leukocytosis reflects cutaneous lesions (infections).
• Biochemistry-high liver enzymes (especially ALP); hypoproteinemia with hypoalbuminemia; euglycemic to fasting hyperglycemia; variable cholesterol and BUN.
• Urinalysis-ammonium biurate crystalluria may reflect hepatic insufficiency.

Other Laboratory Tests

• Total serum bile acids-often increased.
• Insulin-inappropriately increased.
• Plasma glucagon-inconsistently high.
• Plasma amino acids-30%–50% of normal in dogs with cutaneous lesions; moderate reductions in dogs with liver lesions preceding skin lesions.

Imaging

• Abdominal radiography-variable liver size, small, normal, to large liver; rare effusion.
• Abdominal ultrasonography-may see irregular liver margin; characteristic nodular pattern: hypoechoic foci in background hyperechoic parenchyma, “Swiss cheese pattern”; although suggested as pathognomonic, other severe degenerative VH also demonstrates this pattern; occasional diffuse nodularity cannot be imaged; pancreatic mass imaged <20% of dogs.

Diagnostic Procedures

• Aspiration sampling-hepatocytes show VH associated with glycogen and lipid.
• Liver biopsy-needle biopsy may compromise definitive diagnosis by limiting detection of proliferative foci of hepatocytes between massive vacuolated parenchyma; needle biopsy may be best option for dogs with extensive skin lesions; larger laparoscopic samples preferred; avoid laparotomy as dogs with cutaneous lesions may not promptly heal.
• If pancreatic mass imaged, resect for histology and immunohistochemical staining for glucagon and other products.
• Skin biopsy-see Superficial Necrolytic Dermatitis.

Drug(s)

• Manage DM with insulin.
• See Dietary recommendations above.
• Cutaneous or nail bed infections-systemic antimicrobials or antifungals; germicidal baths.
• Zinc supplementation-2–4 mg/kg elemental zinc q24h; avoid zinc methionine if HE.
• Niacinamide-250–500 mg/dog q12h (500 mg for dogs >10 kg); watch for toxic effects; avoid extended-release form.
• Topical glucocorticoids-if unresponsive inflammatory skin lesions, after infection managed (caution: systemic glucocorticoids may promote HE, enteric ulceration, infection, complicate DM management).
• Ketoconazole-for secondary yeast infection; anti-inflammatory and antipruritic effects
• Somatostatin-long-acting octreotide theorized as possible treatment; based on speculated endocrinologic cause; prohibitively expensive.
• Ursodeoxycholic acid-10–15 mg/kg PO daily, divided dose given with food.
• Antioxidants-Vitamin E (10 IU/kg daily PO); S-adenosylmethionine (SAMe) 20 mg/kg PO daily on empty stomach, other beneficial effects additional to antioxidant influence.
• If associated with phenobarbital, discontinue.

Possible Interactions

• HE induction: high protein diet supplements and amino acid infusions.
• Toxic effects of ketoconazole and its interference in drug metabolism.
• Toxic effects of niacinamide and zinc.

Patient Monitoring

• Weekly to monthly physical exam to assess need for amino acid supplements and treatment for secondary infections.
• Daily glucose monitoring at home.
• Fastidious management of diabetes mellitus.
• Weekly to monthly CBC, biochemistry, and urinalysis, initially.

Possible Complications

• Hyperosmolar amino acid solutions may cause thrombophlebitis.
• Ketoacidosis-uncommon.
• Hepatic encephalopathy.
• Sepsis-due to diabetes and skin lesions.
• Pain-from skin lesions require analgesics.

Expected Course and Prognosis

• Some dogs achieve cutaneous remission ∼ 2 year with described therapies; most have unremitting progression, necessitating euthanasia; improved liver lesions with treatment.

Synonyms

• Superficial necrolytic dermatitis
• Necrolytic migratory erythema
• Metabolic epidermal necrosis
• Glucagonoma syndrome
• Hepatocutaneous syndrome

Abbreviations

• DM = diabetes mellitus
• HE = hepatic encephalopathy
• VH = vacuolar hepatopathy