Clinical history

Chucky was presented to the primary veterinary care practice with a 1 month history of hyperkeratosis, crusting and erythema of the skin of all four paws. A previous canine biochemical profile conducted at VPG revealed significantly elevated alkaline phosphatase (ALP), alanine transaminase (ALT), glutamate dehydrogenase (GLDH) and bile acids. A small liver was detected on abdominal ultrasound.

Histology

Haired skin from the feet and an additional lesion in the perianal region were sampled by the veterinarian, fixed in formalin and submitted to VPG for histopathological examination.

The epidermis (surface layer of the skin) was markedly thickened in the samples. Specifically this comprised a thick keratin layer with retention of nuclei (parakeratosis) and overlying this, a prominent neutrophilic crust, an oedematous and pale stratum spongiosum (middle epidermal layer) and a prominently proliferative basal cell layer. This created a distinct ‘red, white and blue’ pattern, colloquially termed the ‘French flag’ sign by pathologists. Surface bacterial colonies were also seen. Some mild separation or splitting through the pale stratum spongiosum was observed (‘necrolysis’). The underlying dermis was variably inflamed with mixed infiltrates of neutrophils, lymphocytes and plasma cells. Adnexa were largely unaffected.

Figure 1. Low magnification image of the skin. The epidermis is markedly thickened (black arrow heads). The underlying dermis is mildly oedematous and inflamed (white arrow heads).

Figure 2. Higher magnification of the epidermal surface reveals a markedly thickened stratum corneum, expanded by parakeratosis  and neutrophilic infiltrates (red). The middle layer is pale and swollen with intracellular and intercellular oedema (white). The basal and suprabasilar layers are hyperplastic (blue). Surface colonies of bacteria are present.

Interpretation: 

Superficial necrolytic dermatitis (SND) or ‘hepatocutaneous syndrome’

More information on superficial necrolytic diagnosis: 

Superficial necrolytic dermatitis (SND; also known as hepatocutaneous syndrome) is a necrotising skin disease, most commonly seen in older dogs, but is rarely recognised in cats (1). It is a rare and poorly understood disease, usually associated with a poor prognosis. Most cases reported are associated with an underlying metabolic liver disease or pancreatic neuroendocrine neoplasia [2].

The precise pathogenesis is yet to be elucidated but is essentially a result of a ‘cutaneous nutritional deprivation’ which results in superficial skin necrosis [1]. It does partly resemble the condition necrolytic migratory erythema (NME) in human beings and could have a similar mechanism. The human NME condition is often a result of a glucagonoma with hyperglucogonaemia thought to play a role – typically associated with pancreatic neoplasia. It is likely involved with a catabolic state and dysregulation of metabolism of amino acids, proteins, zinc and essential fatty acids resulting in deficiencies [1, 3]. Reduced peptide synthesis at the epidermis may be a result of this, and hypoaminoacideamia may also increase arachidonic acid production to increase epidermal inflammation [3]. However,  pancreatic tumours are only associated with a small number of canine SND cases. In dogs, hepatic metabolic dysfunction is still likely to drive a hypoaminicadaemia through catabolism of amino acids [1, 4] with the result of a similar cutaneous insult. Other infrequent case reports indicate other causes of underlying liver damage such as a previous history of phenobarbital administration [5]. Regardless of the underlying cause, hypoaminoacidaemia appears to be consistent.

The most common clinically identified findings reported in a relatively recent review [6] were skin lesions affecting the pawpads or mucocutaneous junctions (100% of cases) and plasma hypoaminoacidaemia (100% of cases) – an amino acid profile was thus suggested by the authors [6] as a possible non-invasive aid for the diagnosis of SND. A further study [7] revealed hypoaminoacidaemia in dogs with SND was associated with marked lysinuria, essentially indicating wasting of this amino acid which is one crucial for collagen synthesis. Clinico-pathological abnormalities in one case study commonly revealed microcystosis (63%) and consistently elevated serum alkaline phosphatase activity (100 %) [8].

Diagnosis in practice

Despite the recent case series describing amino acid profiling (see above),  more often the  diagnosis of SND is made from skin biopsies of intact lesions (which have not become ulcerated or masked by secondary infection) which reveal the pathognomonic ‘red, white and blue’ skin pattern in conjunction with a liver biopsy/or clinical correlation of liver disease (such as abdominal ultrasound examination). Abdominal ultrasound of the affected animal may also help differentiate between obvious hepatic pathology or pancreatic neuroendocrine neoplasia.

Differentials clinically include autoimmune disease such as pemphigus foliaceus/SLE, zinc responsive dermatosis (which also causes parakeratosis/hyperkeratosis) and erythema multiforme [1] – these should be differentiated on histological examination.

In this case, chronic liver disease was suspected to be cause for SND although no further detailed investigation was conducted.

Treatment is typically symptomatic and supportive [1]. A recent study [9] reviews treatment regimes following diagnosis of SND.

References:

1. Gross, T.L., Ihrke, P.J., Walder, E.J. and Affolter, V.K., 2008. Skin diseases of the dog and cat: clinical and histopathologic diagnosis. John Wiley & Sons.
2. Smith, J. (2016). Superficial necrolytic dermatitis. In Vet Times [Internet]. URL: https://www.vettimes.co.uk/app/uploads/wp-post-to-pdf-enhanced-cache/1/superficial-necrolytic-dermatitis.pdf
3. Foss, M. G., Hashmi, M. F., & Ferrer-Bruker, S. J. (2022). Necrolytic migratory erythema. In StatPearls [Internet]. StatPearls Publishing.
4. Outerbridge, C.A., Marks, S.L. and Rogers, Q.R., 2002. Plasma amino acid concentrations in 36 dogs with histologically confirmed superficial necrolytic dermatitis. Veterinary Dermatology, 13(4), pp.177-186.
5. March, Philip A., Andrew Hillier, Steven E. Weisbrode, John S. Mattoon, Susan E. Johnson, Stephen P. DiBartola, and Peter J. Brofman. “Superficial necrolytic dermatitis in 11 dogs with a history of phenobarbital administration (1995–2002).” Journal of Veterinary Internal Medicine 18, no. 1 (2004): 65-74.