Superficial necrolytic dermatitis

INTRODUCTION

Superficial necrolytic dermatitis (SND) is a dermatologic condition affecting humans, dogs, and rarely cats, occurring as a consequence of a metabolic disturbance (1). In human medicine, this condition is often termed “necrolytic migratory erythema” (1,2). In veterinary medicine, it was originally known as “diabetic dermatopathy,” then as “metabolic epidermal necrosis and hepatocutaneous syndrome,” with all names related to the etiopathology (3). Most recently, the term “aminoaciduric canine hypoaminoacidemic hepatopathy syndrome” has been proposed as an umbrella denomination encompassing the metabolic syndrome of hypoaminoacidemia, aminoaciduria, and hepatocutaneous hepatopathy, regardless of presence or absence of skin lesions. The new term suggests a disease spectrum where metabolic disease may precede dermatologic lesions (4).

PATHOPHYSIOLOGY

In human medicine, necrolytic migratory erythema most often occurs in association with glucagon-secreting pancreatic tumors and is a component of glucagonoma syndrome, which presents with hyperglucagonemia, hyperglycemia, and hypoaminoacidemia, along with characteristic skin lesions (3,5,6). There are several reports of SND secondary to a glucagon-secreting tumor in dogs, but SND occurs most commonly in association with a hepatopathy, hence the term “hepatocutaneous syndrome” (1,3,5–7). In cats, the disease is rare, with reported cases due to glucagonsecreting tumors (5,8).

The etiopathogenesis of SND is not fully understood (6). Mycotoxin ingestion and anticonvulsant (phenobarbital and primidone) administration have been suggested to induce the hepatopathy associated with SND (7,9,10). One case series reported chronic phenobarbital administration in 44% of their study population; however, other case series do not report such a frequent association (10). Preexisting endocrine disorders, including diabetes mellitus (DM), hyperadrenocorticism, and hypothyroidism, have been noted in ~40% of dogs with SND (3).

Regardless of whether SND occurs secondary to a glucagon-secreting tumor or hepatopathy, hypoaminoacidemia appears to be a common feature (1,6). Hypoaminoacidemia may be the result of increased hepatic metabolism of amino acids, persistent glucagon-driven gluconeogenesis leading to amino acid depletion, or amino acid wasting through urine due to defects in amino acid transporters (2,3,5). Compromised hepatic metabolism does not explain the hypoaminoacidemia, as changes in amino acid profiles are not consistent with those in acute or chronic hepatopathy (3). Clinical signs associated with SND may be explained by the role of depleted amino acids in the urea cycle, glutathione synthesis, and collagen synthesis. In particular, reduced proline and hydroxyproline may limit collagen synthesis, which may explain the cutaneous disease associated with SND (2).

SIGNALMENT

Superficial necrolytic dermatitis most often affects older, smaller-breed dogs (11). The mean age of onset is 10 y (range: 5 to 15 y) (1–3). Many breeds can be affected, though cocker spaniels, Shetland sheepdogs, shih tzus, West Highland white terriers, and Scottish terriers appear to be most commonly affected (3,4,11). Male dogs appear to be overrepresented in most studies (3–5).

CLINICAL PRESENTATION

Cutaneous lesions are typically present in areas of wear, including foot pads, mucocutaneous junctions, and pressure points such as elbows and hocks (3,7). However, lesions can also be located in the mouth, distal limbs, pinna, and external genitalia (7). Lesions include erythema, crusting, erosion, ulceration, and alopecia (1–3) (Figure 1). Marked hyperkeratosis, crusting, fissuring, and ulceration of foot pads is highly suggestive of SND, as it is exhibited by most affected individuals (1,3,5,10,12) (Figure 2). However, these foot-pad lesions are not pathognomonic, as other diseases can affect the foot pads in a similar fashion (7). Non-cutaneous clinical signs include lameness, lethargy, inappetence, weight loss, and polyuria/polydipsia, with the latter often indicative of concurrent DM (1,3,11).

FIGURE 1.

A dog with superficial necrolytic dermatitis, exhibiting crusting and erosions affecting the muzzle and periocular region.

FIGURE 2.

Foot pads of a dog with superficial necrolytic dermatitis, exhibiting hyperkeratosis and fissures.

DIAGNOSTIC FINDINGS

Based on clinical presentation, differential diagnoses include zinc responsive dermatosis, demodicosis, dermatophytosis, cutaneous adverse drug reactions, and superficial bacterial folliculitis (1,7). Dermatoses affecting the mucocutaneous junctions, e.g., pemphigus foliaceous, toxic epidermal necrolysis, and systemic lupus erythematosus, also need to be considered (1).

On a serum chemistry panel, increased alkaline phosphatase and alanine aminotransferase occur in nearly all cases (2,3,5,11,12). The degree of enzyme elevation may vary; however, alkaline phosphatase is typically elevated more than alanine aminotransferase (12). Elevations in other liver enzymes, including aspartate aminotransferase and gamma-glutamyltranspeptidase, have been reported variably (11,12). Some case series reported no abnormalities on complete blood (cell) count (3,5,12), whereas others reported anemia and leukocytosis in ~50% of animals (1,2,11). Hyperglycemia appears commonly reported, with overt DM occurring in 25 to 40% of animals (1–3,5,11). Hypoalbuminemia and abnormalities in bile-acid concentrations appear variable (1,7,11).

In human medicine, hyperglucagonemia is common secondary to a glucagon-secreting tumor (1). Whereas increased glucagon concentrations are suspected to have a role in the pathogenesis of SND, glucagon concentrations in dogs are usually within normal limits or mildly elevated (4–6). The lack of overt hyperglucagonemia may be due to a lack of sensitivity and specificity of available tests, lack of well-established reference ranges, or increased glucagon action due to a different isoform of glucagon (e.g., enteric form) that is not readily identified; moreover, peripheral blood glucagon concentrations may not accurately demonstrate the concentration of glucagon in portal circulation due to hepatic extraction and dilution (2,5). Finally, even though glucagon concentrations maybe not be overtly high, even a high normal value in a hypoaminoacidemic animal may be considered inappropriate (5).

All dogs with SND appear to have marked hypoaminoacidemia compared to both healthy dogs and those with acute or chronic hepatitis (3). Total plasma amino acid concentration in dogs with SND was as low as 30% of the total plasma amino acid concentration reported in normal dogs (3). Many amino acids were reduced to between 30 and 60% of their reference range (2,3,5,12). Glutamine, hydroxyproline, proline, arginine, threonine, cysteine, glycine, alanine, and citrulline were most commonly reported to be reduced (2,3,5,10,12). Outerbridge et al (3) reported glutamine, arginine, proline, and threonine to be the most significantly reduced, but there were slight variations with respect to which amino acids were reported to be most affected in other case series (2–5,10,12). Plasma concentrations of 1-methylhistidine and cystathionine were suggested to be robust biomarkers for distinguishing dogs with SND from apparently healthy dogs (4).

Whether the degree of hypoaminoacidemia impacts the severity of clinical disease appears uncertain. Loftus et al reported that severity of hypoaminoacidemia is related to severity of clinical signs, as dogs with considerable reduction in plasma lysine concentrations had more extensive cutaneous disease (2). However, Outerbridge et al reported that dogs with a lower mean plasma amino acid concentration survived longer than dogs with a higher mean plasma amino acid concentration (3). Finally, in a more recent report by Loftus et al, plasma amino acid concentrations were not statistically different between dogs with or without cutaneous disease (4).

Aminoaciduria has been more recently reported in dogs with SND, characterized by urinary wasting of lysine, methylhistidine, and proline (2). Lysine and methionine have been proposed as biomarkers for SND, as their concentrations were significantly increased in the urine of dogs with SND compared to healthy controls (4). Urine wasting of amino acids has been proposed as a mechanism of hypoaminoacidemia (2). Since there is no common transporter for the amino acids present in increased concentration in urine, aminoaciduria may be the result of a deficiency in a currently unidentified transporter, dysfunction of multiple transporters, or altered metabolic status of epithelial cells in the proximal renal tubules (2).

An abdominal ultrasonographic examination can aid in the diagnosis of SND. A diffuse, hyperechoic hepatic parenchyma arranged around a network of numerous hypoechoic nodules, known as a “Swiss cheese” or “honeycomb” pattern, is characteristic of the hepatopathy associated with SND (2,7,13). Ultrasonography may also help identify a glucagon-secreting tumor; however, failure to identify neoplasia later identified at necropsy has been reported (7).

Histopathology of the skin or liver provides a definitive diagnosis. Cutaneous biopsies reveal marked parakeratosis of the upper epidermis, inter/intracellular edema, keratinocyte degeneration of the mid-epidermis (stratum granulosum and spinosum), and hyperplasia of the stratum basale (1,3,5,11). From superficial to deep, the epidermis has a characteristic red, white, and blue appearance associated with the parakeratosis, edema, and hyperplasia, respectively (5,11) (Figure 3). Biopsies of the liver reveal vacuolar hepatopathy characterized by foci of ballooning degeneration (glycogen or lipid vacuolation) amid foci of proliferative/hyperplastic hepatocytes and areas of parenchymal collapse (3,5,11,12).

FIGURE 3.

Sample from histopathologic analysis of a patient with superficial necrolytic dermatitis, exhibiting, from superficial to deep epidermis, the characteristic red, white, and blue appearance associated with the parakeratosis, edema, and hyperplasia, respectively. Scale bar: 20 μm.

Image courtesy of Shannon Martinson, BSc, DVM, MVSc, DiplACVP.

TREATMENTS

Canine SND due to an endocrine tumor can be treated with surgery (14,15), but there is an uncertain prognosis due to the propensity for development of life-threatening pancreatitis (14,15). When comorbidities or metastasis precluded surgery, or when clinical signs returned after surgery, treatment with a somatostatin analog, octreotide acetate, inhibited glucagon release, leading to resolution of clinical signs (1,14). In contrast, for SND resulting secondary to hepatopathy, a multimodal treatment approach involving parenteral infusions, enteral supplements, and diet is recommended (16).

Parenteral administration of amino acids has long been considered critical in SND treatment (1–3,7). Intravenous infusion of amino acids administered through a longline jugular, saphenous, or peripheral catheter is commonly recommended. There are multiple protocols; e.g., 25 to 50 mg/kg of 8.5 to 10% intravenous amino acid solution infused over 6 to 8 h (1,16). Thrombophlebitis secondary to peripheral catheter use is possible but not common (16). Two infusions given 1 wk apart are recommended as a starting point, with further therapy tailored to individual response (16). Unfortunately, response is relatively unpredictable; the number of infusions needed to achieve clinical improvement and the frequency of infusions needed to control clinical signs are likewise difficult to predict (16).

Intravenous amino acid infusions are often combined with lipid emulsions (16). Fatty-acid deficiencies have not been reported in dogs with SND as they have in humans, but there was a single case report of a dog managed on intravenous amino acid infusions and lipids for 24 mo (16,17). However, a recent case series by Loftus et al reported independent survival benefit (16).

Parenteral administration of amino acids is preferred in order to bypass portal circulation; however, many supplements, including various amino acids, omega fatty acids, zinc, ursodiol, milk thistle, and vitamin E, plus high-protein diets, have been used to treat SND (1,6,16). Amino acids targeted for supplementation should include those often depleted and participating in collagen supplement (proline and lysine), the urea cycle (arginine and ornithine), and glutathione synthesis (cysteine, glycine, and SAMe) (16). To the best of our knowledge, no studies have investigated individual supplements in a fashion that would document 1 supplement as superior to others or demonstrate direct effect on survival time. However, optimal treatment, resulting in longest survival time, incorporates ≥ 3 enteral supplements as part of the treatment protocol (16).

Manipulation of diet to increase protein content, through administration of egg yolk or high-protein commercial or home-cooked diets, has been suggested to combat hypoaminoacidemia (1,3,5,7,16). In a case series by Loftus et al, a home-cooked diet conferred the greatest independent effect on dog survival time (16). The improved performance of home-cooked versus commercial diets was hypothesized to be a result of the abundance of lysine recommended in home-cooked diets, a slightly higher overall protein content as percentage of metabolizable energy, or improved protein digestibility (16). However, owner-dependant bias regarding acceptability of time-consuming treatments, such as home-cooked diets, and commitment to pursuing therapy in face of poor prognosis may also need to be considered.

Optimal treatment of SND, defined as ≥ 2 intravenous amino acid infusions, ≥ 3 enteral supplements, and high-protein home-cooked diets, achieved significantly longer survival times, supporting multimodal therapy as the standard of care for dogs with SND (16). However, single-treatment approaches should be considered when combination therapy cannot be pursued for financial or logistic reasons (16).

In addition to direct treatment of SND, patients with secondary bacterial or yeast infections should be treated with appropriate topical or parenteral therapy, based on bacterial culture and sensitivity. Additional comorbidities, such as DM, should be treated on a case-by-case basis. Steroids should be avoided, as they can exacerbate development of DM (1).

PROGNOSIS

Traditionally, SND has a poor prognosis, with most dogs surviving only 3 to 6 mo after diagnosis and only a few surviving up to 2 y (1,7,11). The most common reason for euthanasia is perceived poor quality of life due to unmanaged symptoms, particularly those related to the foot pads, which can be painful and impact mobility (11). Loftus et al reported a more optimistic disease survival time of 557 d (range: 1 to 1783 d, with 35% survival to 1783 d) (16). That case series included dogs without cutaneous SND lesions, as a previous paper by the same author suggested that this disease presents on a continuum where hepatic lesions and metabolic disturbances precede skin lesions (4,16). Thus, early recognition, before onset of cutaneous disease, may improve survival times.