Retrospective Study

Medical records from the Cummings School of Veterinary Medicine at Tufts University between 2004 and 2018 were searched for dogs with a diagnosis of SND. The search terms used were “hepatocutaneous syndrome,” “superficial necrolytic dermatitis,” “necrolytic migratory erythema,” and “hyperkeratosis.” When selecting cases, only those with a skin biopsy were included because dermatohistopathology remains the most objective and specific diagnostic finding in dogs with SND.^1–25 Inclusion criteria for the retrospective study included gross dermatologic lesions consistent with SND and compatible findings on skin histopathology. HCS was diagnosed in those cases with SND in which a serum biochemistry panel within a week of skin biopsy demonstrated an increase in serum liver enzyme activity and/or a honeycomb-like liver on ultrasound was found. Dogs with SND due to EN had to have histopathologic confirmation of EN. Medical records were reviewed for signalment, presenting dermatologic lesions, biochemical data including the results of serum liver enzyme activity (alanine aminotransferase [ALT], ALP, aspartate aminotransferase, gamma glutamyl transpeptidase), serum albumin, serum bilirubin, serum glucose, presence of diabetes mellitus (diagnosed as serial blood glucose measurements >200 mg/dL), plasma amino acid levels, glucagon levels, abdominal ultrasound findings, and hepatic histopathology results. In addition, treatment protocols were recorded. Survival length was determined by record review and follow-up with referring veterinarians and owners. Clinical pathology samples were analyzed at the Cummings School of Veterinary Medicine at Tufts University or IDEXX laboratories, and amino acid profiles were analyzed by the University of California Davis Amino Acid Laboratory. Amino acid profiles included the comprehensive measurement of 29 amino acids (nmol/mL).

A board-certified dermatologist reviewed the dermatologic presentation of all cases and all skin histopathology to verify that each case was compatible with SND. Available hepatic biopsies were reviewed by a single board-certified veterinary pathologist in conjunction with the board-certified small animal internist with expertise in hepatology for the presence of vacuolar change (glycogen and/or lipid accumulation), inflammation, fibrosis, and parenchymal loss. Abdominal ultrasound images and video clips were evaluated by a board-certified radiologist to determine hepatic echogenicity, echotexture, and size and contour of the liver as well as the presence of abdominal effusion and masses within the pancreas.

Review of the Literature

The PubMed database was searched from inception to June 2018 for the terms “hepatocutaneous syndrome,” “superficial necrolytic dermatitis,” or “necrolytic migratory erythema” combined with dog or canine. Inclusion criteria for the literature review were the same as those listed above for the retrospective study. The same data for each patient as outlined for the retrospective study were also collected from each manuscript.

Statistical Analysis

For the retrospective study, data were analyzed for normality using tests for kurtosis and skewness. Nonparametric results are presented as median and range. Parametric results are presented as mean and standard deviation. Statistical comparisons between groups of dogs with and without keratinocyte apoptosis on skin histopathology were conducted using either a Mann-Whitney U test or a χ² test. Significance was set at P < .05.

Retrospective Study

The initial medical record search revealed 98 cases of SND; however, 50 were excluded because their final diagnosis was not consistent with SND. Diagnosis in these cases included pyoderma, pemphigus foliaceus, cutaneous neoplasia, atopic dermatitis, discoid lupus erythematosus, trauma, toxic epidermal necrolysis, or endocrinopathies. Of the remaining 48 cases, 23 did not meet inclusion criteria for the current study. Reasons for exclusion included lack of a skin biopsy and lack of documentation of liver involvement.

Twenty-four cases met inclusion criteria for SND/HCS, and one dog met the inclusion criteria for SND/EN. The dog with SND/EN was diagnosed with a glucagonoma at necropsy. This dog was a 7 yr old female spayed hound mix. The median age of dogs with HCS was 10.5 yr (range: 6–14 yr). Sex distribution in these dogs included 17/24 (71%) neutered males, 6/24 (25%) spayed females, and 1/24 (4.1%) intact male. Breeds with HCS included Labrador retriever (n = 3), beagle (n = 2), cocker spaniel (n = 2), German shepherd dog (n = 2), Newfoundland (n = 2), Siberian husky (n = 2), border collie (n = 1), Chihuahua mix (n = 1), cockapoo (n = 1), Italian greyhound (n = 1), Cavalier King Charles spaniel (n = 1), Labrador cross (n = 1), Nova Scotia duck trolling retriever (n = 1), Staffordshire bull terrier (n = 1), rottweiler (n = 1), schipperke (n = 1), and Shetland sheepdog (n = 1). Historical information was available for 18 dogs with HCS on the duration of clinical signs. The median duration was 8 wk (range: 2–32 wk). Signs were present for 5 wk in the dog with glucagonoma.

The location of dermatologic lesions was documented for all dogs with HCS (Table 1). Twenty-three of 24 dogs (96%) had characteristic lesions on the paw pads, making this the most commonly documented skin lesion in this population. Lesions at MCJs were the second most common lesion and affected 11/24 (46%) dogs. Less common lesion locations included involvement of the interdigital area, elbows, nose and periocular areas, limbs, hocks, scrotum, and abdominal or inguinal areas. The number of anatomic sites affected in each dog was also determined. The five anatomic locations were defined as the paw pads, MCJ, interdigital area, elbows, and a category of “other” that included lesions on the nose, periocular region, limbs, hocks, abdomen/inguinal area, and/or scrotum. Ten of 24 dogs (42%) had lesions in two locations, 10 of 24 (42%) dogs had lesions in three locations, and 4 of 24 (17%) dogs had lesions in four locations. No dog with HCS had lesions just at one location. The dog with EN had severe crusting and fissures of all four paw pads and crusting of the nasal planum and ventral abdomen.

TABLE 1 Macroscopic Cutaneous Lesions in 24 Retrospective Cases of Hepatocutaneous Syndrome

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Of the 24 skin biopsies compatible with HCS, 23 were available for review. There was extensive, moderate to severe parakeratotic hyperkeratosis in each biopsy. In the areas of parakeratosis, the stratum granulosum was usually absent or minimal. The epidermis was hyperplastic with prominent acanthosis. The mid epidermal layers presented diffuse intracellular (vacuolar change) and extracellular edema. In 18/23 (78%) cases, there was exocytosis of neutrophils and formation of neutrophilic-rich crusts. In 3/23 (9%) cases, there were subcorneal neutrophilic pustules. There was evidence of bacterial colonies in the crusts or in the hyperkeratotic stratum corneum in 13/23 (57%) cases. In the majority of cases (21/23, 91%), the superficial dermis presented an inflammatory infiltrate of diverse severity and composition. Hair follicle infundibula frequently presented the same changes as the epidermis. No other changes were observed within the hair follicle, except in one case in which Demodex mites were observed. The dog with the EN also had a biopsy available for review that showed similar dermatohistopathology findings as the dogs with HCS.

Six of 23 cases (26%) with HCS had prominent apoptosis of keratinocytes in different layers of the epidermis (Figure 1). This change was severe in three dogs. Although keratinocyte apoptosis has been mentioned in two previous reports on HCS, the significance of this lesion was not investigated.^4,15 When dogs were grouped based on the presence or absence of keratinocyte apoptosis, there were no significant differences between the groups in terms of age, serum ALT or ALP activity, total bilirubin, albumin, or survival. Four out of 6 (66%) of the dogs with keratinocyte apoptosis also had a diagnosis of diabetes mellitus, compared with 1 out of 17 (5.9%) of the dogs without apoptosis. This difference was statistically significant (P < .05). Two of the dogs with apoptosis were already diabetic at the time of diagnosis of HCS. The other two developed diabetes at 7 and 24 days after diagnosis, respectively. The dog without apoptosis was diagnosed with diabetes mellitus at the same time he was diagnosed with HCS.

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Selected clinicopathologic abnormalities are summarized in Table 2 for dogs with HCS. An increase in serum ALP, ALT, and aspartate aminotransferase activity was seen in 96%, 75%, and 71% of the dogs, respectively. The median increase in serum ALP and ALT activity was 4.6× the upper limit of normal (range: 1.9–31.1× the upper limit of normal) and 2.3× the upper limit of normal (range: 1.1–13.5× the upper limit of normal), respectively. In 20/24 (83%) dogs, the fold elevation in increased serum ALP activity was greater than that seen in serum ALT activity. No dog had both a normal ALT and ALP. Five dogs with HCS were also diagnosed with diabetes mellitus. Clinicopathologic abnormalities in the dog with SND/EN included serum ALT activity that was 1.1× above the reference range and hyperglycemia consistent with the concurrent diagnosis of diabetes mellitus.

TABLE 2 Summary of Retrospective Clinicopathologic Data in 24 Dogs with Hepatocutaneous Syndrome

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Serum amino acid levels were available for review in 7/24 (29%) dogs with HCS. Amino acids were not measured in the dog with SND/EN. All dogs showed severe, generalized hypoaminoacidemia, as defined as measured values less than 50% of the reference interval (Table 3). Hypoaminoacidemia was documented for 38–62% of the measured amino acids in each dog. The mean of each amino acid was calculated for the seven dogs and then compared with the reference value. The most severely decreased amino acids were hydroxy-L-proline (6% of reference value), cysteine (10% of reference value), proline (14% of reference value), arginine (15% of reference value), threonine (19% of reference value), ornithine (22% of reference value), glycine (27% of reference value), citrulline (28% of reference value), and glutamine (29% of reference value). In addition, all seven dogs had decreases in asparagine (38% of reference value), alanine (40% of reference value), methionine (46% of reference value), serine (51% of reference value), aspartic acid (51% of reference value), and lysine (65% of reference value). No dogs in the retrospective study had glucagon levels measured.

TABLE 3 Plasma Amino Acid Concentrations in Dogs with Hepatocutaneous Syndrome in Current Retrospective Study

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Abdominal ultrasound images were available for review in 20/24 (83%) dogs with HCS and for the one dog with SND/EN. Of the dogs with HCS, abdominal radiographs were used in addition to ultra-sound findings to determine the size of the liver in 19/20 dogs (95%). Liver size was equally distributed between small, normal, and enlarged. Irregular liver margins were noted in 17/18 (94%) dogs with HCS. On ultrasonographic exam, all cases of HCS had the expected honeycomb-like appearance to the liver. Only one dog had scant effusion. No dog had a mass visualized within the pancreas. The dog with SND/EN had a normal, homogeneous liver that was mildly enlarged with smooth margins. No pancreatic mass was visualized.

Liver biopsies were performed in 11/24 (46%) dogs with HCS. Samples were acquired by ultrasound-guided needle biopsy (7/11), necropsy (2/11), laparotomy (1/11), and laparoscopy (1/11). The ultrasound-guided biopsies were 16 G in four dogs and 18 G in three dogs. All biopsy material was deemed adequate to make a histopathologic diagnosis by a board-certified veterinary pathologist. All but one biopsy was consistent with the expected degenerative vacuolar hepatopathy previously reported in dogs with HCS.^{1,3,5–10,14,21–23} Ten of 11 dogs (91%) had some degree of vacuolar change, typically a combination of glycogen type and lipid change. Eight of 11 dogs (73%) had evidence of parenchymal collapse. Fibrosis was variable within the samples but ranged from absent in 3/11 (27%) to severe in 1/11 (9%). Mild, predominately mononuclear inflammation was present in 4/11 (36%) cases. The one dog without vacuolar change had a diagnosis of copper-associated chronic hepatitis (rhodamine staining was grade 4/5). Hepatic histopathology in the dog with SND/EN, which was evaluated on necropsy, showed hepatic metastatic disease.

Treatment was initiated in 17/24 dogs with HCS. Of the 17 dogs, 15/17 (88%) had amino acid infusions with a 10% amino acid solution^a (19.6–33.1 mL/kg infused over 8–10 hr) in addition to oral amino acid supplementation. Two dogs received oral supplementation alone without infusions. Of the 17 dogs, 13/17 (76%) received oral supplementation with various protein powder mixtures (14–42 g/day), 11/17 (64%) had eggs (4–6/day) added to their diet, 11/17 (64%) received S-adenosyl methionine with or without silymarin (6.8–18 mg/kg/day), 8/17 (47%) received vitamin E supplementation (13–80 IU/kg/day), 7/17 (41%) received oral fatty acid supplementation (doses unknown), and 3/17 (18%) received zinc supplementation (2.1–2.7 mg/kg/day). Two dogs also received oral taurine supplementation (unknown dose), two dogs received oral glutamine (42.4 mg/kg/day in one dog, unknown in the other), and two dogs also received ursodeoxycholic acid (10.9–15.3 mg/kg/day).

Survival time was available for 21/24 (88%) dogs with HCS. Two dogs were still alive at the time of writing—1182 and 1267 days after diagnosis. Of the total dogs with survival times reported, 16/21 (76%) received some form of therapy and 5/21 (24%) received no therapy. The median survival time for all dogs was 45 days (range: 1–1267 days). Of dogs who received therapy, the medial survival time was 82 days (range: 3–1267 days). The median survival time for dogs who did not receive therapy was 4 days (range: 1–45 days). Ten total dogs survived 30 days or less. Fourteen of the dogs (67%) were euthanized because of a poor quality of life and progressive skin lesions. Causes of death for the other five dogs included cardiac arrest in two dogs, progressive pneumonia in two dogs, and acute respiratory distress of unknown etiology in one dog. The dog with SND/EN was euthanized the day after presentation because of the painful lesions of the paw pads and a poor quality of life.

Review of the Literature

The literature search for cases of SND/HCS yielded 27 publications. Thirteen manuscripts did not meet inclusion criteria and were excluded. The remaining 14 papers were reviewed, and the data were collected as indicated. There were eight single case reports, three retrospective studies with at least 20 cases (n = 36, 22, and 20 dogs), and two small retrospective studies (n = 3, 5, and 9 dogs) for a total of 105 dogs.^{1–3,5–10,14,21–23,27} The literature search for cases of SND/EN confirmed via histopathology yielded 12 papers.^{7,11–13,15–19,24–26} Within these 12 papers, there were a total of 13 cases.

The data from the review for dogs with SND/HCS are summarized in supplementary Table 1. Sex was not reported in 13 dogs. In the remaining 92 dogs, there were 62 males and 30 females with a 2.1:1 predominance of males. The median age was 10 yr (range: 6 mo to 16 yr). Breed was reported for 100/105 dogs, and in total 26 breeds were documented. The number of dogs with characteristic lesions on the paw pads, increased serum ALP and/or ALT activity, plasma hypoaminoacidemia, honeycomb-like ultrasonographic appearance to the liver, and degenerative vacuolar changes on hepatic biopsy were tabulated. Of the 105 dogs, 79 had documentation of the locations of their skin lesions, 95 had serum biochemistry panels performed, 43 had an abdominal ultrasound, and 65 had liver biopsies. Seventy-eight of the 79 dogs (98.7%) had lesions on the paw pads. All 95 dogs (100%) with biochemistry profiles had an increased serum ALP or ALT activity. The characteristic honeycomb-like liver was seen in all but one dog (42/43, 98%). The one dog without this change had a nodular pattern with mixed echogenicity on ultrasound.¹⁴ Sixty-two of 65 (95%) dogs with a hepatic biopsy had degenerative vacuolar change. The three dogs without vacuolar change had acute hepatitis, chronic hepatitis, and periportal fibrosis, respectively.^2,14,27 Survival times were reported for 65 dogs. Four dogs were euthanized upon presentation to the hospital.^2,7 Survival time for the rest of the dogs was a median of 90 days (range of 2–1920 days).^{1,3,6–10,14,22,27}

The data from the review for dogs with SND/EN are summarized in supplementary Table 2. The diagnosis in these dogs included a pancreatic glucagonoma (3/13), extrapancreatic hepatic glucagonoma (3/13), pancreatic carcinoma (3/13), glucagon- and insulin-secreting pancreatic tumor (2/13), and a nonspecified pancreatic endocrine tumor (2/13). Of the 13 dogs, there were 8 males and 5 females, with a 1.6:1 predominance of males. The median age was 10 yr (range: 5–13 yr). All 13 dogs had lesions consistent with SND on their paw pads. Only 5 of 13 dogs (38%) had elevated serum liver enzymes. None of the 13 dogs had the characteristic honeycomb-like liver on abdominal ultrasound. Hepatic biopsies were analyzed in 12/13 dogs and showed metastatic disease (7/12, 58%), mild vacuolar change (3/12, 25%), or normal liver parenchyma (2/12, 17%). No dogs with SND/EN had a degenerative vacuolar hepatopathy. Survival times were reported for all 13 dogs. The median survival was 42 days (range: 0–360 days).^{7,11–13,15–19,24–26}

A total of 57 dogs from 11 different studies had amino acid analysis performed, all of which documented plasma hypoaminoacidemia.^{1,3,8–10,12,14,15,18,20,24} Individual plasma amino acid panels and their reference intervals, however, were available for review in only 51 total dogs with SND from eight different studies (Table 4).^{1,3,8,10,14,15,18,24} Of the 51 dogs, 48 had a diagnosis of SND/HCS.^{1,3,8,10,14,20,24} All dogs with SND showed generalized hypoaminoacidemia, defined as measured values less than 50% of the reference interval (Table 4). Hypoaminoacidemia was documented for 52–76% of the measured amino acids in each study.^{1,3,8,10,15,20,24} The mean values for these amino acids were compared with the reference value. The most severely decreased amino acids seen were hydroxyl-L-proline (7% of reference value), proline (14% reference interval), citrulline (16% reference value), glutamine (16% reference value), threonine (19% reference interval), arginine (20% reference interval), alanine (29% reference interval), asparagine (30% reference interval), methionine (31% reference interval), lysine (32% reference interval), glycine (34% reference interval), and serine (36% reference interval).^{3,8,10,15,20,24}

TABLE 4 Comparison of the Plasma Amino Acid Levels in Dogs with Superficial Necrolytic Dermatitis, Other Hepatic Disease, and Nonhepatic Disease

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A total of 14 dogs with SND/HCS in the literature and 9 with SND/EN had glucagon levels measured.^{1,3,7–9,11,12,15,17,18,24,25,27} Three of 14 dogs with SND/HCS (21%) had elevated glucagon levels, 2 of whom also had a concurrent diagnosis of diabetes mellitus.^1,7,27 Of those with SND/EN, all nine (100%) had elevated glucagon levels, and five also had a concurrent diagnosis of diabetes mellitus.^{7,11,12,15,17,18,24,25}