Vet Pat ho i 30:75- 81 ( 1993)

Superficial N ecrolytic Dermatitis

(Necrolytic Migratory Erythema) in Dogs
T. L.

GROSS,

M. D.

S ONG ,

P. J.

H A VEL , AN D

P. J.

IHRKE

Californ ia Dermatopathology Service and California Veterinary Diagnostics, West Sacramento, CA (TLG); and
Schoo l of Veterinary Medicine , Universi ty of California, Davis, CA (MDS, P1H, PJI)
Abstract. Twenty-two dogs with superficial necrolytic derm atiti s were eva luated prospecti vely, twent y-one
of which had charac teristic crus ting lesions of the paw pads. Histologically, epider mal lesions included parak eratosis and lamin ar int racellular ede ma. The plasma amino acid concentrations of eight dogs were markedly
depressed. Nine dogs had term inal diabetes mellitu s. These clinical and morph ologic findings were strikingly
similar to tho se of necrolytic migratory erythema in hum an beings, the most common cause of which is
hyperglucagonemi a due to islet cell tum or of the pancreas. No pancreatic tum ors were found in these dogs;
plasma glucagon concen trations in the five dogs tested were normal. The serum alkaline phosphatase concentrat ions were elevated in all dogs. Severe vacuolar hepatopathy, suggesting metabolically or hormonally induced
hepatic dysfunction, was found in 2 1 dogs at necropsy or by biopsy; one dog had ultrasonograph ic abno rmalities
of the liver. Histo pat hologically, seve re vacuolar alteration resulted in parenchymal collapse and nodu lar regeneration, which grossly mimicked cirrhosis. Although the definitive metabolic stimu lus was not discovered
for the cutaneous and hepat ic lesions, the similarity ofthe cutaneous and biochemical featu res ofcan ine superficial
necrolytic derm at itis to hum an necrolytic migratory erythema warra nts further investigation into possible
underlying pancreatic hormonal dysfunction .
Key words:

Dogs; glucagon; hepatocutaneous syndro me; necrolytic dermat itis.

ficial necrolyt ic de rm at it is in which pan creatic t u m ors
were not found.

Superficial necrol yt ic der matitis is a c ut a neous d isease in d ogs th a t shares many cli nical a nd hi stopa th olog ic features wit h necrolytic m igrato ry eryt he ma of
human beings. Necrolyt ic mi gratory erythe m a is m ost
often associate d wit h hyp erglu cago nemia sec ondary to
glucag on-secreting pancreatic neopla sia . Several ca ses
have bee n reported in wh ich pancreatic end oc ri ne tumors we re not foun d. 5.7. l o , 17. 19
The findings of two dogs wi th glucagon-p ro d uci ng

Materia ls and Me thods

Case histories
Twenty-two dogs with superficial necrolytic dermat itis that
were presented to pri vate veterin ary hospitals or the Vcterinary Med ical Teaching Hospital , University of CaliforniaDavis between 1987 and 1991 were studied. Th e 22 animals
were chosen from a larger group ofdogs for which a diagnosis
of superficial necro lytic der ma titis had been ind icated by
initial skin bio psy; on ly dogs for which further diagnostic
da ta were collected were included in the study.
Fourteen purebred dogs of num erous breeds (one each of
Scottish Terrier, Germa n Shepherd Dog, Schipperke, Miniature Poodle, Standard Poodle, Welsh Corgi, Old English
Sheepdog, Cocker Spaniel, Go lde n Retriever, Beagle, and
Keeshound , and thr ee Shetland Sheepdogs) and eight mixedbreed dogs were selected . Ages ranged from 6 to 16 years,
with a mean of 10.7 years. Fourteen dogs were males and
eight were females ( 1.75: I).
Init ial diagnosis in all 22 dogs was based on clinical dcrmatologic and skin biopsy fi nd ings, Rout ine blood and serum
chem istry panels were performe d for all dogs. Nineteen dogs
(Nos . 1-1 4, 16, 17, 20-2 2) died or were euthanatized; liver
from each dog and the ent ire pancreas in 15 dogs (Nos. I,
4, 5, 7- 14, 17, 20-22) or a porti on of the pancreas in four
dogs (Nos, 2, 3, 6, 16) were mad e ava ilable for histopath o-

pancr eati c e nd ocrine tu m o rs an d su perficia l necrolyti c

dermatiti s ha ve been reported previou sly." In co nt rast
to the hu m an di sease, howe ver , a ll the remaining p revious ly reported ca ses of superficia l necr ol yt ic d erm atitis in dogs ha ve not incl uded inde ntificatio n of
pancreatic ncoplasm s. v-'<" T he term " he pa toc utaneous sy ndro me" has been applied to th is subty pe . One
rec ent report documented lo w le vel elevatio ns in pla srna glu cagon concentrations in five dogs."
Although skin lesion s have been we ll described in
pre vi ous canine cases, th e hepati c di sease has been
in completely characterize d . Cirr hosis was often sta te d
a s th e prin cipal h ist opathol ogic feat ure. ' 4 , ' 8,2o Marked
d epression in the concen trations of pla sma a m ino ac id s, a feat ure ty pical of necrol yti c m igratory erythe ma
in human beings, ha s n ot been d ocumented pre viously
in dogs. T his rep o rt d esc rib es the gross, bi ochem ical ,
a nd mi cro scopic changes in 22 cases o f ca n ine super75

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Gross ct al.

76

Vet Pat hoI30:1, 1993

logic exa m inat ion. Dog Nos. 15, 18, and 19 were alive at th e
co m plet ion of th e study but had ev ide nce of liver di sease by
ultrason ography (dog No. 18) or on biop sy (dog Nos . 15, 19).
A depression in th e plasma am ino acid concentrations typical
for the di sease was ev iden t for all th ree livin g dogs.
Gro ss and light microscopic evaluation
To sea rch for neoplasm s, th e pancreas was exam ined gross ly th roughout its available length by tran sverse incisio n at
3-m m int ervals. Specimens of liver and pan creas for light
m icroscopi c exam ina tion were fixed in 10% neutral buffered
form alin and processed for standa rd par affin im bed me nt prior to sectio ning at 5 ,urn and stai ning with hematoxylin an d
eos in. Sections of liver from dog Nos . 5-7 , 9, and 12 were
also stai ned with Masson 's tri chrome and Snoo k's retic ulin.
Fo rma lin-fixed liver from these five dogs was frozen-section ed at 12 ,urn and stained with oil red O.
Glucagon and amino acid assays
Blood from five dogs (Nos. 10, II , 17-1 9) was co llected
in chilled ethylenedia mi nctetraacetic acid- coated tubes with
10% trasylol added (100 ,ullml who le blood), placed on wet
icc, and imm ed iat ely sp un in a 15 C centrifuge at 2,500 rpm
for 10 minutes. Plasma was separated and froze n at - 40 C
until assayed. Immunoreacti ve glucago n was measu red in
unextracted plasma with a rad ioimmunoassay using antise ra
0 4A (D r. Roger H . U nger , Unive rsity of Texas Southwes tern
Med ical Center, Dallas), as previou sly described ." Plasm a
fro m eight dogs (Nos . 4, 10-1 2, 15, 17-1 9) was assayed for
a mino acid levels by colorime tr ic ana lysis using a Beckm an
System 7300 high- performan ce ami no acid analyzer.

Results
Clinica l cutaneous finding s

Twenty-one of 22 dogs (all except dog No. 13) were

presented with crusting lesion s of the paw pad s (Fig.
1). Thirteen dogs (Nos. 1, 7, 9-12, 15-21) had crusting
and ulcerati on of the oral, ocular , anal , and/o r genital
mu cocutaneou s j unctio ns. Fiv e dogs (Nos. 7,9, 11, 19,
20) had crusting of the ears; six dogs (Nos. I, 14, 16,
17, 19, 22) had sim ilar lesion s of the pressure points
(hocks, elbows, hips, stifles), especially the elbows. Dog
Nos. 5, 6, and 13 had lesion s of the scrotum. Severely
affected animals often had marked erythema and crus ting in the axillae and groin. Dog No s. 14 and 19 had
paronychia resulting in deform ed and pliable nails.
Dog No . 19 developed stomatitis.
H istopathologic cutaneous findings

Cutaneous hist opathologic lesions were var iable.

Acanthotic epidermis characteristically had a mark ed
lam inar distribution of superficial parakeratosis , subjacent lam inar epidermal pallo r and keratin ocyte vacuolation (" necrolysis" ), and basilar epiderma l cell hyperpl asia (Fig. 2). Th is condition often produ ced a
str ikingly layered "red , white, an d blue" appearance;
th e superficial kerat in accumulation stained red (eo-

Fig. 1. Left rear paw, supe rficial necrol ytic derm atitis;
dog No . I I. T he digita l paw pads are cha racter istica lly crusted and cracke d.

sinophilic), the middle vac uolated pale layer whit e, and

the deep hyperplasti c layer blue (basoph ilic). In many
skin biop sy specime ns, par akeratosis pred omi nated
(Fig. 3). In some lesions , there was pron oun ced super ficial pustulation and crusting (Fig. 4). Th ere was
often colonization of the superficial keratin and crust
with bacteria and occasionally yeast (Ma lassez ia sp.).
Large clefts through the necrolytic and ede ma to us layer
were sometimes observed; superficial epiderma l necrosis, ero sion s, and ulcers were commonly observed.
In the superficial dermis, ede ma with vascular ectasia
and congestion was accompanied by a mixed inflammatory infiltrate of lymphocytes, macroph ages, neutrophils, and plasm a cells.
Clinical hematologic findings

All 22 dogs in the study had eleva ted concentrations

of serum alkaline pho sphatase, ranging from 264 to
12,608 IV/liter (norma l = 10-1 50 IV/liter). Th e mean
eleva tion in concentration of serum alkaline pho spha tase was 2,280 IU/l iter; elevations greater than 1,000
IV/liter were seen in 12 dogs (Nos . 2-7, 11-1 3, 1921). Serum concentratio ns of alan ine aminotransferase
were eleva ted in 18 dogs (all except Nos. 3, 6, 8, 10)
and ranged fro m 84 to 1,483 IUzliter (normal = 5-80
IU/l iter); mean eleva tio n in concentration was 376 IU/
liter. Nin e dogs (Nos. 1, 2, 4, 10-14, 19) had coexistent

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Vet Patb ol 30: I, 1993

Superficial Necro lytic Dermatitis

77

hyperglycemia and di ab etes mellitus. In mo st cases ,

di ab etes mellitus occ ur red lat e in the course of th e
di sease, after liver and cutaneo us disease were identified . Insul in conce ntra tions were elevated in 5/ 6 dogs
tested (Nos. 10, 11, 17-20) and ranged from 37 to 85
j.LU/ m l (no rmal = 1- 20 j.LU/ml); mean elevation in concentra tion was 63 j.LU/ m l.
All eight dog s tested (Nos. 4, 10- 12, 15, 17-1 9) had
seve re dep ression in conce ntration of mo st pla sm a
ami no acid s (Table I). Conce ntra tions were oft en 3050% of normal; con centrat ion s of hydroxypr oline,
threonine, glutamine, prolin e, alanine, citru lline , and
arginine were oft en eve n m or e seve rely red uced. Six
of th e eight dogs test ed showed occasi onal, isolated
elevation of a few of th e am ino acids which were genera lly reduced in concentrati on in the other dog s tested
(Tabl e I). Consistent depression also was not ob served
in conce ntra tions of gluta m ic acid , alpha -am ino-n-butyric acid, cystathionine, phen ylalan ine, ornithine, and
3- methylhis tid ine; althou gh so me do gs showed reduction in th e conce nt rations of th ese am ino acids, many
show ed eleva tio n (Table I).
Plasm a glucago n concentration was variable in th e
five dogs tested (Nos. 10, II , 17-1 9; T abl e 2). Plasm a
glucago n levels were not eleva ted .
C linica l th erapeutic findings

Ad mi nis tra tio n of egg yolks as a suppleme nta tio n to

th e di et in six dogs (Nos. 10, II , 14, 15, 18, 19) caused
rapid parti al to co m plete rever sal of th e cutaneo us lesio ns; retesting of am ino ac id levels in two dogs (Nos .
10, I I) showe d mild to mod erat e eleva tions in th ose
a m ino acid s th at had previou sly been reduced . Dog
Nos. 10, II , and 14 were euthana tize d within 3 month s
aft er supplem entation was begun becau se of diabete s
mellitus. Dog N os. 15, 18, and 19 remained on egg
yolk suppleme ntation and were alive at th e end of th e
study; dog No . 15 had been maintained for I year at
th e tim e of writing.
Hepatic findings

Fig. 2. Skin , sup erficial necrolytic derm atiti s; dog No.

18. Th e epide rm is has a striki ng la m ina r d istribution of superficial parakera tosis , subjace nt epide rmal necrol ysis, and
basilar hyperplasia. H E.
Fig. 3. Ski n, superfic ial necrol ytic derma titis; dog No .9.
Chronic lesion s ar e character ized by sev ere par a kerat osis and
crusting, H E.
Fig. 4. Skin, superficia l necrol ytic derma titis; dog No .
14 . T he epiderm is co ntain s a la rge superfic ial pustul e. H E.

G ross ly, livers had round edges, were slightly enlarged , and had a stri kingly nodular appearance in all
19 dogs exami ned postmortem (Fig. 5). Red , brown ,
o r yellow soft nodules, 4- 12 mm in di ameter , were
inters perse d amo ng depressed and firmer ar eas of parenchyma.
Microscopica lly, th ere was mod erate to sev ere vacuolati on of hep at ocytes acco m pa nied by par ench ym al
colla pse (Fig. 6) in all 19 dogs exa m ined at necrop sy
and in two of three living dogs eva luated by biop sy
(Nos. 15, 19). Large hyperpl ast ic nodules were frequ entl y int erspersed and corres po nded to th e nodul es
observe d grossly. Vacuolated hepat ocytes were often
seve rely ballooned and cyto plasm was froth y or contain ed large clear vac uoles with di screte borders. Co l-

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Gross et al.
Table 1.

Vet PathoI30:1. 1993

Plasma amino acid concentrations (N mo ls/ m l) in eight dogs with superfici al necrolytic dermatitis.

Amino Acid
Taurine
Aspart ic acid
Hydroxyprolin e
Threonin e
Serin e
Asparagine
Glutamic acid
Glutamine
Proline
Gl ycine
Alanin e
Citrulline
o-a m ino-n-butyric acid
Valine
Methi onin e
Cystathio nine
Isoleucine
Leucine
Tyrosine
Phenylalan ine
T ryptoph an
Orni thine
Lysine
Histidine
3-Meth ylhistidin e
Arginine

Dog No.
4

10

30
9
0
17
22
0
16
28
16
38
28
0
2
41
0
0
4
8
0
6
28

22
6
0
22
57
15
56
108
36
61
136

II
7

28
14
3

II

5
107
9
0
49
72
47
92
47
14
78
81
12
28

11

16
4
0
27

50
II

14
140
14
67
91
8
5
90
20
0
25
73

30
78
121
II

63
58
0
10

lapsed paren ch yma ex te nd ed as thin branches tra versing th e vac uo lated parenchyma and often co n ta ine d
prominent bile ducts. Inflammation wa s sca n t; hepato cellular necrosi s wa s not evident.
In liver from five dogs, oil red 0 st aining d emonstrated prominent fat d eposition multifocally within
vacuolated hepatocytes. Masson's trichrome stain of
th e sam e specimens revealed only minimally increased
collagen in portal area s; reticulin sta in showe d d eli cate
fibrils of conden sed co nne ctive tis su e in areas o f paren ch ymal colla pse (Fig. 7).

12

15

17

18

19

Normal

60
7
0
31
49
9
32
82
26
58
124
8
9
70
10

29
6
0
29
37
9
16
178
20
46
81
12
2
73
15
0
22
56
24
72
66
8
37
49
18
15

5
7
0
87
68
24
28
329
34
102
94
7
22
123
21
3
48
94
31
84
41
33
88
63
26
0

29
4
8
47
57
9
48
94
32
84
101
9
4
120
24
3
45
88
34
82
37
6
49
56
13
13

12
4
0
30
41
5
15
105
13
55
54
5
4
52
10
2
12
30
15
44
55
5
53
51
5
8

128 23

20
42
12
47
29
38
65
52
12
61

II
10
192
11 7
26
28
967
172
191
436
39
6
212
58
3
80
156
48
60
65
19
190
83
6
138

4
19
8
3
4
53
31
15
39
I

2
22
6
I
II

19
4
6
7
3
22
5
I

12

pale n odular foci were observed. Pan creatic en docrine

tumors we re not found .
Microscopic lesions were variable. In 5/1 9 d ogs for
which pancreatic ti ssue was exam ined (Nos. 2, 4, 79), th ere was ev ide nce of mild to focall y moderate acute
and/or chronic pancreatitis. Interstitial fibrosis wa s mild
to moderate and was accompanied by atrophy and
mild infiltrations of lymphocytes a nd macrophages .
Peri pancreatic adipose tissue had sm a ll scattered a nd

Pancreatic findings
Pancreatic tissue wa s grossly normal in most ca ses
exa m ine d; some small foci of increased firmne ss or
Table 2. Plasma glucagon concentration in fi ve dogs with
superficial necrolytic dermatitis.
Dog No.

Glucagon (pg/ml)*

10
11

114
65
68
75
87

17

18
19
* Normal = 109 23 pg/ml.

Fig. 5. Liver ; dog No. 17. Parenchymal collapse is interm ingled with nodul es of regenerati ve hyperplasia. Note
resembl ance to cirrhosis.

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Superfi cial Necrolytic Dermat itis

Vet PathoI 30: 1. 1993

discrete foci of acute inflam ma tio n cha racte rized by

moder at e numbers of neutrophi ls within necrotic sa ponified fat. Nodular exocrine hyperpl as ia was also
observed ra ndom ly in m ost dog s.
Di scussion
Clinically, 2 1/22 d ogs with supe rficial necro lyt ic dermatitis had lesion s o f th e paw pad s. O the r frict ion al
or pr essure areas wer e a ffected less co m m only. In hum an bein gs, lesion s also are m ost co m m on in areas
subjected to frict ion a nd pr essu re. ':" Sto ma ti tis, whic h
is oft en present in human bein gs.s-' was observed in
on ly one d og in thi s study . The histopathologic lesion s
of canine supe rficial necrolyt ic dermatiti s wer e iden tica l to tho se of hum a n necrolytic m igratory eryt he ma
a nd included superficial parakeratosis and mid-epi dermal con flue nt va cu olation of ker ati nocy tes, crea ting
a n appearance of di ssolution or " necro lysis." Basila r
epide rmal hyperpl asia occ ur red , presumabl y as a n attempt to rege ne ra te damaged su pe rficia l epide rm is.
Va ria tio n in th e mi croscop ic appearance of skin included severe pa rak erat osis with out epidermal pall or,
severe epide rmal clefting, supe rficial epide rmal necr osis, and superficial pu stu lat ion and crus ti ng. Hi stologic
variation also occurs in human cases of necrolyt ic m i-

79

gra to ry erythe ma.' ? D ifferential d iagnoses in h uma n

beings a nd dogs, based on ski n b iop sy, incl ude acrode rmat it is enteropathica , pellagra (niacin deficien cy), zincresp on sive dermatosis (for lesi on s cha rac te rized principally by parakeratosis), gen eric d og food diseas e, a nd
superficia l bacterial or fungal infection (lesion s with
supe rficia l pu stul ati on and crus ting).
Clin ica lly, eleva ted conce ntra tio ns o flive r enzy mes,
particul arl y seru m alka line ph osph at ase, reflected the
severe vac uo lar a nd degen er ati ve liver di sease observed a t necrop sy. Altho ugh so me dogs had received
prior steroid th er ap y, most had not at th e tim e of ad mi ssion . G ross ly, livers we re m arkedl y nodula r du e to
regen erati ve hyp erplasia. Mi croscopi c hepatic lesion s
consisted of hyperplastic nod ules int erposed am on g
sever e vac uo lation a nd parenchymal co llapse with out
inflamm at ion. These hep ati c lesion s suggested a severe
metab olic, horm on al , or toxic ca use for th e liver di sease .
The most co m mon associated findi ng in necrolytic
mi grat ory ery the ma in human beings is the presence
ofa glucago n- secreti ng pan creat ic islet cell tum or leading to hyperglucagon em ia . Alth ou gh two cases of superficial necrolyt ic dermatitis due to glucagon-pro d ucing pan creatic tum or have been reported in th e do g"

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Gross ct al.

(and other cases ha ve been spo radica lly des cribed to

th e autho rs), a ll of th e othe r previou sly reported cases
in which necropsy was performed , as well as th e d ogs
of thi s re port, had no visible pan cr eat ic neop lasm . Ad d it ion all y, th e two previou s repo rted cases o f ca ni ne
superficial necr olyti c dermat itis associated with glucago n-prod uci ng pan creatic islet cell tum or had only
mild hep at ic cha nges , prov iding furthe r ev ide nce for
two sepa ra te and di stinct syndromes o f supe rficia l neero lytic dermatitis in th e dog."
Cases of nec ro lytic migrato ry erythe m a wit hout glucagono ma a lso have been describ ed in th e human litera ture a nd wer e as so ciated with chro n ic pan creatitis, 17
chro n ic sm a ll bowel disease," !' int estinal ad eno car cinoma,19and cirrhosis. ' Pan creatiti s was evident in 5/1 9
d ogs exa m ine d , but lesions wer e mi ld ; th eir relati on ship to th e clinical findings, including severe hypoa m inoacid emia, is not kn own. Intestinal tumors wer e not
identified . None o f th e dogs had di a rrh ea or other signs
o f intes tina l disorder.
T wo re ports in th e human lit eratu re describe cirrh osis a nd nec rolyt ic mi grat or y ery the ma in th e absence of a glucagono rna. >'? howe ver, th e hep ati c lesio ns of th e d ogs o f th is re po rt were no t co m pa ti ble
with hep ati c cirrhosis, as has been rep orted pr evio us ly.1 4.1 8.2o Masson' s sta ins were negati ve for pr ominent inc reases in co llage n , a prer equisite feature of ci rrh osis. Co lla pse d a nd co nde nse d reti culin fra mework
m a y easily be mi sinterpreted as inc rease in co llage n
m icroscopicall y and m ay ex plain th e di screpancy between th e find ings in thi s a nd previous ca nine re po rts .
Sim ila rly, th e regen erati ve nodules o bse rve d grossly in
th ese d ogs in co nj unc tio n with co lla pse d hepatic paren ch ym a mim icked th e gross a ppearance of cirrhosis.
Severe hyp oaminoacidemia is pr esent in most cases
o f human ne crolyt ic migrat ory ery the m a 3.7 13 and was
di scovered in a ll eight do gs test ed. Persistent glucagon
sec retion may produce depression in plasma a m ino
aci d co nce ntrations th rough gluco neogenesis. I - 3.13 In
human beings, support for thi s th eory is provided by
reversa l of th e skin lesion s whe n intra ven ou s a m ino
aci d infusion is perfo rm ed .1.3 In six dogs of thi s rep ort,
m arked improvement in cuta neous lesion s was not ed
whe n egg yo lks, a co nce ntra ted so urce of pro tei n , were
used to suppleme nt th e di et , suggesti ng si mi lar pathogenesis. O ra l high-prot ei n di ets in human beings a lso
ha ve been recommended to decrease th e severity of
th e associated skin lesions in cases o f ino pe ra b le glucagono rna. ? D epression in a mino aci ds may pr oduce
di rect pr ot ein depl eti on o f th e epide rmis a nd lead to
necrol ysis. The relati on ship of dep ressed a m ino ac id
co nce ntratio ns to abnorma l zinc met aboli sm in human
pat ients a lso ha s been sugges ted as a facto r in th e pr odu ction o f skin di sease. 13
Severe depression in plasm a a m ino ac id co ncentra -

Vet Pathol

30:I. 1993

tion s, hist op ath ologic cuta neous lesion s ide ntica l to

hum an necrolyt ic m igrat o ry ery the ma, and developm ent o f di ab et es m ell itus a ll sugges t th e in fluence of
inc reased glucagon secretion. The severe vac uo la r liver
di sease supports underlyin g metaboli c/h orm on al dys func tio n rather th an prima ry liver disease. Prol o nged
gluconeogenes is as in du ced by persistent elevations in
glucagon secretion m ight prod uce th e fatty cha nges observed ; o ther as yet undetermi ned factors co ntri buting
to th e severe vacuo lar hep at opath y also may be present. A ltho ugh dep ression o f plasm a a mi no ac id co nce ntrations has been descr ibed in dogs with dim ethyln it ro samine-induced hep at ic d isea se,15.1 6 th e degree o f
depressio n was not as striking as in th e dogs of th is
re po rt, th e number of a m ino ac ids affected was fewer
than in th e dogs o f thi s study, a nd seve ral amin o ac id
co nce ntra tio ns were, in fact , elev ated.u- T hu s, deve lopme nt o f hyp oam inoacid emi a to th e degree o bserved in th e do gs of th is re po rt secondary to vac uo la r
liver d isease a lon e see ms unl ikely. O ne of th e previ o us ly repo rted human cases of necrol yt ic m igrat ory
erythe ma associated with hepat ic cirrhos is did docume nt hyp erglu cagon emia.> The ca use was post ula ted
as either portal-sys te mic shu nti ng leadi ng to decreased
upta ke of glucagon or true hyp er secret ion perha ps
sti m ula ted by elevated plasma concen tra tio ns of tyrosi ne a nd m eth ionine. Concentrations of neither of
these two plas ma a mino aci ds were elevated in the
dogs of th is st udy .
Becau se th e cli nical, b ioch emi cal , and cuta neo us histologic find ings are strikingly si mi la r to th ose of hum an
bei ngs with hyp erglu cagon emi a a nd necrol yti c mi gra tory erythe ma , it is difficult to explain th e lack of increase in plasm a glucagon co nce ntra tio ns in th e five
d ogs tested . A pr evi ou s rep ort o f superficia l necrolyti c
derm at iti s seco ndary to liver d isea se id entical to th at
of th e dogs of thi s repo rt (" hep at ocutan eous syndrom e" ) rep orted plasm a glucago n ass ays from two
sepa ra te la borato ries.14 Low level elevatio ns were documented in five d ogs; ho wever , glucagon va lues obta ined fro m th e sa me dogs were inconsiste nt bet ween
the two assays. 14 The assay of this previo us repo rt m ight
ha ve lacked sensi tivi ty or specificity . Ano the r pot ential
ex pla na tio n for th e low plasm a glucagon co ncentra tion s of th is st udy is th at peripheral plasm a glucagon
concentratio ns are no t always a reliable an d sensitive
index of increase d pancreatic glucagon secretio n. Fo r
exa m ple, hep at ic ex trac tion ofglucagon may be as high
as 50% in th e dog. In addi tion, th e secreted glucagon
is subs ta ntia lly diluted whe n it enters th e periph eral
ci rc ulation. In dogs, a tripl ing of pa ncreatic glucagon
sec retion ca n occ ur witho ut signi ficant increases of peri phe ra l plasm a glucagon." T hus , a n increase in portal
glucagon deli very to th e liver, whic h co uld result in
increased hep a tic gluco neogenesis and hyp oam inoac-

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Su perfi cia l Nccro lytic Derm a titis

Vel Pal ho i 30 : I, 19 93

idem ia, might not be read ily detected in peripheral

plasm a if it is atte nua ted by hepat ic extraction and
periph eral di lutio n.
Altern atively, increased glucago n actio n in dogs with
superficia l necro lytic dermatitis may not be att ributab le to glucagon of pan creat ic origin but may result
fro m th e increase d secretio n of a nonimmunoreacti ve
form of glucagon of enteric origin. Certain sma ller forms
of enteric glucago n, or glicentin, reta in signi ficant biological activi ty" yet may not be detected by th e COO H
ter m inal- specific anti sera used to measur e plasm a glucago n in th e present stud y. Eleva ted plasma enteroglucagon has been reported in a human pati ent with
necrolytic migratory ery the ma. I I Th e celiac dis ease in
thi s pati ent manifested as d iarrh ea and weight loss;
no ne of th e dog s of th is study presented with sim ilar
signs.
A per sistently low-level increase in glucagon secretion , or perhaps a co m bi na tio n of hormon al or m etabo lic abno rmalities yet to be elucida ted , may be implicated in th e pathogenesis of cani ne superfic ial
necrolytic dermatitis. The possibility of primary metabo lic or toxic liver d isease leadi ng to seco ndary neerolytic m igrat ory ery the ma -like lesion s canno t be totall y excluded; ho wever, t he se vere am in o ac id
dep ression and d iabetes mellitus are not typical of other canine hepat opathies and therefor e ca nno t be easi ly
explained if prim ary liver di sease is postul ated.

10

II

12

13
14

Acknowledgements
We tha nk Mr. Dani el Won g a nd Dr. Q uinto n Rogers for
a m ino acid ana lyses. Ph ot ograph fo r Fig. 5 courtesy W . L.
Spa ngler.

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Request reprints from Dr. P. J . Ihrk e, Dep artment of Medi cin e, VM M ED/M ED , Schoo l of Veterin a ry Med icin e, U niversi ty
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