See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/237253088

Oral Manifestations of Systemic Disorders in Dogs and Cats

Article

CITATIONS READS

9 4,977

3 authors, including:

Boaz Arzi Frank Verstraete

University of California, Davis University of California, Davis
154 PUBLICATIONS   1,640 CITATIONS    204 PUBLICATIONS   3,019 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Oral and maxillofacial surgery - biomechanical studies View project

Temporomandibular joint studies View project

All content following this page was uploaded by Boaz Arzi on 09 March 2015.

The user has requested enhancement of the downloaded file.

 Oral Manifestations of Systemic Disorders in
Dogs and Cats
Boaz Arzi, DVM; Jamie G. Anderson, DVM MS DAVDC DACVIM;
Frank J.M. Verstraete, DrMedVet MMedVet DAVDC DECVS

An animal with oral lesions presents the veterinarian with a diagnostic challenge. Many systemic
disorders have oral manifestations, and therefore the oral cavity might be considered a window for
making a diagnosis. These oral manifestations must be recognized for the patient to receive ap-
propriate diagnosis and treatment. The literature and clinical cases with disorders involving one or
more organs or tissues and pathological manifestations in the oral cavity were reviewed.
Key Words: systemic, disorders, oral, lesions, dogs, cats

Introduction sions of systemic origin are usually present

with other more specific signs of the pri-
A n animal with oral lesions presents
the veterinarian with a diagnostic
challenge. The oral cavity might be consi-
mary disease process; these signs are evi-
dent elsewhere in the body.
The oral tissues respond to trauma
dered a window to the body because oral and stress in one or more of the following
manifestations accompany many systemic ways: vasodilatation resulting in hyper-
disorders. These oral manifestations must emia, hypertrophy or atrophy of the epithe-
be properly recognized if the patient is to lium, capillary rupture with submucosal
receive appropriate diagnosis and for hemorrhage and infarction, and ulceration
treatment. The approach to diagnosis of and necrosis.1 This article focuses on oral
oral lesions must be systematic, logical manifestations of systemic disease
and comprehensive. A veterinarian must processes that may be encountered in dogs
always remain suspicious of underlying and cats. Diagnostic and treatment modali-
systemic disease processes when evalua- ties are beyond the scope of this discussion.
ting atypical oral presentations.
An expeditious and accurate diagno-
sis depends on a complete clinical history Table 1.
and thorough oral and physical examina- DAMNIT-V Scheme: approach to differential di-
tion. Once a problem list has been formu- agnosis
lated, the clinician can utilize the DAM- D  Degenerative 
NIT-V scheme (Table 1) to systematically A  Anomalous 
progress from a broad disease category to M  Metabolic 
a definitive diagnosis. In situations where   Malformation 
trauma or known toxins are involved, the N  Neoplastic 
history often provides the definitive diag-   Nutritional 
nosis. In other situations, it is the location I  Infectious 
of the lesion within the oral cavity that   Inflammatory 
provides the definitive diagnosis. In some
  Immune 
instances, the gross appearance of a lesion
  Iatrogenic 
is specific enough to be pathognomonic
for a particular disease state. Many oral le-   Idiopathic 
T  Traumatic 
From the Veterinary Medical Teaching Hospital (Arzi) and
the Department of Surgical and Radiological Sciences   Toxic 
(Anderson, Verstraete), School of Veterinary Medicine, V  Vascular 
University of California, Davis, California 95616, USA
Correspondence: Dr. Frank J.M. Verstraete
   
E-mail: fjverstraete@ucdavis.edu
112 JVCS, Vol. 1, No. 4, October 2008
 Oral manifestation of systemic disorders

Anomalous and Genetic Disorders described in cats. One type is described in

Siamese cats and is due to partial deficien-
Bird Tongue
cy of uroporphyrinogen 3 cosynthetase.7 A
Bird tongue is a lethal glossopharyn-
second type of porphyria has been de-
geal defect in basset hounds inherited as a
scribed in domestic cats in which the clini-
simple, recessive autosomal gene in ho-
cal signs are only discoloration of teeth
mozygous conditions.2
and urine due to the presence of uropor-
The oral lesions include upward and
phyrin, coproporphyrine and porphobili-
inward curling of the tongue, which gives
nogen. The disorder in cats is inherited au-
the tongue a narrow and pointed appear-
tosomal dominant.7
ance. Suckling and swallowing are diffi-
cult.
Cleft Palate and Lip
Cleft palate and lip is an abnormal
Von Willebrand’s Disease (vWD)
communication between the oral and the
Von Willebrand’s disease is the most
nasal cavities involving the soft palate,
common inherited bleeding disorder in
hard palate, incisive bones, and/or lip.8
dogs but it is rare in cats.3 Dogs with the
This is a congenital disease of the primary
disease typically have a decreased concen-
and secondary palate that has been re-
tration or activity (type I) or absence (type
ported in both dogs and cats. Associations
III) or low-to-normal concentration of ab-
with other skeletal defects also occur. The
normal vWF (type II). vWD results in mild
primary palate consists of the lip and inci-
(if any) spontaneous bleeding or more
sive bones, whereas the secondary palate
likely, in prolonged surgical bleeding.3 Pa-
comprises the hard and soft palate.9 The
tients with Type III disease, such as Scot-
incomplete closure of these structures is
tish terriers, may hemorrhage severely.4,5
attributed to inherited, nutritional, hor-
The disorder is more common in Dober-
monal, mechanical and toxic factors. The
man pinschers, German shepherd dogs,
incidence of cleft palate is higher in bra-
poodles, golden retrievers and Shetland
chycephalic breeds, although other breeds
sheepdogs.
have been affected.9 The oral lesions in-
The oral lesions include spontaneous
clude cleft palate and/or lip and associated
gingival bleeding or excessive bleeding as-
drainage of milk from nares, poor growth,
sociated with tooth extraction or oral sur-
sneezing, rhinitis, and aspiration pneumo-
gery.
nia.
Mucopolysaccharidosis
Mucopolysaccharidosis encompasses
a group of genetic disorders involving dis- Metabolic Disorders
turbances in mucopolysaccharide metabol-
Acromegaly
ism, resulting in increased storage of acid
Acromegaly is a rare condition of
mucopolysaccharides in various tissues.6
chronic excessive secretion of growth
The clinical manifestations result from the
hormone (GH) that results in overgrowth
accumulation of mucopolysaccharides
of connective tissue, bone and viscera.6 In
(glycosaminoglycans) in various organs.
cats and humans, the most common cause
The only documented mucopolysacchari-
is a functional adenoma of the somatotrop-
dosis in domestic animals are reported in
ic cells of the pituitary pars distalis. All
domestic shorthair cats, Siamese cats and
cats with acromegaly have concurrent di-
miniature pinschers in which facial dys-
abetes mellitus. In dogs, acromegaly is
morphism may occur.
seen most commonly after prolonged ad-
ministration of progestagens (especially
Porphyria
medroxyprogesterone acetate) or during
Two forms of porphyria have been
the diestrual phase of the estrus cycle in
JVCS, Vol. 1, No. 4, October 2008 113
 Arzi et al
6
the intact older bitch.
The oral lesions are enlargement of
the mandibles and the maxillas with sec-
ondary separation of the teeth due to al-
veolar and gingival overgrowth (Figures
1a and 1b). Condylar hyperplasia and con-
comitant bone formation produce maloc-
clusion and mandibular prognathism.
Thickened oral mucosa, increased salivary
gland tissue, macroglossia and prominent
lips are also noted.
1a
1b
Figure 1a and 1b — A cat with acromegaly. Note
the enlargement of the mandibles, maxillas and
gingiva.
Hyperparathyroidism
114
Hyperparathyroidism may be one of
three types: primary, secondary or heredi-
tary. Primary hyperparathyroidism is a
disorder resulting from excessive, relative-
ly uncontrolled secretion of parathyroid
hormone (PTH) by one or more abnormal
parathyroid glands.6 Secondary hyperpara-
thyroidism is usually associated with
chronic renal failure or malnutrition. PTH
is continuously produced in response to
chronic low levels of serum calcium. The
resultant rubber jaw syndrome is a classic
manifestation of excessive calcium mobi-
lization from bone. Demineralization is
particularly evident in the mandibles and
the maxillas (Figures 2a and 2b).
The oral lesions include increased
tooth mobility and malocclusion; patho-
logic fractures may occur. In addition, me-
taplastic soft tissue calcification may arise
in the oral cavity. Intraoral radiographs re-
veal bone demineralization, a ground-glass
appearance and partial or total loss of la-
mina dura.
Hyperadrenocorticism (Cushing’s Dis-
ease)
Cushing’s disease is classified as pi-
tuitary-dependent, adrenocortical-
dependent or iatrogenic.6 Pituitary-
dependent hyperadrenocorticism (PDH) is
most common and accounts for approx-
imately 80-85% of cases. A functional
adrenocorticotrophic hormone (ACTH)-
secreting pituitary tumor is usually found
in 85% of dogs with PDH. The disease
usually develops in dogs 6 years of age or
older. Breed predispositions include
poodles, dachshunds, and beagles.
There are no specific oral manifesta-
tions; however, moderate to severe peri-
odontitis is common, and poor healing of
tissues is seen after oral surgery if the pet
has not received treatment.
Rounding of the face from fat deposi-
tion and calcinosis circumscripta may be
noted. Calcinosis circumscripta is a depo-
sition of amorphous calcified material that
can occur in the skin, subcutis, tongue and
buccal mucosa. The lesions are white spots
of chalky, gritty nodules (Figure 3).
JVCS, Vol. 1, No. 4, October 2008
 Oral manifestation of systemic disorders
2a
2b
Figure 2a and 2b — A dog with primary hyperpara-
thyroidism. Note the bone loss on the computerized
tomography 3D reconstructive image.
Hypoadrenocorticism (Addison’s Dis-
ease)
Hypoadrenocorticism is classified as
primary or secondary adrenocortical insuf-
ficiency. Primary adrenocortical insuffi-
ciency is the most common form and in-
volves a deficiency of both mineralocorti-
coid and glucocorticoid secretions.6 The
etiology is usually immune-mediated, or
iatrogenic associated with acute withdraw-
JVCS, Vol. 1, No. 4, October 2008
Figure 3 — Calcinosis circumscripta in a dog with
iatrogenic Cushing’s disease.
al of chronic exogenous glucocorticoids.
The oral lesions that may be present
include a diffuse or patchy brown pigmen-
tation of the oral mucosa caused by excess
melanin production.
Hypothyroidism
Structural or functional abnormalities
of the thyroid gland can lead to deficient
production of thyroid hormone. Primary
hypothyroidism is the most common form
in dogs. It usually results from destruction
of the thyroid gland due to lymphocytic
thyroiditis (immune-mediated) and idi-
opathic atrophy of the thyroid gland.6 The
pathogenesis for oral lesions in hypothyro-
id animals includes a potential underlying
immune-mediated process and bleeding
tendency.
In breeds prone to hypothyroidism
(e.g., golden retriever, Labrador retriever)
extensive periodontal disease and mucosal
bleeding can be seen.
Diabetes Mellitus (DM)
DM is a chronic metabolic disorder
characterized by hyperglycemia, asso-
ciated with irregularities in the metabolism
of carbohydrates, lipids, proteins; and sus-
ceptibility to the development of specific
forms of renal, ocular, neurological and
cardiovascular diseases.10 DM increases
the susceptibility to erosion and ulceration
of the mucosa.10
Oral manifestations may include ke-
totic malodor, high frequency of periodon-
tal disease, xerostomia, bone resorption,
115
 Arzi et al
periodontal abscess, gingival overgrowth,
vascular alterations, candidiasis , blood
coagulation and delayed wound healing
(Figure 4). The oral mucosa may also lose
resilience. In addition, DM increases the
osteoclastic activity of bone tissue in the
mandibles and maxillas.10
Figure 4 — A cat with diabetes mellitus and asso-
ciated xerostomia and periodontal disease.
Amyloidosis
Amyloidosis is a progressive disease
that is characterized by the extracellular
deposition of non-branching fibrillar pro-
teins that stack into β-pleated sheet con-
formation.6 Amyloidosis in dogs and cats
is a reactive systemic form in which amy-
loid may be deposited in several organs.
Amyloid nodules on the tongue, macrog-
lossia and xerostomia (due to amyloid in-
filtration of the salivary glands) may be
present.
Icterus
Icterus in dogs and cats is the yellow
staining of serum or tissue by an excessive
amount of bile pigment or bilirubin. Bili-
rubin is a waste product of heme protein
degradation. Causes of icterus can be pre-
hepatic (e.g., hemolysis), hepatic (e.g., liv-
er failure) and post-hepatic (e.g., cholesta-
sis and pancreatitis). The yellowish to
orange discoloration of bilirubin may ac-
cumulate in the oral mucosa, lingual frenu-
lum and soft palate. The soft palate
represents one of the first places that jaun-
dice becomes evident.
116
Neoplasia (metastatic)
Lymphoma
Lymphoma is defined as a lymphoid
malignancy that originates from solid or-
gans (e.g., lymph nodes, liver, spleen).11 In
dogs, the etiology of lymphoma is consi-
dered multifactorial because no single eti-
ologic agent has been identified. However,
a genetic component is evident in certain
bloodlines (e.g., golden retrievers, cocker
spaniels and Rottweilers). The anatomic
classification system for lymphoma in cats
and dogs includes multicentric, mediastin-
al, alimentary, and extranodal. The multi-
centric form is most common in dogs and
mediastinal and alimentary forms in cats.
The oral presentation of lymphoma
varies with the site of origin and tumor
type; but most present as a mass or an ul-
cerated mass and resemble squamous cell
carcinoma or salivary neoplasm.10 Nasal
discharge (mucopurulent or hemorrhagic),
exophthalmos, and facial deformity are re-
ported in the most common extranodal
form in the cat.11 Primary lymphoma of the
gingival tissues may also be seen.
Leukemia
Leukemia refers to a malignant neo-
plasm that originates from hematopoetic
precursor cells in the bone marrow.11
These cells are unable to undergo terminal
differentiation, thus they self-replicate as a
clone of usually immature cells.11 Leuke-
mia can be classified phylogenetically into
two broad categories according to the cell
line they originate from: myeloid and lym-
phoid. Leukemia can also be classified as
acute or chronic. Acute leukemia is cha-
racterized by aggressive biologic behavior.
Chronic leukemia has a protracted and of-
ten indolent course.
Oral complications may include gin-
gival hypertrophy, petechiae, ecchymoses,
mucosal ulcers, and hemorrhage. Less fre-
quently palatal ulceration and necrosis,
gingivitis and mucositis may be noted.
Bacterial infections in the oral cavity are
also common in these patients due to im-
munosuppression.
JVCS, Vol. 1, No. 4, October 2008
 Oral manifestation of systemic disorders
Myeloma-Related Disorders (MRD)
Myeloma-related disorders (MRD)
arise from neoplastic transformation of
plasma cells or immunoglobulin-secreting
B lymphocyte precursors.12 MRD are rare
in the cat, accounting for 0.003-0.1% of all
malignancies reported.13,14 By contrast,
MRD account for ~1% of all tumors in
dogs.15 Multiple myeloma (MM) is the
archetypal MRD and diagnostic criteria in-
clude the presence of neoplastic cells in
the bone marrow accompanied by one or
more of the following: serum paraprotein-
emia, immunoglobulin light chain (Bence-
Jones) proteinuria or osteolytic bone le-
sions. Extramedullary plasmacytoma
(EMP) is defined as neoplastic plasma cell
formation in soft tissue without primary
evidence of bone marrow involvement.
Cutaneous and non-cutaneous forms are
seen.12
The oral lesions may include nodular
lesions at the area lateral to the palato-
glossal folds and oral bleeding.
Nutritional
Structures with a rapid cell turnover
(which are continually exposed to chemi-
cal, mechanical, thermal and microbial in-
sults) are particularly susceptible to injury
when compromised by malnutrition.1 The
tongue has the highest rate of cell turnover
in the mouth and therefore manifests a par-
ticular susceptibility to nutritional defi-
ciencies.16
Iron Deficiency Anemia
Iron deficiency anemia may be due to
inadequate dietary intake, impaired ab-
sorption, chronic blood loss, gastrointes-
tinal bleeding, aspirin ingestion and in-
creased demand as experienced in early
age and pregnancy.
The tongue may become red, painful
and smooth. Angular cheilitis, glossitis
and generalized oral mucosal atrophy may
be noted.10
Protein-Calorie Deficiency
Oral lesions have been described in
JVCS, Vol. 1, No. 4, October 2008
malnourished animals with depressed cell-
mediated immunity 17 and in conditions of
protein-losing enteropathy or nephropathy.
Oral manifestations also occur secondary
to stress resulting in diminished immunog-
lobulin A secretion and concomitant in-
creased susceptibility to pathogens.18
Linear ulceration of the dorsum of the
tongue is commonly seen.
Niacin (Vitamin B3) Deficiency
Niacin acts as a coenzyme for oxida-
tion-reduction reactions. Foods containing
niacin include lean meat, peanuts and yeast.
Chronic niacin deficiency results in black
tongue.6
Oral lesions include reddening and
ulceration of the oral mucus membrane
and tongue.
Cobalamine (Vitamin B12) Deficiency
Cobalamine is synthesized by bacte-
ria and is found in animal products.19 It is
important in several metabolic reactions.
Glossitis and cheilitis may be present.
Vitamin K Deficiency
In small animals, Vitamin K deficien-
cy usually results from the ingestion of vi-
tamin K antagonists (warfarin, diphaci-
none), or their derivatives (brodifacoum
and bromadiolone).3 It can also occur in
animals with chronic obstructive cholesta-
sis, inflammatory bowel disease and liver
disease. 3 Four clotting factors are vitamin
K-dependent: factors 2, 7, 9 and 10. A ge-
netic vitamin K deficiency occurs in the
Devon Rex.3
The oral lesions include pale mucus
membranes and gingival and mucosal
bleeding.
Infectious and Inflammatory
Disorders
Chronic oral infections are a common
problem among domestic cats.20 Primary
oral infections are usually associated with
various microbes that invade the tissue for
unknown reasons.21 Secondary oral infec-
tions are considered to be opportunistic in
117
 Arzi et al

nature. Most inflammatory oral lesions in The oral lesions are similar in cause
cats are associated primarily or secondarily and presentation to those in FIV infection.
with bacteria,21 but viruses may also play a
role in oral tissue. A number of viruses in Feline Herpesvirus Type-1 (FHV-1)
cats are carried in oral tissue and shed in Rhinotracheitis
saliva including feline immunedeficiency Feline herpesvirus type-1 (FHV-1) is
virus (FIV), feline leukemia virus (FeLV), a pathogen that infects only cats.24 The in-
feline herpesvirus type-1 (FHV-1), feline fection has a high prevalence within the
calicivirus (FCV), and feline syncytium- worldwide population of cats and causes
forming virus (FeSFV). Although these vi- significant morbidity. Although cats are
ruses replicate in the oral cavity, it is un- typically infected at a young age, the virus
certain whether or not they actually cause can cause lifelong problems due to latency
disease in oral tissue; and if they do, and reactivation. FHV-1 is transmitted via
whether their role is causal or indirect.22 close contact and exchange of bodily flu-
ids, particularly respiratory and ocular se-
Feline Immunodeficiency Virus (FIV) cretions. Over-crowded conditions and
Feline immunodeficiency virus (FIV) close housing such as a catteries and shel-
is an exogenous single stranded RNA virus ters greatly increase the likelihood of viral
in the family Retroviridae, subfamily Len- transmission.24 Kittens are most suscepti-
tivirinae.23 FIV produces reverse transcrip- ble to primary infections, especially as ma-
tase enzyme to catalyze the insertion of ternal antibodies wane.
viral RNA into the host genome. FIV in- Clinical manifestations of rhino-
fection of cats has a worldwide distribu- tracheitis are seen with varying degrees of
tion. Aggressive biting behavior is thought gingivitis, and oral ulceration on the rostral
to be the primary route of transmission of part of the tongue (Figure 5).
FIV. Male, outdoor cats older than six
years of age are most commonly infected.
Postnatal transmission from FIV-infected
queen to kittens in milk has been docu-
mented.23
The oral lesions are believed to occur
due to the systemic immune-suppressive
effect of the virus and include various de-
grees of gingivitis, gingival proliferation,
gingival and mucosal ulcerations, exuda-
tion and periodontitis.
Feline Leukemia Virus (FeLV)
Feline leukemia virus (FeLV) is a
single-strand RNA virus in the family Ret-
roviridae, subfamily Oncovirinae. The vi-
rus produces reverse transcriptase which
catalyzes formation of provirus of FeLV
and its insertion into the host cell ge-
nome.23 The principal route of infection by
FeLV is prolonged contact with infected
cat saliva or nasal secretions; grooming or
sharing of common water or food sources
effectively result in infection. FeLV infec-
tion has a worldwide distribution. Infec- Figure 5 — Ulcerative glossitis caused by herpesvi-
tion is most common in outdoor male cats rus in a cat.
between one and six years of age.
118 JVCS, Vol. 1, No. 4, October 2008
 Oral manifestation of systemic disorders
Feline Calicivirus (FCV)
Feline calicivirus (FCV) is a single-
strand RNA virus and is a major cause of
acute oral and upper respiratory tract dis-
ease in domestic cats.25 Calicivirus is high-
ly contagious and moderately environmen-
tally persistent. It is spread by direct con-
tact, by fomites over significant time and
distance.
Varying degrees of gingivitis, oral ul-
cerations and exudation, glossitis and oral
vesicles may be seen.
Canine Distempervirus (CDV)
Canine distempervirus (CDV) is
usually seen as a multi-systemic disease
with multifocal progressive involvement
of the central nervous system (CNS).26
Clinical signs may vary, depending on the
virulence of the virus strain, environmental
conditions, and host age and immune sta-
tus.26 Young, unvaccinated dogs are most
commonly affected by severe generalized
distemper. In infected dogs, non-neurologic
signs (ocular and nasal discharge, cough-
ing, vomiting, diarrhea) are seen first; then
neurologic signs begin one to three weeks
after the dogs start to recover from system-
ic illness.26
Multiple dental developmental ab-
normalities may be noted in the permanent
dentition such as unerupted teeth, partial
eruption, oligodontia, enamel hypoplasia
and root hypoplasia, which can be loca-
lized but in most cases is generalized.
Enamel and dentin hypoplasia result from
damage by the virus to the ameloblasts
while the teeth are developing.
Rabies (RABV)
Rabies (RABV) is a Lyssavirus in the
family Rhabdoviridae. Foxes, coyotes and
wolves are among the most susceptible to
RABV infection. Skunks, raccoons, bats,
cows, and cats are considered highly sus-
ceptible while domestic canines, sheep,
goats and horses are only moderately sus-
ceptible.27 Young of every species are
more susceptible than mature animal.28 A
bite by an animal shedding virus in saliva
is the most common method of transmis-
JVCS, Vol. 1, No. 4, October 2008
sion of the virus. Contact with infected sa-
liva with mucous membranes and open
wounds rarely cause disease. 29 The two
classical clinical presentations have been
divided into “furious or psychotic” and
“dumb or paralytic”.
Oral manifestations include excessive
salivation, diminished facial sensation,
dropped jaw and lingual lacerations.
Fungal Cryptococcosis in Cats
Cryptococcus neoformans causes a
common systemic fungal disease in cats.30
The most common route of infection is
through inhalation.31 Cutaneous and sub-
cutaneous routes of infection may also oc-
cur. In addition to the upper and lower res-
piratory tract and cutaneous and subcuta-
neous involvements, oral lesions may oc-
casionally be noted.30 The oral lesions may
include diffuse ulcerations of the oral mu-
cosa, tongue, gingival, and palate. In addi-
tion, gingival proliferation may be noted.30
Leptospirosis
Leptospires are 0.1-0.2 µm wide by
6-12 µm long motile, filamentous spiro-
chetes that infect animals and humans.23
Infection by leptospires occurs in both ru-
ral and suburban environments. Clinical
cases are most commonly diagnosed in the
summer and early fall. Leptospires are
passed in urine and enter the body through
abraded skin or intact mucous membranes.
Transmission also occurs by bite wounds,
veneral contact, transplacental and inges-
tion. Leptospirosis is a multisystemic dis-
ease caused by various species such as
Leptospira canicola, L. icterohaemorrha-
giae, and L. pomona.1
The oral lesions depend on the spe-
cies. L. canicola causes severe congestion
of oral mucus membranes, potential ure-
mia-related oral ulcerations, hemorrhage,
glossitis and necrosis especially at the tip
of the tongue.1 L. icterohaemorrhagiae
causes severe oral mucus membrane con-
gestion and thrombocytopenia-related pe-
techiation and hemorhage.
119
 Arzi et al

Immune-mediated disorders (IMD) cutaneous diseases characterized by epi-

thelial blistering affecting the cutaneous
Occasionally the immune system recog-
and/or mucosal surfaces.32 The term pem-
nizes the host’s tissue as foreign and di-
phigus is derived from the Greek Pemphix,
rects a humoral or cellular immune re-
which translates to bubble or blister. The
sponse against specific target organs or tis-
pathogenesis of pemphigus vulgaris in-
sues.3 In most cases true auto-antibodies
volves antibodies directed against epitheli-
(i.e., antibodies against the host’s own an-
al intercellular components, especially
tigens) are not produced, but rather anti-
cadherins and desmogleins. 32 There is ge-
gen-antibody complexes are deposited in
netic basis to many cases.
certain tissue or organs. Most immune-
Pemphigus vulgaris is the most com-
mediated disorders that develop in dogs
mon form and frequently involves the
and cats are thought to be idiopathic or
mouth. Blisters, erosions and ulcers of the
primary. However, IMD occasionally de-
buccal mucosa, palate and lips are com-
velops during or after drug therapy or
mon manifestations (Figures 6a and 6b).
shortly after vaccination with modified-
Erosive gingivitis is noted less frequently.
live vaccine.

Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is typi-
cally a chronic multisystemic disease in
which antibodies are directed against a va-
riety of tissues or tissue components.3 In
addition, circulating immune complexes
precipitate type 3 hypersensitivity reac-
tions (i.e., immune complex deposition
mediated tissue damage). The disease is 6a
well characterized in dogs but not in cats.
The oral lesions include petechiae,
ecchymoses, icteric mucous membranes,
and ulcerations. Erythema and keratosis
may be noted.10

Immune-Mediated Hemolytic Anemia

(IMHA)
Immune-mediated hemolytic anemia
constitutes the most common form of he-
molysis in dogs.3 Most cases of IMHA in
dogs are idiopathic; however, immune-
mediated destruction of red blood cells can
occur in response to drugs (e.g., ß-lactam
antibiotics). In this disorder red blood cells
become coated with IgG or by MPS.3
The range of oral lesions include pale
and/or icteric mucous membranes, pete-
chiae, ecchymoses, erythema of the tongue
due to the atrophy of the papillae.10
Pemphigus
Pemphigus is a group of potentially
life-threatening immune-mediated muco-
120
6b
Figure 6a and 6b — A dog with bullous pemphigoid.
Idiopathic Disorders
Adverse Drug Reactions (ADR)
An ADR is defined by the World
Health Organization as a “drug response
that is noxious and unintended and occur
in responses to a medicinal product”.33
Many drugs have the potential to induce
adverse reactions in the mouth. Adverse
oral drug reactions are responsible for oral
lesions and manifestations that can mimic
JVCS, Vol. 1, No. 4, October 2008
 Oral manifestation of systemic disorders
34
local or systemic diseases. Their patho-
genesis, especially of the mucosal reac-
tions, is largely unknown and appears to
involve complex interactions between the
drug in question, other medications, the
patient’s underlying disease and genetic
factors. Type A reactions are dose depen-
dent and predictable and are based on the
pharmacology of the drug. Type B reac-
tions are mostly immune-mediated and are
unpredictable reaction to drug. 34 These
reactions may or may not be dose-related.
In this group are included idiosyncratic
reactions that cannot be predicted from the
known pharmacology of the drug. Several
oral reactions to systemic medications are
non-immunologic and therefore not anti-
body-dependent.35
Xerostomia (dry mouth) is the most
common adverse drug-related effect in the
oral cavity. The drugs implicated most
commonly in xerostomia include tricyclic
antidepressants, benzodiazepines, atropin-
ics, beta-blockers, antihistamines, and H2-
receptor antagonists.35
Epithelial necrosis and ulcerations
may result from direct application to the
mucosa of medications such as aspirin,
hydrogen peroxide, and potassium tablets.
Drug eruptions in the oral cavity often ap-
pear initially as areas of edema and ery-
thema that lead to localized, non-specific
ulceration. The labial mucosa is most
commonly involved.36 Other drugs that are
implicated in the development of oral ul-
cers are sulphonamides, barbiturates, beta-
blockers, non-steroidal anti-inflamma- tory
drugs, salicylates and tetracycline. Ulcera-
tion of the oral mucosa is a common ad-
verse effect of variety of chemotherapeutic
agents, including methotrexate, melphalan,
5-fluorouracil and doxorubicin.37
Gingival enlargement is one of the
most common adverse effects of drugs on
the periodontium. It is gradual and genera-
lized overgrowth of the fibrous component
of the gingiva (Figure 7). In general, gin-
gival enlargement develops within a few
months of the commencement of drug
therapy. It is usually generalized and
JVCS, Vol. 1, No. 4, October 2008
Figure 7 — A cat with drug-induced gingival en-
largement.
responds variably to improved plaque con-
trol and/or withdrawal or reduction of the
drug therapy.38 Drugs most commonly as-
sociated with gingival overgrowth are cal-
cium channel blocker such as nifedipine,
diltiazem, verapimil and amlodipine, and
the immunosuppressive drug cyclosporine.
Cyclosporine is causing gingival enlarge-
ment by increasing fibroblast production
of collagen and matrix while decreasing
collagenase activity.38
Mucosal pigmentation is induced by
various drugs that stimulate melanocyte
activity such as phenothiazines and heavy
metals. Tetracycline can permanently stain
teeth if administered during pregnancy or
early age.39,40
Angioedema is common clinical ma-
nifestation of a group of allergic condi-
tions with different etiologic pathways. It
is rapid swelling of the lips and adjacent
structures in susceptible patients. Most
cases of acquired angioedema are me-
diated by an IgE immune reaction, particu-
larly when penicillin or other antimicro-
bials are implicated.
Osteonecrosis of the jaws is a recent-
ly described adverse reaction of bisphos-
phonate therapy and is characterized by
exposure and necrosis of areas of the jaw-
bone. Bisphosphonate is an anti-osteoro-
sis drug that is a non-metabolized analog
of pyrophosphate. It significantly reduces
121
 Arzi et al

the rate of bone turnover by inhibiting os-

teoclastic activity.41 They also have anti-
angiogenesis properties resulting in de-
creased circulating endothelial growth fac-
tors.

Feline Eosinophilic Granuloma

Complex
Feline eosinophilic granuloma com-
plex is a rare ill-defined condition that in-
cludes indolent ulcer, eosinophilic plaque
and linear granuloma.42 It is not certain
that these disease are related. The etiology
of this disorder is unknown and middle-
aged cats are mainly affected.42
The oral lesions include an indolent
ulcer on the lip or oral mucosa, or a linear
granuloma that may be single or multiple
and presents on the tongue, palate, lips,
and gingiva. The linear granuloma is
usually a raised pinkish-yellow mass and
may become secondary infected.
Toxic disorders
Uremic Stomatitis
Renal failure occurs when approx-
imately 75% of the nephrons of both kid-
neys cease to function.43 As a result, nitro-
gen waste is elevated in the blood. The
urea is diffused into the saliva where bac-
teria metabolize it to produce ammonia.
Ammonia irritation, relative dehydration
and uremia related clotting abnormalities
result in oral inflammation.1 As a result of
uremic intoxication and protein and calorie
malnutrition, the immunocapacity of urem-
ic patients is compromised.1
The oral lesions include a brownish
discoloration of the dorsal tongue surface,
gingivitis, necrosis and mucosal sloughing,
xerostomia, and mucosal hemorrhage
(Figure 8a and 8b). In addition, odor of
ammonia can be detected.
Chemotherapy and Radiation Treat-
ment-Related Oral Disorders
Drug or radiation cancer therapy, es-
pecially those that target the head and neck,
may involve a frequent and serious com-
plication in the oral cavity.
122
8a
8b
Figure 8a and 8b — A cat with uremic gingivitis.
The infectious, hemorrhagic, cytotox-
ic, nutritional, and neurologic signs of
drug toxicity are reflected in the mouth by
changes in the color, character, comfort,
and continuity of the mucosa.44 Oral com-
plications of radiation therapy are physical
and physiological, transient or lasting in
duration, and can be reversible or irrevers-
ible in type.44 Various tissues can be dam-
aged by radiation insult; salivary glands,
oral mucosa, oral musculature, alveolar
bone, and teeth. Oral manifestations vary
in pattern, duration, intensity and number,
and not every patient develops every com-
plication. Local infections resulting from
overgrowth of opportunistic organisms or
activation of latent viruses are common.44
Xerostomia, trismus, facial dermati‐
tis, stomatitis, facial malformation, al‐
tered tissue resilience, ulcerations, and 
increased risk of caries and periodontal 
disease may occur. Osteoradionecrosis 
may also be noted and is associated 
with a high morbidity.45,46
JVCS, Vol. 1, No. 4, October 2008
 Oral manifestation of systemic disorders
References
1. Anderson JG. Approach to diagnosis of canine oral
lesions. Compend Cont Educ Pract Vet 1991;
13: 1215-1226.
2. Hutt FB, De Lahunta A. A lethal glossopharyngeal
defect in the dog. J Hered 1971; 62: 291-293.
3. Nelson WR, Couto CG. Hematology and immunol-
ogy. In: Nelson WR, Couto CG, 2nd ed. Small ani-
mal internal medicine. St. Louis: Mosby, 1998;
1159-1238.
4. Callan MB, Bennett J, Phillips D, et al. Inherited
platelet delta-storage pool disease in dogs causing
severe bleeding: an animal model for a specific
ADP deficiency. Thromb Haemost 1995; 74: 949-
953.
5. Giger U, Callan M, Phillips D, et al. Inherited plate-
let gamma storage pool disease in dogs causing se-
vere bleeding: an animal model. Proceedings,
American Society of Hematology Annual Meeting,
1993.
6. Nelson WR, Couto CG. Endocrine disorders. In:
Nelson WR, Couto CG, 2nd ed. Small animal inter-
nal medicine. St. Louis: Mosby, 1998; 671-798.
7. Thrall MA. Regenerative anemia. In: Veterinary
hematology and clinical chemistry. Philadelphia:
Lippincot Williams& Wilkins, 2004; 115.
8. Fossum TW. Small animal surgery. 2nd ed. St.
Louis: Mosby, 2002; 285-286.
9. Nelson AW. Upper respiratory diseases. In: Slatter
DH, ed. Textbook of small animal surgery. 3rd ed.
Philadelphia: WB Saunders Co, 2003; 815-818.
10. Regezi JA, Sciubba JJ, Jordan RC. Oral pathology -
clinical pathologic correlations. 4th ed. Philadel-
phia: WB Saunders Co, 2003.
11. Nelson WR, Couto CG. Oncology. In: Nelson WR,
Couto CG, 2ed. Small animal internal medicine. St.
Louis: Mosby, 1998; 1123-1143.
12. Mellor PJ, Haugland S, Murphy S, et al. Myeloma-
related disorders in cats commonly present as
extramedullary neoplasms in contrast to myeloma in
human patients: 24 cases with clinical follow-up. J
Vet Intern Med 2006; 20: 1376-1383.
13. Carpenter JL, Andrews LK, Holzworth J. Tumours
and tumour-like lesions. In: Holzworth J. Diseases
of the cat: medicine and surgery. Philadelphia: WB
Saunders Co, 1987; 406-596.
14. Engle GC, Brody RS. A retrospective study of 395
feline neoplasms. J Am Anim Hosp Assoc 1969; 5:
21-31.
15. Priester WA, McKay FW. The occurrence of tumors
in domestic animals. Natl Cancer Inst Monogr 1980;
(54): 1-210.
16. Cutright DE, Bauer H. Cell renewal in the oral mu-
cosa and skin of the rat. I. Turnover time. Oral Surg
Oral Med Oral Pathol 1967; 23: 249-259.
17. Sheffy BE, Williams AJ. Nutrition and the immune
response. J Am Vet Med Assoc 1982; 180: 1073-
1076.
18. Jemmolt J, Barysenko J, Barysenko M, et al. Aca-
demic stress, power motivation, and decrease in se-
cretion rate of salivary secretory immunoglobulin A.
Lancet 1983; 1: 1400-1402.
19. Hupp JR, Williams TP, Firriolo FJ. Dental clinical
advisor. St. Louis: Mosby, 2006; 335-337.
20. Frost P, Williams CA. Feline dental disease . In: Vet
Clin North Am 1986; 16: 851-873.
21. Mallonee DH, Harvey CE, Venner M, et al. Bacte-
JVCS, Vol. 1, No. 4, October 2008
riology of periodontal disease in the cat. Arch Oral
Biol 1988; 33: 677-683.
22. Tenorio AP, Franti CE, Madewell BR, et al. Chron-
ic oral infections of cats and their relationship to
persistent oral carriage of feline calici-, immunode-
ficiency, or leukemia viruses. Vet Immunol Immu-
nopathol 1991; 29: 1-14.
23. Nelson WR, Couto CG. Infectious diseases. In: Nel-
son WR, Couto CG, 2nd ed. Small animal internal
medicine. St. Louis: Mosby, 1998; 1273-1301.
24. Stiles J. Feline herpesvirus. Clin Tech Small Anim
Pract 2003; 18: 178-185.
25. Gaskell R, Dawson S. Feline respiratory disease. In:
Greene CE, ed. Infectious diseases of the dog and
cat. 2nd ed. Philadelphia: WB Saunders Co, 1998;
97-106.
26. Nelson WR, Couto CG. Neuromuscular disorders.
In: Nelson WR, Couto CG, 2nd ed. Small animal in-
ternal medicine. St. Louis: Mosby, 1998; 1013-1016.
27. Greene CE, Rupprecht CE. Rabies and other lyssa-
virus infections. In: Greene CE, ed. Infectious dis-
eases of the dog and cat. 2nd ed. Philadelphia: WB
Saunders Co, 2006; 167-183.
28. Blancou J, Aubert MFA, Artois M. Fox rabies. In
Baer GM, ed. The natural history of rabies. 2nd ed.
Boca Raton: CRC press, 1991; 258-285.
29. Jackson AC. Rabies pathogenesis. J Neurovirol
2002; 8: 267-269.
30. Odom T, Anderson JG. Proliferative gingival lesion
in a cat with disseminated cryptococcosis. J Vet
Dent 2000; 17: 177-181.
31. Gerds-Grogan S, Dayrell-Hart B. Feline cryptococ-
cosis: a retrospective evaluation. J Am Anim Hosp
Assoc 1997; 33: 118-122.
32. Scully C, Challacombe SJ. Pemphigus vulgaris: up-
date on etiopathogenesis, oral manifestations, and
management. Crit Rev Oral Biol Med 2002; 13:
397-408.
33. Edwards IR, Aronson JK. Adverse drug reactions:
definitions, diagnosis, and management. Lancet
2000; 356: 1255-1259.
34. Femiano F, Lanza A, Buonaiuto C, et al. Oral ma-
nifestations of adverse drug reactions: guidelines. J
Eur Acad Dermatol Venereol 2008; 22: 681-691.
35. Scully C. Drug effects on salivary glands: dry
mouth. Oral Dis 2003; 9: 165-176.
36. Scully C, Azul AM, Crighton A, et al. Nicorandil
can induce severe oral ulceration. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2001; 91: 189-
193.
37. Scully C, Bagan JV. Adverse drug reactions in the
orofacial region. Crit Rev Oral Biol Med 2004; 15:
221-239.
38. Vescovi P, Meleti M, Manfredi M, et al. [Pathoge-
nesis of cyclosporine induced gingival overgrowth].
Minerva Stomatol 2003; 52: 219-229.
39. Majcherczyk J, Szymanska-Jachimczak EI. Verfar-
bung der Zahne und Knochen bei jungen Tieren
durch Tetracycline [Discoloration of the teeth and
bones in young animals caused by tetracycline].
Zahnarztl Prax 1965; 16: 61-3.
40. Bennett IC, Law DB. Incorporation of tetracycline
in developing enamel and dentin in dogs. J Dent
Child 1967; 34: 93-5.
41. Yoneda T, Hashimoto N, Hiraga T. Bisphosphonate
actions on cancer. Calcif Tissue Int 2003; 73: 315-
123
 Arzi et al
318.
42. Nelson WR, Couto CG. Disorders of the oral cavity,
pharynx and esophagus. In: Nelson WR, Couto CG,
2nd ed. Small animal internal medicine. St. Louis:
Mosby, 1998; 410.
43. Nelson WR, Couto CG. Urinary tract disorders. In:
Nelson WR, Couto CG, 2nd ed. Small animal inter-
nal medicine. St. Louis: Mosby, 1998; 614-622.
44. Dreizen S. Oral complications of cancer therapies.
Description and incidence of oral complications.
124
View publication stats
NCI Monogr 1990; (9): 11-15.
45. Schwartz HC, Kagan AR. Osteoradionecrosis of the
mandible: scientific basis for clinical staging. AM J
Clin Oncol 2002; 25: 168-71.
46. Teng MS, Futran ND. Osteoradionecrosis of the
mandible. Curr Opin Otolaryngol Head Neck Surg
2005; 13: 217-21.
JVCS, Vol. 1, No. 4, October 2008