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This article discusses
the essential role of the canine immune system in maintaining the
body's overall general health and resistance to disease. The focus
will be on environmental factors or events which may cause or
trigger immune dysfunction leading to either immune deficiency or
immune stimulation (reactive or autoimmunity). Related to these
events is the development of cancer which is a disruption of cell
growth control.
Overview of the Immune
System
Immune competence is
provided and maintained by two cellular systems which involve
lymphocytes. Lymphocytes are cells produced by the body's primary
(bone marrow and thymus) and secondary (lymph nodes and spleen)
lymphatic organs. They are descendants of the bone marrow's pool of
stem cells, and produce a circulating or humoral immune system
derived from B-cells (bursa-dependent or bone marrow derived), and a
cellular or cell-mediated immune system that derives from T-cells
(thymus dependent).
B-Cell Immunity
B-cell immunity includes
the circulating antibodies or immunoglobulins such as IgG, IgM, IgA,
IgD, and IgE. These antibodies provide an important defense
mechanism against disease in healthy individuals but can become
hyperactive or hypoactive in a variety of disease states.
Hyperactive or increased levels of immunoglobulins can occur in two
ways: acutely, as a reaction to disease or inflammatory insult
("acute phase" reaction); or chronically, as in autoimmune or
immune-mediated diseases, chronic infections, and certain types of
bone marrow and organ cancers. Hypoactive or decreased levels of
immunoglobulins can result from rare genetically based
immunodeficiency states such as agammaglobulinemia or
hypogammaglobulinemia, and from the immune suppression associated
with chronic viral, bacterial, or parasitic infection, cancers,
aging, malnutrition, drugs, toxins, pregnancy, lactation, and
stress.
T-cell Immunity
T-cell, or cell-mediated
immunity is the cellular mechanism whereby T-cells act as
coordinators and effectors of the immune system. Cell-mediated
immunity involves the lymph nodes, thymus, spleen, intestine
(gut-associated lymphoid tissue), tonsils, and a mucosal secretory
immunity conveyed by IgA. The major classes of T-cells are
designated as helper, cytotoxic, and suppressor cells. The helper
cells "help" coordinate the immune response whereas the cytotoxic
cells comprise the effector network that participates in removing
virus-infected cells from the body. The third class of suppressor
T-cells is important in dampening the immune response when it
becomes overactive or out of regulatory control. Finally,
cooperation between the various T-cell classes and between T- and
B-cells is an important component of the normal humoral and cellular
immune response. Hyperactive cellular immune responses produce
autoimmune and other immune-mediated diseases while hypoactive
cell-mediated immunity causes immune suppression and incompetence.
Classical examples of this latter situation occur with retroviral
infection such as human AIDS or the animal equivalents (e.g. feline
immunodeficiency virus, feline leukemia virus, bovine leukemia
virus, equine infectious anemia).
Introduction to
Autoimmune Diseases
The term "autoimmunity"
literally means "immunity against self" and is caused by an
immune-mediated reaction to self-antigens (i.e., failure of
self-tolerance). Susceptibility to autoimmune disease has a genetic
basis in humans and animals. Numerous viruses, bacteria, chemicals,
toxins, and drugs have been implicated as the triggering
environmental agents in susceptible individuals. This mechanism
operates by a process of molecular mimicry and/or non-specific
inflammation. The resultant autoimmune diseases reflect the sum of
the genetic and environmental factors involved. Autoimmunity is most
often mediated by T-cells or their dysfunction. As stated in a
recent review, "perhaps the biggest challenge in the future will be
the search for the environmental events that trigger
self-reactivity" (Sinha, Lopez and McDevitt; Science, 248: 1380,
1990). Table 1 lists factors commonly associated with autoimmune
diseases.
The four main causative
factors of autoimmune disease have been stated to be: genetic
predisposition; hormonal influences, especially of sex hormones;
infections, especially of viruses; and stress.
Immune-Suppressant
Viruses
Immune-suppressant
viruses of the retrovirus and parvovirus classes have recently been
implicated as causes of bone marrow failure; immune-mediated blood
diseases; hematologic malignancies (lymphoma and leukemia);
dysregulation of humoral and cell-mediated immunity; organ failure
(liver, kidney); and autoimmune endocrine disorders, especially of
the thyroid gland (thyroiditis), adrenal gland (Addison's disease),
and pancreas (diabetes). Viral disease and recent vaccination with
single or combination modified live-virus vaccines, especially those
containing distemper, adenovirus 1 or 2, and parvo virus are
increasingly recognized contributors to immune-mediated blood
disease, bone marrow failure, and organ dysfunction. Genetic
predisposition to these disorders in humans has been linked to the
leucocyte antigen D-related gene locus of tile major
histocompatibility complex, and is likely to have parallel
associations in domestic animals. Drugs associated with aggravating
immune and blood disorders include the potentiated sulfonamides (trimethoprim-sulfa
and ormetoprim-sulfa antibiotics), the newer combination or monthly
heartworm preventives, and anticonvulsants, although any drug has
the potential to cause side effects in susceptible individuals.
Immune Deficiency
Diseases
Immune deficiency
diseases sire a group of disorders in which normal host defenses
against disease are impaired. These include disruption of the
body's mechanical barriers to invasion (e.g., normal bacterial
flora; the eye and skin; respiratory tract cilia); defects in
non-specific host defenses (e.g., complement deficiency; functional
white blood cell disorders), and defects in specific host defenses
(e.g., immunosuppression caused by pathogenic bacteria, viruses and
parasites; combined immune deficiency; IgA deficiency; growth
hormone deficiency).
Thyroid Disease and the
Immune System
Thyroid dysfunction is
the most frequently recognized endocrine disorder of the dog. The
most common form of canine thyroid disease is autoimmune thyroiditis
(equivalent to Hashimoto's disease of humans), which is a familial
autoimmune disease of inherited predisposition. As the thyroid
gland regulates metabolism of all body cellular functions, reduction
of thyroid function leading to hypothyroidism can produce a wide
range of clinical manifestations (Table 2). Because so many of the
clinical signs of thyroid dysfunction mimic symptoms resulting from
other causes, it is difficult to make an accurate diagnosis of
thyroid-related illness without appropriate veterinary laboratory
tests combined with an experienced professional interpretation of
the test results. More specific details about the accurate
diagnosis of thyroid disease can be found in the literature cited at
the end of this article.
Genetic Screening for
Thyroid Disease
Complete baseline
thyroid panels and thyroid antibody tests can be used for genetic
screening of apparently healthy animals to evaluate their fitness
for breeding. Any dog having circulating antithyroid autoantibodies
can eventually develop clinical symptoms of thyroid disease or be
susceptible to other autoimmune diseases because his immune system
is impaired. Therefore, thyroid prescreening can be very important
for selecting potential breeding stock.
Thyroid testing for
genetic screening purposes is unlikely to be meaningful before
puberty. Screening is initiated, therefore, once healthy dogs and
bitches have reached sexual maturity (between 10-14 months in males
and during the first anestrous period for females following their
maiden heat). Anestrus is a time when the female sexual cycle is
quiescent thereby removing any influence of sex hormones on baseline
thyroid function. This period generally begins 12 weeks from the
onset of the previous heat and lasts 1 month or longer. The
interpretation of results from baseline thyroid profiles in intact
females is more reliable when they are tested in anestrus. Thus,
testing for health screening is best performed at 12-16 weeks
following the onset of the previous heat. Screening of intact
females for other parameters like vWD, hip dysplasia, inherited eye
disease, and wellness or reproductive checkups should also be
scheduled in anestrus.
Once the initial thyroid
profiles are obtained, dogs and bitches should be rechecked on an
annual basis to assess their thyroid and overall health. Annual
results provide comparisons for early recognition of developing
thyroid dysfunction. This permits treatment intervention, where
indicated, to avoid the appearance or advancement of clinical signs
associated with hypothyroidism. For optimal health, young dogs
under 15-18 months of age should have thyroid baseline levels in the
upper half of the adult normal ranges. This is because puppies and
adolescent dogs require higher levels of thyroid hormones as they
are still growing and maturing. Similarly, older animals beyond 8
or 9 years of age have slower metabolisms and so baseline thyroid
levels of normal (euthyroid) dogs may be slightly below midrange.
For optimum thyroid function of breeding stock, levels should be
close to the midpoint of the laboratory normal ranges, because lower
levels may be indicative of the tarry stages of thyroiditis among
relatives of dog families previously documented to have thyroid
disease.
The difficulty in
accurately diagnosing early thyroid disease is compounded by the
fact that some patients with typical clinical signs of
hypothyroidism have circulating thyroid levels within the normal
range. A significant number of these patients will improve
clinically when given thyroid medication. In such cases, blood
levels of the hormones can be normal but tissue levels are
inadequate to maintain health, and so, the patient shows clinical
signs of hypothyroidism. This situation pertains in selenium
deficiency (discussed below). While animals in this category should
respond well to thyroid medication, only experienced clinicians are
likely to recognize the need to place these dogs on a 6-8 week
clinical trial of thyroid supplementation. This approach is safe
and clinically appropriate, but it requires rechecking blood levels
of thyroid hormones towards the end of the 6-8 week period to assure
that the patient is receiving the correct dose of medication.
Other Factors
Influencing Thyroid Metabolism
Because animals with
autoimmune thyroid disease have generalized metabolic imbalance and
often have associated immunological dysfunction, it is advisable to
minimize their exposures to unnecessary drugs, toxins, and
chemicals, and to optimize their nutritional status with healthy
balanced diets. Wholesome nutrition is a key component of
maintaining a healthy immune system. In our experience, families of
dogs susceptible to thyroid and other autoimmune diseases show
generalized improvement in health and vigor when fed premium
cereal-based diets preserved naturally with vitamins E and C
(without the addition of chemical antioxidant preservatives such as
BHA, BHT, or ethoxyquin). Fresh home-cooked vegetables with herbs,
low fat dairy products, and meats such as lamb, chicken, and turkey
can be added as supplements. Challenging the immune system of
animals susceptible to these disorders with polyvalent modified-live
vaccines has been associated with adverse effects in some cases (see
below). Table 1 lists other agents that should be avoided in
susceptible or affected animals.
Nutritional influences
can have a profound effect on thyroid metabolism. For example,
iodine deficiency in areas where cereal grain crops are grown on
iodine-deficient soil will impair thyroid metabolism because this
mineral is essential for formation of thyroid hormones. Recently an
important link has been shown between selenium deficiency and
hypothyroidism. Again, cereal grain crops grown on
selenium-deficient soil will contain relatively low levels of
selenium. While commercial pet food manufacturers compensate for
variations in basal ingredients by adding vitamin and mineral
supplements, it is difficult to determine optimum levels for so many
different breeds of dogs having varying genetic backgrounds and
metabolic needs. The selenium-thyroid connection has significant
clinical relevance, because blood levels of total and free T4 rise
with selenium deficiency. However, this effect does not get
transmitted to the tissues as evidenced by the fact that blood
levels of the regulatory thyroid-stimulating hormone (TSH) are also
elevated or unchanged. Thus, selenium-deficient individuals showing
clinical signs of hypothyroidism could be overlooked on the basis
that blood levels of T4 hormones appeared normal. The selenium
issue is further complicated because chemical antioxidants can
impair the bioavailability of vitamin A, vitamin E and selenium, and
alter cellular metabolism by inducing or lowering cytochrome p-450,
glutathione peroxidase (a selenium-dependent enzyme), and
prostaglandin levels. As manufacturers of many premium pet foods
began adding the synthetic antioxidant, ethoxyquin, in the late
1980's, its effects, along with those of other chemical
preservatives (BHA BHT), are surely detrimental over the long term.
The way to avoid this problem is to use foods preserved with natural
antioxidants such as vitamin E and vitamin C.
Immunological Effects of
Vaccines
Combining viral
antigens, especially those of modified live virus (MLV) type which
multiply in the host, elicits a stronger antigenic challenge to the
animal. This is often viewed as desirable because a more potent
immunogen presumably mounts a more effective and sustained immune
response. However, it can also overwhelm the immunocompromised, or
even a healthy host, that is continually bombarded with other
environmental stimuli and has a genetic predisposition that promotes
adverse response to viral challenge. This scenario may have a
significant effect on the recently weaned young puppy that is placed
in a new environment. Furthermore, while the frequency of
vaccinations is usually spaced over a 2-3 week span, some
veterinarians have advocated vaccination once a week in stressful
situations. To me, this practice makes no sense from a scientific
or medical perspective. While young puppies exposed this frequently
to vaccine antigens may not demonstrate overt adverse effects, their
relatively immature immune systems may he temporarily or more
permanently harmed from such antigenic challenges. Consequences in
later life may be the increased susceptibility to chronic
debilitating diseases. Some veterinarians trace the increasing
current problems with allergic and immunological diseases to the
introduction of MLV vaccines some 20 years ago. While other
environmental factors no doubt have a contributing role, the
introduction of these vaccine antigens and their environmental
shedding may provide the final insult that exceeds the immunological
tolerance threshold of some individuals in the pet population.
Vaccine Dosage
Manufacturers of MLV
combination vaccines recommend using the same dose for animals of
all ages and different sizes. It has never made any sense to
vaccinate toy and giant breed puppies (to choose two extremes) with
the same vaccine dosage. While these products provide sufficient
excess of antigen for the average sized animal, it is likely to be
either too much for the toy breeds or too little for the giant
breeds. In addition, combining certain specific viral antigens such
as distemper with adenovirus 2 (hepatitis) has been shown to
influence the immune system by reducing lymphocyte numbers and
responsiveness.
Hormonal State During
Vaccination
Relatively little
attention has been paid to the hormonal status of the patient at the
time of vaccination. While veterinarians and vaccine manufacturers
are aware of the general rule not to vaccinate animals during any
period of illness, the same principle should apply to times of
physiological hormonal change. This is particularly important
because of the known role of hormonal change alone with infectious
agents in triggering autoimmune disease. Therefore, vaccinating
animals at the beginning of, during, or immediately after an estrous
cycle is unwise, as would he vaccinating animals during pregnancy or
lactation. In this latter situation, adverse effects can accrue not
only to the dam but also because a newborn litter is exposed to shed
vaccine virus. One can even question the wisdom of using MLV
vaccines on adult animals in the same household because of exposure
of the mother and her litter to shed virus. Recent studies with MLV
heroes virus vaccines in cattle have shown them to induce necrotic
changes in the ovaries of heifers that were vaccinated during
estrus. The vaccine strain of this virus was also isolated from
control heifers that apparently became infected by sharing the same
pasture with the vaccinates. Furthermore, vaccine strains of these
viral agents are known to be causes of abortion and infertility
following herd vaccination programs. If one extrapolates these
findings from cattle to the dog, the implications are obvious.
Killed Versus Modified
Live Vaccines
Most single and
combination canine vaccines available today are of MLV origin. This
is based primarily on economic reasons and the belief that they
produce more sustained protection. A long-standing question
remains, however, concerning the comparative safety and efficacy of
MLV versus killed (inactivated) virus vaccines. A recent
examination of the risks posed by MLV vaccines concluded that they
are intrinsically more hazardous than inactivated products. The
residual virulence and environmental contamination resulting from
the shedding of vaccine virus is a serious concern. More
importantly, the ability of new infective agents to develop and
spread poses a threat to both wild and domestic animal populations.
The controversy in weighing the risks and benefits of MLV versus
killed vaccines is building. Vaccine manufacturers seek to achieve
minimal virulence (infectivity) while retaining maximal
immunogenicity (protection). This desired balance may he relatively
easy to achieve in clinically normal, healthy animals but may be
problematic for those with even minor immunologic deficit. The
stress associated with weaning, transportation, surgery, subclinical
illness, and a new home can also compromise immune function.
Furthermore, the common viral infections of dogs cause significant
immunosuppression. Dogs harboring latent viral infections may not
be able to withstand the additional immunological challenge induced
by MLV vaccines. The increase in vaccine-associated distemper and
parvovirus diseases are but two examples of this potential. So --
why are we causing disease by weakening the immune system with
frequent use of combination vaccine products? After all vaccines
are intended to protect against disease.
It is well-recognized by
experts in the field, like the late Dr. Jonas Salk, that a properly
constituted killed vaccine is preferable to one of MLV origin.
Killed vaccines do not replicate in the vaccinated animal, do not
carry the risk of residual virulence and do not shed attenuated
viruses into the environment. On the other hand, MLV vaccines are
capable of stimulating a more sustained protective response. So
what does the future hold here? Veterinarians, scientists, breeders
and owners need to voice their concern and discontent with the
present industrial vaccine practices. We need to urge manufacturers
to seek alternatives. Even if killed vaccines are proven to be
somewhat less efficacious (produce lower levels or less sustained
protection) than MLV products, they are more safe. All killed
vaccines on the market today have passed current efficacy and safety
standards in order to be licensed for use by the USDA. The issue is
to what extent being more effective elicits a benefit rather than a
risk. The future will evolve new approaches to vaccination
including sub-unit vaccines, recombinant vaccines using DNA
technology, and killed products with new adjuvants to boost and
prolong protection. These are not simple solutions to a problem,
however, because early data from recombinant vaccines against some
human and mouse viruses have shown potentially dangerous side
effects by damaging T-lymphocytes. Contributing factors were shown
to be the genetic background of the host, the time or dose of
infection, and the makeup of the vaccine. We are obviously still a
long way from producing a new generation of improved and safe
vaccines. In the meantime, we need to consider using killed
products whenever they are available and should consider giving them
more often (twice yearly rather than annually) for high-risk
exposure situations. Vaccines, while necessary and generally safe
and efficacious, can be harmful or ineffective in selected
situations.
Cancer and Immunity
Proper regulation of
cellular activity and metabolism is essential to normal body
function. Cell division is a process under tight regulatory
control. The essential difference between normal and tumor or
cancerous cells is a loss of growth control over the process of cell
division. This can result from various stimuli such as exposure to
certain chemicals, viral infection, and mutations, which cause cells
to escape from the constraints that normally regulate cell
division. Proliferation of a cell or group of cells in an
uncontrolled fashion eventually gives rise to a growing tumor or
neoplasm. Of course, tumors can he both benign (a localized mass
that does not spread) or malignant (cancerous), in which the tumor
grows and metastasizes to many different sites via the blood or
lymph.
Tumor cells also express
a variety of proteins called "neoantigens" on their surface, and
many of these are different from antigens found on normal cells.
These new or altered proteins are recognized as foreign by the
immune system, and so trigger an immunological attack. There are a
large number of them known as tumor-specific or tissue-specific
antigens, whereas others recognize the blood group systems,
histocompatibility complex, and viruses. The situation in cancer is
complex because not only can immunologically compromised individuals
become more susceptible to the effects of cancer-producing viral
agents and other chemical carcinogens, the cancer itself can be
profoundly immunosuppressive. The form of immunosuppression usually
varies with the tumor type. For example, lymphoid tumors (lymphomas
and leukemia) tend to suppress antibody formation, whereas tumors of
T-cell origin generally suppress cell-mediated immunity. In
chemically induced tumors, immunosuppression is usually due to
factors released from the tumor cells or associated tissues. The
presence of actively growing tumor cells presents a severe protein
drain on an individual which may also impair the immune response.
Blocking factors present in the serum of affected animals exist
which can cause enhancement of tumor growth. Additionally,
immunosuppression in tumor-bearing animals can be due to the
development of suppressor cells.
The body also contains a
group of complimentary factors that provide a protective effect
against tumors and other immunologic or inflammatory stresses.
These are mixtures of proteins produced by T-cells and are referred
to as "cytokines." Cytokines include the interleukins, interferons,
tumor-necrosis factors, and lymphocyte-derived growth factors.
Recent studies have shown that normal levels of zinc are important
to protect the body against the damaging effects of the specific
cytokine, tumor-necrosis factor (TNF). Inadequate levels of zinc
have been shown to promote the effect of TNF in disrupting the
normal endothelial barrier of blood vessels. This could have a
significant effect in promoting the metastasis of tumor cells to
different sites, thereby hastening the spread and growth of a
particular cancer.
Currently shout 15% of
human tumors are known to have viral causes or enhancement. Viruses
also cause a number of tumors in animals and no doubt the number of
viruses involved will increase as techniques to isolate them
improve. The T-cell leukemias of humans and animals are examples of
those associated with retroviral infections. This same class of
viruses has been associated with the production of autoimmunity and
immunodeficiency diseases. The recent isolation of a retrovirus
from a German Shepherd with T-cell leukemia exemplifies the
potential role of these agents in producing leukemia and lymphomas
in the dog.
The increased prevalence
of leukemia and lymphomas in the Golden Retriever and several other
breeds is a case in point. Similarly, there has been an increase in
the prevalence of hemangiosarcomas (malignant tumors of the vascular
endothelium) primarily in the spleen, but also in the heart, liver
and skin. They occur most often in middle age or older dogs of
medium to large breeds. The German Shepherd dog is the breed at
highest risk, but other breeds including the Golden Retriever and
Vizsla have shown a significantly increased incidence, especially in
certain families. This suggests that genetic and environmental
factors play a role. It is tempting to speculate that environmental
factors that promote immune suppression or dysregulation contribute
to failure of immune surveillance mechanisms. These protect the
body against the infectious and environmental agents which induce
carcinogenesis and neoplastic change.
Nutritional Factors and
the Immune System
As alluded to above, an
adequate nutritional state is important in managing a variety of
inherited and other metabolic diseases as well as for a healthy
immune system. Examples where nutritional management is important in
inherited disorders include: adding ingredients to the diet to make
it more alkaline for Miniature Schnauzers with calcium oxalate
bladder or kidney stones; use of the vitamin A derivative,
etretinate in Cocker Spaniels and other breeds with idiopathic
seborrhea of the skin; management with drugs and diet of diseases
such as diabetes mellitus and the copper-storage disease prevalent
in breeds like the Bedlington Terrier, West Highland White Terrier,
and Doberman Pinscher; and treatment of vitamin B-12 deficiency in
Giant Schnauzers. Other nutritional influences include the vitamin
K-dependent coagulation defect elicited in Devon Rex cats following
vaccination; hip dysplasia in puppies fed excessive calories;
osteochondritis dissecans in dogs fed high levels of calcium; and
hypercholesterolemia in inbred sled dogs fed high fat diets.
Nutritional factors that
play an important role in immune function include zinc, selenium and
vitamin E, vitamin B-6 (pyridoxine),and linoleic acid. Deficiencies
of these compounds impair both circulating (humoral) as well as
cell-mediated immunity. The requirement for essential nutrients
increases during periods of rapid growth or reproduction and also
may increase in geriatric individuals, because immune function and
the bioavailability of these nutrients generally wanes with aging.
As with any nutrient, however, excessive supplementation can lead to
significant clinical problems, many of which are similar to the
respective deficiency states of these ingredients. Supplementation
with vitamins and minerals should only be given with the advice of a
professional nutritionist and should not be viewed as a substitute
for feeding premium quality fresh and/or commercial dog foods.
Bibliography
Ackerman L. Tile
benefits of enzyme therapy Veterinary Forum, October: 4, 5, and 6,
1993.
Berry M.J. Larsen P.R.
The role of selenium in thyroid hormone action. Endocrine Reviews,
13 (2): 207-219, 1992.
Cargill J. Thorpe-Vargas
S. Feed that dog. Parts IV-VI.Dog World, 78 (10-12): 36-42, 28-31,
36-41, 1993.
Dodds W.J. Autoimmune
thyroid disease. Dog World, 77 (4): 3640, 1992.
Dodds W.J. Genetically
based immune disorders: Autoimmune diseases. Parts 1-3. Veterinary
Practice STAFF 4 (1, 2, and 3): 8-10, 1, 26-31, 35-37, 2.
Dodds W.J. Immune
deficiency diseases: Genetically based immune disorders, Part 4.
Veterinary Practice STAFF, 4 (5): 19-21, 1992.
Dodds W.J. Unraveling the autoimmune mystery. Dog World, 77 (5):
4448, 1992.
Dodds W.J. Vaccine safety and efficacy revisited. Veterinary Forum,
May: 68-71. 1983.
Dodds W.J., Donoghue S.
Interactions of clinical nutrition with genetics. Chapter 8. In: The
Waltham Book of Clinical Nutrition of the Dog and Cat. Pergamon
Press Ltd., Oxford, 1994, pp.105-117.
Tizard I. Veterinary
Immunology: An Introduction, 4th Ed. W Saunders Company,
Philadelphia. 992, pp. 498.
TABLE 1. FACTORS
ASSOCIATED WITH AUTOIMMUNE DISEASE
Sex (2:1 females)
Genetic or familial
history
Increasing frequency
Pregnancy
Stunted
fetal growth
Congenital malformations
Stress
environmental
emotional
physiological
Hormonal Irregularities
polyglandular autoimmunity (endocrinopathy)
pituitary-thyroid axis dysfunction
reproductive failure
abnormal
heat cycles
pyometra
false
pregnancy
hypogonadism
oliogospermia
aspermia
anestrus
Nutritional Influences
deficiency or imbalances
trace
minerals
nutrients
vitamins
chemical
preservatives
toxins in
feeds
chemical
or drug residues
spoiled
feeds
Adverse Drug Reactions
trimethoprim-sulfas
ormetoprim sulfa
nitrofurans
butazolidin
phenobarbital
primidone
diethylcarbamazine-oxybendazole
ivermectin
milbemycin oxime
Viral Infection
parvovirus
retroviruses
cytomegalovirus
measles
and distemper viruses
hepatitis
viruses
Frequent or Recent Use
of MLV Vaccines
parvovirus
distemper
hepatitis
- Lyme (vaccines alone or in combination)
Bordetella
rabies
Underlying or
Concomitant Disease
lymphoma
or leukemia (retrovirus infections)
bone
marrow failure (low red and white cells, platelets)
immune
dysregulation
humoral -
cellular (immunodeficiency )
chronic
infections
bacterial
viral
parasitic
fungal
Other Autoimmune
Disorders
Hashimoto's thyroiditis
Addison's
disease
rheumatoid arthritis
lupus
crythematosus
idiopathic thrombocytopenic purpura
hemolytic
anemia
chronic
active hepatitis
diabetes
mellitus
hypogonadism
myasthenia gravis
pemphigus,
vitiligo
glomerulonephritis
alopecia
Graves'
disease
hypoparathyroidism
seizures
and other neurologic manifestations
uveitis
and other immunologic eye diseases
TABLE 2. CLINICAL SIGNS
OF CANINE HYPOTHYROIDISM
Alterations in Cellular
Metabolism
lethargy
mental
dullness
exercise
intolerance
neurologic signs
polyneuropathy
seizures
weight gain
cold
intolerance
mood
swings
hyperexcitability
stunted
growth
chronic
infections
Neuromuscular Problems
weakness
stiffness
laryngeal
paralysis
facial
paralysis
"tragic"
expression
knuckling
or dragging feet
muscle
wasting
megaesophagus
head tilt
drooping
eyelids
Dermatologic Diseases
dry,
scaly skin and dandruff
coarse,
dull coat
bilaterally symmetrical hair loss
"rat
tail"; "puppy coat"
hyperpigmentation
seborrhea
or greasy skin
pyoderma
or skin infections
myxedema
chronic
offensive skin odor
Reproductive Disorders
infertility
lack of
libido
testicular atrophy
hypospermia
aspermia
prolonged
interestrus interval
absence
of heat cycles
silent
heats
pseudopregnancy
weak,
dying or stillborn pups
Cardiac Abnormalities
slow
heart rate (bradycardia)
cardiac
arrhythmias
cardiomyopathy
Gastrointestinal
Disorders
constipation
diarrhea
vomiting
Hematologic Disorders
bleeding
bone
marrow failure
low - red
blood cells (anemia), white blood cells, platelets
Ocular Diseases
corneal
lipid deposits
corneal
ulceration
uveitis
keratoconjunctivitis sicca or "dry eye"
infections of eyelid glands (Meibomian gland)
Vogt-Koyanagi-Harada
syndrome
Other Associated
Disorders
IgA
deficiency
loss of
smell (dysosmia)
loss of
taste
glycosuria
chronic
active hepatitis
other
endocrinopathies
adrenal
pancreatic
parathyroid
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