Vol.19, No.
1 January 1997
Continuing Education Article
FOCAL POINT
★In the United States,
hepatozoonosis is most
commonly diagnosed by
muscle biopsy.
KEY FACTS
■ In the United States,
hepatozoonosis is no longer
limited to the Texas Gulf Coast
region.
■ There are differences between
the clinical syndrome of
hepatozoonosis in the United
States and that in other parts of
the world; clinical signs in the
United States include muscle
pain, ocular discharge, cachexia,
and leukocytosis.
■ Common abnormal laboratory
values in American
hepatozoonosis include marked
leukocytosis, hypoglycemia,
hypoalbuminemia, and low blood
urea nitrogen.
■ Treatment with oral
trimethoprim–sulfadiazine
(15 mg/kg every 12 hours),
pyrimethamine (0.25 mg/kg
every 24 hours), and clindamycin
(10 mg/kg every 8 hours) may
induce remission, but relapses
are common.
Canine
Hepatozoonosis:
Pathophysiology,
Diagnosis, and
Treatment
Auburn University Hebrew University of Jerusalem
Nancy Vincent-Johnson, DVM Gad Baneth, DVM
Douglass K. Macintire, DVM, MS
T he causative agent for canine hepatozoonosis is Hepatozoon canis, a pro-
tozoal organism from the phylum Apicomplexa.1 Since its discovery in
India in 1905,2 the organism has been reported in dogs in many re-
gions of the world, including Africa,3,4 southern Europe,5–8 Israel,9,10 Japan,11
Malaysia,12 the Philippines,13 and the United States.14 In addition to infecting
dogs, various stages of H. canis or closely related, undetermined species have
been reported in coyotes,15 bobcats,16 and ocelots17 in the U.S.; foxes in Portu-
gal18; African lions3,19,20; jackals, hyenas, cheetahs, a leopard,3 and an impala21 in
South Africa; and domesticated cats throughout the world.22–27 There is one
report of an organism resembling H. canis in the blood of a human from the
Philippines.28 Other species of Hepatozoon infect rodents,29 raccoons,30 squir-
rels,31 and reptiles.32
LIFE CYCLE AND TRANSMISSION
H. canis is a two-host organism. The definitive host is the brown dog tick
(Rhipicephalus sanguineus), and the intermediate host is the dog.33 While feed-
ing on an infected dog, nymphal ticks ingest gametocytes in the dog’s neu-
trophils and monocytes (Figure 1). Two gametocytes fuse in the gut of the tick
to form an ookinete. The ookinete penetrates the gut wall and enters the
hemocoelom, where it matures into an oocyst as the tick molts to the adult
stage. Numerous sporocysts are formed in the developing oocyst. In each
sporocyst, 12 to 24 sporozoites form.
Unlike the parasites that cause most other tick-borne diseases, these organ-
Small Animal The Compendium January 1997

isms remain in the hemocoelom of the tick and do not sis in the U.S. compared with that which occurs in the
migrate to the salivary glands or mouthparts. The or- rest of the world. These differences include the severity
ganism is transmitted by ingestion of an infected tick, and type of clinical signs, clinical laboratory findings,
not by a tick bite. Once the tick is ingested, the sporo- the frequency with which gametocytes are evident, and
zoites in the tick are released and penetrate the intesti- the tissue stages of the organism. The differences in the
nal tract of the dog. The organisms are then carried by clinical signs and tissue stages associated with canine
blood or lymph to mononuclear phagocyte cells of the hepatozoonosis in the U.S. indicate that the causative
spleen, bone marrow, muscle, liver, and lung. After in- agent may be a species of Hepatozoon that is distinct
vading these cells, the organisms form schizonts, which from H. canis found in the rest of the world.
undergo asexual division. Merozoites formed in schi-
zonts are released and invade additional cells. After AMERICAN HEPATOZOONOSIS
multiple cycles of schizogony, merozoites invade leuko- Canine hepatozoonosis was first reported in the U.S.
cytes and produce gamonts in them, completing the in 1978 near the Gulf Coast region of Texas.14 Later re-
life cycle. ports involved dogs originating from the neighboring
Oocysts of H. canis have been reported in Haema- states of Oklahoma 40 and Louisiana. 41 In addition,
34
physalis longicornis and Hae. flavas ticks in Japan as many cases have been reported in Alabama and Georgia
well as Amblyomma habraeum, A. marmoreum, R. ap- in recent years; the disease is apparently spreading geo-
pendiculatus,35 and R. simus 3 ticks in Africa. Structures graphically.42,43
resembling H. canis oocysts have been identified recent- Although hepatozoonosis has traditionally been con-
ly in A. maculatum ticks removed from a dog with clin- sidered to be an opportunistic infection, immunosup-
ical signs of hepatozoonosis in the U.S.36 pression or concurrent illness is apparently not neces-
Experimental transmission of H. canis via ingestion sary for the organism to cause disease in the U.S. In a
of infected ticks has been reported.3,37,38 In the only retrospective study, secondary disease entities were
study performed in the U.S., immunosuppressed re- identified in only 50% of infected dogs.42 In some
search dogs were infect-
ed via ingestion of ex-
posed R. sanguineus
ticks; attempts to infect
the dogs by allowing
ticks to feed on them
were unsuccessful. 38
Other species of Hepa-
tozoon have been trans-
mitted via ingestion of
cysts present in inter-
mediate hosts. 32 It has
been speculated that H.
canis may be transmit-
ted via ingestion of in-
fected tissue, but no ex-
perimental data support
this hypothesis.
Vertical transmission
of H. canis has been re-
ported. Puppies born to
infected bitches and
raised in a tick-free en-
vironment demonstrat-
ed gametocytes shortly
after birth.39
There are major dif- Figure 1—Life cycle of H. canis in the dog and the R. sanguineus tick. (From Craig TM: Hepato-
ferences in the syn- zoonosis, in Greene CE [ed]: Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders
Co, 1990, p 779. Reproduced with permission.)
drome of hepatozoono-

MONONUCLEAR PHAGOCYTE CELLS ■ INTERMEDIATE HOSTS ■ VERTICAL TRANSMISSION

The Compendium January 1997 Small Animal

households, several dogs Mucopurulent ocular dis-

were diagnosed as having charge is common and re-
the disease. In most of these sults in the appearance of
cases, the dogs were unrelat- matted eyes. This discharge
ed; an inherited suscepti- is frequently but not always
bility to the organism or a associated with decreased
common underlying im- tear production; it may
munosuppression was un- come and go with the fever
likely. Although it has been spikes. Owners often report
reported that dogs greater this as the first noticeable
than 4 to 6 months of age sign during a relapse.
are resistant to experimental Despite the illness, dogs
infection, age is apparently often maintain a fair ap-
not an important factor in petite. Weight loss associat-
the expression of natural dis- Figure 2—A dog with American hepatozoonosis. Note the ed with chronic cachexia,
ease; clinical hepatozoonosis stance associated with muscle pain, the severe muscle atro- muscle atrophy, and emaci-
occurs in dogs of various phy, and the bilateral ocular discharge. ation is common. Polyuria
ages. and polydipsia may be evi-
dent. Transient bloody diar-
Clinical Signs rhea occasionally occurs.
Dogs are typically present-
ed with gait abnormalities Laboratory and
that range from stiffness to Radiographic Findings
complete recumbency, gen- The most outstanding
eralized pain, and deteriora- laboratory finding is a high
tion of body condition. The white blood cell count,
most common findings on consisting primarily of an
physical examination are increased number of seg-
fever, generalized pain or hy- mented neutrophils. White
peresthesia, muscle atrophy, blood cell counts general-
weakness, depression, reluc- ly range from 20,000 to
tance to rise, and muco- 200,000 cells/mm3; means
purulent ocular discharge of 76,807 44 and 85,700
(Figure 2). Body tempera- have been reported. 42 Al-
ture ranges from normal though the leukocytosis is
t o 106˚F (41˚C); fevers usually characterized by ma-
of 104˚F to 105˚F are com- ture neutrophilia, a left shift
mon. Temperature tends to may be evident. On a blood
fluctuate with waxing and smear, many of the seg-
waning of clinical signs. mented neutrophils may ap-
Muscle pain results from pear hypersegmented. A de-
inflammation associated creased platelet count is rare
with stages of the organism. unless concurrent infection
The pain may result in in- Figure 3—Periosteal proliferation of the femurs in a dog with Ehrlichia canis or E.
ability or reluctance to rise, with American hepatozoonosis. Lesions may be dramatic, platys is present; in fact, the
stiffness of gait, and hyperes- as in this case, with smooth laminar thickening. platelet count is sometimes
thesia. The dog may display elevated. Mild to moderate
a so-called master’s-voice normocytic, normochro-
stance in an attempt to guard the cervical region. With mic, nonregenerative anemia is typical.
chronic disease, muscle atrophy becomes apparent. All On serum chemistry evaluation, a mild elevation in
muscles may be affected, including those of the pelvic serum alkaline phosphatase is usually present. Creatine
and thoracic limbs, muscles of mastication, and lumbar phosphokinase is normal in most cases of hepatozoono-
muscles. Weakness is secondary to muscle atrophy. sis. Blood glucose is frequently decreased, in the range

GAIT ABNORMALITIES ■ OCULAR DISCHARGE ■ CHRONIC CACHEXIA

Small Animal The Compendium January 1997

of 40 to 60 g/dl and occa- dogs in one study 44; they

sionally as low as 5 g/dl. The were seen in 0 of 22 dogs in
low glucose is a laboratory another study.42 When pre-
artifact caused by increased sent, the infected cells rarely
metabolism in vitro by the exceed 0.1% of the leuko-
elevated white blood cell cytes; it may be necessary to
numbers. If blood is drawn examine several thousand
in sodium fluoride tubes, leukocytes before finding
the glucose is usually within an infected one. Buffy coat
the reference range. The smears increase the chance
blood urea nitrogen (BUN) of detecting gametocytes.
is often below the reference Gametocytes apparently exit
range. Some researchers at- leukocytes rapidly after
tribute this finding to de- blood is drawn, leaving be-
creased protein intake.42 The Figure 4—Gametocytes of H. canis in canine neutrophils. hind an empty capsule that
typical decrease in albumin The intracellular inclusions are oblong and average 11.4 by is easily missed. A delay in
is attributed to decreased 5.3 µm in size. The intensity of the parasite nucleus varies making the blood smears
protein intake, chronic in- with the type of stain used. (May-Grunwald stain, original thus may hinder the detec-
flammation, or renal loss. magnification ×400)
tion of gametocytes.
Hyperglobulinemia is an Various stains have been
infrequent finding, but used in attempts to make
serum protein electropho- the infected cells stand out
resis may demonstrate an better. Of the three stains
increase in the α 2- and β- evaluated in one study,45 a
globulin range. Because modified Wright-Giemsa
acute-phase proteins are stain demonstrated the least
located in this region, it is morphologic differentiation
likely that this increase rep- of the parasite from the
resents a switch to produc- host cell; the capsule of the
tion of these proteins in gamont stained clear to
response to the persistent in- light blue, with slight or
flammatory changes associ- no staining of the nucleus.
ated with tissue stages of the Although Giemsa stain
organism. The impression of revealed the nucleus of the
decreased BUN, albumin, Figure 5—H. canis cyst in the skeletal muscle of a dog with parasite, it stained with the
and glucose suggests hepatic American hepatozoonosis. (H&E stain, original magnifica- same intensity as the host-
failure; however, bile acids tion ×200) cell nucleus, making the
(fasting and postprandial) two difficult to differenti-
are usually within reference ate. The best procedure
ranges or slightly elevated. evaluated for differentiating parasite from host cell was
Radiography frequently demonstrates periosteal pro- the use a naphthol-ASD-chloroacetate stain followed
liferation of various bones, including the ilium, hum- by a Giemsa stain. The cytoplasm of normal neutro-
erus, radius, ulna, femur, tibia, fibula, and vertebrae phils contains red granules that are absent in infected
(Figure 3). This proliferation may be subtle or dramatic cells. After the Giemsa stain, there was a difference in
and ranges from irregularity to a smooth laminar thick- the intensity of the staining of the parasite’s nucleus
ening. Proliferation occurs at the attachments of muscle compared with that of the host cell.
and probably results from the severe myositis that can Because of the infrequency with which gametocytes
develop. are evident, even with buffy coat smears, muscle biopsy
is a more consistent method of obtaining a definitive
Diagnosis diagnosis. The American form of hepatozoonosis differs
In dogs with American hepatozoonosis, gametocytes significantly from hepatozoonosis elsewhere in the
are infrequently found on peripheral blood smears (Fig- world by the myositis and the stages of the organism
ure 4). Gametocytes were evident in 9 of 15 infected seen in skeletal muscle.46

LOW GLUCOSE ■ HYPERGLOBULINEMIA ■ SEVERE MYOSITIS

Small Animal
Muscle lesions consist of
large cysts, pyogranulomas,
and myositis. The cysts are
round to ovoid and range
from 250 to 500 µm in
diameter (Figure 5). The
center of the cyst usually
contains a single, round,
centrally located basophilic
nucleus but occasionally
contains numerous small,
round, basophilic bodies
grouped together. Surround-
ing the nucleus or round
basophilic bodies are con- Figure 6—Pyogranuloma in the skeletal muscle of a dog Occasional findings include
centric layers of slightly with American hepatozoonosis. (H&E stain, original mag- pulmonary congestion,
basophilic, fine laminar nification ×100)
membranes with a so-called
onion-skin appearance. In
most cases, no inflammatory response is associated with
the cysts. These cystic structures have not been report-
ed outside the U.S.
The pyogranulomas consist of large accumulations of
macrophages and neutrophils, many of which contain
round, intracellular parasites (Figure 6). Myositis with
muscle atrophy, necrosis, and infiltration of inflamma-
tory cells between muscle fibers is a frequent finding.
The most common muscles examined by biopsy are the
biceps femoris, semitendinosus, and the lumbar mus-
cles. Lesions have been found in clinically ill dogs; cysts served.33
have also been seen in biopsies from dogs in clinical re-
mission.44 These cysts are believed to represent resting
stages of the organism, like the tissue cysts of Toxoplas-
ma gondii.47
Bone marrow aspirates usually demonstrate granulo-
cytic hyperplasia with an increased myeloid:erythroid
ratio. Lymph node aspirates may exhibit lymphoid
hyperplasia. Neither procedure is useful in making a
definitive diagnosis because the organisms are not typi-
cally seen in these samples.
Necropsy of infected dogs reveals the large cysts not
only in the skeletal muscle but also in the cardiac mus-
cle, intestinal smooth muscle, pancreas, spleen, lymph
node, liver, skin, and lung. Other lesions that are evi-
dent on necropsy include pyogranulomas in the skeletal
muscle, cardiac muscle, pancreas, tongue, lymph node,
and kidney. Grossly, the pyogranulomas may appear
as multiple, 1- to 2-mm diameter, white-to-tan foci
diffusely scattered throughout these organs. Infiltrates
of macrophages and neutrophils have been evident in
alveoli of the lungs. Vascular changes in various organs
include fibrinoid degeneration of vessel walls, mineral-
ization and proliferation of vascular intima, and pyo-
MUSCLE LESIONS ■ BONE MARROW ASPIRATES ■ LIVER LESIONS
The Compendium January 1997
granulomatous vasculitis.
Roughening and thicken-
ing of bone surfaces may be
apparent. Histologic exami-
nation may demonstrate
bone exostosis with intra-
trabecular fibrosis and in-
creased osteoblastic and
osteoclastic activity. Sur-
rounding periosteum and
fascia exhibit pyogranulo-
mas, with periosteal vessels
demonstrating inflamma-
tion and mineralization.
splenic coagulative necrosis,
lymphadenopathy, and con-
gestion of the gastric mu-
cosa. Renal lesions that may be present consist of mul-
tifocal pyogranulomas, lymphoplasmacytic interstitial
nephritis, and mesangioproliferative glomerulonephri-
tis. In chronic hepatozoonosis, amyloid deposits may
be apparent in the spleen, lymph nodes, small intes-
tine, liver, and kidney. Unless amyloidosis is present,
liver lesions are usually minimal. Schizonts with the
characteristic wheel-spoke pattern typically seen in the
spleen, lymph nodes, lungs, and liver of infected dogs
from countries outside the U.S. have not been ob-
Treatment
Treatment for American hepatozoonosis consists of
specific therapy using antiprotozoal drugs and palliative
therapy with nonsteroidal antiinflammatory drugs
(NSAIDs). Because of the waxing and waning nature of
the clinical signs, the efficacy of treatment is difficult to
judge. Imidocarb dipropionate is commonly used in
other countries; in the U.S., this drug is classified as
investigational and is not readily available. The agent
clears parasitemia but does not necessarily produce clin-
ical improvement. In one case, clinical improvement
was associated with the use of diminazene aceturate,
but the effect may have been coincidental to sponta-
neous remission.14 An excellent initial response was
associated with the use of the coccidiostat toltrazuril;
however, the drug failed to prevent relapse in most dogs
and is no longer available in the U.S.
Drugs that are effective against T. gondii also have
efficacy in treating American hepatozoonosis. A com-
bination of a sulfonamide with pyrimethamine and
clindamycin has resulted in remission of clinical signs.
The following oral dosages were given for 14 days:
Small Animal
trimethoprim–sulfadiazine at 15 mg/kg every 12 hours,
pyrimethamine at 0.25 mg/kg every 24 hours, and clin-
damycin at 10 mg/kg every 8 hours.42 Like the other
drugs, this combination is apparently not effective
against the resting stages of the organism and thus does
not prevent relapses. New antiprotozoal agents show
some promise in preventing relapses. Palliative therapy
with aspirin or other NSAIDs has been useful in reliev-
ing fever and pain. The dosage and frequency should
be adjusted for each dog based on response. Although
corticosteroids offer relief, they may exacerbate the dis-
ease in the long run.
Prognosis
The prognosis for patients with American hepato-
zoonosis is guarded. A few dogs may undergo sponta-
neous remission and exhibit no further clinical signs.
After successful treatment, some dogs become clinically
normal, with resolution of leukocytosis and serum
chemistry abnormalities. Most dogs tend to relapse 3 to
6 months after treatment. In some dogs, clinical signs
associated with relapse are less severe than the initial
episode. In many of these dogs, leukocytosis and chem-
istry abnormalities return despite exhibition of few
clinical signs.
Many dogs with hepatozoonosis exhibit proteinuria
secondary to glomerulonephritis or amyloidosis. These
dogs develop classical signs of the nephrotic syndrome
with hypoalbuminemia and hypercoagulability. Death
frequently results from thromboembolism in the pul-
monary vasculature or gastrointestinal tract.
In two studies of American hepatozoonosis (totaling
37 dogs), 60% of the subjects died or were euthana-
tized because of chronic wasting, severe pain, or renal
failure.42,44 The average survival time for those that died
was 10.5 months. Of the 11 dogs that were alive at the
end of studies, seven became asymptomatic and four
continued to have episodes of clinical disease. The re-
maining dogs were lost to follow-up.
HEPATOZOONOSIS BEYOND
THE UNITED STATES
Outside the U.S., H. canis infections range from sub-
clinical to severe, life-threatening disease. Gametocytes
of H. canis have been reported as incidental findings
in apparently healthy animals11 and in animals with
concurrent infection (e.g., ehrlichiosis10 or toxoplasmo-
sis48). A few dogs exhibit high parasitemia and severe
disease characterized by lethargy, fever, anorexia, weight
loss, anemia, neutrophilia, hyperglobulinemia, hypoal-
buminemia, and elevations in creatine kinase and alka-
line phosphatase activity.
In one report from Israel, parasitemia in two dogs
PALLIATIVE THERAPY ■ PROTEINURIA ■ CONCURRENT INFECTION
The Compendium January 1997
ranged from 60% to 90% of peripheral neutrophils.9
Both patients were positive for antibodies against E.
canis; this factor may have played a role in enabling the
H. canis to disseminate. One of the dogs died after con-
tinued weight loss, muscle wasting, and the development
of icterus. The other dog returned to normal 3 months
after initial admission and antiprotozoal treatment. No
gametocytes were detected in blood smears at the time.
A recent seroepidemiologic survey demonstrated that
more than 33% of dogs in Israel have antibody titers of
at least 1:32 against H. canis.49 Only 1% of dogs sur-
veyed were parasitemic when samples were taken. This
indicates a high degree of exposure and subclinical in-
fection with H. canis in Israel. In Nigeria, H. canis is
reportedly the most prevalent hematozoan parasite in
dogs; 22% of the dogs examined at one institute exhib-
ited circulating gametocytes.4 A survey of dogs at vet-
erinary clinics in Malaysia demonstrated an incidence
of 1.2% based on the observation of gametocytes in
blood smears.12 In one region in Spain, a survey in
1990 demonstrated a parasitemia rate of 30% in dogs.5
Clinical Signs
Although a number of dogs with hepatozoonosis may
be asymptomatic or exhibit clinical signs attributed to
concurrent infection, several reports describe various
clinical presentations. The most commonly reported
clinical signs are fever, pale mucous membranes, de-
pression, anorexia, and weight loss. Less commonly
reported signs include lymphadenopathy, poor hair-
coat or skin condition, bilateral mucopurulent ocular
or nasal discharge, hyperesthesia, weakness of the
hindlimbs, petechiae, ecchymoses, and epistaxis. In
some cases, the dogs had concurrent ehrlichiosis, leish-
maniasis, babesiosis, distemper, or other infections; it
was difficult to determine which disease was responsi-
ble for the various clinical signs.5
Laboratory and Radiographic Findings
Most dogs with hepatozoonosis outside the U.S. have
a white blood cell count that is within the reference
range. Extreme leukocytosis occurs in some cases8,9 but
is less common than in dogs with American hepato-
zoonosis. Anemia, which is sometimes severe, is a com-
mon finding. Thrombocytopenia and proteinuria have
been reported.
Reports of serum chemistry results are sparse. The two
highly parasitemic dogs from Israel reportedly had hy-
perglobulinemia, hypoalbuminemia, and elevated crea-
tine kinase and alkaline phosphatase activity.9 Mild to se-
vere proteinuria (indicating possible glomerulonephritis)
was found in 8 of 11 dogs in a study from Greece; other-
wise, secondary renal disorders have not been reported.6
Small Animal
There is one report of ra-
diographic lesions associated
with hepatozoonosis outside
the U.S. 11 Gametocytes of
H. canis were evident in
blood smears of a dog after
surgery for intervertebral
disk protrusion. Periosteal
new bone formation of the
radii, ulnae, ilia, and femur
was seen 23 days after
surgery but had not been
noted before surgery. No
clinical signs attributed to
H. canis were evident. In an- Figure 7—Schizont of H. canis in the spleen of a dog from
other study, seven dogs were Israel. The wheel-spoke pattern is typical of schizonts in
radiographed but exhibited the spleen and other organs of dogs with disseminated
no periosteal lesions.5 hepatozoonosis outside the U.S. (H&E stain, original
magnification X400)
Diagnosis
Non-American H. canis infection is diagnosed by ob-
serving gametocytes on blood smears (Figure 4). The
gametocytes are found as intracellular inclusions in
neutrophils and monocytes. The size reportedly aver-
ages 11.4 µm long by 5.39 µm wide.50 Parasitemia can
vary from less than 1% to more than 90% of the neu-
trophils being infected.6,9 In most cases, parasitemia is
low and affects approximately 1% of the neutrophils.
On necropsy, schizonts with the characteristic wheel-
spoke pattern can be found in the spleen, liver, lymph
nodes, kidneys, lungs, pancreas, and bone marrow (Fig-
ure 7). Although 6 of the 11 dogs from Greece report-
edly had signs of muscle pain, no evidence of muscular
parasitism was reported. The presence of organisms in
skeletal muscle and the large cysts seen in American
dogs with hepatozoonosis have not been reported in
dogs outside the U.S.
An indirect immunofluorescence test has been devel-
oped in Israel to detect antibodies against H. canis.51
The test uses gametocytes as the source of antigen. The
test will apparently be useful in diagnosing hepato-
zoonosis, especially in dogs with very low or intermit-
tent parasitemia.
Treatment
The most commonly reported drug used to treat hepa-
tozoonosis is imidocarb dipropionate. This agent is typi-
cally given subcutaneously at a dose of 5 mg/kg. Some
clinicians pretreat with atropine at 0.04 mg/kg to limit
the anticholinesterase effect.5 In Nigeria, imidocarb
cleared H. canis gametocytes from the blood in 98% of
dogs within 24 hours of a single treatment.52 The game-
tocytes frequently reappeared within 6 weeks.
INTRACELLULAR INCLUSIONS ■ IMIDOCARB DIPROPIONATE ■ IMMUNOSUPPRESSION
The Compendium January 1997
At the Hebrew University
of Jerusalem, Koret School
of Veterinary Medicine, the
standard protocol is treat-
ment with imidocarb at 5
mg/kg subcutaneously every
14 days until no parasites
are evident on blood smears.
Treatment may continue for
60 days or more before
elimination of gametocytes
is complete. Tetracyclines,
including doxycycline and
minocycline, are often used
in conjunction with imido-
carb. Diminazene aceturate
has been used but has not
proven effective in eliminat-
ing parasitemia.9
Prognosis
Although most dogs with hepatozoonosis recover, the
disease may become disseminated and fatal in very
young animals and in animals with underlying im-
munosuppression. Although mortality is uncommon in
dogs with low H. canis parasitemia, dogs that develop
high parasitemia have severe disease and a low survival
rate.
HEPATOZOONOSIS IN CATS
Hepatozoonosis has been reported in domesticated
cats in India,22 Nigeria,23 South Africa,24 the U.S.,25 and
Israel.26,27 In a survey of 100 necropsies of cats in Israel,
36 exhibited schizonts of a Hepatozoon species in the
myocardium.26 Of the cats surveyed, 50 had been sub-
mitted to the laboratory for rabies examination and 50
were healthy strays that had been used in laboratory
demonstrations. No parasites were evident in the pe-
ripheral blood, spleen, or lymph nodes of these cats.
In a cat from Israel, hepatozoonosis was diagnosed by
the presence of gametocytes on a blood smear.27 The cat
exhibited signs of weakness, hypersalivation, superficial
ulceration in the lingual mucosa, mild gingivitis, halito-
sis, and lymphadenopathy. The body temperature was
normal, and the only abnormal laboratory values were
lymphopenia and elevated lactate dehydrogenase and
creatine phosphokinase. The cat recovered after daily
treatment with oral doxycycline at 5 mg/kg for 10 days.
Titers against H. canis were 1:128 at presentation and
1:64 one year later.
Organisms resembling a species of Hepatozoon were
reported in the liver of a cat in the U.S.25 The cat origi-
nated from Hawaii and became ill shortly after arrival
 Small Animal The Compendium January 1997
Produce the ultimate
in dental x-rays in California. Clinical signs included weight loss, ulcer-
ative glossitis, intermittent anorexia, pyrexia, progres-
Atlas of Canine & Feline sive anemia, and serous oculonasal discharge. Laborato-
ry abnormalities included extreme leukocytosis, severe
DENTAL RADIOGRAPHY anemia, azotemia, and icterus. On necropsy, numerous
cigar-shaped organisms were found in the portal areas
Thomas W. Mulligan • Mary Suzanne Aller • of the liver but not elsewhere.
Charles A. Williams Nondomesticated felids (including lions, cheetahs,
Mary Suzanne Aller, Editor bobcats, and ocelots) in Africa and the U.S. are known
to harbor Hepatozoon species. In various surveys, as
248 pages, 846 radiographs with arrow many as 100% of lions have been infected with a Hepa-
overlays to indicate notable features tozoon species in the peripheral blood or the myocardi-
um.19,20,35 It is currently not known whether the infec-
tions in domesticated and wild cats are caused by H.
canis or another Hepatozoon species.

SUMMARY
Infection with H. canis is manifested in various clini-
cal presentations. In the U.S., hepatozoonosis is often a
severe, life-threatening disease characterized by chronic
wasting. Glomerulonephritis, amyloidosis, and the
RATED nephrotic syndrome are common sequelae to the dis-
★★★★★ ease. Diagnosis usually requires muscle biopsy because
of the infrequency with which gametocytes are evident
in the blood. Muscle lesions are unique to American ca-
nine hepatozoonosis and consist of large cystic struc-
tures, pyogranulomas, and pyogranulomatous myositis.
$
80 Outside the U.S., the rate of exposure to H. canis is
$89 high in some regions; most infections apparently are
subclinical. Gametocytes of H. canis are often evident

% off! First in the field in the blood of apparently asymptomatic dogs and
0
1 846 reference radiographs dogs with other infectious diseases. A few dogs may
develop a more severe disease that is sometimes fatal.
These dogs are typically young, immunosuppressed,
■ Practical tips throughout or affected by concurrent disease. Hepatozoon infec-
■ More than 840 real-case images with indicative tions have been recognized in cats. The unique clini-
arrows cal syndrome in American dogs with hepatozoonosis
■ State-of-the-art techniques for the beginning suggests the presence of a strain or subspecies of the
practitioner, technician, and specialist H. canis organism distinct from that which causes
hepatozoonosis in domesticated dogs worldwide.
■ Precise information on positioning, supplies
Further research is needed to clarify the differences
and equipment, processing, safety, film
reported here.
handling, and more

About the Authors

VLS
VE T E R I N A RY
BOOKS
L E A R N I NG SYS T E M S
Drs. Vincent-Johnson and Macintire are affiliated with the
Department of Small Animal Surgery and Medicine, Col-
lege of Veterinary Medicine, Auburn University, Auburn,
CALL OR FAX TODAY TO ORDER Alabama. Dr. Baneth is with the Koret School of Veteri-
800-426-9119 • Fax: 800-556-3288 nary Medicine, Hebrew University of Jerusalem, Rehovot,
Israel.
Price valid only in the US, Canada, Mexico, and
the Caribbean. Request international pricing.
Email: books.vls@medimedia.com

WEIGHT LOSS ■ AZOTEMIA ■ ICTERUS ■ PYREXIA

The Compendium January 1997
REFERENCES
1. Levine ND: The Protozoan Phylum Apicomplexa. Boca Ra-
ton, FL, CRC Press, 1988, pp 129–133.
2. Bentley CA: Preliminary note on a leukocytozoan of the
dog. Br Med J 1:988, 1905.
3. McCully RM, Basson PA, Bigalke RD, et al: Observations
on naturally acquired hepatozoonosis of wild carnivores and
dogs in the Republic of South Africa. Onderstepoort J Vet Res
42:117–134, 1975.
4. Ezeokoli CD, Ogunkoya AB, Abdullahi R, et al: Clinical
and epidemiological studies on canine hepatozoonosis in
Zaria, Nigeria. J Small Anim Pract 24:455–460, 1983.
5. Jauregui Latorre E, Lopez Giron M: Canine hepatozoonosis.
Vet Int 7:30–38, 1995.
6. Kontos V, Koutinas A: Canine hepatozoonosis: A review of
11 naturally occurring cases. Bull Hellen Vet Med Soc 41:
73–81, 1990.
7. Fischer S, Hartmann K, Gothe R: Hepatozoon canis: Eine
importierte parasitäre Infektion bei Hunden. Tierarztl Prax
22:172–180, 1994.
8. Hervas J, Carrasco L, Gomez-Villamandos JC, et al: Acute
fatal hepatozoonosis in a puppy: Histopathological and ul-
trastructural study. Vet Rec 137:518–519, 1995.
9. Baneth G, Harmelin A, Presentey BZ: Hepatozoon canis in
two dogs. JAVMA 206:1891–1894, 1995.
10. Elias E, Homans PA: Hepatozoon canis infection in dogs:
Clinical and hematological findings—Treatment. J Small
Anim Pract 29:55–62, 1988.
11. Murata T, Shiramizu K, Hara Y, et al: First case of He-
patozoon canis infection of a dog in Japan. J Vet Med Sci
53(6):1097–1099, 1991.
12. Rajamanickam C, Wiesenhutter E, Zin FMD, Hamid J:
The incidence of canine haematozoa in peninsular Malaysia.
Vet Parasitol 17:151–157, 1984.
13. Novilla MN, Kwapien RP, Peneyra RS: Occurrence of ca-
nine hepatozoonosis in the Philippines. Proc Helminthol Soc
Washington 44(1):98–101, 1977.
14. Craig TM, Smallwood JE, Knaver KW, McGrath JD: Hepa-
tozoon canis infection in dogs: Clinical, radiologic, and
hematologic findings. JAVMA 173(8):967–972, 1978.
15. Davis DS, Robinson RM, Craig TM: Naturally occurring
hepatozoonosis in a coyote. J Wildl Dis 14:244–246, 1978.
16. Lane JR, Kocan AA: Hepatozoon sp. infection in bobcats.
JAVMA 183:1323–1324, 1983.
17. Mercer SH, Jones LP, Rappole JH, et al: Hepatozoon sp. in
wild carnivores in Texas. J Wildl Dis 24:574–576, 1988.
18. Conceicao-Silva FM, Abranches P, Silva-Pereira CD, Janz
JG: Hepatozoonosis in foxes from Portugal. J Wildl Dis
24:344–347, 1988.
19. Averbeck GA, Bjork KE, Packer C, Herbst L: Prevalence of
hematozoans in lions (Panthera leo) and cheetah (Acinonyx
jubatus) in Serengeti National Park and Ngorongoro Crater,
Tanzania. J Wildl Dis 26:392–394, 1990.
20. Dubey JP, Bwangamoi O: Microbesnoitia leoni Bwangamoi,
1989, from the African lion (Panthera leo) redetermined as a
junior synonym of Hepatozoon canis (James, 1905) Wenyon,
1926. J Parasitol 80(2):333–334, 1994.
21. Basson PA, McCully RM, Bigalke RD, van Niekerk JW:
Small Animal
Observations on a Hepatozoon-like parasite in the impala.
J S Afr Vet Med Assoc 38(1):12–14, 1967.
22. Patton WS: The haemogregarines of mammals and reptiles.
Parasitology 1:318–321, 1908.
23. Leeflang P, Ilemobade AA: Tick-borne diseases of domestic
animals in northern Nigeria. Trop Anim Prod 9:211–218,
1977.
24. Van Amstel S: Hepatozoonosis in ‘n Kat. J S Afr Vet Med
Assoc 50:215–216, 1979.
25. Ewing GO: Granulomatous cholangiohepatitis in a cat due
to a protozoan parasite resembling Hepatozoon canis. Feline
Pract 7:37–40, 1977.
26. Klopfer U, Nobel TA, Neumann F: Hepatozoon-like parasite
(schizonts) in the myocardium of the domestic cat. Vet
Pathol 10:185–190, 1973.
27. Baneth G, Lavy E, Presentey BZ: Hepatozoon sp. parasitemia
in a domestic cat. Feline Pract 23:10–12, 1995.
28. Carlos ET, Cruz FB, Cabiles CC, et al: Hepatozoon sp. in the
WBC of a human patient. UP Veterinarian 15:5–7, 1971.
29. Krampitz HE, Haberkorn A: Experimental treatment of
Hepatozoon infections with the anticoccidial agent toltra-
zuril. J Vet Med 35:131–137, 1988.
30. Clark KA, Robinson RM, Weishuhn LL, et al: Hepatozoon
procyonis infections in Texas. J Wildl Dis 9:182–193, 1973.
31. Clark GM: Hepatozoon griseisciuri n. sp.: A new species of
Hepatozoon from the grey squirrel (Sciurus carolinensis
Gmelin, 1788), with studies on the life cycle. J Parasitol
44:52–63, 1958.
32. Smith TG: The genus Hepatozoon. J Parasitol 82:565–585,
1996.
33. Craig TM: Hepatozoonosis, in Greene CE (ed): Infectious
Diseases of the Dog and Cat. Philadelphia, WB Saunders Co,
1990, pp 778–785.
34. Murata T, Inoue M, Taura Y, et al: Detection of Hepatozoon
canis oocyst from ticks collected from the infected dogs. J
Vet Med Sci 57:111–112, 1995.
35. Penzhorn BL, de Waal DT, Lopez Rebollar LM: Identifica-
tion of some haematozoa from lions. J S Afr Vet Med Assoc
63:96, 1992.
36. Vincent-Johnson NA, Macintire DK, Lindsay DS, Baneth
G: Preliminary studies in the transmission of H. canis. Proc
14th Annu ACVIM Forum:761, 1996.
37. Wenyon CM: Experimental infection of dogs with Hepato-
zoon canis. Trans Roy Soc Trop Med Hyg 25:6, 1931.
38. Nordgren RM, Craig TM: Experimental transmission of the
Texas strain of Hepatozoon canis. Vet Parasitol 16:207–214,
1984.
39. Murata T, Makoto I, Susumu T, et al: Vertical transmission
of Hepatozoon canis in dogs. J Vet Med Sci 55:867–868,
1993.
40. Baker JL, Craig TM, Barton CL, Scott DW: Hepatozoon ca-
nis in a dog with oral pyogranulomas and neurologic disease.
Cornell Vet 78:179–183, 1988.
41. Gossett KA, Gaunt SD, Aja DS: Hepatozoonosis and ehrli-
chiosis in a dog. JAAHA 21:265–267, 1985.
42. Macintire DK, Vincent-Johnson N, Dillon AR, et al: Ca-
nine hepatozoonosis: A retrospective study of 22 naturally
occurring cases (1989–1994). JAVMA, accepted for publica-
tion.
The Compendium January 1997
43. Macintire DK, Vincent-Johnson NA, Lindsay DS, et al: Ca-
nine hepatozoonosis in 22 dogs from Alabama and Georgia.
Proc 14th Annu ACVIM Forum:761, 1996.
44. Barton CL, Russo EA, Craig TM, Green RW: Canine hepa-
tozoonosis: A retrospective study of 15 naturally occurring
cases. JAAHA 21:125–134, 1985.
45. Mercer SH, Craig TM: Comparison of various staining pro-
cedures in the identification of Hepatozoon canis gamonts.
Vet Clin Pathol 17:63–65, 1988.
46. Craig TM, Jones LP, Nordgren RM: Diagnosis of Hepato-
zoon canis by muscle biopsy. JAAHA 20:301–303, 1984.
47. Landau I: A comparison of the life cycles of Toxoplasma and
Hepatozoon with reference to the general phenomenon and
the role of cyst formation in the coccidia. Ann Trop Med
Parasitol 67:403–407, 1973.
Small Animal
48. Harmelin A, Dubey JP, Yakobson B, et al: Concurrent Hep-
atozoon canis and Toxoplasma gondii infections in a dog. Vet
Parasitol 43:131–136, 1992.
49. Baneth G, Shkap V, Presentey BZ, Pipano E: Hepatozoon
canis: The prevalence of antibodies and gametocytes in dogs
in Israel. Vet Res Commun 20:41–46, 1996.
50. Waner T, Baneth G, Zuckerman A, Nyska A: Hepatozoon
canis: Size measurement of the gametocyte using image anal-
ysis technology. Comp Haematol Int 4:1–3, 1994.
51. Shkap V, Baneth G, Pipano E: Circulating antibodies to
Hepatozoon canis demonstrated by immunofluorescence.
J Vet Diagn Invest 6:121–123, 1994.
52. Ogunkoya AB, Adyanju JB, Aliu YO: Experiences with the
use of imizol in treating canine blood parasites in Nigeria.
J Small Anim Pract 22:775–777, 1981.