Veterinary Quarterly

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Avian hepatic granuloma. A review

I.K.E. Supartika , M.J.M. Toussaint & E. Gruys

To cite this article: I.K.E. Supartika , M.J.M. Toussaint & E. Gruys (2006) Avian hepatic
granuloma. A review, Veterinary Quarterly, 28:3, 82-89, DOI: 10.1080/01652176.2006.9695213
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 82

Veterinary Quarterly 2006; 28(3): 82-89

Avian hepatic granuloma. A review

I.K.E. Supartika1'2, M.J.M. Toussaint1'3 and E. Gruys1

'Department of Pathobiology, Faculty of Veterinary Medicine,
University of Utrecht, The Netherlands
2Animal Health Laboratory Region VI Denpasar, Bali, Indonesia

TABLE OF CONTENTS

Summary and keywords 83

Introduction 83

Etiology 83

Specific diseases associated with hepatic granuloma in birds . 84

Avian reovirus 84

Mycobacteriosis 84

Staphylococcosis 84

Streptococcosis 85

Coligranuloma 85

Hepatic granuloma due to Eubacterium tortuosum 85

86
0

Aspergillosis
Coccidiosis 86

Ascariasis 86

Diagnostic methods of avian hepatic granuloma 87

Conclusions 87

References 88

3Corresponding author
Address: Department of Pathobiology, Faculty of Veterinary Medicine, University of Utrecht,
P.O. Box 80158, 3508 TD Utrecht, The Netherlands
E-mail: H.Toussaintavet.uuml
 83

Avian hepatic granuloma. A review

I.K.E. Supartika, M.J.M. Toussaint and E. Gruys

SUMMARY
Hepatic granuloma is a chronic inflammatory disease characterized by a granulomatous reaction with
accumulation of macrophages and/or epithelioid cells, which may fuse to form multinucleated giant
cells. The hepatic granulomas typically have a surrounding rim of lymphocytes and fibrous tissues.
The etiology of some hepatic granulomas in birds is well known. It could be due to viral, bacterial,
fungal, protozoal, or helminthic infection. The presence of these pathogens in the liver is usually
through systemic infections that might preferentially colonize the liver or be opportunistic invaders.
Persistence of these pathogens infecting the liver can lead to granulomatous inflammation with
different gross lesions and histopathologic patterns depending on the causative agent. This review
describes the etiology, clinical signs, pathological changes, and diagnosis in a wide variety of diseases
associated with hepatic granulomas in birds in which the detection of granulomatous inflammation is
an aid in the differential diagnosis.
Keywords: Avian diseases; Bird diseases; Hepatic granuloma; Liver diseases; Review
differential diagnosis.
Introduction
The liver is a specialized organ for metabolism, Etiology
host defense and immunity. The characteristic
structure and organization of the liver enables it to A broad range of causative agents of hepatic
perform vital roles in regulating, synthesizing, granuloma in birds is known. It could be due to
storing, secreting, transforming, and breaking viral, bacterial, fungal, protozoal or helminthic
down many different substances in the body. It is infection. The presence of these pathogens in the
actively screening and capturing antigens in the liver is usually the result of a systemic infection in
blood by the powerful specialized macrophages which the pathogen preferentially colonizes the
known as Kupffer cells, which directly face to the liver or as opportunistic invader. Different causes
bloodstream (33). The topological position within of hepatic granuloma in birds, with examples, are
the liver sinusoid makes the Kupffer cells the first listed in Table 1.
macrophages to come into contact with foreign or
noxious material including viruses, bacteria, Causes Example References
unicellular eukaryotes and their products that enter
the circulation by the way of the portal vein (15). Viruses Reovirus infection 45
Together with dendritic cells (65), liver sinusoidal
Mycobacteriosis
endothelial cells (53), stellate cells (52) and other Bacteria 9,17,18,24,29,57
inflammatory cells, they clear the blood from Staphylococcosis 36
whether antigenic or
particulate material, Streptococcosis 22
pathogenic, by efficient phagocytosis to prevent
Coligranuloma 6,13,14,35,47,
damage to hepatocytes and systemic infection.
58,59
However, some pathogenic microorganisms, fungi
and parasites, through their virulence have evolved Granulomas due to 4,20,21,23,31
a series of strategies to invade the host and to Eubacterium tortuosum
to
evade host defense mechanism leading Fungi Aspergillossis 1,44,48,54,55,64
granulomatous inflammation in the liver. Protozoa Coccidiosis 10,11,12,16,30,
The aim of the present review is to summarize the 41,42,43
information to date regarding the etiology, clinical Helminths Ascariasis 7,38,39,40,51,62
signs, pathological changes, and diagnosis in a
wide variety of diseases associated with hepatic
Table 1. Causes and examples of diseases of hepatic
granuloma in birds in which the detection of
in the granulomas in birds
granulomatous inflammation is an aid
 84
Specific diseases associated with hepatic
granuloma in birds
Avian reovirus
Avian reovirus infection is commonly found in
broilers and turkeys (34) with clinical manifestati-
on varying from arthritis/tenosynovitis, malabsorp-
tion syndrome or respiratory disease. The disease
has also been reported in psittacine birds (50), and
pheasants (37) with a range of clinical signs such
as depression, diarrhea, and respiratory symptoms.
At least 11 serotypes of avian reovirus have been
identified, although there was considerable cross
neutralization among heterologous types (63). The
epithelial cells of small intestine and the bursa of
Fabricius are the main sites of infection and are
concerned as the portal of entry of the virus to
spread to the other organs. The liver could be a
target organ in reovirus infection, especially when
the infecting dose is large although the persistence
of the virus in the liver was short (2,26,27).
Roessler and Rosenberger (49) reported that highly
pathogenic avian reovirus persisted and produced
microscopic lesions in the gastrocnemius tendons
as long as 22 weeks post infection. Persistence of
the virus in the hock joint induces an inflammatory
process leading to arthritis, however, this lesion is
not pathognomonic for avian reovirus infection
(27,28).
Granulomatous-like structures in the liver of young
geese caused by reovirus have been reported in
Hungary by Palya et al. (45). The birds showed
clinical signs predominantly consisting of locomo-
tor disorders and lameness. Gross lesions of the
disease were characterised by splenitis and hepati-
tis with miliary necrotic foci during the acute
phase, and epicarditis, arthritis and tenosynovitis
during the subacute or chronic phase. At light
microscopy, miliary foci of vacuolated, necrotic
hepatocytes or granuloma-like foci with necrotic
centres and proliferating macrophages at the
periphery were seen in the liver. In the portal
region, there was infiltration with heterophils and
histiocytes. Under experimental infection, avian
reovirus could be recovered from liver, tendon,
spleen, and heart in all cases.
Mycobacteriosis
Avian mycobacteriosis is a chronic granulomatous
disease primarily caused by Mycobacterium avium
(9,18,24). It occurs in many kinds of birds,
including poultry, game birds, cage birds, wild
birds, and zoological birds (24,61). Stress, age,
immune status and preexisting disease are predis-
position factors for birds to become more suscepti-
ble to mycobacteriosis (24). Transmission of the
bacteria in birds usually occurs via ingestion of
soil, litter and faeces contaminated with virulent
bacteria. However, aerosol transmission has also
been reported. Birds with mycobacteriosis may
manifest a variety of clinical signs such as
anorexia followed by cachexia, weakness, dark
greenish-yellow droppings, and hepatomegaly.
Mycobacteriosis is a chronic, generalized, granulo-
matous disease that affects various organs. The
lesions are most commonly seen in the liver,
spleen, intestine serosa, and bone marrow (9,17,
18,57). However they may also be found in the
lungs, mesentery, pleura, ovaries, oviducts and
other organs (9,24,29). The lesions are
characterized by irregular, grey-white nodules,
varying in size from pin-point to large masses
which are randomly distributed throughout the
affected organ/tissues. Some nodules may have
central caseous material. On cut surface, the
nodules are firm, and contain numerous small
yellowish granules and caseous necrotic debris (9,
18,24,57). Histopathologic examination revealed
multiple granulomatous lesions, with central
caseous necrosis surrounded by epithelioid cells,
giant cells, variable numbers of lymphocytes and
plasma cells. Ziehl-Neelsen (ZN) acid-fast staining
for mycobacteria revealed numerous intracellular
and extracellular bacilli within the cytoplasm of
the giant cells at the periphery of the granulomas
(9,18,24).
Staphylococcosis
Staphylococcal infections constitute a common
bacterial disease of Poultry caused by Staphylococ-
cus spp. and all avian species appear to be
susceptible to these species of bacteria. Staphylo-
cocci frequently isolated from poultry include S.
aureus and S. epidermidis (3), which are normally
present on the skin, mucous membrane and in the
gastrointestinal tract of poultry. Staphylococcal
infections most often manifest as purulent arthritis
and tenosynovitis, with lameness being the most
common clinical presentation.
Munger and Kelly (36) have reported granuloma-
tous lesion attributed to S. aureus in the lung and
liver of a Leghorn hen. No specific clinical signs
 85
were observed, except death and dropped egg
production. Necropsy showed a slightly enlarged
liver with numerous small, whitish, discrete
nodules scattered throughout the liver. The nodules
were less than 1 mm. in diameter. Histopathologic
examination of the liver revealed a granulomatous
reaction. Large areas of coagulation necrosis were
surrounded by a ring of giant cells. The same
granulomas pattern as in the liver was also found
in the lung. Brown and Brenn stains of affected
tissue showed bacterial colonies consisting of
gram-positive cocci. Bacterial cultures from affec-
ted liver and lung yielded pure cultures of S.
aureus.
Streptococcosis
The disease associated with streptococci is world-
wide distributed and most birds are susceptible to
these bacteria. Infections might result in an acute
or chronic disease. Streptococcus spp. are non-
pathogenic bacteria, and are considered as part of
the normal flora of the skin, mucosal membrane
and gastrointestinal tract of poultry. On rare
occasions, Streptococcus spp. cause septicaemia in
birds. The acute disease signed by diarrhea,
is
dyspnea, paresis and conjunctivitis, while arthritis
and endocarditis occur when the disease becomes
more chronic (19).
In 1972, Hernandez et al. (22) studied an acute-
chronic septicaemia form of streptococcosis in
turkeys which was experimentally reproducible.
Streptococcus faecalis var. liquefaciens (now be
considered as Enterococcus faecalis) was isolated
during a field outbreak of hepatic granulomas in
Columbia. In the chronic phase, no clinical
manifestation was observed. At necropsy, a granu-
lomatous reaction signed by whitish foci of varied
size was found in liver, heart, and spleen. The
cm. in
largest focal lesion was approximately 1
diameter, and was found primarily in the liver. At
light microscopy, areas of coagulation necrosis
were infiltrated by heterophils, and ringed by
zones of giant and epithelioid cells. No fibrous
capsule formation was observed. A section with
granulomas was stained with Brown and Brenn
stain, demonstrating the presence of gram-positive
(E.
cocci consistent with Enterococcus faecalis
faecalis).
Coligranuloma
Coligranuloma (Hjarre's disease) is an uncommon
form of systemic colibacillosis characterized by
multiple granulomas in liver, caeca, duodenum,
and mesentery but not in spleen (6). A mucoid
strain of Escherichia coli was often isolated from
the granulomatous lesion, although Hjärre's
disease could not be reproduced experimentally in
all cases (59). The disease occurred primarily in
chickens and turkeys. However, quail (13), psitta-
cine birds (47), wild turkeys (Meleagris gallopavo)
(14), and free-living common buzzard (Buteo
buteo) (58) were also reported to be susceptible.
The pathogenesis is unknown. The respiratory
tract, digestive tract and skin are portals of entry
of the disease. Clinical signs of birds suffering
from coligranuloma include depression, nasal
discharge, sneezing, ruffled feathers, and whitish-
yellow droppings (35,47).
Gross lesions of avian coligranuloma revealed the
presence of multifocal whitish-gray nodules with a
smooth surface. Firm consistencies were present in
the mesentery, intestine, gizzard, heart, uterus,
ovaries and liver. Histologically, nodules were
frequently found adhering to serosas of organs and
sometime penetrating the parenchyma. There were
small areas of coagulation necrosis with hemorrha-
ge, surrounded by scarce heterophils, lymphocy-
tes, plasma cells, macrophages, epithelioid cells,
and proliferation of fibrous connective tissue
(13,35,59).
Hepatic granuloma due to
Eubacterium tortuosum
Granuloma is a common liver lesion found in
poultry slaughterhouses (4,21,23,31). According to
poultry meat inspection regulation, the entire
carcass of bird with liver abnormalities including
hepatic granuloma should be condemned. Often the
bird carcasses with hepatic granuloma were descri-
bed as being in good condition. However, in some
cases emaciated birds were also encountered (21,
23). Granulomas were found primarily in the
spleen and liver, but in sporadic cases, granulomas
were also found in the lung, kidney, heart,
pancreas, bursa of Fabricius, intestinal tract and
mesentery.
Macroscopically, the spleen was enlarged, slightly
mottled with nodular or irregular surface,
sometimes with white or granular foci. Focal or
multifocal to coalescing necrotic white foci were
observed in the liver, and in other organs. At light
microscopy, the granulomas were characterized by
 86
caseation necrosis surrounded by a palisading ring
of multinucleated giant cells and epithelioid cells.
There were some lymphocytes, scattered foci of
heterophils adjacent to necrotic areas and fibrous
connective tissue surrrounding granulomas.
Gram-positive filamentous bacteria were found
intracellulary in the cytoplasm of giant cells and in
hepatocytes (4,21,23,31). Some bacteria (Eubacte-
rium tortuosum, Corynebacterium sp. Propionibac-
terium sp. Staphylococcus epidermidis) were
isolated and identified from splenic and hepatic
granulomas of slaughtered chickens and turkeys
(20,31). Experimental Eubacterium infection in
turkeys and chickens by intravenous inoculation,
facilitated induction of hepatic and splenic granulo-
mas similar as in the natural disease (4,20).
Aspergillosis
Pulmonary aspergillosis due to Aspergillus fumiga-
tus is a common fungal disease of captive and wild
birds. Stress, immunosuppression, prolonged
administration of exogenous corticosteroid may
play a role in aspergillosis in birds. The route of
infection is initially by inhalation of aspergilli and
the lower respiratory tract is the location where A.
fumigatus tends to initially colonization (55).
Hematogenous dissemination of aspergilli to the
other visceral organs including liver may occur as
a result of colony extension into blood vessels,
direct extension into pneumatic bone, the peritone-
al cavity, and surrounding structures (44). Clinical
signs of birds with systemic aspergillosis vary. It
depends on the organ affected. However, respira-
tory signs such as dyspnea, hyperpnea, and
accelerated breathing are commonly encountered.
Blindness, torticollis, lack of equilibrium, droo-
ping wing and head, and stunting were observed in
cases with central nervous system involvement
(1,48) and hepatomegaly and green discoloration
of urates if lesions involved the liver (44).
In disseminated aspergillosis, the lungs and air
sacs were the main targets of Aspergillus fumigatus
producing lesions characterized by diffuse
yellowish-white nodules. Multifocal yellowish-
white nodules were also found in the liver, kidney,
spleen, heart and peritoneum (8,54,64). At light
microscopy, the granulomas were often characteri-
zed by a necrotic centre surrounded by hetero-
phils, macrophages, lymphocytes, plasma cells,
and giant cells, and by an outer layer of thin
fibrous tissue.Numerous fungal hyphae were
found within the necrotic debris in the areas of
granulomas (8,54).
Coccidiosis
Disseminated Visceral Coccidiosis (DVC), found
in captive sandhill cranes (Grus canadensis) and
whooping cranes (Grus americana) caused by
Eimeria spp. have been described by Carpenter et
al. (11) in 1979. Later, this Eimeria spp. was
identified as Eimeria reichenowi and Eimeria gruis
where cranes might be the host specific for these
eimerians (16). Eimeria reichenowi and Eimeria
gruis mostly inhabit the intestinal tract of the
cranes, invade and multiply systemically through
blood vessels and complete their development in
both digestive and respiratory tracts.
The clinical signs of cranes with acute DVC
included depression, anorexia, weight loss and
greenish diarrhea. The disease can develop into
chronic infections signed by granulomatous
nodules in various organs and tissues. Mortality
and death of birds were associated with widespread
merogony resulting in necrosis and granulomatous
inflammation in a number of major organs, inclu-
ding the intestine, heart, liver, spleen, and kidney
(30,41,46).
Gross lesion of cranes with DVC are characterized
by granulomatous nodules, which can be found in
the oral mucosa, eyelids, esophagus, lung, heart,
descending aorta, liver, spleen, kidney, small
intestine, cloaca, mesenteries, and parietal
peritoneum. At light microscopy, granulomatous
inflammation was found in many organs and
tissues. Areas of necrosis with many asexual and
sexual coccidial stages were infiltrated by cellular
infiltrate including heterophils, lymphocytes,
plasma cells, macrophages and were surrounded
by a thin layer of fibrous tissue (10,12,30,41,46).
Persisting parasitic granulomas contained uninucle-
ated and multinucleated parasites, that may be the
source of merozoites that re-infect various organs
and tissues of the host, prolonging the eimerian
infection (42,43).
Ascariasis
Ascaridia spp. are, common nematodes found in
the intestine of domestic chickens (32). They can
be of significant economic impact to poultry farms
due to reducedgrowth and feed conversion.
Disseminated Ascaridia dissimilis (A. dissimilis)
was reported to cause hepatic granuloma in turkey
flocks (38,39), while A. dissimilis is the common
intestinal roundworm parasite of turkeys (62).
 87
Although some turkeys are harboured by large
numbers of this parasite, there were no associated
gross or microscopic lesions or body weight
changes (51). The presence of the worms in the
liver by aberrant migration may directly cause
hepatic lesions. Disseminated A. dissimilis can
migrate through the portal circulation system into
the liver where for a time they wander along the
sinusoids and can cause direct damage to liver by
mechanical injury. The visceral migration of A.
dissimilis in turkeys appears to be a biological
dead end, because the migration ends in the death
of the parasite (40).
At necropsy, livers infected with A. dissimilis
showed typical round white foci with a diameter of
about 1 mm. Microscopically, these granulomas
were characterized by a zone of central necrosis
surrounded by histiocytes, multinucleated macro-
phages, diffuse and nodular aggregates of
lymphoid tissues. Intralesional nematode fragments
or larvae were commonly found and were infiltra-
ted by lymphocytes and eosinophils (7,39).
Diagnostic methods of
avian hepatic granuloma
Diagnosis of granulomatous diseases involving the
liver of birds requires appropriate diagnostic
methods. A complete diagnostic evaluation inclu-
ding history, clinical observations, necropsy, and
laboratory examination of samples taken from
suspect cases is initiated in order to isolate and
identify the causative agent.
The clinical signs of birds with hepatic granuloma
are not specific. Hepatomegaly and green discolo-
ration of urates could be an indication of diseases
if the lesion involves the liver (44). Macroscopical
examination may provide useful information for
the differential diagnosis of hepatic granuloma.
For example, the size of granuloma, their colour,
confluence of granulomas or caseation necrosis can
give indications of the causative agent of hepatic
granuloma. The histopathologic changes occurring
within the hepatic granuloma might be an indicati-
on of the likely cause of the lesion and can be
useful for an early diagnosis before a definitive
diagnosis is made through isolation and identifica-
tion of the causative agent. Granulomas with many
heterophils or microabscesses or large abscesses
with a granulomatous periphery are likely to be
related to infection caused by bacteria. Eosinophi-
lic granular necrosis is typical of granulomas
associated with helminthic infections. The type of
necrosis can be helpful
for the differential
diagnosis. Caseous necrosis is typical of tuberculo-
sis but it can also be seen in some mycotic
granulomas (25).
The presence of pathogens, such as bacteria,
fungi, and parasites
directly in the area of
granulomatous lesions detected by special staining
forms the key diagnostic of hepatic granuloma.
For example Brown and Brenn stain for detection
of gram-positive and gram-negative bacteria
(22,36), Gridley or periodic acid-Schiff (PAS)
staining techniques for fungi (8), and ZN or
Truant stains for mycobacteria (56). By using
special stains pathogens could be detected directly
in the areas of granulomatous lesions. Culture is
the best method to make a definitive diagnosis of
hepatic granuloma in birds. However, certain
etiologies of hepatic granuloma in birds are
difficult to be cultured using standard culture
media. Nowadays, molecular and immunopatholo-
gic techniques have been used as diagnostic tool
for the detection of the causative agent of hepatic
granuloma.
The presence of specific pathogens in the area of
granulomatous lesions can be detected by means of
immunohistochemistry (5,8) using specific mono-
clonal antibodies or by molecular techniques
through detection of the nuclei acid of the
pathogens using the polymerase chain reaction
(PCR) technique (9,56). The advantages of immu-
nohistochemical techniques are the facts that these
are more sensitive than conventional stains because
of their ability to detect fragmented microbial
components, and more specific, enabling species
identification (60). Other methods, such us
imaging scan, fluorescence microscopy, scanning
electron microscopy and electron microscopy could
also be applied to detect pathogens in the hepatic
granuloma of birds.
Conclusions
Hepatic granulomas in birds can be caused by
viral, bacterial, fungal, protozoal and helminthic
infections. The clinical signs of hepatic granuloma
in birds are not specific. Macroscopical and histo-
pathological patterns of hepatic granuloma in birds
are different, and depend on the causative agent.
Definitive diagnosis of hepatic granuloma in birds
can be obtained through a complete diagnostic
evaluation involving clinical observations,
necropsy, and laboratory examination including
isolation and identification of the agent.
 88
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