Hepatic Granulomas
A Review With Emphasis on Infectious Causes
Laura W. Lamps, MD
 Context.—Many diseases that cause granulomas or
granulomatous inflammation involve the liver. Some of
these disease processes are intrinsic hepatic diseases,
whereas others are disseminated systemic diseases that
involve the liver as well as other organs.
Objective.—To review the evaluation of granulomas in
the liver with an emphasis on infectious causes, as well as
the use of special stains, serologic studies, and molecular
diagnostic techniques. Pertinent noninfectious causes of
G ranulomas are reportedly present in 2% to 10% of all
liver biopsy specimens examined in general practice,
and of those, it is reported that 13% to 36% have no
discoverable etiology even after extensive evaluation of the
specimen and the patient.1–7 Hepatic granulomas may
represent an infectious process, either primary or systemic;
an adverse drug effect; a reaction to foreign material or
nearby tumor; or have no clinical importance whatsoever.
This review emphasizes infectious causes of granulomas but
also includes some important noninfectious entities includ-
ed in the differential diagnosis.
Granulomas are aggregates of macrophages, often
admixed with other inflammatory cells, which typically
are a result of chronic antigen presentation. Many diseases
that produce granulomas involve the liver; some are
intrinsic hepatic diseases, whereas others are disseminated
systemic diseases that involve the liver as well as other
organs. There are several classification schemes that
address types of granulomas/granulomatous inflamma-
tion, but regardless of the scheme, the morphology of the
granulomas may provide clues to the diagnosis2–5 (Table
1). Hepatic granulomas/granulomatous inflammation may
be roughly divided into the following morphologic
categories:

Epithelioid granulomas, with or without necrosis. These
are discrete lesions with distinct edges. Necrotizing
granulomas in infectious disease processes often do not
Accepted for publication July 14, 2014.
From the Department of Pathology, University of Arkansas for
Medical Sciences, Little Rock.
The author has no relevant financial interest in the products or
companies described in this article.
Reprints: Laura W. Lamps, MD, Department of Pathology,
University of Arkansas for Medical Sciences, 4301 W Markham St,
Shorey Bldg 4S/09, Little Rock, AR 72207 (e-mail: lampslauraw@
uams.edu).
Arch Pathol Lab Med—Vol 139, July 2015
hepatic granulomas that are in the differential diagnosis
are also discussed.
Data Sources.—Literature review and cases acquired
during years of practice.
Conclusions.—A wide variety of infectious and nonin-
fectious entities cause hepatic granulomas.
(Arch Pathol Lab Med. 2015;139:867–875; doi: 10.5858/
arpa.2014-0123-RA)
respect the architecture of the liver and may destroy
adjacent structures. Necrotizing epithelioid granulomas
quite frequently have an infectious etiology, although no
specific organism may be found.
 Stellate abscesses with associated granulomatous inflam-
mation. This pattern is also most often associated with
infectious etiologies.
 Granulomatous inflammation with or without prominent
suppurative inflammation. In contrast to epithelioid
granulomas, ‘‘granulomatous inflammation’’ suggests
poorly formed granulomas with indistinct edges, often
with admixed inflammatory cells of other types. When
suppurative inflammation predominates, certain infec-
tious etiologies should be suspected (Table 1). Granulo-
matous inflammation with associated hepatocellular and/
or duct damage is often associated with drug-induced
liver injury.
 Microgranulomas. Some have defined these as 3 to 7 cells
in cross-section, often admixed with other inflammatory
cells and/or apoptotic hepatocytes. This pattern is very
nonspecific.
 Foamy macrophage aggregates. This pattern of granulo-
matous inflammation is usually due to infection, fre-
quently in immunocompromised patients. There may be
very little associated additional inflammatory response,
particularly if the patient is severely immunocompro-
mised.
 Fibrin-ring granulomas. This distinctive form of hepatic
granuloma deserves special mention. This lesion con-
sists of an epithelioid granuloma with a central lipid
vacuole surrounded by a fibrin ring (Figure 1). Although
classically described in association with Q fever, these
lesions are quite nonspecific and have been observed in
the context of a growing list of diseases including
leishmaniasis, Rickettsia typhus, boutonneuse fever,
Hodgkin disease, allopurinol reaction, toxoplasmosis,
cytomegalovirus infection, mononucleosis, Mycobacteri-
Hepatic Granulomas—Lamps 867
 Table 1. Classification of Hepatic Granulomatous Processes by Histologic Pattern
Fibrin-Ring
Granuloma Microgranuloma Lipogranuloma
Infectious Infectious Mineral oil
Q fever Listeria (rare) Fatty liver disease
Toxoplasmosis Other (controversial)
Salmonella Usually a
CMV nonspecific
EBV reaction to
MAI liver injury
Leishmaniasis
Other
Drug reaction
Lupus
Metastases
Abbreviations: CMV, cytomegalovirus; CVID, common variable immunodeficiency; EBV, Epstein-Barr virus; MAI, Mycobacterium avium-
intracellulare complex.
um avium-intracellulare infection, and typhoid fe-
ver.2–5,8,9
 Lipogranulomas. These contain lipids and are associated
with mineral oils in foods. An association with fatty liver
disease and with hepatitis C infection has also been
proposed.
In addition to the morphology of the granulomas,
pathologists should evaluate the location of the granulomas;
the presence or absence of necrosis; the nature of the
infiltrate that accompanies the granulomas, if any; if there is
anything in the granulomas, such as organisms or foreign
material; and other associated morphologic changes in the
liver biopsy specimen. Special stains for microorganisms
and, more and more frequently, molecular testing for
infectious causes are also invaluable in evaluating granulo-
matous processes in the liver. It is also important to decide
whether or not the presence of granulomas represents a true
pathologic process, or is incidental to another primary
disease process (such as hepatitis C infection). It may be
difficult, if not impossible, to make this distinction on
morphologic grounds alone.
SELECTED EXAMPLES OF BACTERIAL INFECTIONS
FEATURING PREDOMINANTLY GRANULOMATOUS
INFLAMMATION
Mycobacterium tuberculosis
Liver involvement is seen in almost all cases of miliary
tuberculosis and is common in both localized extrapulmo-
nary tuberculosis and in association with pulmonary
tuberculosis.2,10,11 Signs and symptoms of liver disease
may be the dominant or presenting features of tubercular
infection and may rarely occur in the absence of pulmonary
findings. Patients may present with fever, hepatomegaly,
and right upper quadrant pain, or may be asymptomatic.
Bilirubin and transaminases are variably elevated, often
with a disproportionately high alkaline phosphatase
concentration. 2,10 Confluent granulomas can lead to
radiographically apparent masses (tuberculomas) and
periportal lymphadenopathy.11,12
The histologic hallmark of hepatic tuberculosis is the
epithelioid granuloma, often with caseation and giant cells
(Figure 2, A). There may be a surrounding ring of
868 Arch Pathol Lab Med—Vol 139, July 2015
Predominantly
Stellate Microabscess Suppurative,
With Granulomatous Foamy Macrophage þ/ Granulomatous
Inflammation Aggregates Inflammation
Actinomycosis Rhodococcus equi Tularemia
Nocardia Whipple disease Listeriosis
Bartonella MAI Melioidosis
Tularemia (immunocompromised
Candida patients)
Other fungi Lepromatous leprosy
Other Histoplasmosis
Chronic granulomatous Leishmaniasis
disease
lymphocytes and histiocytes. Granulomas are usually
small but may coalesce to form nodules with central
liquefactive necrosis. Older lesions may be fibrotic or
calcified.2 Similar lesions are often found in periportal
lymph nodes (Figure 2, B). There is often an accompany-
ing nonspecific reactive hepatitis. It may be difficult to
detect mycobacteria on special stains for acid-fast bacillus;
thus, culture and polymerase chain reaction assays may be
invaluable. However, performing polymerase chain reac-
tion on acid-fast bacillus–negative tissue sections often
will not yield a positive result.13 It is also important to
recognize that current culture methods and molecular
tests cannot distinguish bacillus Calmette-Guerin from M
tuberculosis.
Mycobacterium avium-intracellulare
Infection with M avium-intracellulare is most commonly
associated with, but not limited to, patients with AIDS. The
liver is involved in more than 50% of disseminated cases.14,15
Most involved liver biopsy specimens show some form of
granulomatous inflammation. Occasional patients, particu-
larly those who are immunocompetent, have discrete,
epithelioid granulomas with associated neutrophils and
lymphocytes; giant cells and necrosis are rare in these cases.
In immunocompromised patients, the granulomatous in-
flammation often consists of aggregates of foamy macro-
phages in the parenchyma and portal tracts (Figure 3, A).8,9
Fibrin-ring granulomas are rarely seen as well. Organisms
are usually abundant on acid-fast stains in immunocom-
promised patients (Figure 3, B) but are rare in immuno-
competent persons. Culture and polymerase chain reaction
may be useful diagnostic adjuncts. The differential diagnosis
includes other causes of foamy macrophage aggregates,
such as Rhodococcus equi and Whipple disease. Other
nontubercular mycobacteria occasionally cause liver disease
as well, including Mycobacterium kansasii and bacillus
Calmette-Guerin.
Mycobacterium leprae
Liver involvement in leprosy is often subclinical, yet more
than 60% of patients with lepromatous leprosy have hepatic
involvement, and approximately 20% of patients with
tuberculoid leprosy do as well.16–18 Histologically, the
findings depend on the type of leprosy. In lepromatous
Hepatic Granulomas—Lamps
 Table 1. Extended

Epithelioid Granuloma, Epithelioid Granuloma,

Infectious Causes Other Causes
Mycobacterium tuberculosis Drug reaction
(usually caseating) Foreign body
Brucellosis reaction
MAI (immunocompetent Sarcoidosis
patients) Autoimmune diseases
Listeria (rare) Primary biliary cirrhosis
Tuberculoid leprosy CVID
Tertiary syphilis Hodgkin disease
Chlamydia Other paraneoplastic
Whipple disease (rare) conditions
Schistosomiasis Chronic granulomatous
Fungal infections disease of childhood
Viral infections (rare)

leprosy, there are aggregates of foamy histiocytes (lepra

cells) within portal tracts and lobules, containing numerous
acid-fast bacilli. Giant cells and discrete granulomas are
rarely seen, and accompanying inflammation is minimal. In
tuberculoid leprosy, there are usually discrete, tuberculoid
granulomas with associated giant cells (Figure 4). Bacilli are
rare in this variant.16–18 Some cases have features of both
lepromatous and tuberculoid granulomatous lesions.
Bartonella Species
Bartonella henselae is the most common cause of cat
scratch disease. Although patients usually present with
isolated lymphadenoapthy in an area draining a cat scratch
inoculation, a small percentage of patients (1%–2%)
develop disseminated infection.19,20 These patients usually
lack the characteristic skin papule and superficial adenop-
athy, but have generalized symptoms such as weight loss,
fever, and malaise. Liver lesions are often multiple and
have associated abdominal lymphadenopathy. Patients
with hepatic cat scratch disease are typically not immuno-
compromised,20 and generally respond well to antibiotic
therapy.
The characteristic histologic lesion consists of irregular,
stellate microabscesses surrounded by an inner layer of
palisading histiocytes, a middle layer of mononuclear cells,
and an outermost layer of thick fibrous tissue (Figure 5).
This outer fibrous zone is very pronounced in the liver. The
lesions may vary widely within the same specimen, ranging
from early stellate microabscesses to older lesions consist-
ing of fibrosis and granulation tissue. The differential
diagnosis primarily includes other infections.20 Diagnostic
aids include patient history with specific questions per-
taining to cat exposure, silver impregnation stains (War-
thin-Starry or Steiner), immunohistochemistry, molecular Figure 1. A fibrin-ring granuloma consists of an epithelioid granuloma
assays, and enzyme-linked immunosorbent assay at some with a central lipid vacuole surrounded by a delicate fibrin ring (case
centers. courtesy of Joseph Misdraji, MD) (hematoxylin-eosin, original magni-
fication 3300).
Brucella Species
Figure 2. A, Hepatic tuberculosis, featuring confluent epithelioid
Hepatic involvement is seen in approximately 50% of granulomas with numerous giant cells. B, Periportal lymph nodes are
cases of brucellosis. Because disease occurs primarily in often involved, containing confluent granulomas with prominent case-
domestic and barnyard animals, humans contract infection ation (hematoxylin-eosin, original magnifications 330 [A] and 3150 [B]).
through occupational exposure and/or by ingesting con-
taminated food. Patients generally present with fever, granulomatous inflammation, sometimes with accompany-
malaise, headache, and arthralgias; lymphadenopathy and ing giant cells. Granulomas may be discrete and epithelioid
hepatosplenomegaly are variably present.21–23 Liver biopsy or small and poorly formed. Organisms are difficult to
specimens often (although not always) show noncaseating culture and are only rarely seen on special stains. Serologic
Arch Pathol Lab Med—Vol 139, July 2015 Hepatic Granulomas—Lamps 869
Figure 3. Mycobacterium avium-intracellulare. A, Portal foamy macrophage aggregate with little attendant inflammation is typical of hepatic M
avium-intracellulare infection in immunocompromised patients. B, Numerous acid-fast organisms are seen on Ziehl-Neelsen stain (hematoxylin-
eosin, original magnification 3150 [A]; original magnification 3600 [B]).
Figure 4. Discrete, epithelioid granulomas in the liver in a case of tuberculoid leprosy (hematoxylin-eosin, original magnification 3300).
Figure 5. The characteristic histologic lesion of hepatic cat scratch disease features irregular, stellate microabscesses surrounded by an inner layer of
palisading histiocytes, a surrounding rim of lymphocytes, and an outermost thick layer of fibrous tissue (hematoxylin-eosin, original magnification
360).
Figure 6. A, The typical hepatic lesion in tularemia features discrete suppurative microabscesses with occasional surrounding macrophages. B,
Periportal lymph nodes show discrete, well-delineated areas of cortical necrosis, characteristic of tularemia (hematoxylin-eosin, original
magnifications 3150 [A] and 360 [B]).

studies and an appropriate exposure history are most helpful
in making the diagnosis.21–23
Rickettsia Organisms and Similar Species
Most rickettsial illnesses affect the liver, although
involvement may be subclinical. Coxiella burnetii (causative
agent of Q fever) is associated with fibrin-ring granulomas;
many Q fever granulomas are intermediate between
epithelioid and fibrin-ring types.24,25 Rickettsia conorii, the
causative agent of boutonneuse fever and South African
tick bite fever, may also cause granulomas.26 Organisms
are difficult to detect in the rickettsial illnesses, thus
immunofluorescent stains and serologic studies may be
very helpful.
SELECTED EXAMPLES OF BACTERIAL INFECTIONS
FEATURING MIXED SUPPURATIVE
AND GRANULOMATOUS INFLAMMATION
Tularemia
Tularemia remains a rare but potentially fatal disease that
is endemic in many areas of North America.27 Francisella
tularensis is a gram-negative coccobacillus that is primarily
transmitted to humans from rodents and rabbits. Hepatic
involvement is often a component of disseminated infec-
tion.28,29 Patients with hepatic involvement typically have
elevated transaminase levels, hepatomegaly, and rarely
jaundice28,29; hepatic involvement may be subclinical,
870 Arch Pathol Lab Med—Vol 139, July 2015
however. Histologically, there are typically suppurative
microabscesses with occasional surrounding macrophages
(Figure 6, A); as the lesions evolve they may become more
granulomatous. 29 Periportal lymph nodes may show
discrete, well-delineated areas of cortical necrosis (Figure
6, B).29 Organisms are rarely seen on special stains; thus,
cultures, serologic tests, and molecular testing are useful
diagnostic modalities.
Listeria monocytogenes
Listeria is a foodborne illness that primarily affects
immunocompromised patients, including neonates, preg-
nant women, and patients with underlying malignancies,
diabetes, organ transplants, and cirrhosis.30 Histologically,
scattered microabscesses are seen, often with small
granulomas.31 Sometimes an exclusively microgranulom-
atous pattern, and rarely, true epithelioid granulomas,
may be present.31 Occasionally, short pleomorphic gram-
positive rods may be identified, but blood culture is the
most important diagnostic test. DNA probes and immu-
nohistochemistry may be useful but are not widely
available.
Other hepatic bacterial infections that may cause
granulomas include Whipple disease (Tropheryma whippe-
lii),32 ‘‘typhoid nodules’’ (Salmonella), syphilis, Chlamydia
infection, R equi infection, with a granulomatous inflam-
matory pattern that mimics that of M avium-intracellulare;
Hepatic Granulomas—Lamps
Figure 7. The inflammatory reaction in hepatic candidiasis is typically granulomatous, often with a necrotic central area and peripheral fibrosis.
There may be surrounding palisading histiocytes, similar to hepatic cat scratch disease (courtesy of Lisa Yerian, MD) (hematoxylin-eosin, original
magnification 330).
Figure 8. A, Portal lymphohistiocytic aggregates typical of hepatic histoplasmosis. B, Hematoxylin-eosin/methenamine silver stain highlights
organisms within both portal and sinusoidal macrophages (hematoxylin-eosin, original magnification 360 [A]; original magnification 3300 [B]).
Figure 9. This liver biopsy specimen shows infection with Cryptococcus, with only focal positivity with mucicarmine stain, indicating a capsule-
deficient strain. Note that there is essentially no inflammatory reaction in this severely immunocompromised patient (original magnification 3600).

and melioidosis (Pseudomonas pseudomallei), with either
small neutrophilic microabscesses or granulomas.2,3
SELECTED EXAMPLES OF HEPATIC FUNGAL INFECTIONS
FEATURING GRANULOMATOUS INFLAMMATION
Hepatic fungal infections are usually part of a dissem-
inated process in immunocompromised patients, although
cases are rarely described in immunocompetent persons.
The clinical features are similar regardless of the fungus
involved and include hepatomegaly, abdominal pain, and
elevated transaminase and bilirubin levels. Fungi can
sometimes be correctly classified in tissue sections by
morphology33; they are often visible on routine hematox-
ylin-eosin sections when numerous, but Grocott methe-
namine silver and periodic acid–Schiff stains remain
invaluable diagnostic aids. It should be emphasized,
however, that culture or molecular diagnosis are more
reliable tools for accurate speciation, which is extremely
Arch Pathol Lab Med—Vol 139, July 2015
important as antifungal therapy may vary according to the
type of fungus.
The typical inflammatory reaction in hepatic candidiasis
is granulomatous, often with a necrotic central area33,34
(Figure 7). Giant cells are occasionally present. There may
be surrounding palisading histiocytes and a fibrous scar,
similar to hepatic cat scratch disease.34 Nonspecific findings
such as cholestasis, portal inflammation, ductular prolifer-
ation, and sinusoidal dilatation near the inflammatory
lesion are often present in the hepatic parenchyma.
Histoplasmosis features portal lymphohistiocytic inflam-
mation and sinusoidal Kupffer cell hyperplasia, and
organisms are generally present within both portal macro-
phages and Kupffer cells (Figure 8, A and B).35 Discrete
granulomas and giant cells are seen in only a minority of
cases.
The inflammatory response in aspergillosis ranges from
minimal to a marked neutrophilic infiltrate; granulomatous
inflammation is sometimes seen, and the pathology of
mucormycosis, and related zygomycetes infections, is
Hepatic Granulomas—Lamps 871

Figure 10. A, Granulomatous reaction to Schistosoma eggs in hepatic
schistosomiasis (courtesy of Joseph Misdraji, MD). B, As lesions age,
they become fibrotic, often with numerous calcified eggs. C,
Schistosome pigment is often seen within Kupffer cells (courtesy of
Joseph Misdraji, MD) (hematoxylin-eosin, original magnifications 3150
[A and B] and 3300 [C]).
similar to that of aspergillosis.33 The inflammatory reaction
in Cryptococcus infection is variable and depends on the
immune status of the host, ranging from a suppurative,
necrotizing inflammatory reaction with granulomatous
872 Arch Pathol Lab Med—Vol 139, July 2015
features, to virtually no reaction at all in immunocompro-
mised hosts36–38 (Figure 9). Purely granulomatous respons-
es are sometimes seen. Cryptococcosis may also involve
the biliary tree. Some strains are capsule deficient and are
either negative for mucicarmine or only focally positive,
and thus a Fontana-Masson stain may be useful in
diagnosis.
Other fungal infections that are rarely seen in the liver
include those caused by Pneumocystis carinii, Blastomyces
dermatitidis, Paracoccidioides brasiliensis (South American
blastomycosis), and Coccidioides immitis.2,3,33
SELECTED EXAMPLES OF HEPATIC PARASITIC
INFECTIONS FEATURING GRANULOMATOUS
INFLAMMATION
Schistosomiasis
Schistosomiasis is the most common cause of portal
hypertension in the world. Most hepatobiliary disease is
caused by Schistosoma mansoni, Schistosoma japonicum, or
Schistosoma mekongi, as these prefer mesenteric and portal
veins. Adult worms copulate within portal and mesenteric
veins and produce thousands of eggs in their lifetimes.
Approximately 50% of the eggs remain within the patient’s
body, thus reaction to the eggs themselves is the underlying
cause of disease, and the resultant inflammation leads to
fibrosis and obstructive hepatobiliary disease. Symptomatic
patients present with splenomegaly and signs of portal
hypertension, particularly bleeding. Hepatic function is
usually preserved.39,40
Grossly, livers are enlarged and nodular; on cut surface,
the pattern of fibrosis known as pipestem or Symmers
fibrosis may be seen. Histologic features vary with
duration of disease, and in chronic schistosomiasis there
is typically a granulomatous reaction to the eggs, which
are present in varying numbers both within granulomas
and fibrotic areas (Figure 10, A). Ultimately, portal tracts
become large and densely sclerotic, and fibrous septa link
portal tracts together; eggs are often calcified (Figure 10,
B). Sinusoidal fibrosis may also develop. As the fibrosis
progresses, eggs may be increasingly difficult to find.
Granulomas and fibrosis affect portal vein branches as
well, since they are the primary site of egg production,
leading to phlebitis, sclerosis, and thrombosis. Eventually
portal veins are obstructed and destroyed, with subse-
quent proliferation of hepatic arterial branches.39,40 Schis-
tosome pigment, which is a product of hemoglobin
catabolism by adult worms, is often visible as a brown
pigment in both granulomas and sinusoidal Kupffer cells
(Figure 10, C).41
Visceral Leishmaniasis (Kala-Azar)
Visceral leishmaniasis is most often seen in patients with
AIDS. The liver typically shows hyperplastic Kupffer cells
containing organisms; organism-laden macrophages may
form small nodules or loosely formed granulomas (Figure
11). Fibrin-ring and epithelioid granulomas have also been
described.42,43
Enterobius vermicularis (Pinworms)
Pinworms are one of the most common human parasites.
The rare hepatic pinworm granuloma consists of a
hyalinized nodule with peripheral inflammation. Central
necrosis with eggs and worm remnants may be present.44,45
Hepatic Granulomas—Lamps
Figure 11. Loosely formed aggregates of organism-laden macrophages in visceral leishmaniasis (kala-azar) affecting the liver (photograph courtesy
of George F. Gray Jr, MD) (hematoxylin-eosin, original magnification 360).
Figure 12. Small portal epithelioid granulomas are seen in a minority of hepatitis C infections (courtesy of Joseph Misdraji, MD) (hematoxylin-eosin,
original magnification 3150).
Figure 13. A, Confluent, noncaseating epithelioid granulomas in sarcoidosis. B, Trichrome stain highlights the associated fibrosis (courtesy of Joseph
Misdraji, MD). C, In a subset of cases, sarcoidosis involves the biliary tree and causes duct destruction and lymphocytic cholangitis lesions
indistinguishable from primary biliary cirrhosis (hematoxylin-eosin, original magnifications 360 [A] and 3150 [C]; original magnification 360 [B]).
Figure 14. Portal granulomas with numerous eosinophils in a case of idiopathic eosinophilic enteritis involving the biliary tree (hematoxylin-eosin,
original magnification 3150).

Other parasites that can cause granulomatous hepatic GRANULOMAS IN VIRAL INFECTIONS
inflammation include Fasciola hepatica,46 which may cause Small Kupffer cell clusters and, rarely, discrete nonca-
calculi, cholangitis, obstructive jaundice, and a granuloma- seating granulomas or fibrin-ring granulomas, may be
tous hepatitis; Toxoplasma gondii47,48; Capillaria hepatica, seen in Epstein-Barr virus infection of the liver.3–5
Ascaris, Strongyloides stercoralis49; and Giardia lamblia,50 which Epithelioid and fibrin-ring granulomas have also been
rarely causes granulomatous hepatitis and cholangitis. described in association with cytomegalovirus.5,51,52 Fur-
thermore, granulomas that are not attributable to any
other underlying etiology have been reported in a
minority of hepatitis C (Figure 12) and hepatitis B
Table 2. Selected Noninfectious Causes of Hepatic biopsies53,54; in the former, they may portend a favorable
Granulomas response to interferon therapy.
Cause Examples
Primary cholestatic Primary biliary cirrhosis, primary SELECTED NONINFECTIOUS CAUSES
disorders sclerosing cholangitis OF HEPATIC GRANULOMAS
Chronic gastrointestinal Idiopathic eosinophilic A comprehensive discussion of noninfectious causes of
diseases gastroenteritis
Chronic idiopathic inflammatory
hepatic granulomas is beyond the scope of this review, but
bowel disease some of the more important noninfectious entities that are
Vasculitides Polyarteritis nodosa, lupus in the differential diagnosis of infectious granulomas in the
Drug-induced injury Isoniazid, quinidine, allopurinol liver are summarized in Table 2, and a limited discussion of
Metal toxicity Beryllium, copper toxicity some of these entities follows.
Foreign material Talc, starch
Extruded cell Lipogranulomas, bile granulomas Sarcoidosis
components
Inherited diseases Chronic granulomatous disease The liver is secondary only to the lungs and lymph nodes in
Neoplasms Hodgkin disease, hepatocellular frequency of involvement by granulomas, and the incidence of
carcinoma, metastases hepatic granulomas in sarcoidosis has been reported to be 50%
Other Sarcoidosis to 100%.2 Sarcoid granulomas are epithelioid with variable
Common variable giant cells, and lesions may be confluent (Figure 13, A).
immunodeficiency
Caseation is usually absent, but there may be central fibrinoid
Arch Pathol Lab Med—Vol 139, July 2015 Hepatic Granulomas—Lamps 873

Figure 15. Hepatic arteriole with fibrinoid necrosis in polyarteritis
nodosa (hematoxylin-eosin, original magnification 3150).
Figure 16. A, Loosely formed microgranulomas with associated
eosinophils in the liver biopsy specimen of a patient receiving
propylthiouracil. B, Well-developed epithelioid granulomas in a case
of allopurinol toxicity (hematoxylin-eosin, original magnifications 3150
[A] and 330 [B]).
necrosis. Many types of inclusions have been described, most
commonly the asteroid body. Granulomas are often located in
portal tracts with associated lymphocytic inflammation, and
there may be associated spotty lobular inflammation and
874 Arch Pathol Lab Med—Vol 139, July 2015
hepatocyte necrosis. Sarcoid granulomas are often accompa-
nied by fibrosis (Figure 13, B), which may lead to cirrhosis.2,55–57
Some patients with chronic hepatic sarcoidosis manifest signs
of portal hypertension in the absence of cirrhosis, which may
be due to compression of the portal vein by involved portal
lymph nodes, or to compression of small portal vein branches
by parenchymal granulomas.58 A subset of patients with
sarcoid develop a chronic cholestatic process that resembles
primary biliary cirrhosis, with progressive destruction of bile
ducts (Figure 13, C).57
Chronic Biliary Diseases
Granulomas are reported in 18% to 64% of primary biliary
cirrhosis cases. They may be portal or lobular, but are often
associated with duct lesions. Granulomas are also seen in a
minority of cases of primary sclerosing cholangitis, in which
they are usually well formed, nonnecrotizing, and epithe-
lioid.2–4
Chronic Gastrointestinal Diseases
Granulomas have been reported in a small minority of
patients with ulcerative colitis, Crohn disease, and idio-
pathic eosinophilic gastroenteritis.2–4 It is unclear whether
the granulomas associated with chronic idiopathic inflam-
matory bowel disease could be due to diseases such as
primary sclerosing cholangitis or an adverse drug reaction.
Granulomas may also be a feature of idiopathic eosinophilic
enteritis involving the hepatobiliary tree by the disease
(Figure 14).59 Sarcoidlike granulomas are also well described
in the liver in patients with common variable immunode-
ficiency.60
Vasculitis/Collagen Vascular Diseases
Granulomas may involve the hepatic vasculature in
collagen vascular diseases or vasculitic diseases including
(but not limited to) polyarteritis nodosa (Figure 15), giant
cell arteritis, Churg-Strauss disease, and lupus.2–4
Adverse Drug Reaction
A complete discussion of granulomatous lesions caused
by drugs and toxins is beyond the scope of this review, and
the pathology of drug-associated granulomatous processes
is very diverse (Figure 16, A and B). Granulomas associated
with adverse drug reactions may be well or poorly formed,
but necrosis is very rare. Giant cells may be present, and
there is a variable associated inflammatory infiltrate that
may include lymphocytes, plasma cells, and eosinophils.
There may be associated duct and/or vascular injury. The
combination of granulomatous inflammation with signifi-
cant hepatocellular injury should strongly suggest drug-
associated liver injury. A few notable drug culprits include
allopurinol, nitrofurantoin, isoniazid, phenytoin, quinidine,
and hydralazine.1–4,61
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