Granulomatous Liver

Disease
Steven L. Flamm, MD

KEYWORDS
 Hepatic granuloma  Sarcoidosis  Primary biliary cirrhosis
 Medication hepatotoxicity  Alkaline phosphatase  GGT
 Liver biopsy

GRANULOMATOUS LIVER DISEASE

Granulomatous liver disease is a common problem and often provides a clue to the
presence of underlying systemic disease. Findings of hepatic granulomata on liver
biopsy often confuse the clinician and consultant. Granulomatous liver disease may
present with an abnormal liver panel but no symptoms. Patients may present with
manifestations of the systemic process. Identification of the systemic process may
allow proper therapy and improvement in the natural history of the underlying disease
state. Careful assessment of systemic symptoms and appropriate laboratory testing
frequently permits a specific diagnosis. This article reviews how to address consulta-
tion regarding a finding of hepatic granulomata on liver biopsy.

HISTOPATHOLOGY

Granulomatous liver disease is defined by the histologic findings on liver biopsy. Gran-
ulomata may be found in different tissues and represent many different disease
processes.1 A granuloma is a distinct lesion that is characterized by an accumulation
of mononuclear cells, primarily macrophages, in the center. There is a surrounding rim
with fibroblasts and lymphocytes. The lesion may or may not be well circumscribed,
but it is separate from adjacent, uninvolved tissue (Fig. 1). Hepatic granulomata
may be located anywhere in the hepatic lobule, but involvement of different sites
may be helpful in the differential diagnoses of specific disease processes.
Granulomata develop over time as an immunologic response to exogenous and/or
endogenous antigenic stimuli. The granuloma may appear as punched-out clusters of
lymphocytes or histiocytes. Mononuclear cells, such as macrophages, are activated
by various cytokines. These activated macrophages resemble epithelial cells and
are called epithelioid cells. Macrophages may fuse to form multinucleated giant cells.
Eosinophils may or may not be present.

Division of Hepatology, Northwestern University Feinberg School of Medicine, 676 North Saint
Clair Street, Suite 1900, Chicago, IL 60611, USA
E-mail address: s-flamm@northwestern.edu

Clin Liver Dis 16 (2012) 387–396

doi:10.1016/j.cld.2012.03.013 liver.theclinics.com
1089-3261/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
388 Flamm

Fig. 1. Hepatic granuloma.

Four different types of hepatic granulomata have been described, and each is asso-
ciated with different etiologies2: Caseating granulomata, characterized by central
necrosis; noncaseating granulomata, do not have central necrosis; fibrin-ring granulo-
mata, characterized by the histologic feature of a central vacuole with a fibrin-ring, sur-
rounded by epithelioid cells; and lipogranulomas, containing a central lipid vacuole.

ASSOCIATED DISEASE STATES

Numerous disease states have been associated with hepatic granuloma. Different
disease processes may be more or less common depending on the area of the world
where it occurs. The presence of a single granuloma in a liver biopsy may be a spurious
finding and may not indicate the presence of granulomatous liver disease.3 In addition,
hepatic granulomata may occasionally be observed in patients with known chronic
liver disease and may not necessarily indicate that a second process is ongoing.4
The presence of hepatic granulomata on diagnostic liver biopsy should spur a workup
to identify the underlying cause.
Categories of disease states that may involve the liver with granulomata include the
following:

1. Sarcoidosis
2. Autoimmune
3. Infectious diseases
4. Drugs
5. Cancer
6. Idiopathic.

Sarcoidosis
One of the most common causes of hepatic granulomata in the United States is
sarcoidosis.1,5 A systemic disease of unknown etiology that may or may not be auto-
immune, sarcoidosis, can affect people of any age, gender, and race. However, it is
more common in young African Americans.6,7 Sarcoidosis affects many organ
systems, most notably the lungs. However, involvement of the gastrointestinal system
is common although frequently asymptomatic. In the liver, hepatic granulomata are
often identified. Even when numerous granulomata are present, clinical evidence of
chronic liver disease is rare. Occasionally, portal vein thrombosis and/or cirrhosis is
observed.
 Granulomatous Liver Disease 389

The diagnosis of hepatic sarcoidosis is based on clinical presentation, biochemical

profile, and characteristics of the hepatic granulomata. The patient may have a known
history of sarcoidosis or may have signs and symptoms related to chronic pulmonary
disease, such as cough or shortness of breath. Involvement of other organ systems,
such as the eyes or skin may provide a clue to the diagnosis. Chest radiograph may reveal
changes consistent with sarcoidosis. From a biochemical standpoint, patients frequently
show elevated levels of serum alkaline phosphatase and g-glutamyltransferase (GGT).
Slight elevations in the level of bilirubin may be observed but are less common. In addi-
tion, the epithelioid cells of the hepatic granuloma in sarcoidosis often secrete
angiotensin-converting enzyme (ACE), and ACE levels are elevated in 75% of patients.8,9
The hepatic granuloma in sarcoidosis is usually in the portal tract and is noncaseating.
Because hepatic sarcoidosis most commonly has a benign course and there is no
definitive test to confirm the diagnosis, other causes of hepatic granulomatosis must
be ruled out to the satisfaction of the consultant.
Treatment of hepatic sarcoidosis is usually not recommended, despite the elevated
levels of alkaline phosphatase.10 If patients have evidence of portal hypertension and
cirrhosis, a short course of corticosteroids can be considered. However, it is unclear if
this is helpful, and the endpoints of therapy or outcome measures are not defined.

Autoimmune
Another common cause of hepatic granulomata in the United States is primary biliary
cirrhosis (PBC).1,5,11 A disease primarily of middle-aged women, patients may be
asymptomatic or may present with progressive fatigue and/or pruritus. PBC may be
associated with other autoimmune disorders such as sicca syndrome or CREST
syndrome, and patients may have related symptoms such as dry eyes and/or mouth,
heartburn or Raynaud syndrome.12 The biochemical profile is similar to sarcoidosis;
patients typically have elevated levels of alkaline phosphatase and GGT. Bilirubin
levels are often not elevated early in the course and only modest levels of elevations
are typically noted even in advanced disease.
Patients with PBC have a positive antimitochondrial antibody (AMA) in greater than
90% of cases. Elevated serum immunoglobulin (Ig) M levels also may be observed.13
Based on histology, hepatic granulomata resemble the ones seen in sarcoidosis.
However, patients with PBC may also have bile duct inflammation (cholangitis) on liver
biopsy.
The diagnosis of PBC is suggested by the presence of symptoms, such as progres-
sive fatigue and pruritus (although symptoms are frequently absent) in a middle-aged
woman. A cholestatic profile is noted. AMA positivity and/or elevated IgM levels allow
for a definitive diagnosis.
Treatment of PBC involves ursodeoxycholic acid (13–15 mg/kg/d in divided
doses).14 Treatment is not curative, and the condition may continue to progress and
develop cirrhosis.
Other autoimmune diseases in which hepatic granulomata have been described
include Crohn disease and Wegener granulomatosis (polyangiitis).15,16

Infectious Diseases
Many infectious diseases have been associated with hepatic granulomatosis and
must be ruled out to the satisfaction of the consultant (Box 1).17

Tuberculosis
Hepatic granulomata are observed in approximately 20% of patients with pulmonary
tuberculosis, approximately 75% of patients with extrapulmonary tuberculosis, and
390 Flamm

Box 1
Infectious etiologies of granulomatous liver disease

Bacterial
Tuberculosis
Mycobacterium avium-intracellulare complex
Brucellosis
Lepromatous leprosy
Bacille Calmette-Guérin infection
Listeriosis
Melioidosis
Tularemia
Yersiniosis
Psittacosis
Whipple disease
Cat scratch fever
Viral
Cytomegalovirus
Epstein-Barr virus
Hepatitis A, B, and C
Infectious mononucleosis
Fungal
Histoplasmosis
Coccidioidomycosis
Cryptococcus
Nocardiosis
Candidiasis
Blastomycosis
Parasitic
Toxoplasmosis
Schistosomiasis
Visceral larva migrans
Visceral leishmaniasis
Rickettsial
Coxiella burnetii (Q fever)
Boutonneuse fever
Spirochetal
Secondary syphilis
Chlamydia
Psittacosis
 Granulomatous Liver Disease 391

more than 90% of patients with miliary tuberculosis. Systemic symptoms such as
fevers, weight loss, anorexia, and night sweats may be present. The patient may or
may not have known pulmonary tuberculosis. If systemic symptoms are present
including fever or if the patient has pulmonary symptoms including cough and/or
shortness of breath, a diagnosis of tuberculosis must be considered.18
The biochemical profile typically reveals an elevated level of alkaline phosphatase
and GGT, bilirubin levels may be elevated but elevations are usually not prominent.
Hepatic granulomata are usually in the portal tract and may or may not be caseating.
A description of the specific diagnostic strategy and treatment of tuberculosis is
beyond the scope of this review. A diagnosis of tuberculosis must be considered
and ruled out to the satisfaction of the consultant when hepatic granulomata are
observed. Appropriate treatment should be instituted expeditiously if the diagnosis
is confirmed. If the diagnosis of tuberculosis cannot be ruled out and remains of
concern, antituberculous therapy should be considered before an empiric course of
corticosteroids.

Mycobacterium avium-intracellulare complex

Mycobacterium avium-intracellulare complex (MAC) is associated with hepatic gran-
ulomatosis and is observed in immunocompromised patients, such as ones with
HIV.19 In patients with a cholestatic biochemical profile and fevers, a diagnosis of
MAC should be considered, particularly if the patient is HIV positive and if hepatic
granulomatosis has been confirmed on liver biopsy.

Fungal infections
Fungal infections should be considered in the differential diagnosis of hepatic granu-
lomatosis.20–24 Histoplasmosis and coccidioidomycosis are among the more common
causes in the United States. Histoplasmosis should be considered in particular in
patients who live or have lived in the Southern or Central United States. Coccidioido-
mycosis should be considered in patients from the Southwestern United States.
Hepatic granulomata may also be observed in candidiasis, blastomycosis, or
cryptococcosis.
A review of the diagnostic strategy and treatment of these entities is beyond the
scope of this article. However, fungal infections should be considered in the differen-
tial diagnosis of patients with hepatic granulomata.

HIV-related diseases
Patients with AIDS are vulnerable to infections that are associated with hepatic gran-
ulomatosis, including tuberculosis, MAC, and fungal infections, such as histoplas-
mosis, toxoplasmosis, and cryptococcosis. Each infection should be ruled out in
a patient with HIV and hepatic granulomatosis.

Brucellosis
Brucellosis is caused by infection with Brucella abortus, Brucella suis, Brucella canis,
and Brucella melitensis.25 Brucella is acquired from animals either with contact from
infected cattle, goats, and swine or by ingestion of unpasteurized dairy products.
The most common symptom is fever. Other symptoms may be present including
decreased appetite, fatigue, weight loss, and night sweats. Symptoms may be abrupt
or insidious, and can oscillate over a period of months. Many organ systems may be
involved. If the liver is involved, hepatic granulomatosis may be observed. Serum
agglutinins for Brucella are obtained as a diagnostic test.
392 Flamm

Q fever
Q fever is caused by infection with Coxiella burnetti, a rickettsial organism. Coxiella
can be acquired by inhalation, ingestion, or from tick bites. Q fever most commonly
presents as pneumonia with fevers, myalgias, and headaches. If the liver is involved,
hepatic granulomatosis may be involved.26 The granuloma, known as a fibrin-ring
granuloma, is characterized by a fibrinoid necrotic ring surrounded by histiocytes
and lymphocytes.

Schistosomiasis
Schistosomiasis may be observed as a cause of hepatic granulomatosis.27 Granulo-
mata often contain abundant eosinophils.

Chronic viral hepatitis B or C

Granulomata have been observed rarely in patients with chronic hepatitis B or C viral
infections. Granulomata are described as epithelioid and nonnecrotizing.28,29

Other infectious causes

Various other infections have been associated with hepatic granulomata. These
include Lyme disease (Borrelia burgdorferi), toxoplasmosis, nocardiosis, actinomy-
cosis, salmonellosis, cytomegalovirus, and Epstein-Barr virus infections.

Cancer
Hodgkin lymphoma is the most common malignancy associated with hepatic granu-
lomatosis. Hepatic granulomata may also be observed in non–Hodgkin lymphoma and
renal cell carcinoma.30–32

Drugs
Many commonly used medications have been associated with hepatic granulomato-
sis including sulfa drugs, allopurinol, isoniazid, chlorpropamide, and quinidine
(Box 2).5,33 Granulomata of variable size may be located anywhere in the liver. Eosin-
ophils may be present, a clue to a drug-related etiology. A recommendation by the
consultant to discontinue unnecessary medications associated with hepatic granulo-
matosis is in order.

Foreign Body
Granulomata typically comprises macrophages forming giant cells. Talc in intravenous
drug users or suture material after surgery may be implicated.34

Lipogranuloma
Lipogranuloma have been associated with ingestion of mineral oil. The lipogranuloma
is characterized by fat droplets surrounded by macrophages and lymphocytes. They
are small and contain multinucleated giant cells. The lipogranuloma does not result in
significant liver injury.35

Idiopathic
An exhaustive workup of the causes of hepatic granulomatosis is unremarkable.1
Patients may have symptoms such as myalgias, arthralgias, fevers, and hepatosple-
nomegaly.36 The sedimentation rate may be highly elevated. This syndrome is called
idiopathic granulomatous hepatitis.
 Granulomatous Liver Disease 393

Box 2
Medications associated with granulomatous liver disease (alphabetical order)

Allopurinol
Amoxicillin-clavulanic acid
Carbamazepine
Chlorpropamide
Diltiazem
Gold
Halothane
Hydralazine
Interferon alfa
Mebendazole
Methyldopa
Nitrofurantoin
Phenylbutazone
Phenytoin
Procainamide
Quinidine
Sulfa drugs

TREATMENT

Treatment recommendations depend on the underlying diagnosis. Infectious etiolo-

gies of hepatic granulomatosis should be treated with the appropriate antibiotic, anti-
fungal, or antimycobacterial agent. Treatment of PBC includes ursodeoxycholic acid.
Medication-induced hepatic granulomatosis is treated by removal of the offending
agent. Malignancy-related hepatic granulomatosis is treated by therapy of the associ-
ated malignancy.
Hepatic granulomatosis secondary to sarcoidosis is usually not treated. Concomitant
pulmonary sarcoidosis may be treated with corticosteroids, but treatment of hepatic
sarcoidosis alone is rarely recommended. A short course of corticosteroids can be
considered if patients have portal hypertension related to hepatic sarcoidosis, but the
outcome measures and length of therapy is unclear. Tuberculosis must be ruled out
for the satisfaction of the consultant before commencing therapy with corticosteroids.
Idiopathic granulomatous hepatitis may also be treated with an empiric course of corti-
costeroids. However, as previously discussed, one must be careful to rule out tuberculosis
before treatment with corticosteroids. If tuberculosis remains in the differential diagnosis,
an empiric course of antituberculous therapy for 4 to 8 weeks should be considered before
a therapeutic course with corticosteroids. Methotrexate can be considered if symptomatic
granulomatous hepatitis remains after a course of corticosteroids.37

APPROACH BY THE CONSULTANT

Hepatic granulomata are not infrequently observed in diagnostic liver biopsies, and 1
or 2 granulomata do not necessarily implicate a relevant disease process. However, if
394 Flamm

hepatic granulomatosis is definitive, a thorough history, physical examination, and

blood testing workup should be obtained. Regarding the history, symptoms such as
fevers, weight loss, arthralgias, and myalgias should be sought. Pulmonary symp-
toms, such as cough and shortness of breath, may be observed in patients with
sarcoidosis or infectious causes such as tuberculosis, MAC, or Q fever. A careful travel
history should be obtained, with particular attention to contact with animals or inges-
tion of unpasteurized milk. Patients with PBC may complain of pruritus or severe
fatigue, or symptoms such as dry eyes and/or mouth (sicca syndrome) or heartburn
and/or Raynaud syndrome (CREST syndrome). Medication history should also be
reviewed carefully. On physical examination, fevers may be a clue to underlying infec-
tion. Lymphadenopathy may be present in Hodgkin disease. Excoriations may be
present in PBC.
A chest radiograph may show findings consistent with pulmonary sarcoidosis or
tuberculosis. Blood testing should be obtained, including a liver panel (which usually
reveals hepatic cholestasis with elevated alkaline phosphatase and GGT, AMA, serum
IgM levels, and serum ACE inhibitor levels. Appropriate serologic studies should be
obtained if specific infectious diseases are sought. A sedimentation rate may be
elevated in several of the causes of hepatic granulomatosis. HIV testing should be
considered in individuals with tuberculosis and MAC. QuantiFERON testing and/or
placement of a purified protein derivative should be considered if tuberculosis remains
in the differential diagnosis.
The liver biopsy results should also be reviewed with the pathologist to determine if
there are any clues to the diagnosis from the appearance or location of the hepatic
granulomata. Caseating granulomata are characteristic of tuberculosis. Fibrin-ring
granulomata may be observed in Q fever or Hodgkin disease.

SUMMARY

Hepatic granulomatosis is a relatively common and vexing problem for which gastro-
enterology consultation may be sought. A careful history, physical examination, and
blood testing workup can frequently identify the cause and allow design of an appro-
priate treatment approach.

REFERENCES

1. Drebber U, Kasper HU, Ratering J, et al. Hepatic granulomas: histological and

molecular pathological approach to differential diagnosis—a study of 442 cases.
Liver Int 2008;28:828.
2. Maddrey WC. Granulomas of the liver. In: Schiff ER, Sorrell MF, Maddrey WC,
editors. Schiff’s diseases of the liver. 8th edition. Philadelphia: Lippincott-Raven;
1989. p. 1572.
3. Klatskin G, Yesner R. Hepatic manifestations of sarcoidosis and other granuloma-
tous diseases; a study based on histological examination of tissue obtained by
needle biopsy of the liver. Yale J Biol Med 1950;23:207.
4. Tahan V, Ozaras R, Lacevic N, et al. Prevalence of hepatic granulomas in chronic
hepatitis B. Dig Dis Sci 2004;49:1575.
5. Zakim D, Boyer TD. 3rd edition. Hepatology, a textbook of liver diseases, vol. 3.
Philadelphia: WB Saunders; 1996. p. 1472.
6. Rybicki BA, Iannuzzi MC. Epidemiology of sarcoidosis: recent advances and
future prospects. Semin Respir Crit Care Med 2007;28:22–35.
7. Ayyala US, Padilla ML. Diagnosis and treatment of hepatic sarcoidosis. Curr Treat
Options Gastroenterol 2006;9:475–83.
 Granulomatous Liver Disease 395

8. Ishak KG. Granulomas of the liver. Adv Pathol Lab Med 1995;8:247.
9. Studdy PR, Bird R. Serum angiotensin converting enzyme in sarcoidosis—its
value in present clinical practice. Ann Clin Biochem 1989;26(Pt 1):13.
10. Vatti R, Sharma OP. Course of asymptomatic liver involvement in sarcoidosis: role
of therapy in selected cases. Sarcoidosis Vasc Diffuse Lung Dis 1997;14:73.
11. Gaya DR, Thorburn D, Oien KA, et al. Hepatic granulomas: a 10 year single
centre experience. J Clin Pathol 2003;56:850–3.
12. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology
2009;50:291–308.
13. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med 2005;353:
1261–73.
14. Poupon RE, Poupon R, Balkau B, The UDCS-PBC Study Group. Ursodiol for the
long-term treatment of primary biliary cirrhosis. N Engl J Med 1994;330:1342–7.
15. Maurer LH, Hughes RW, Folley JL, et al. Granulomatous hepatitis associated with
regional enteritis. Gastroenterology 1967;53:301–5.
16. Holl-Ulrich K, Klass M. Wegener s granulomatosis with granulomatous liver
involvement. Clin Exp Rheumatol 2010;28:88–9.
17. Lamps LW. Hepatic granulomas, with an emphasis on their infectious causes.
Adv Anat Pathol 2008;15:309–18.
18. Alvarez SZ, Carpio R. Hepatobiliary tuberculosis. Dig Dis Sci 1983;28:193.
19. Horsburgh CR. Mycobacterium avium complex infection in the acquired immuno-
deficiency syndrome. N Engl J Med 1991;324:1332–8.
20. Lewis JH, Patel HR, Zimmerman HJ. The spectrum of hepatic candidiasis. Hep-
atology 1982;2:479–87.
21. Smith JW, Utz JP. Progressive disseminated histoplasmosis. A prospective study
of 26 patients. Ann Intern Med 1972;103:533–8.
22. Davies SF, Khan M, Sarosi GA. Disseminated histoplasmosis in immunologically
suppressed patients. Am J Med 1978;64:94–100.
23. Kovacs JA, Kovac AA, Polis M, et al. Cryptococcosis in the acquired immunode-
ficiency syndrome. Ann Intern Med 1985;103:533–8.
24. Deresinski SC, Stevens DA. Coccidioidomycosis in compromised hosts: experi-
ence at Stanford University Hospital. Medicine 1974;54:377–95.
25. Akritidis N, Tzivras M, Delladetsima I, et al. The liver in brucellosis. Clin Gastro-
enterol Hepatol 2007;5:1109.
26. Hofmann CE, Heaton JW. Q fever hepatitis. Gastroenterology 1982;83:474–9.
27. Warren KS. The pathogenesis of “clay-pipe stem cirrhosis” in mice with chronic
schistomsomiasis mansoni, with a note on the longevity of the schistosomes.
Am J Pathol 1966;49:477–89.
28. Emile JF, Sebagh M, Féray C, et al. The presence of epithelioid granulomas in
hepatitis C virus-related cirrhosis. Hum Pathol 1993;24:1095–7.
29. Kanno A, Murakami K. A transient emergence of hepatic granulomas in a patient
with chronic hepatitis B. Tohoku J Exp Med 1998;185:281–5.
30. Kadin ME, Donaldson SS, Dorfman RF. Isolated granulomas in Hodgkin’s
disease. N Engl J Med 1970;283:859.
31. Braylan RC, Long JC, Jaffe ES, et al. Malignant lymphoma obscured by concom-
itant extensive epithelioid granulomas: report of three cases with similar clinico-
pathologic features. Cancer 1977;39:1146.
32. Chagnac A, Gal R, Kimche D. Liver granulomas: a possible paraneoplastic mani-
festation of hypernephroma. Am J Gastroenterol 1985;80:989–92.
33. Ishak KG, Zimmerman HJ. Drug-induced and toxic granulomatous hepatitis. Bail-
lieres Clin Gastroenterol 1986;2:463–80.
396 Flamm

34. Co DO, Hogan LH, Il-Kim S, et al. T cell contributions to the different phases of
granuloma formation. Immunol Lett 2004;92:135–42.
35. Boitnott JK, Margolis S. Mineral oil in human tissues. II. Oil droplets in lymph no-
des of the porta hepatis. Bull Johns Hopkins Hosp 1966;118:414–22.
36. Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown
origin: a study of 13 patients. Medicine (Baltimore) 1973;52:1.
37. Knox TA, Kaplan MM, Gelfand JA, et al. Methotrexate treatment of idiopathic
granulomatous hepatitis. Ann Intern Med 1995;122:592.