Granulomatous Liver Diseases.7

Received: 10 November 2023 | Accepted: 18 December 2023
DOI: 10.1097/HC9.0000000000000392
REVIEW
Granulomatous liver diseases

Downloaded from http://journals.lww.com/hepcomm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX
Maria Mironova1 | Harish Gopalakrishna1 | Gian Rodriguez Franco1 |

Steven M. Holland2 | Christopher Koh1 | David E. Kleiner3 | Theo Heller4
1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 06/01/2024
1
Liver Diseases Branch, National Institute of
Diabetes and Digestive and Kidney Diseases, Abstract
National Institutes of Health, Bethesda,
Maryland, USA A granuloma is a discrete collection of activated macrophages and other
2
Laboratory of Clinical Immunology and inflammatory cells. Hepatic granulomas can be a manifestation of localized liver
Microbiology, National Institute of Allergy and
Infectious Diseases, National Institutes of
disease or be a part of a systemic process, usually infectious or autoimmune. A
Health, Bethesda, Maryland, USA liver biopsy is required for the detection and evaluation of granulomatous liver
3
Department of Pathology, National Cancer diseases. The prevalence of granulomas on liver biopsy varies from 1% to 15%.
Institute, National Institutes of Health,
Bethesda, Maryland, USA They may be an incidental finding in an asymptomatic individual, or they may
4
Translational Hepatology Section, National represent granulomatous hepatitis with potential to progress to liver failure, or in
Institute of Diabetes and Digestive and Kidney
Diseases, Bethesda, Maryland, USA chronic disease, to cirrhosis. This review focuses on pathogenesis, histological
features of granulomatous liver diseases, and most common etiologies,
Correspondence
Theo Heller, Translational Hepatology Section, knowledge that is essential for timely diagnosis and intervention.
National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health
Building 10, Room 9B16, 10 Center Drive MSC
1800, Bethesda, MD 20892-1800, USA.
Email: [email protected]
INTRODUCTION for making the correct underlying diagnosis. The

physician’s role is to stratify the risks and to decide
Granulomas are a collection of activated macrophages whether the incidental finding of granulomas requires
and other inflammatory cells and may be the result of a further investigation. This review details pathogenesis,
variety of conditions, usually infectious or autoimmune. established common and emerging causes of granulo-
Granulomas are found in diseases isolated to the liver or matous liver diseases (GLD), and histological features.
may reflect systemic illness, and the disease severity may
range from an asymptomatic state to severe granuloma-
tous hepatitis with portal hypertensive complications. EPIDEMIOLOGY
Diagnosis of hepatic granulomas relies on liver
biopsy and the most common scenario leading to the The prevalence of granulomas on liver biopsy ranges
discovery of granulomas is that of a liver biopsy from 1% to 15%.[1,2] It is challenging to make accurate
performed for the workup of abnormal liver enzymes estimates of the real prevalence of hepatic granulo-
or for confirmation of hepatic involvement in a systemic mas since not every patient evaluated by a hepatol-
process that shows granulomas. When granulomas are ogist undergoes a liver biopsy. The etiologies of
found incidentally, there is often a diagnostic challenge; hepatic granulomas differ geographically. While
a comprehensive history and physical exam are crucial in the Western world, noninfectious autoimmune
Abbreviations: BCG, Bacillus Calmette-Guerin; CGD, chronic granulomatous disease; CT, computerized tomography; CVID, common variable immunodeficiency;
FUO, fever of unknown origin; GLD, granulomatous liver diseases; ICI, immune checkpoint inhibitors; NCPH, noncirrhotic portal hypertension; PBC, primary biliary
cholangitis; PH, portal hypertension; TB, tuberculosis; Th1, T helper type 1; Th2, T helper type 2; TNF-α, tumor necrosis factor-alpha; UDCA, ursodeoxycholic acid;
US, ultrasound.
Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States
Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of
employees of the Federal Government.
Hepatology Communications. 2024;8:e0392. www.hepcommjournal.com | 1

2
| HEPATOLOGY COMMUNICATIONS
conditions such as primary biliary cholangitis (PBC) PATHOGENESIS

are prevalent, in the Middle East and Asia infections
remain the leading causes of hepatic granulomas. Exposure to a foreign body, bacteria, mycobacteria,
Tuberculosis (TB), leishmaniasis, and viral hepatitis fungi, or antigenic stimuli triggers an initial immune
account for the most frequent causes in the developing response and recruitment of inflammatory cells. Gran-
world (Table 1). ulomas are a manifestation of inflammation, most often
The prevalence and etiology differ among different part of an effort to biochemically degrade a foreign
patient subpopulations, especially those who are predis- substance, bacteria, or persistent antigenic stimulus.
posed to hepatic granulomas by virtue of an underlying The latter may be exemplified by sarcoidosis or
condition, usually an inborn or acquired immuno- DILI.[1,2,20] The pathophysiological cascade in GLD
deficiency or immunosuppression. GLD was found in involves innate and adaptive immunity and consists of
about one-third of the patients infected with HIV, who had several steps: initial innate immune response, macro-
a liver biopsy as a workup of hepatomegaly, fever of phage activation, T-cell and B-cell activation, and finally,
unknown origin (FUO), or elevated transaminases.[14,15] granuloma formation, all of which may eventually result
Opportunistic infection with various mycobacteria, espe- in hepatic fibrosis.
cially Mycobacterium tuberculosis, remains the leading Granuloma formation represents helper T-cell–medi-
cause of liver granulomas in patients with HIV prior to and ated delayed hypersensitivity reaction, and the two
during the antiretroviral therapy eras.[14–17] In a single- primary components of this process are resident
center study of 301 patients with HIV, hepatic granulo- macrophages and CD4+ T-cells.[20] Antigenic stimulus
matous inflammation was present in 29% of the patients, through toll-like receptors attracts macrophages to the
with more than half having TB immune reconstitution site of inflammation as a part of an innate immune
inflammatory syndrome.[18] In another study, the preva- response. Macrophages engulf and try to destroy the
lence of granulomas in solid organ and hemopoietic stem invader through phagocytosis. Macrophages, B-cells,
cell transplant recipients was explored. Hepatic granulo- and dendritic cells serve as Ag-presenting cells in the
mas were found in 0.8% of all recipients of transplanta- generation of the adaptive immune response and play a
tion, with most of them thought to be noninfectious (72%). role in CD4+ T helper cell modulation and initiation of
Eighty-nine percent were found in recipients of liver CD4+ T helper type 1 (Th1) and 2 (Th2) cytokine
transplant with the most frequent underlying cause being responses. Activation of macrophages by cytokines is
graft-versus-host disease and idiopathic, presumed further required for granuloma formation (Figure 1). Th1
noninfectious.[19] activation dominates in granulomatous inflammation
TABLE 1 Top etiologies of hepatic granulomas in cohorts from different countries

References Top cause Other
[3]
United States Idiopathic (50%) Sarcoidosis (22%), drug-related (6%), PBC (5%), histoplasmosis
(5%), and TB (3%).
Pakistan[4] TB (88.9%) Sarcoidosis (7.4%), PBC (3.7%).
Iran[5] TB (53%) Visceral leishmaniasis (8.3%), visceral larva migrans, PBC, and
hepatitis C (4.2% each).
Saudi Arabia[6] TB (42.6%) Hepatitis C (14.8%), idiopathic (14.8%), schistosomiasis (5%),
sarcoidosis (5%).
Greece[7] PBC (62%) Sarcoidosis (7.5%), hepatitis B and C (7.5%), autoimmune hepatitis
(6%), idiopathic (6%).
Turkey[8] PBC (44.2%) Infections - mycobacterial, echinococcal, and hepatitis C (39.5%)
malignancy—HCC, cholangiocarcinoma, and others (5.8%),
sarcoidosis (4.7%), and foreign body (3.5%).
Portugal[9] TB (35.8%) PBC (15.0%), idiopathic (12.5%), hepatitis C (6.3%).
[10]
Germany PBC (48.6%) Undiagnosed/idiopathic (36%), sarcoidosis (8.4%).
Ireland[11] PBC (23.8%) Sarcoidosis (11.1%), idiopathic (11.1%), hepatitis C (9.5%), drug-
related (7.9%), PBC/autoimmune hepatitis overlap (6.3%),
Hodgkin disease (6.3%), autoimmune hepatitis (4.8%), TB (4.8%).
Australia[12] Chronic liver disease: alcoholic hepatitis/cirrhosis, Sarcoidosis (12%), infections - cytomegalovirus, Q fever, hepatitis
hepatitis B, secondary hemochromatosis (20%) B, Coxsackie B (12%), malignancy (8%), drug-related (7%), TB
(7%).
India[13] TB (55%) Leprosy (17.6%), Hodgkin’s disease (3.6%).
Abbreviations: PBC, primary biliary cholangitis; TB, tuberculosis.
GRANULOMATOUS LIVER DISEASES
| 3
Antigens
Toll-like MHC II
receptor BCR
Dendritic B cell
Macrophage cell
Innate Adaptive
response response
CD4+
T cell
Phagocytosis
Th1 Th2
TNFα IFNγ IL-2 IL-12 IL-4 IL-5 IL-13

• Macrophage activation
• Aggregation of granuloma
• Increased microbicidal and • Activation of eosinophils
cytotoxic activity of macrophages and fibroblasts
Granuloma
Fibroblast
Epitheloid cells
Eosinophil
Neutrophil
Multinucleated
giant cell
F I G U R E 1 Pathogenesis of granuloma formation. Bacteria or any foreign organism can be phagocytosed by macrophages as a part of the
innate immune response. In the adaptive response, antigen is presented to the CD4+ T-cells through Ag-presenting cells: macrophages, dendritic
cells, and B-cells. The Th1 pathway involves the release of TNF-α, INF-γ, IL-2, IL-12, and other pro-inflammatory cytokines and it is critical in
sarcoidosis and tuberculosis. The Th2 response is mediated through IL-4, IL-5, and IL-13, and it plays a role in helminth infections such as
schistosomiasis. Abbreviations: INF-γ, interferon-gamma; Th2, T helper type 2; TNF-α, tumor necrosis factor-alpha).
4
that usually involves intracellular pathogens such as but are not limited to, recombination-activating gene 1
mycobacteria, leishmania, or idiopathic inflammatory and nuclear factor kappa B subunit 1.[31]
diseases like sarcoidosis. It is mainly facilitated by
pro-inflammatory cytokines interferon-gamma, tumor
necrosis factor-alpha (TNF-α), and IL-2, IL-6, and IL- H I ST O PA T H O L O G Y
12. Th2 cytokine response with IL-4, IL-5, IL-10, and IL-
13 is most prominent in parasitic infections, such as Liver biopsy plays a pivotal role in the diagnosis of GLD.
schistosomiasis.[21] Interestingly, in schistosomiasis It can be done for investigation of a systemic disorder

the initial response is Th1, then ova Ags promote the with liver involvement, or an isolated hepatic process.
switch to Th2 response shortly after an infection. In The histological term used for activated macrophages,
schistosomiasis, the ova cause the most pronounced “epithelioid histiocyte,” is based on their appearance and
granulomatous response, and the Th2 response helps it is reflected in the names of some types of granulomas
to prevent further inflammation. An additional source of (Table 2 and Figure 2). Compared to the inactive
IL-4 in parasitic infections is eosinophils.[22] Interferon- macrophages, the epithelioid histiocytes have more
gamma-γ may play a protective role against fibrosis in cytoplasm with fewer lysosomes, a regular elongated
schistosomiasis, while IL-10 may control excessive Th1 shape, and sometimes multiple, peripherally-located
and Th2 polarization of granulomatous response.[23] nuclei.[32,33] They also lose their pseudopods, giving the
In animal studies, levels of IL-13 correlate with cell a smooth outline. The location of granulomas in the
collagen deposition, fibrosis, and the severity of portal liver depends on the etiology. Suture granulomas are
hypertension in schistosomiasis.[24] found in the vicinity of prior surgery, while talc
Activated macrophages further aggregate to form granulomas are most of the time located in portal
organized granulomas. Granulomas are dynamic areas. Sarcoidosis, PBC, and infectious granulomas
structures, and they may undergo fibrosis, a common often spread diffusely in the liver affecting portal, intra-
outcome, or necrosis as they mature. Fibrosis is acinar, periductal, and ductal areas.[32] The peri-
facilitated through the secretion of growth factors and granulomatous liver tissue may be unchanged, or it
extracellular matrix proteins by macrophages, and it may may show increased lymphocytic inflammation.[1]
occur in both noninfectious settings, such as foreign body Microgranulomas are small collections of macro-
granulomas, and in infection-related granulomas.[25] In phages, only 3 to 7 cells in cross-section, and they
schistosomiasis, the fibrotic response is coordinated by represent a nonspecific reaction to a liver injury.[20] They
HSC, which secrete a range of profibrotic chemokines, are frequently seen in metabolic dysfunction–associated
including chemokine (C-X-C motif) ligand 1 and steatotic liver disease, PBC, and DILI. They do not have
chemokine (C-C motif) ligand 2.[26] Granulomas, espe- independent significance and are unlikely to be associ-
cially those of infectious etiology, can undergo necrosis. ated with major parenchymal abnormalities.[12]
One of the remarkable examples is the caseating Lipogranulomas represent a collection of vacuolated
tuberculous granuloma, where necrosis is associated fat droplets, and they were initially considered an
with increased bacterial proliferation. Proteomic analysis incidental finding without clinical significance. The use
of necrotic foci has shown large amounts of pro- of mineral oil in the food industry was thought to be
inflammatory eicosanoids, such as leukotriene B4, and responsible for the increased incidence of lipogranulo-
prostanoids, such as cyclooxygenase-1 and 2. Animal mas in liver biopsies.[34] It was subsequently shown that
models have shown an abundance of TNF-α and lipogranulomas are associated with steatosis of any
reactive oxygen species within necrotic foci, which play etiology, including metabolic dysfunction–associated
microbicidal roles, but also may be destructive to the
tissues.[27] TABLE 2 Histological types of granulomas and the associated
A genetic predisposition may contribute to suscepti- conditions
bility to granulomatous disease. Human leukocyte Ag Type of granuloma Associated disease
DRB1 was recognized as a marker of predisposition to Microgranuloma Nonspecific
sarcoidosis.[28] Analysis of familial and sporadic cases
Lipogranuloma Steatotic liver disease, hepatitis C
of sarcoidosis identified a variant of butyrophilin-like 2
gene BTNL2 that is a risk factor for sarcoidosis Fibrin-ring granuloma Q fever (Coxiella), leishmaniasis,
toxoplasmosis, Hodgkin disease,
independent of Human leukocyte Ag predisposition.[29] ICIs-related granulomas
Whole exome sequencing in patients with common
Epithelioid necrotizing TB, nocardiosis, fungal infections
variable immunodeficiency (CVID) has shown that granuloma
patients with identifiable underlying monogenic causes
Epithelioid non- Sarcoidosis, hepatitis C, PBC, DILI
(about 30% of CVID cases) are more likely to have
necrotizing granuloma
complicated courses, including granulomatous infil-
trates, rather than infections only.[30] Potential genes Abbreviations: ICIs, immune checkpoint inhibitors; PBC, primary biliary chol-
angitis; TB, tuberculosis.
associated with hepatic granulomas in CVID include,
| 5
steatotic liver disease, and less frequently, alcohol.[35] of Q fever, they are found in other etiologies as well. In a
They are usually located within portal or acinar areas, study of 23 biopsies with evidence of fibrin-ring
especially adjacent to hepatic veins. Large portal granulomas, Q fever accounted for 43% of the
lipogranulomas may lead to portal expansion and give cases, followed by visceral leishmaniasis in 22% and
a false impression of “fibrosis.” Variable amounts of boutonneuse fever, caused by various species of
collagen fibers may be seen within and around Rickettsia, in 13%. A smaller proportion of cases were
lipogranulomas, as well as rare eosinophils.[32,36,37] In associated with toxoplasmosis, allopurinol-induced
58 patients with lipogranulomas on the liver biopsy, the liver injury, and Hodgkin’s disease.[41] Association
most frequent underlying etiology was either hepatitis C with autoimmune conditions such as systemic lupus
or steatotic liver disease.[38] Lipogranulomas were erythematosus and giant cell arteritis are also
evident in 19% of biopsies done for the workup of reported.[42,43] The current focus has shifted from
DILI.[39] infections toward DILI: fibrin-ring granulomas are

Fibrin-ring granulomas were initially described in reported in patients with granulomatous hepatitis due
association with granulomatous hepatitis in Coxiella to immune checkpoint inhibitors (ICI), both anti-CTLA-4
burnetii infection (Q fever) by Bernstein.[40] Their distinct and anti-PD-L1.[44,45]
feature is the presence of a central round fat vacuole Epithelioid granulomas are mostly composed of
surrounded by a fibrin ring and an outer layer of epithelioid cells but may also contain lymphocytes and
histiocytes. They are usually small in size and intra- other inflammatory cells and fibroblasts. They are often
lobular. Masson trichrome stain is useful for staining the associated with specific infectious and noninfectious
eosinophilic fibrin ring.[20,41] Although highly suggestive disorders, and they are categorized as non-necrotizing
(A) (B) (C)
(D) (E) (F)
(G) (H) (I)
F I G U R E 2 Histological features of hepatic granulomas. (A) Microgranuloma in metabolic dysfunction–associated steatohepatitis, H&E, ×600.
(B) Lipogranuloma in metabolic dysfunction–associated steatohepatitis, H&E, ×400. (C) Fibrin-ring granuloma in drug-induced injury due to the
ICIs ipilimumab and nivolumab, H&E, ×400. (D) Non-necrotizing epithelioid granuloma in autoimmune lymphoproliferative syndrome, H&E, ×400.
(E) Necrotizing epithelioid granuloma in eosinophilic hepatitis, H&E, ×200. (F) Florid duct lesion of primary biliary cholangitis, H&E, ×400. (G)
Mycobacterial granuloma, H&E, ×200. (H) Mycobacterium tuberculosis on acid-fast bacilli stain, ×600. (I) Granulomas in sarcoidosis, H&E, ×200.
Abbreviations: H&E, hematoxylin and eosin; ICI, immune checkpoint inhibitors.
6
and necrotizing. Necrosis is found in the center of the majority of the patients being asymptomatic.[97,98] Having
epithelioid granuloma. “Caseating necrosis” is a term hepatic involvement at the time of diagnosis
to describe the macroscopic picture associated with is a predictor of chronic disease in sarcoidosis.[98]
complete loss of tissue structure, with TB being a classic Symptomatic patients often present with nonspecific
example.[46] Necrotizing epithelioid granulomas are complaints such as fatigue, night sweats, and fever.
prevalent in infections such as nocardiosis, fungal Hepatic symptoms often resemble cholestatic liver
infections, including histoplasmosis, and fascioliasis; an disease, PBC, or primary sclerosing cholangitis, mani-
association with DILI has been reported as well.[47–50] festing with pruritus, jaundice, anorexia, and elevated
Non-necrotizing epithelioid granulomas may be either alkaline phosphatase.[99] Sarcoidosis may involve up to
poorly or well-formed. Well-formed granulomas are seen 90% of the liver volume, which can lead to intrahepatic
in sarcoidosis and infections like hepatitis C.[20,51] Poorly and extrahepatic biliary obstruction. Non-necrotizing
formed granulomas are infiltrated by lymphocytes, which granulomas are a predominant feature of hepatic
can obscure the normal cohesive granuloma structure. sarcoidosis, although bile duct injury, chronic portal
They may be found in immune-mediated conditions, inflammation, and vascular changes, such as sinusoidal
PBC, DILI, or T-cell–mediated rejection after a liver dilation and nodular regenerative hyperplasia, may also
transplant.[2,52] “Granulomatous inflammation” refers to be seen on the biopsy.[100] Fibrosis and cirrhosis are
an inflammatory reaction involving epithelioid cells when encountered in 20–29% of the biopsies,[100,101] and may
granulomas fail to form.[32] Epithelioid granulomas that eventually become complicated by portal hypertension
are not associated with a known etiology should be (PH). In a case series of 12 patients with PH due to
stained for infectious organisms. sarcoidosis, 7 patients died, 6 of them due to complica-
tions of PH, and 2 patients received liver transplants.[102]
Sarcoidosis is also a known cause of noncirrhotic portal
ETIOLOGY hypertension (NCPH);[99] reversal of NCPH in sarcoid-
osis with steroid treatment has been reported.[103]
The etiologies of hepatic granulomas can be broadly
categorized as infectious and noninfectious (Table 3).
The diagnosis of idiopathic granuloma is made when no Primary biliary cholangitis
underlying cause can be identified. In this section, the
focus is made on the most common etiologies. PBC, formerly known as primary biliary cirrhosis or
nonsuppurative destructive cholangitis, is an auto-
immune slowly progressive, cholestatic liver disease
Foreign body granuloma associated with inflammation and destruction of the
small bile ducts. Granulomas are usually evident in
Granuloma formation is a localized inflammatory early disease, characterized by portal inflammation,
response that occurs in an attempt to react and isolate sometimes called the florid duct lesion stage.[62] The
exogenous material. It includes materials like sutures, florid duct lesion is a diagnostic histological feature of
sponges, implants, or other particles that enter the body PBC and represents a damaged bile duct, surrounded
during an injury.[92,93] Hepatic and splenic granulomas by lymphocytes and plasma cells, with adjacent
containing microscopic metallic particles were found in granulomas. Granulomas are mostly epithelioid,
38% of the autopsies of patients with a history of hip or non-necrotizing, and are poorly formed, with many
knee replacement. Foreign body granulomas may also infiltrating lymphocytes that disrupt the structure.
cause hepatitis with fatigue, jaundice, and weight loss.[94] As the disease evolves, granulomas become less
Isolated elevation of alkaline phosphatase and non- prominent.[104] Immunological studies showed that
necrotizing granulomas containing silicone material are dendritic cells and immunoglobulin M are key factors
described in patients with ruptured breast implants.[95] in the formation and evolution of granulomas in
PBC.[105] The presence of granulomas is thought to
be associated with better patient survival;[106] this is
Sarcoidosis likely explained by the fact that the granulomas are an
early finding in PBC. While granulomas are a hallmark
Sarcoidosis is a systemic disorder, mostly prevalent in of PBC, in primary sclerosing cholangitis they are
women of young and middle age between 20 and usually an incidental finding.[20]
50 years. The pathogenesis of sarcoidosis is poorly
understood, and it is thought to develop due to a
combination of factors, including genetic predisposition, Inborn errors of immunity
environmental, and even bacterial triggers.[96] It usually
affects the lungs and mediastinal lymph nodes, but it can Advancements in medicine and the use of prophylactic
also involve the liver in 6%–18% of the cases with the antibiotics have dramatically increased survival in
| 7
TABLE 3 Most common etiologies of hepatic granulomas

Infectious etiologies Noninfectious etiologies
Bacterial infections Autoimmune disease
Nocardiosis[47] Sarcoidosis[53]
Mycobacterial infections, including M. tuberculosis, M. bovis, Eosinophilic granulomatosis with
M. avium[17,54] polyangiitis[55]
Brucellosis[56] Giant cell arteritis[57]
Q fever (Coxiella burnettii)[12] Granulomatosis with polyangiitis[58]

[59]
Cat-scratch disease (Bartonellosis) Crohn’s disease[60]
Syphilis[61] Primary biliary cholangitis[62]

[63]
Actinomycosis Immunodeficiencies, inborn and acquired
Fungal infections Common variable immunodeficiency[64]
Histoplasmosis[65] Chronic granulomatous disease[66]
Blastomycosis[67] Human immunodeficiency virus infection[18]
[68]
Coccidioidomycosis Medications
[69]
Candidiasis (in the setting of neutropenia) Acetaminophen[70]
Viral infections Allopurinol[71]
Hepatitis A, B, C[6,51,72] Albendazole[73]
Epstein-Barr virus[74] Amoxicillin-clavulanate[75]
Cytomegalovirus[76] Diltiazem[77]
Parasitic infections: Etanercept[78]
Helminthic infections: Infliximab[79]
Ascaridosis[80] Ipilimumab[81]
Fascioliasis[82] Mebendazole[83]
Schistosomiasis, including S. japonicum and S. mansoni[67] Mesalamine[84]
Protozoal infections: Nivolumab[81]
Toxoplasmosis[85] Vemurafenib[86]
Leishmaniasis[87] Rosiglitazone[88]
Sulfasalazine[89]
Quinidine[90]
Hodgkin’s disease[91]
Foreign body
Talc[20]
Surgical material[92,93]
Prosthetic devices[94]
Implants[95]
Idiopathic granulomas
patients with inborn errors of immunity, and as a result, nodular regenerative hyperplasia. These conditions
recognition of hepatic disorders. Hepatic granulomas altogether lead to NCPH, the most common and morbid
are a signature of CVID and chronic granulomatous sequela of which are variceal bleeding, ascites, and
disease (CGD).[107] CVID refers to a spectrum of spontaneous bacterial peritonitis.[64,109,110] CGD is due
disorders typically associated with adult-onset antibody to defects in the NADPH oxidase complex, which is
deficiency, but a subgroup of cases have granulomas in required for the production of reactive oxygen species
the lung, liver, and spleen. Liver disease has been by phagocytes. CGD leads to impaired innate and
associated with higher mortality in CVID.[108] Up to 22% adaptive immune responses and with resulting suscep-
of the patients with CVID may develop granulomas, with tibility to infection with organisms such as Staphylococ-
about one-third of them located in the liver. Hepatic cus aureus, Serratia marcescens, Burkholderia cepacia
granulomatosis in CVID is frequently associated with complex, Nocardia species, and Aspergillus and other
8
fungi.[66] Along with liver abscesses, non-necrotizing Iatrogenic granulomatous hepatitis was reported
granulomas are the most common histological finding in after injection of Bacillus Calmette-Guerin (BCG), a live
CGD and are found in up to 74% of the patients. attenuated Mycobacterium bovis used for vaccination
Granulomas may alter the architecture of small portal against TB and also as immunotherapy for bladder
veins and lead to an obliterative portal venopathy and cancer and melanoma.[119–121] Mutations in genes
nodular regenerative hyperplasia, and as a result lead responsible for the generation and response to INF-
to NCPH.[111,112] gamma and IL-12 are associated with an increased risk
of disseminated BCG infection.[122] Animal studies

showed that liver injury in BCG infection is likely
Inflammatory bowel disease mediated through TNF-receptor 1.[123] In the case of
disseminated infection following BCG instillation for
Abnormal liver enzymes have been reported in up to bladder cancer, granulomatous hepatitis is usually an
30% of all patients with inflammatory bowel disease, early complication with occurrence after a median of 1
with chronic liver disease developing only in 6% of the week, compared to cardiovascular and bone injury that
patients.[113] GLD is an infrequent complication that is develops after a year. Up to 18% of all cases of
encountered more in Crohn’s disease than in ulcera- disseminated BCG infection after use for bladder cancer
tive colitis. Hepatic granulomas have been reported in involve the liver.[54]
6% of liver biopsies of patients with Crohn’s Tyrosine kinase inhibitors and ICIs are medications
disease.[60] In a study from Northern Ireland, only of current interest in DILI research. They improve
1.8% of GLD was accounted for by Crohn’s disease. survival in patients with melanoma, head and neck
Well-circumscribed epithelioid granulomas within por- cancer, non-small-cell lung cancer, and many others,
tal tracts were a characteristic feature found on but at the same time, they are associated with immune-
biopsy.[114] Symptomatic patients usually present with mediated adverse events. ICI treatment in particular
signs of cholestasis. Granulomatous hepatitis may may be complicated by systemic granulomatous sar-
also be induced by sulfasalazine or mesalamine coid-like reactions.[124] Granulomatous hepatitis was
therapies used for the treatment of inflammatory bowel reported in association with the tyrosine kinase inhib-
disease.[84,89] itors vemurafenib, and the ICIs nivolumab and
ipilimumab.[81,86] The granulomatous injury with ICIs
may present in hepatocellular, cholestatic, or mixed
Drug-induced liver injury patterns.[125] The presence of pre-existing antinuclear
antibodies along with granulomas on histology may
Granulomas due to DILI are suspected when there is a serve as potential markers of ICI-related hepatitis.[126]
temporal association with exposure to a drug and other,
more common causes of GLD have been excluded.
Several medications have been linked to GLD, the most Bacterial infections
common are mentioned in Table 2. Granulomatous
injury may have acute or delayed onset and it may be Granuloma formation is a distinct feature of multisystem
accompanied by features of hypersensitivity such as mycobacterial infections like TB or leprosy. TB remains
rash, eosinophilia, and fever. Liver enzymes are a global health challenge: the estimated death toll in
often elevated in a cholestatic pattern. Drug-induced 2021 was 1.6 million people.[127] It usually presents as a
granulomas are usually non-necrotizing, epithelioid, and pulmonary infection, with hepatic TB in an extrapulmo-
located in portal areas, and they may lead to vascular or nary location. Up to 85% of hepatic TB occurs as part of
duct injury. The presence of eosinophils supports a drug systemic infection, and rarely as an isolated finding.
etiology.[20,115] In the study by Kleiner et al, the finding of Symptomatic patients present with fever, weight loss,
granulomas and eosinophils in DILI was linked to mild jaundice, and hepatosplenomegaly, sometimes associ-
cases.[39] ated with portal hypertension.[128,129] Hepatic TB can be
Several cases of GLD have been reported in disseminated, miliary, or focal in the form of tuber-
association with the anti-TNF modulators, infliximab, culoma or abscess; the main histological feature of both
and etanercept, used for psoriasis and rheumatoid forms is the epithelioid necrotizing granuloma.[17] Its
arthritis, among other diseases; discontinuation of the function is to contain infection: in TB the inner part of
medications led to normalization of liver function.[78,79,116] granuloma has a pro-inflammatory environment, while
At the same time, infliximab has been successfully used the outside layer is anti-inflammatory. The balance
for off-label treatment in sarcoid granulomatosis and between these two is thought to be responsible for the
idiopathic granulomatous hepatitis.[117,118] Variations in host’s ability to isolate infection and prevent
pro-inflammatory and immunoregulatory TNF properties dissemination.[27] The histological diagnosis is con-
in different diseases may correlate with the variability in firmed with acid-fast bacilli stain and culture, although
the response to anti-TNF therapies. the acid-fast bacilli stain cannot distinguish between the
| 9
different types of mycobacteria. PCR and the PCR- Fungal infections

based MTB/RIF assay are more sensitive in the
diagnosis of pulmonary and extrapulmonary TB than Fungal infections predominantly impact immuno-
acid-fast bacilli stain alone.[130] compromised hosts. In the case of invasive candidiasis
Hepatic granulomas are associated with many other in acute leukemia, hepatosplenic involvement may be
bacterial infections. Fibrin-ring granulomas are typical seen in up to 29% of patients. The most common hepatic
lesions of Coxiella burnettii infection or Q fever, although lesions are granulomas and microabscesses.[69,136]
granulomas without characteristic annular arrangement Histoplasma and Coccidioides enter the host by inhala-
or fibrinoid material can be also found.[131] Up to half of tion of the spores and usually result in asymptomatic
the patients with liver disease due to brucellosis present pulmonary infection. In approximately half of infected
with tender hepatomegaly and increased serum liver immunocompromised individuals, histoplasmosis may
enzymes. In the study by Cervantes et al, non- disseminate. Patients with hepatic histoplasmosis pres-
necrotizing granulomas were found in 70% of the liver ent with fever and hepatomegaly, as well as diarrhea and
biopsies and most of them had disease durations less abdominal pain due to gastrointestinal involvement.
than 100 days. This suggests that granulomas in Granulomas are seen in both portal and lobular areas
brucellosis may be a feature of acute disease.[56] Cat- and are found in 19% of the patients with hepatic
scratch disease, due to Bartonella henselae, is usually a histoplasmosis.[65] In a study of 7 patients with hepatic
self-limiting disease, although rare cases of granuloma- coccidioidomycosis, all presented with febrile illness and
tous hepatitis have been reported in children and young had multiple granulomas containing spherules on liver
adults. Positive Bartonella serologies and bacteria visible biopsy.[68] Disseminated fungal infections usually lead to
on the silver stain confirm the diagnosis.[59,132] Actino- fatal outcomes if untreated.
mycosis is typically associated with cervicofacial infec-
tions, but it also causes abdominal disease with the liver
being involved in 15%–20% of cases as abscesses or Parasitic infections
granulomas mimicking metastasis.[63,124,133] Poorly
formed non-necrotizing granulomas are found in 36% Schistosomiasis is a tropical disease that impacts more
of the patients with hepatic involvement in secondary than 250 million individuals worldwide, with the majority
syphilis. Granulomas are also associated with a hepatic of those infected living in Sub-Saharan Africa. It is
fibroinflammatory mass lesion, which may represent caused by Schistosoma species such as S. mansoni
early gumma or granuloma of tertiary syphilis.[61] and S. japonicum; the typical source of larvae is
contaminated water. The parasites penetrate the skin
and reach the liver via hematogenous spread. The eggs
induce an immunological cascade in the portal tracts
Viral infections causing granuloma formation and fibrosis, resulting in
partial or complete obliteration of portal veins. Early
Granulomas are occasionally reported in association with infection presents in an acute form, also called
hepatotropic viruses like hepatitis A, B, and C.[7,9,12] Katayama fever, with fever, pruritic rash, myalgias,
Transient fibrin-ring granulomas were observed in a and tender hepatosplenomegaly.[67] Untreated infection
patient with acute hepatitis A and disappeared during the may progress to advanced fibrosis, complicated by PH
recovery phase.[72] Transient epithelioid granulomas were and risk for HCC. Schistosomiasis is the main cause of
found in 2% of the patients with hepatitis C; the authors NCPH in endemic-developing countries.[137] Granulo-
had explored the possible association of granulomas with matous disease and complications of PH such as
interferon-alpha treatment; however, only 1 patient of the 5 variceal bleeding and encephalopathy are included in a
identified had granulomas on posttreatment biopsy and predictive model to estimate 1-year mortality in
lacking specific features of DILI.[51] Another study reported advanced S. japonicum infection.[138]
2 cases of granulomatous hepatitis likely caused by GLD is reported with fascioliasis, another type of liver
interferon-alpha treatment, 1 in hepatitis C and another in fluke, which spreads to the liver after ingestion and
hepatitis B, which led to treatment cessation in both.[134] penetration of the intestinal wall by immature worms.
The advent of direct-acting antiviral agents for hepatitis C Untreated acute infection is characterized by right upper
has led to a marked decrease in interferon treatment. quadrant pain, fever, and hepatomegaly, and is followed
Nonhepatotropic viruses like cytomegalovirus and by a chronic phase with necrotic granulomas and the
Epstein-Barr may lead to granulomatous hepatitis and growth of worms within the biliary tree leading to
fulminant liver failure, particularly in immunocompromised cholestasis and recurrent cholangitis.[67] The macro-
hosts.[74,76] Although the knowledge of hepatic involvement scopic appearance of the liver shows scarring and
with SARS-CoV-2 is still limited, GLD has not been yellow nodules that may mimic metastasis.[82] Helminth
reported in association with this infection.[135] infections require systemic treatment; paradoxically,
10
granulomatous hepatitis has been reported in associa- liver enzyme abnormalities.[145] Similar trends are
tion with mebendazole and albendazole.[73,83] observed in DILI;[39] however, in ICI-related granuloma-
The most common protozoal organisms associated tous hepatitis equal numbers of patients had either
with GLD are Leishmania species, although rare cases of cholestatic or hepatocellular injury.[125] Liver enzyme
hepatic granulomas are also reported in toxoplasmosis elevation in hepatic sarcoidosis may correlate with the
and giardiasis.[85,139] Leishmaniasis is endemic to Asia, severity of granulomatous inflammation and the degree
the Middle East, East Africa, and the Mediterranean of fibrosis.[145] Disease-specific tests may point toward
region. Patients with visceral leishmaniasis present certain etiologies: angiotensin-converting enzyme ele-
primarily with fever, weight loss, and hepatosplenome- vation in sarcoidosis, 1,3-β-D-glucan levels, blood/
galy. Infection may cause extensive granulomatous biopsy cultures in fungal infection, viral serologies in
hepatitis with fibrin-ring granulomas being the predomi- viral infections, and autoimmune panel in PBC.
nant lesions.[87,140] Imaging augments the laboratory workup in the

diagnosis of GLD. Cross-sectional methods such as
computerized tomography (CT) or MRI are helpful in the
Workup of fever of unknown etiology evaluation of hepatic lesions and the complications of
portal hypertension. While many GLDs present with
GLD may be found when a liver biopsy is pursued for nonspecific findings, such as increased liver echoge-
the workup of FUO. An early study by Simon et al found nicity on ultrasound, or liver nodularity on cross-
granulomatous hepatitis in 6.5% of the patients with sectional imaging, some have pathognomonic features.
prolonged fever; a definite diagnosis, Hodgkin’s dis- The presence of calcified septa perpendicular to the
ease, was made in only 1 patient.[141] In the study by capsule on CT in a “turtleback” pattern is a distinct
Holtz et al, 4 out of 24 liver biopsies done for FUO were feature of schistosomiasis, which becomes more
diagnostic (16.7%); they found 3 cases of histoplasmo- prominent as the disease advances. In a study by Araki
sis and 1 case of TB.[142] In another study, the diagnosis et al, calcifications on CT correlated with the degree of
was established in 26% of cases of FUO: those patients fibrosis in schistosomiasis; calcifications were also
had Coxiella (Q fever), mycobacterial infection, and found in those who developed HCC.[146] In schistoso-
histoplasmosis.[143] miasis, ultrasound is useful to assess the degree of
periportal fibrosis and to monitor the response to
treatment.[147] Healed mycobacterial or fungal granulo-
DIAGNOSIS mas may also present as calcifications on CT.[148] The
contrast-enhanced ultrasound is useful in the diagnosis
Unexplained biochemical liver abnormalities or of infectious granulomas: 93% of lesions present as
unexplained systemic symptoms are the 2 commonest hypoechoic and irregular in shape, and 60% demon-
scenarios leading to the suspicion of GLD. Liver strate hyperenhancement in the arterial phase.[149]
histology is required for diagnosis, in combination with Granulomas can exhibit increased metabolic activity
thorough history taking, physical exam, concurrent mimicking metastasis on the positron-emission tomog-
laboratory tests, and imaging techniques (Figure 3). raphy CT.[150,151]
Travel history or being born in endemic regions for
parasitic infections or TB, family or personal history of
autoimmune disease or immunodeficiency, temporal TREATMENT AND FOLLOW-UP
association with medication use—all of these may hint
at certain types of GLD. Most common etiologies, such Treatment is guided by the underlying disorder and its
as sarcoidosis or TB should be considered first. The severity. Hepatic granulomas in infections should be
presentation usually depends on the underlying etiol- treated with appropriate antimicrobial, antifungal, anti-
ogy, but the diagnosis may be challenging because of viral, or antiprotozoal medications. Patients with hepatic
the nonspecificity of the symptoms. Some patients may TB demonstrate excellent response to anti-TB drug
be asymptomatic, while others may exhibit fatigue, regimens: in a study by Liu et al, all 25 patients who
abdominal pain, fever, and pruritus, which are seen in completed treatment had resolution of lesions on the CT
both noninfectious and infectious etiologies.[128,144] and improvement in symptoms.[128] In the case of DILI,
Although there is no specific pattern of liver enzyme the offending medication should be withheld;
abnormalities in GLD, a cholestatic picture with eleva- rechallenge is offered if clinically necessary and only
tion in alkaline phosphatase and gamma-glutamyl after normalization of liver function. Patients with
transferase (GGT) is the most common, followed by a hepatitis due to DILI may be treated with steroids and
mixed pattern characterized by elevation of alkaline ursodeoxycholic acid (UDCA).[110,125,152] UDCA is a first-
phosphatase, gamma-glutamyl transferase, as well line therapy for PBC, and it has been shown to improve
serum aminotransferases. In hepatic sarcoidosis, most transplant-free survival.[153] Asymptomatic patients with
patients have either a cholestatic or a mixed picture of hepatic sarcoidosis often do not require treatment and
| 11
Incidental granuloma on liver histology
Microgranuloma Lipogranuloma, fibrin-ring, epithelioid necrotizing or

non-necrotizing granuloma
Unlikely associated with any

specific underlying disorder. Work up for most common etiologies: PBC, TB,
Consider routine follow up if sarcoidosis, viral hepatitis, DILI

asymptomatic.
History and physical exam Diagnostic

History: Physical exam: Laboratory work up:
1. Past medical history - Right upper quadrant - Hepatic panel: ALT, AST, ALP,
2. Family history tenderness GGT, total and direct bilirubin
3. Travel history - Hepatosplenomegaly - Liver synthetic function: albumin,
4. Medications and - Signs of portal prothrombin time, platelet count
duration of treatment hypertension: ascites, spider - Angiotensin-converting enzyme
angiomas, palmar erythema - Viral serologies: anti-HBs,
Review of systems: - Jaundice HBsAg, anti-HBc, anti-HCV, anti-
- Rash, excoriations HAV IgM
Systemic symptoms -
- Autoimmune panel: anti-
fatigue, weight loss, night
mitochondrial antibody, anti-
sweats, cough, insomnia,
smooth muscle antibody,
fever, change in bowel
antinuclear antibody, anti-liver-
movements
kidney antibody
Liver-related symptoms - - Infections: QuantiFERON Gold
jaundice, pruritus, Imaging:
abdominal swelling, easy - Ultrasound of the liver
bruising - Chest radiograph
Diagnosis established?
YES NO
Initiate appropriate follow Further work up: cross-sectional imaging, stool test
up and/or treatment for ova and parasites, 1-3-b-D-glucan assay, specific
staining of liver biopsy.
F I G U R E 3 Workup of incidental granuloma on the liver biopsy. Abbreviations: ALT, alanine aminotransferase; AST, aspartate amino-
transferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; PBC, primary biliary cholangitis; TB, tuberculosis.
the disease may be self-limiting. If cholestatic liver synthetic function every 6–12 months is reasonable.
disease or signs of PH develop, prompt treatment with Patients with chronic forms of GLD should be
steroids, UDCA, antimetabolites, or anti-TNF medica- approached as any other patient with chronic liver
tions is indicated.[53,117] In the study by Graf et al, disease including appropriate vaccination and screen-
patients with hepatic sarcoidosis demonstrated similar ing. If the patient progresses to cirrhosis, noninvasive
biochemical responses to both steroids and UDCA.[144] tests to evaluate for PH and imaging every 6 months
In patients with an incidental finding of granulomas to screen for HCC are indicated. A liver transplant
on biopsy, periodic monitoring of liver enzymes and should be considered in case of decompensated liver
12
disease. Disease recurrence in the transplanted liver Steven M. Holland https://orcid.org/0000–0003–

is reported in CVID, sarcoidosis, and PBC.[102,154,155] 3207–5464
There is not enough evidence to link the presence of David E. Kleiner https://orcid.org/0000–0003–3442–
TB granulomas in the pretransplant with the develop- 4453
ment of TB in the posttransplant period.[156] Patients Theo Heller https://orcid.org/0000–0002–2643–6289
with inborn errors of immunity should be considered
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Received: 10 November 2023 | Accepted: 18 December 2023

Granulomatous liver diseases

Maria Mironova1 | Harish Gopalakrishna1 | Gian Rodriguez Franco1 |

INTRODUCTION for making the correct underlying diagnosis. The

Hepatology Communications. 2024;8:e0392. www.hepcommjournal.com | 1

conditions such as primary biliary cholangitis (PBC) PATHOGENESIS

TABLE 1 Top etiologies of hepatic granulomas in cohorts from different countries

TNFα IFNγ IL-2 IL-12 IL-4 IL-5 IL-13

schistosomiasis.[21] Interestingly, in schistosomiasis It can be done for investigation of a systemic disorder

DILI.[39] infections toward DILI: fibrin-ring granulomas are

(A) (B) (C)

(D) (E) (F)

(G) (H) (I)

TABLE 3 Most common etiologies of hepatic granulomas

Q fever (Coxiella burnettii)[12] Granulomatosis with polyangiitis[58]

Syphilis[61] Primary biliary cholangitis[62]

of disseminated BCG infection.[122] Animal studies

different types of mycobacteria. PCR and the PCR- Fungal infections

nant lesions.[87,140] Imaging augments the laboratory workup in the

Incidental granuloma on liver histology

Microgranuloma Lipogranuloma, fibrin-ring, epithelioid necrotizing or

Unlikely associated with any

Consider routine follow up if sarcoidosis, viral hepatitis, DILI

History and physical exam Diagnostic

disease. Disease recurrence in the transplanted liver Steven M. Holland https://orcid.org/0000–0003–

2. Matheus T, Muñoz S. Granulomatous liver disease and

Squadrini F. Primary hepatic actinomycosis. J Infect. 1986;12:65–9. enterol. 1999;94:1973–4.

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