This document discusses histopathology of granulomatous liver disease. It defines granulomas and outlines the differential diagnosis, which includes primary biliary cirrhosis, sarcoidosis, infection, drug-induced liver injury, and lipogranuloma. Primary biliary cirrhosis is characterized by florid duct lesions containing loose granulomas surrounding injured bile ducts. Sarcoidosis features well-formed, epithelioid granulomas that are often accompanied by multinucleated giant cells. Infection may cause caseating or noncaseating granulomas depending on the pathogen. Drug-induced liver injury can result in small, lobular microgranulomas with associated hepatitis. Lip

1. Histopathology of granulomatous liver
disease

2. Presentation outlines
Introduction
Differential diagnosis
Primary biliary cirrhosis
Sarcoidosis
Infection
Drug-induced liver injury
Lipogranuloma

3. Granuloma
Defined as
A histologic pattern of tissue reaction which appears following cell injury. Granulomatous
inflammation is caused by a variety of conditions including infection, autoimmune, toxic,
allergic, drug, and neoplastic conditions. The tissue reaction pattern narrows the pathologic and
clinical differential diagnosis and subsequent clinical management
From a morphological standpoint,
 granulomas may be either loose or well-formed (epithelioid) , caseating or noncaseating.
 Sometimes the histiocytic will fuse together forming multinucleated giant cells.
Granulomas are relatively common in liver samples, identified in 2% to 10% of cases.
Clinically, they may be restricted to the liver or reflect hepatic involvement by a systemic process.
 Histologically, they may be seen in the portal tracts, hepatic lobules, or both.

4. Differential diagnosis of liver
granulomatous disease

8. Primary biliary cholangitis
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis
Definition
Is an autoimmune disease of the liver. It results from a slow, progressive destruction of
the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a
condition called cholestasis. Further slow damage to the liver tissue can lead to scarring,
fibrosis, and eventually cirrhosis.
Causes:
most people >90 % have anti-mitochondrial antibodies (AMAS) against pyruvate
dehydrogenase complex (pdc-e2), an enzyme complex that is found in the mitochondria

9. Primary biliary cholangitis
Signs and symptoms:-
fatigue
dry skin and eyes
Itching (pruritus)
jaundice in severe PBC.
Impairs bone density with increased risk of fracture.
Xanthelasma may be present as a result of increased cholesterol levels.
Complications :-
(progress to cirrhosis) ascites, enlarged spleen, oesophageal varices and
hepatic encephalopathy, including coma in extreme cases in more
advanced disease.

10. Primary biliary cholangitis
Pathogenesis
Evidence for autoimmune etiology
• Aberrant expression MHC class II molecules on bile duct epithelial cells
• Autoreactive T cells around bile ducts
• Hypergammaglobulinemia with complement activation and circulating immune complexes
Associated extrahepatic autoimmune diseases
• Sjogren syndrome, scleroderma, thyroiditis, rheumatoid arthritis, membranous glomerulonephritis

11. Primary biliary cholangitis
Diagnose
• Elevated gamma-glutamyl transferase and alkaline phosphatase (alp) are found in
early disease. Elevations in bilirubin occur in advanced disease.
• Antimitochondrial antibodies are the characteristic serological marker for pbc, being
found In 90-95 percent of patients.
• Abdominal ultrasound, MRI scanning (mrcp) or a CT scan is usually performed to rule
out blockage to the bile ducts. An endoscopic investigation of the bile duct, may be
performed.

12. Primary biliary cholangitis
Morphology
• Most patients can be diagnosed without invasive investigation however, a liver biopsy is needed to
determine the stage of disease.
The florid duct lesion, chronic nonsuppurative destructive cholangitis, is the pathological hallmark.
• Granulomas are essential component of the florid duct lesion. Although they may rarely be
epithelioid, a more typical appearance is that of a loose collection of histiocytes surrounding an
injured bile duct.
• There is disruption of the bile duct basement membrane and infiltration by lymphocytes.
• Presence of florid duct lesions varies with the stage of the disease. They are more common early in
the course and diminish in frequency as PBC progresses and burns out.

13. Histopathology stages of PBC:-
Stage 1 – portal stage:
• normal sized triads; portal inflammation, subtle bile duct damage. Granulomas are often
detected in this stage.
Stage 2 – periportal stage:
• enlarged triads; periportal fibrosis and/or inflammation. Typically characterized by the
finding of a proliferation of small bile ducts.
Stage 3 – septal stage
• active and/or passive fibrous septa.
Stage 4 – biliary cirrhosis:
• nodules present; garland or jigsaw puzzle pattern.

14.  Heavily inflamed portal tract
containing a typical florid
duct lesion. The bile duct (white
arrow) is encircled by a loose
aggregate of histiocytes (black
arrows).
 Dense lymphoplasmacytic
inflammation is also present in the
portal tract histiocytes and
lymphocytes of the florid duct
lesion are directly injuring the bile
duct, with disruption of the
basement membrane and nuclear
irregularity.

15. PBC: EARLY HISTOPATHOLOGY
Early stage PBC (florid duct lesion): portal mononuclear inflammation
destroying bile duct with granulomatous response (arrowheads)
Fig. 18-35, PBFD 9th ed, 2015
Residual bile
duct epithelium

16. Granulomatous cholangitis in primary biliary cirrhosis (PBC). Detail from
a portal tract with dense lymphoplasmacytic infiltrate and lymphoid
aggregate (left). The interlobular bile duct (center) shows a focal rupture
of its cholangiocytic lining, at the site of an adjacent epithelioid
granuloma. (H&E)

17. Granulation tissue with a poorly formed
granuloma to the left of centre. Within this
area there is a multinucleate giant cell of
the Langhans type

18. (A) Primary biliary cirrhosis. Note the significant
inflammatory response and expansion of portal areas in a
granulomatous reaction.
(B) note the inflammatory cells spilling over into the adjacent
liver lobule resulting in an interface hepatitis (arrow).

19. Sarcoidosis
is a multisystem condition of unknown etiology thought to represent a reaction to
one or more antigens.
 Worldwide prevalence is 2 to 60/100,000 people.
 It is defined by the presence of noncaseating epithelioid granulomas in affected
organs or sites.
 Most frequent sites of involvement are the lung (>90%), lymph nodes, and liver.
Although liver involvement is common (50%-70% of sarcoid livers histologically
contain granulomas), only 20% to 40% of patients will have elevated lfts. Less than
20% of patients will have clinically significant liver disease.

20. Sarcoidosis
Noncaseating epithelioid granulomas are present in both the portal tracts and hepatic
lobules.
Roughly one-third of liver biopsies of hepatic sarcoidosis may have changes similar to
those of pbc (19%) or primary sclerosing cholangitis (13%).However, in the majority of
cases, the granulomatous infiltrates of PBC and sarcoidosis are sufficiently different to
allow one to distinguish them.
 Sarcoid granulomas are typically larger, more numerous, better defined, not directed at
the bile duct, and often associated with multinucleated giant cells.

21. Large, noncaseating granuloma from patient with sarcoid.

22.  Tight, well-formed, noncaseating
epithelioid granuloma of sarcoidosis.
 There is a cuff of lymphocytes (black
arrows) and Langhans giant cell (white
arrow). Note how the nuclei of the giant
cell are arranged in a ring along the
periphery, in contrast with foreign body
type giant cells. Although not specific,
Langhans type giant cells are
characteristic of sarcoidosis

23. In contrast with PBC, the
epithelioid granuloma of
sarcoidosis (open arrow) is
well formed and usually not
directed at the bile duct
(closed arrow).

24. In some cases, the epithelioid
granulomas (white arrows)
fuse to become tumefactive
nodules.
Note the numerous giant cells
that are present (black
arrows)

25. (A) Sarcoidosis. Note the portal distribution and excessive
fibrosis around granuloma (arrow; trichrome stain)
(B) sarcoidosis, extensive fibrosis (arrow; trichrome stain

26. Histological and clinical features of
PBC and sarcoidosis
Diagnosis Granuloma
Location
Bile Duct
Destruction
Granuloma
Type
Confluent
Granulomas
Giant Cells AMA Systemic
Disease
PBC Portal based Present Poorly formed Absent Absent to rare Positive Absent
Sarcoidosis Portal and
lobular
Absent to rare Well formed Occasional Common Negative Present

27. Infection
A variety of bacterial, viral, fungal, and parasitic organisms may induce a
granulomatous reaction in the liver.
From a practical, clinical perspective, special stains for acid-fast bacilli and fungal
organisms (GMS or periodic acid–schiff) are performed anytime a newly diagnosed
granulomatous process is encountered in the liver.
Granulomas with central, caseating necrosis are considered infectious until proven
otherwise. Conditions such as PBC and sarcoidosis are not associated with caseating
necrosis.

28. Caseating epithelioid granuloma:
typically associated with infections, most notably tuberculosis.
Suppurative granuloma:
(granulomatous inflammation with stellate abscess formation or suppurative inflammation):
bartonellosis, yersinosis, listerosis, actinomycosis and fungal infection.
Fibrin ring granuloma:
(also known as doughnut granuloma; central fat globule surrounded by a circumferential rim
of fibrin and histiocytes)could be associated with mycobacterial infection, staphylococcal
bacteremia, leishmaniasis, toxoplasmosis, cytomegalovirus, epstein-barr virus, acute hepatitis
a, systemic lupus erythematosus, allopurinol toxicity and lymphoma.

29. 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

30. (A) Granulomatous hepatitis associated with AIDS. Note the
ill-defined, nature of granulomas (arrows) (B) example of a better-defined granuloma in granulomatous
hepatitis of AIDS.
(C) large numbers of Mycobacterium avium intracellulare
within and around loosely arranged aggregates of epithelioid
histiocytes (arrow). (D) clusters of acid fast bacilli (arrow; Fite acid fast stain)

31. Q fever is characterized by hepatitis with granulomas showing a central clearing
surrounded by a fine hyaline ring. However, not all granulomas in Q fever show
this feature. Conversely, other processes, such as allopurinol toxicity and
cytomegalovirus mononucleosis, may also have such “donut-hole” granulomas

32. Fibrin ring granuloma central
fat globule surrounded by a
circumferential rim of fibrin
and histiocytes

33. Liver biopsy showing a
granulomatous reaction against
the ovum.
Schistosomiasis of liver. Note Schistosoma hematobium
egg with terminal spine in the center

34. Drug-induced liver injury
Drug-induced liver injury (DILI) most commonly manifests histologically as cholestasis.
 Granulomas may be identified in a minority of cases.
One study demonstrated granulomatous hepatitis in 3.6% of patients with documented
DILI.
Granulomas are not tumefactive (as seen in sarcoidosis) or typically directed at the bile
ducts (as seen in PBC). Instead, they are usually small and present within the hepatic lobule,
accompanied by a portal and lobular inflammatory infiltrate (i.E. Granulomatous hepatitis).
Eosinophils are typically present.
Numerous drugs and medications have been implicated in granulomatous dili, with the
most common being antibiotics, nonsteroidal anti-inflammatory and antirheumatic agents,
antituberculous medications, and antiepileptics.

35. small, lobular microgranuloma.
Microgranulomas such as this are
typically less than seven cells in
diameter.
Note its presence next to a central
vein in zone 3 of the hepatic
lobule.

36. (A) Granulomatous hepatitis, hypersensitivity to medication.
Notice the lobular distribution of granuloma (arrow).
(B) extensive eosinophilic reaction in the inflammatory cuff of
the granuloma (arrow).

37. Lipogranuloma
The lipogranuloma is a special type of granuloma composed of lipid-containing
macrophages with associated lymphocytes.
 Initial studies suggested that these formed as a reaction to mineral oil in some foods
and medications.
However, it has subsequently been demonstrated that they may also form when
histiocytes ingest fat droplets released by ruptured hepatocytes in the setting of fatty
liver disease.

38. central fat globule
surrounded by
histiocytes

39. (A) Granulomatous response in liver (black arrow)
associated with a metastatic malignant neoplasm, an islet
cell carcinoma, a neuroendocrine neoplasm (red arrow)
(B) higher power view of the epithelioid granuloma (arrow)

40. SUMMARY

41. References
• STERNBERG’S SURGICAL PATHOLOGY
• ROSAI AND ACKERMAN‘ S SURGICAL PATHOLOGY
• LEWIS, J., 2018. HISTOPATHOLOGY OF GRANULOMATOUS LIVER DISEASE. CLINICAL LIVER
DISEASE, 11(3), PP.77–80. AVAILABLE AT: HTTP://DX.DOI.ORG/10.1002/CLD.695.