Histopathology of granulomatous liver disease

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Abbreviations

DILI

drug‐induced liver injury

PBC

primary biliary cholangitis

A granuloma is a collection of specialized tissue macrophages known as histiocytes. There is often a lymphocytic component, either intermingled with or forming a cuff around the histiocytes, but it is the aggregation of macrophages that is required to classify an inflammatory process as granulomatous. From a morphological standpoint, granulomas may be either loose or well‐formed (epithelioid) and caseating or noncaseating. Sometimes the constituent histiocytes will fuse together forming multinucleated giant cells (Fig. 1).

Figure 1.

Several foreign body type multinucleated giant cells, formed by the fusion of adjacent histiocytes. Notice the jumbled arrangement of nuclei within the cells.

Granulomas are relatively common in liver samples, identified in 2% to 10% of cases.1 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; there may be no accompanying inflammation (bland granulomas) or an associated lobular inflammatory infiltrate (granulomatous hepatitis). The location and type of granuloma(s), background changes within the liver, and the presence or absence of systemic involvement help provide clues to the diagnosis. Clinical diseases associated with hepatic granulomas are listed in Table 1.1, 2, 3, 4, 5 The most common etiologies will be discussed briefly in the following sections.

Table 1.

Causes of Hepatic Granulomas/Granulomatous Hepatitis

PBC

Sarcoidosis

DILI

Infection (bacterial, viral, parasitic, fungal)

Histoplasma, Mtb, MAI, hepatitis C, Schistosoma

Malignancy

Lymphoma, hepatocellular carcinoma, metastatic carcinoma

Primary sclerosing cholangitis

Toxin exposure/foreign body

Lipogranuloma

Idiopathic

Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is an autoimmune condition that targets the small, intrahepatic bile ducts.6 The florid duct lesion, initially designated chronic nonsuppurative destructive cholangitis, is the pathological hallmark.7 Granulomas are a requisite 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 (Fig. 2). 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.

Figure 2.

(A) 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. (B) Higher‐power view illustrating how the histiocytes and lymphocytes of the florid duct lesion are directly injuring the bile duct, with disruption of the basement membrane and nuclear irregularity.

Sarcoidosis

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.8 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.9 Although liver involvement is common (50%‐70% of sarcoid livers histologically contain granulomas), only 20% to 40% of patients will have elevated LFTs.5 Less than 20% of patients will have clinically significant liver disease.8

Noncaseating epithelioid granulomas are present in both the portal tracts and hepatic lobules (Fig. 3). Roughly one‐third of liver biopsies of hepatic sarcoidosis may have changes similar to those of PBC (19%) or primary sclerosing cholangitis (13%).4 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. The granulomas may even coalesce to form tumefactive nodules occupying >90% of the tissue sample in a small number (6%) of cases.4 These may be mistaken for neoplasms by imaging. One never encounters this degree of granulomatous inflammation in PBC. Table 2 outlines the pathological and clinical features that are helpful in distinguishing sarcoidosis from PBC. Sarcoid granulomas are associated with end‐stage fibrosis (cirrhosis) in only 6% to 8% of patients.4, 8 Vascular abnormalities, including portal hypertension (with or without cirrhosis) and Budd‐Chiari syndrome, are rare but do occasionally occur.5

Figure 3.

(A) 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. (B) In contrast with PBC, the epithelioid granuloma of sarcoidosis (open arrow) is well formed and usually not directed at the bile duct (closed arrow). (C) In some cases, the epithelioid granulomas (white arrows) fuse to become tumefactive nodules. Note the numerous giant cells that are present (black arrows).

Table 2.

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

Infection

A variety of bacterial, viral, fungal, and parasitic organisms may induce a granulomatous reaction in the liver. A comprehensive review of infectious granulomas of the liver is beyond the scope of this article. Interested readers should see Lamps1 for a thorough and authoritative review.

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. Sequential biopsies for previously diagnosed conditions (e.g., sarcoidosis, Crohn's disease, or PBC) would not require special stains.

Granulomas with central, caseating necrosis are considered infectious until proven otherwise. As detailed earlier, conditions such as PBC and sarcoidosis are not associated with caseating necrosis (sarcoid granulomas may rarely contain fibrinoid necrosis). Unfortunately, histochemical stains lack sensitivity, so a negative result does not preclude an infectious process.

Drug‐Induced Liver Injury

Drug‐induced liver injury (DILI) most commonly manifests histologically as cholestasis.10 Granulomas may be identified in a minority of cases. One study demonstrated granulomatous hepatitis in 3.6% (4/110) of patients with documented DILI.10 Granulomas are not tumefactive (as seen in sarcoidosis) or typically directed at the bile ducts (as seen in PBC). Instead, they are usually small (Fig. 4) 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.10, 11

Figure 4.

DILI‐related 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.

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.12