Granulomatous Liver Disease

Vishal S. Chandan, MD

Tsung-Teh Wu, MD, PhD

11.1 INTRODUCTION

Granulomas are localized collections of macrophages and other inflammatory cells, such as lymphocytes, that usually develop in response to chronic antigen exposure. Granulomas also may contain multinucleated giant cells due to fusion of the macrophages. The prevalence of granulomas within liver biopsies ranges from 2% to 15% and up to a third of cases may not have a known etiology, even after full clinical workup.¹, ², ³, ⁴, ⁵, ⁶ Granulomas within the liver may be related to primary hepatic disease (PBC), or may be due to systemic diseases involving the liver and other organ systems, or may even be just an incidental finding. Table 11.1 summarizes the causes of hepatic granulomas. Sarcoidosis, primary biliary cirrhosis, drug-induced liver injury, and infection are the most common identifiable causes of hepatic granulomas in the United States.¹,⁷ In developing countries such as India, tuberculosis infection is the most common cause of hepatic granulomas. Careful assessment of the morphology and location of the granulomas can provide helpful clues regarding the etiology and a prioritized differential, information that can be very helpful to our clinical colleagues. In contrast, simply listing the generic differential for hepatic granulomas in the surgical pathology report is not of much help to most physicians. The term granulomatous hepatitis is used when the granulomas are poorly formed and are associated with significant inflammation within the liver parenchyma.

11.2 MORPHOLOGY OF GRANULOMAS AND THEIR DISEASE CORRELATES

Hepatic granulomas can be broadly divided in the following morphologic types.

Epithelioid granulomas

Epithelioid granulomas are composed of distinct collections of histiocytes, often with admixed lymphocytes. They often have well-defined edges separating them from the adjacent tissue (Fig. 11.1). Epithelioid granulomas are one of the most frequently seen types of granuloma within the liver and are associated with both primary and secondary

liver diseases. Special stains for microorganisms should be performed, as epithelioid granulomas can be associated with infectious organisms.

Table 11.1 Causes of hepatic granulomas

Infections
Bacterial
	Mycobacterium tuberculosis Mycobacterium avium-intracellulare Mycobacterium leprae Bartonella henselae (cat scratch disease) Brucella Rickettsia (Q fever)
Fungal
	Histoplasmosis Cryptococcus
Parasitic
	Schistosomiasis Visceral leishmaniasis (kala-azar)
Viral
	Hepatitis C virus Cytomegalovirus Epstein-Barr virus Hepatitis A virus Hepatitis B virus
Sarcoidosis
Intrinsic liver disease
	Primary biliary cirrhosis Primary sclerosing cholangitis Acute cellular rejection
Drugs
	Allopurinol Sulfonamides Isoniazid Phenytoin Hydralazine Quinidine
Neoplasms
	Hodgkin lymphoma Leukemia Hepatic adenoma Hepatocellular carcinoma Metastatic carcinoma
Other diseases
	Crohn’s disease Chronic ulcerative colitis Common variable immunodeficiency Chronic granulomatous disease Collagen vascular diseases

Figure 11.1 Epithelioid granuloma. A well-defined collection of histiocytes is seen.

Figure 11.2 Necrotizing granuloma. A central area of necrosis is surrounded by histiocytes and lymphocytes.

Necrotizing/caseating granulomas

These granulomas show central “dirty” necrosis composed of nuclear debris and are almost always infectious in origin, although no organisms are found in many cases (Fig. 11.2). The mononuclear cells tend to be palisading at the periphery. These granulomas often destroy the adjacent liver parenchyma and do not respect the hepatic architecture.

Microgranulomas

These are small collections (about 3 to 7) of Kupffer cells in the hepatic lobules and can be admixed with other inflammatory cells or apoptotic hepatocytes (Fig. 11.3). Microgranulomas usually represent a reparative response to an episode of acute lobular injury and are nonspecific in nature. The macrophage cytoplasm may contain light pigment and they are usually highlighted on the periodic acid-Schiff (PAS) stain. Although this pattern is important to recognize within the liver, the term microgranuloma is probably best avoided in the pathology report as the clinical colleagues may misunderstand this term.

Granulomatous inflammation

Sometimes the granulomas are so indistinct that it is better to use the term granulomatous inflammation. These are poorly formed, ill-defined histiocytic aggregates that often are admixed with other inflammatory cells (Fig. 11.4). This pattern can be seen with a wide variety of conditions. Portal-based granulomatous inflammation is more likely to be associated with drug effect or biliary tract disease, whereas lobular granulomatous inflammation is more likely to be infectious or drug-induced.

Figure 11.3 Microgranuloma. A small collection of a few histiocytes and lymphocytes is seen.

Figure 11.4 Granulomatous inflammation. An ill-defined aggregate of histiocytes and other inflammatory cells is seen.

Florid duct lesions and granulomatous inflammation

A florid duct lesion is characterized by lymphocytes and plasma cells cuffing a medium-sized bile duct. The bile duct epithelium is damaged/injured by infiltrating lymphocytes and is associated with granulomatous inflammation (Fig. 11.5). Sometimes the florid duct lesion can be associated with epithelioid granulomas. Florid duct lesions are typically associated with primary biliary cirrhosis or less commonly with drug effects.

Figure 11.5 Florid duct lesion and granulomatous inflammation. In this portal tract, granulomatous inflammation is associated with bile duct injury.

Fibrin-ring granulomas

Fibrin-ring granulomas are epithelioid granulomas with a central lipid droplet surrounded by an eosinophilic fibrin ring that stains positively with Masson trichrome stain and phosphotungstic acid hematoxylin (PTAH) stain (Fig. 11.6).⁸,⁹ They were first described in association with Q fever, but are now considered quite nonspecific, as they can be seen in a number of conditions such as hepatitis A, chronic hepatitis C, Epstein-Barr virus (EBV) infection, cytomegalovirus (CMV) infection, toxoplasmosis, leishmaniasis, Rickettsia typhus, Hodgkin disease, allopurinol reaction.¹,⁵,⁸,¹⁰,¹¹ Nonetheless, fibrin-ring granulomas are most commonly associated with infections or drug effects.

Figure 11.6 Fibrin-ring granuloma. Epithelioid granulomas with a central lipid droplet surrounded by an eosinophilic fibrin ring.

Figure 11.7 Foreign body granuloma. This biopsy in patient with IV drug use showed aggregates of histiocytes and giant cells containing the foreign brownish titanium pigment.

Foreign body granulomas

Foreign body granulomas contain particulate material within cytoplasmic vacuoles. The foreign material may be seen on hematoxylin and eosin (H&E) stain or on polarization of the granuloma (Figs. 11.7 and 11.8). Foreign body granulomas in the liver can be caused by silicone, starch, or talc from injection drug use. They also may be related to prior abdominal surgery or therapeutic tumor embolization.

Lipogranulomas

Lipogranulomas are composed of small aggregates of histiocytes surrounding vacuoles of lipid/mineral
oil and may be stained with Oil red O on frozen sections (Fig. 11.9). Lipogranulomas often have a bit of associated fibrosis, but overall do not contribute to liver fibrosis. They are commonly associated with fatty liver disease or chronic hepatitis C but can also be incidental findings. They are usually found within the portal areas or next to the central veins.

Figure 11.8 Foreign body granuloma, polarized light. Same case as in Figure 11.6, highlighting the titanium granules under polarized light.

Figure 11.9 Lipogranuloma. A collection of histiocytes surrounds vacuoles of fat in a portal tract.

11.3 GRANULOMAS ASSOCIATED WITH BACTERIAL INFECTIONS

Mycobacterium tuberculosis

Almost all cases of miliary tuberculosis have liver disease characterized by granulomas, which typically involving the portal areas.¹² Hepatic involvement is also commonly seen in cases of pulmonary tuberculosis and cases of localized extrapulmonary tuberculosis.¹⁰,¹³,¹⁴ Tuberculous hepatic granulomas are especially prevalent in HIV-positive populations. Sometimes on radiography, the confluent granulomas are concerning for a neoplastic process because the liver has a mass lesion and there can be periportal lymphadenopathy.

Mycobacterium tuberculosis granulomas are usually small to medium-sized epithelioid granulomas with caseating necrosis, often surrounded by a ring of lymphocytes and histiocytes. These granulomas may coalesce by central liquefactive necrosis to form larger nodules. Older granulomas may also be calcified or fibrotic. The Mycobacterium tuberculosis organisms are small and often sparse and hence may be difficult to identify on the acid-fast bacillus (AFB) stain. A repeat AFB stain on the deeper sections may be useful. Polymerase chain reaction (PCR) and cultures are also important tools for detecting this infection.

Mycobacterium avium-intracellulare

This infection is frequently seen in HIV-positive or other severely immunosuppressed individuals. Liver involvement can be seen in more than 50% of patients with disseminated Mycobacterium avium-intracellulare (MAI) infection.¹⁵,¹⁶ In immunosuppressed patients, MAI infections within the liver usually show aggregates of foamy histiocytes in the hepatic parenchyma and portal tracts (Fig. 11.10). Immunocompetent patients may have well-defined epithelioid granulomas with other inflammatory cells, such as lymphocytes and neutrophils. Large numbers of organisms are identified on the AFB stain in immunosuppressed patients, whereas organisms are usually rare in immunocompetent individuals (Fig. 11.11). In such cases performing culture and PCR studies may be useful. Infections such
as Whipple’s disease and Rhodococcus equi may also cause foamy histiocytic aggregates within the liver.

Figure 11.10 Mycobacterium avium-intracellulare. Aggregates of foamy histiocytes are found within the lobule.

Figure 11.11 Mycobacterium avium-intracellulare, Fite stain. A Fite stain highlights numerous acid-fast microorganisms within the histiocytes.

Mycobacterium leprae

Studies have shown liver involvement in greater than 50% of patients with lepromatous leprosy and in up to 20% of patients with tuberculoid leprosy.¹⁷, ¹⁸, ¹⁹ In lepromatous leprosy, scattered aggregates of foamy histiocytes containing multiple acid-fast bacilli are usually seen within the hepatic lobules and the portal areas, with minimal accompanying inflammation. Epithelioid granulomas with giant cells are usually seen in tuberculoid leprosy, but the organisms are difficult to identify on the AFB stains.

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