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Granulomatous Liver Disease


Key Points

  • 1

    Granulomas consist of activated macrophages (epithelioid macrophages) accompanied by T lymphocytes and other immune cells, which infiltrate liver tissue as nodular lesions in reaction to indigestible or foreign antigen or are due to triggering of an untoward immunologic reaction (e.g., drug-induced liver injury [DILI]).

  • 2

    The major causes of hepatic granulomas include infectious agents (especially tuberculosis), sarcoidosis, primary biliary cholangitis (PBC), drugs, systemic diseases (e.g., Crohn disease), and neoplasms (e.g., Hodgkin lymphoma).

  • 3

    An elevated serum alkaline phosphatase level is the chief abnormality in serum liver biochemical tests.

  • 4

    The cause of hepatic granulomas may remain unknown in up to 50% of cases.

  • 5

    The workup for hepatic granulomas includes a complete history of therapeutic drugs, tests for antimitochondrial antibodies and angiotensin converting enzyme (ACE), and staining liver specimens with acid-fast and silver stains for mycobacteria and fungi, respectively.

Overview of Granulomas

Definition and Pathogenesis

  • 1.

    Granulomas are rounded 1- to 2-mm nodular collections of activated macrophages, T lymphocytes, and other immune cells that can infiltrate many tissues, including the liver, in response to an indigestible or foreign antigen or as a manifestation of an untoward immunologic response to a drug, bile duct injury (e.g., PBC), or other factors ( Fig. 28.1 ).

    Fig. 28.1, Histopathology of a noncaseating hepatic granuloma (sarcoidosis). Epithelioid macrophages occupy the center of the granulomas with peripherally dispersed lymphocytes (hematoxylin and eosin [H&E]).

  • 2.

    The principal immune cells in granulomas are activated macrophages resembling epithelial cells (epithelioid macrophages); CD4+ T cells (T helper [Th] lymphocytes); and sometimes multinucleated giant cells that develop from macrophage fusion.

  • 3.

    The cause of the granuloma influences the constituent immune cells and secreted products: type 1 T helper (Th1) cells and cytokines predominate in mycobacterial granulomas, whereas type 2 T helper (Th2) cells and cytokines predominate in schistosomal granulomas ( Fig. 28.2 ).

    Fig. 28.2, Generalized and specialized structural and functional characteristics of hepatic granulomas. The cellular constituents of hepatic granulomas are diagrammed at the bottom. Note that tuberculosis macrophage-rich granulomas show a type 1 T helper (Th1)–predominant lymphocytic response, with release of Th1 cytokines. In schistosomiasis, in contrast, enhanced numbers of eosinophils are present within the granulomas (mediated by secretion of interleukin 5 [IL-5]). In addition, release of IL-13 in schistosomiasis is an important factor resulting in portal fibrosis in the disease. IFN-γ, Interferon-gamma; iNOS, inducible nitric oxide synthetase; TNF-α, tumor necrosis factor alpha.

  • 4.

    Granulomas evolve by the elaboration of secretory products (cytokines and chemokines) by their constituent cells (interferon-gamma and interleukin-2 from Th lymphocytes), expansion of macrophage and T-cell pools, and specialization of macrophages for antigen digestion ( Fig. 28.3 ).

    Fig. 28.3, Development of a granuloma (red rods represent mycobacteria). Step 1: A macrophage engulfs mycobacterium. Step 2: Macrophage presentation of mycobacterial protein product(s) to a receptor on CD4+ lymphocytes. Step 3: CD4+ lymphocytes differentiate to precursor T helper lymphocytes (Th0), later differentiating into Th1 lymphocytes. Step 4: Th1 lymphocytes secrete interleukin 2 (IL-2), a clonal expander of CD4+ cells, as well as interferon gamma (IFN-γ), which upregulates lysosomal enzymes and reactive oxygen species (ROS) in macrophages in step 5. Step 6: Further recruitment of macrophages and lymphocytes with ongoing digestion of mycobacteria.

  • 5.

    Granulomas ultimately may persist, resolve, or undergo fibrosis or calcification.

Morphologic Types

Several types of granulomas are described in liver disease and are based on their histologic features and constituents ( Table 28.1 ). The presence of abundant eosinophils within granulomas warrants exclusion of DILI and parasite infestation.

TABLE 28.1
Types of Granuloma
Type Histologic Features Cause(s)
Caseating Peripheral macrophages ± giant cells; central necrosis Tuberculosis
Noncaseating Cluster of macrophages ± giant cells Sarcoidosis
Drugs
Lipogranuloma Lipid vacuole(s) surrounded by macrophages and lymphocytes Fatty liver
Mineral oil
Fibrin-ring (doughnut granuloma) Central lipid vacuole or empty space
Macrophages and lymphocytes
Ring of fibrin		 Q fever
Allopurinol
Hodgkin lymphoma

Incidence and Location

  • 1.

    Granulomas are found in 2.4% to 14.6% of liver biopsy specimens, according to surveys by and , although the figure of 10% is often quoted.

  • 2.

    Granulomas are found in any of the following microscopic sites in the liver, alone or in combination:

    • ▪

      Lobular (tuberculosis, sarcoidosis, drugs)

    • ▪

      Portal/periportal (sarcoidosis)

    • ▪

      Periductal (PBC)

    • ▪

      Perivenous (mineral oil lipogranulomas)

    • ▪

      Periarterial and intraarterial (phenytoin)

Causes of Hepatic Granulomas

The etiology is multifactorial; the major causes and examples are shown in Table 28.2 .

TABLE 28.2
Causes of Hepatic Granulomas
Etiology Specific Cause(s)
Infection Viral: Cytomegalovirus, infectious mononucleosis, hepatitis C virus infection
Bacterial: Brucellosis, tuberculosis
Rickettsial: Q fever
Spirochetal: Treponema pallidum infection
Fungal: Histoplasmosis
Parasitic: Schistosomiasis
Primary biliary cholangitis Early stages most commonly
Foreign body Suture, talc
Systemic disease Sarcoidosis, Crohn disease
Drug Allopurinol, phenytoin, penicillin
Neoplasia Hodgkin lymphoma

Clinical and Biochemical Features

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