Granulomas are found in as many as 10%of liver biopsies, often unexpectedly encountered in biopsies performed for various indications. There are many identifiable causes, including infections and parasitic infestations (4,7,8,9,10,14,16,26,27,30,35,38,44,55,58,59), immune responses (3,7,11,17,41), foreign materials, and reactions to many drugs (22,23,33,43,45,54,61) (Table 12.1). In as many as one third of cases, the cause may not be determined even when all clinical data are examined and all histologic methods are applied (e-Figs. 12.1-12.4) (1,2,15,18,19,25,28,32,56,57,67). Even after applying special techniques, histologic and immunohistochemical, the cause will still be undetermined in as many as half of the cases studied. Molecular approaches, including polymerase chain reaction (PCR) to identify organisms (e.g., Histoplasma (10)), Mycobacteria (e-Figs. 12.5, 12.6) are useful but not yet widely applied.
TYPES OF GRANULOMAS
Liver granulomas resemble those seen in other organs. Nonnecrotizing, noncaseating epithelioid and giant cell granulomas are characteristically seen in association with sarcoidosis (Fig. 12.1, e-Figs. 12.7-12.15) (13,28,29) and drug reactions, as well as immune responses, although the sarcoid granulomas may sometimes show slight central necrosis with polymorphonuclear leukocytic infiltration. Older sarcoid lesions show varying degrees of hyalinization and may even disappear to be replaced by collagenous scars (e-Figs. 12.13, 12.14). Sarcoidosis typically has clusters of granulomas (e-Figs. 12.13, 12.14) in the portal and periportal region with eventual fibrosis. The granulomas of drug reaction and primary biliary cirrhosis (PBC) are sarcoid-type but, unlike sarcoid, are sporadic and, often, individual. PBC granulomas tend to be in portal tracts close to the bile duct. Drug-induced granulomas can involve any area of the liver. Many cases reported as “granulomatous hepatitis consistent with sarcoidosis” are actually instances of drug-induced granulomatous disease. The natural history of drug-induced granulomas is not known. Granulomas, without necrosis, are seen in some viral disorders, including hepatitis C (16,65).
Granulomas with necrosis suggest, but do not prove, infectious cause. The prototype, of course, is tuberculosis, with typical central caseation. In early tuberculosis, including miliary, there may be little or no necrosis (e-Figs. 12.5, 12.6) and, instead, a polymorphonuclear response may be prominent. Other organisms, including bacteria, fungi, and protozoa, also cause necrotizing granulomas. Patients treated for malignancy with bacillus Calmette-Guérin (bCG) also have necrotizing granulomas (3). In chronic granulomatous disease (CGD) of childhood, granulomas contain homogeneous eosinophilic material, necrotic debris, or typical acute inflammatory exudate (28,47). CGD portal tracts show chronic inflammation and fibrosis, as well as ceroid-type pigment. Specific organisms can sometimes be demonstrated with special stains.
|
TABLE 12.1 Causes of Hepatic Granulomas |
|
|
Foreign body granulomas sometimes include recognizable material, such as talc, silicon, or suture material, and can also be seen with specific organisms, such as schistosomiasis (e-Fig. 12.16) (1,51,56).
|
|
|
FIGURE 12.1 Photomicrograph of liver biopsy from a patient with sarcoidosis showing multiple noncaseating epithelioid and giant cell granulomas in the portal tract and periportal (zone 1) portion of the liver (hematoxylin-eosin, original magnification × 100). |
|
|
|
FIGURE 12.2 Photomicrograph of Q fever, showing characteristic, but not pathognomonic, fibrin ring granuloma (hematoxylin-eosin, original magnification ×400). |
Lipogranuloma is a special form of granuloma developing in various conditions (5,40,63) after rupture of steatotic hepatocytes or when excess lipid enters the liver from abdominal and mesenteric sites. They are most often seen in alcoholic liver disease. The usual lipogranuloma consists of focal accumulations of macrophages, which may be epithelioid (e-Fig. 12.17). Alternatively, leukocytes, including polymorphonuclear forms, are seen without epithelioid or giant cell clusters. Lipogranulomas can be indistinguishable from other granulomas since their lipid component is irregularly distributed and not seen in every level of sectioning. Lipogranulomas ultimately become fibrotic. At one time, mineral oil ingestion was considered the principal cause of lipogranuloma, but this is unlikely.
Fibrin-ring granulomas are distinctive, but not etiologically specific (Fig. 12.2) (28,39,46). Previously considered diagnostic for Q fever (e-Figs. 12.18-12.23) (21,49,51,60), they are recognized in other conditions, including cytomegalovirus (37), Epstein-Barr infection (48), hepatitis A (53,66), leishmaniasis (45), allopurinol hypersensitivity (62), and others (21,39,46).
Incomplete (poorly formed) granulomas are seen in patients with acquired immune deficiency syndrome (e-Figs. 12.24, 12.25) (28,64). These generally consist of small clusters of epithelioid cells, without giant cells and generally without necrosis. Despite their relatively modest appearance, they may contain innumerable Mycobacterium avium-intracellulare complex (MAI) acid-fast bacilli (Fig. 12.3, e-Fig. 12.26).
DISTRIBUTION OF GRANULOMAS
In some disorders the granulomas almost always occur in a specific area, whereas in other disorders they may be randomly distributed (Table 12.2).
For example, sarcoid-like PBC granulomas are portal, usually close to the bile duct (Fig. 12.4), and are distinctly unusual in the lobule. In sarcoidosis, granulomas are usually portal or periportal (Fig. 12.1).
|
|
|
FIGURE 12.3 Photomicrograph of poorly formed (incomplete) granuloma from a patient with acquired immunodeficiency syndrome, with innumerable acid-fast bacilli of Mycobacterium avium-intracellularecomplex (MAI). (A. Hematoxylin-eosin, original magnification × 400; B. Ziehl-Neelsen, × 400). |
Infectious disorders generally do not display a particular geographic preference. The granulomas of tuberculosis and fungal or bacterial disorders may be distributed throughout the liver. Similarly, drug-associated granulomas may be anywhere in the liver. Drug-induced granulomas, as well as those with parasitic disorders, can show many eosinophils in addition to the usual lymphocytes and monocytes.
|
TABLE 12.2 Examples of Distribution Patterns of Hepatic Granulomas |
||||||||
|
IDENTIFYING THE CAUSE OF THE GRANULOMA
Hepatic granulomas can be considered to belong to one of four groups (12): (i) the cause is obvious on the initial liver biopsy specimen; (ii) the cause is determined with special histochemical or immunohistochemical methods, or with supporting clinical information; (iii) the cause remains unproven but is strongly favored by histologic findings; and (iv) the cause cannot be established. Some examples of these are the following:
1. A granuloma whose cause is obvious with hematoxylin-eosin is schistosomiasis (42) (Fig. 12.5, e-Fig. 12.16).
|
|
|
FIGURE 12.4 Photograph of sarcoid-type granuloma in a patient with primary biliary cirrhosis, showing close proximity to injured bile duct (hematoxylin-eosin, original magnification × 200). |
|
|
|
FIGURE 12.5 Photomicrograph of portal tract granuloma showing partially digested shells of Schistosoma mansoni(hematoxylin-eosin, original magnification × 200). |
2. Special histochemical or immunohistochemical methods may be required to identify tuberculosis and other infectious disorders. In situ hybridization can confirm cytomegalovirus in the immunosuppressed liver transplantation patient (Fig. 12.6). Simple polarizing lenses can demonstrate foreign material. In PBC, the typical clinical presentation of granuloma, characteristic laboratory findings, including elevated titers of antimitochondrial antibodies, coupled with bile duct injury explains the nature of the characteristic granuloma. In drug-induced granulomas, eosinophils are often prominent, and when this etiology is suggested, a detailed history may suggest a likely cause (28).
|
|
|
FIGURE 12.6 Photomicrograph of liver biopsy showing a poorly formed granuloma with cytomegalovirus in a patient 8 days after orthotopic liver transplantation (hematoxylin-eosin, original magnification ×400). |
|
|
|
FIGURE 12.7 Photomicrograph of autopsy specimen showing characteristic granuloma of syphilis (gumma) (hematoxylin-eosin, original magnification ×100). |
3. Some granulomas, such as the fibrin-ring granuloma of Q fever (Fig. 12.6, e-Figs. 12.18-12.23) or the gumma of syphilis (Fig. 12.7), can help direct the clinical studies that establish cause. The clustering of epithelioid granulomas in sarcoid, although not specific, is strongly suggestive of that diagnosis (Fig. 12.1, e-Figs. 12.14, 12.15).
4. In many instances a diagnosis cannot be established (e-Figs. 12.1-12.4). In these cases, drug reaction or exposure to toxin is generally suspected, but the possibility of a remote neoplasm, including lymphoma (31,50), should be considered.
Key features are summarized in Table 12.3.
|
TABLE 12.3 Key Features of Hepatic Granulomas |
|
|
REFERENCES
1. Alexander JF, Galambos JT. Granulomatous hepatitis. Am J Gastroenterol 1973;59:23-30.
2. Anderson CS, Nicholls J, Rowland R, et al. Hepatic granulomas: a 15-year experience in the Royal Adelaide Hospital. Med J Aust 1988;148:71-74.
3. Artz, MR, Forouhar F. Granulomatous hepatitis as a complication of intravesical bacillus Calmette-Guérin therapy for bladder carcinoma. Ann Clin Lab Sci 1995;25:409-413.
4. Bach N, Thiese ND, Schaffner F. Hepatic histopathology in the acquired immunodeficiency syndrome. Semin Liv Dis 1992;12:205-212.
5. Baptista A, Bianchi L, Groote J, et al. Alcoholic liver disease: morphological manifestations. Lancet 1981;1:707-711.
6. Cathebras PJ, Mosnier JF, Gouilloud S, et al. Hepatic granulomatosis in a patient with Graves' disease. Eur J Gastroenterol Hepatol 1995;7:905-908.
7. Chavenet P, Dillon D, Lancon JP, et al. Granulomatous hepatitis associated with Lyme disease. Lancet 1987;2:623-624.
8. Chien RN, Liu NJ, Lin PY, et al. Granulomatous hepatitis associated with scrub typhus. J Gastroenterol Hepatol 1995;10:484-487.
9. Chien RN, Lin PY, Liaw YF. Hepatic tuberculosis: comparison of miliary and local form. Infection 1995;23:5-8.
10. Collins MH, Jiang B, Croffie JM, et al. Hepatic granulomas in children. A clinicopathologic analysis of 23 cases including polymerase chain reaction for Histoplasma. Am J Surg Pathol 1996;20:332-338.
11. de Bayser L, Roblot P, Ramassamy A, et al. hepatic fibrin-ring granulomas in giant cell arteritis. Gastroenterology 1993;105:272-273.
12. Denk H, Scheuer PJ, Baptista A, et al. Guidelines for the diagnosis and interpretation of hepatic granulomas. Histopathology 1993;25:209-218.
13. Devaney K, Goodman, ZD, Epstein MS, et al. Hepatic sarcoidosis. Clinicopathologic features in 100 patients. Am J Surg Pathol 1993;17:1272-1280.
14. De Vega T, Echevarria S, Crespo J, et al. Acute hepatitis by Listeria monocytogenes in an HIV patient with chronic HBV hepatitis. J Clin Gastroenterol 1992;15:251-255.
15. Drebber U, Kasper HU, Ratering J, et al. Hepatic granulomas: histological and molecular pathological approach to differential diagnosis - a study of 442 cases. Liver Int 2008;28(6):828-834. 2008 Feb 26 [Epub ahead of print].
16. Emile JF, Sebagh M, Feray C, et al. The presence of epithelioid granulomas in hepatitis C virus-related cirrhosis. Hum Pathol 1993;24:1095-1097.
17. Everett GD, Mitros FA. Eosinophilic gastroenteritis with hepatic eosinophilic granulomas. Am J Gastroenterol 1980;74:519-521.
18. Fauci AS, Wolff SM. Granulomatous hepatitis. In: Popper H, Schaffner F, eds. Progress in Liver Diseases, vol. 5. New York: Grune & Stratton, 1976:609-621.
19. Ferrell LD. Hepatic granulomas: a morphologic approach to diagnosis. Surg Pathol 1990;3:87-106.
20. Ferrell LD, Lee R, Brixco C, et al. Hepatic granulomas following liver transplantation. Clinicopathologic features in 42 patients. Transplantation 1995;60:926-933.
21. Font J, Bruguera M, Perez-Villa F, et al.. Hepatic fibrin-ring granulomas caused by Staphylococcus epidermidis generalized infection. Gastroenterology 1987;93:1449-1451.
22. Habior A, Walewska-Zielecka B, Butruk E. Hepatocellular-cholestatic liver injury due to amoxycillin-clavulanic acid combination. Clin Invest 1994;72:616-618.
23. Harrison RF, Elias E. Amiodarone-associated cirrhosis with hepatic and lymph node granulomas. Histopathology 1993;22:80-82.
24. Hofmann CE, Heaton JW Jr. Q fever hepatitis: clinical manifestations and pathologic findings. Gastroenterology 1982;83:474-479.
25. Holtz T, Mosely RH, Scheiman JM. Liver biopsy in fever of unknown origin. J Clin Gastroenterol 1993;17:29-32.
26. Ishibashi H, Shimamura R, Hirata Y, et al. Hepatic granuloma in toxocaral infection: role of ultrasonography in hypereosinophilia. J Clin Ultrasound 1992;20:204-210.
27. Jain R, Sawhney S, Bhargava DK, et al. Hepatic granulomas due to visceral larva migrans in adults: appearance on US and MRI. Abdom Imaging 1994;19:253-256.
28. James DG, Scheuer PJ. Hepatic granulomas. In: Bircher J, Benhamou J-P, McIntyre N, et al., eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press, 1999: 1099-1108.
29. James DG, Sherlock S. Sarcoidosis of the liver. Sarcoidosis 1994;11:2-6.
30. Johnson TL, Barnett JL, Appelman HD, et al. Candida hepatitis: histopathologic diagnosis. Am J Surg Pathol 1988;12:716-720.
31. Kadin ME, Donaldson SS, Dorfman RF. Isolated granulomas in Hodgkin's disease. N Engl J Med 1970;283:859-861.
32. Kurumaya H, Kono N, Makanuma Y, et al. Hepatic granulomata in long-term hemodialysis patients with hyperalbuminemia. Arch Pathol Lab Med 1989;113: 1132-1134.
33. Larrey D, Vial T, Micaleff A, et al. Hepatitis associated with amoxycillin-clavulanic acid combination; report of 15 cases. Gut 1992;33:368-371.
34. Le Bail B, Jouhanole H, Deugnier Y, et al. Liver adenomatosis with granulomas in two patients on long-term oral contraceptives. Am J Surg Pathol 1992;16:982-987.
35. Lee JD, Kim PG, Jo HJ, et al. A case of primary hepatic actinomycosis. J Korean Med Sci 1993;8:385-389.
36. Liaw YF, Huang MJ, Fan KD, et al. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study. Ann Intern Med 1993;118:424-428.
37. Lobdell DH. “Ring” granulomas in cytomegalovirus hepatitis. Arch Pathol Lab Med 1987;111:881-882.
38. Malatack JJ, Jaffe R. Granulomatous hepatitis in three children due to cat-scratch disease without peripheral adenopathy. Am J Dis Child 1993;147:949-953.
39. Marazuela M, Moreno A, Yebra M, et al. Hepatic fibrin-ring granulomas: a clinicopathologic study of 23 patients. Hum Pathol 1991;22:607-613.
40. Markin RS, Wisecarver JL, Radio SJ, et al. Frozen section evaluation of donor livers before transplantation. Transplantation 1993;56:1403-1409.
41. Mauer LH, Hughes RW, Folley JH, et al. Granulomatous hepatitis associated with regional enteritis. Gastroenterology 1967;53:301-305.
42. McKerrow JH, Sun E. Hepatic schistosomiasis. Prog Liver Dis 1994;12:121-135.
43. Mirada Canals A, Monteagudo Jiminez M, Sole Villa J, et al. Methyldopa-induced granulomatous hepatitis. DICP 1991;25:1269-1270.
44. Mondou EN, Gnepp DR. Hepatic granuloma resulting from Enterobius vermicularis. Am J Clin Pathol 1989;91:97-100.
45. Moreno A, Marazuela M, Yebra M, et al. Hepatic fibrin-ring granulomas in visceral leishmaniasis. Gastroenterology 1988;95:1123-1126.
46. Murphy E, Griffiths MR, Hunter JA, et al. Fibrin-ring granulomas: a non-specific reaction to liver injury? Histopathology 1991;19:91-93.
47. Nakhleh RE, Glock M, Snover DC. Hepatic pathology of chronic granulomatous disease of childhood. Arch Pathol Lab Med 1992;116:71-75.
48. Nevert M, Mavier P, Dubuc N, et al. Epstein-Barr virus infection and hepatic fibrin-ring granulomas. Hum Pathol 1988;19:608-610.
49. Qizilbash AH. The pathology of Q fever as seen on liver biopsy. Arch Pathol Lab Med 1983;107:364-367.
50. Pak HY, Friedman NB. Pseudosarcoid granulomas in Hodgkin's disease. Hum Pathol 1981;12:832-837.
51. Pelligrin M, Delsol G, Auvergnat JC, et al. Granulomatous hepatitis in Q fever. Hum Pathol 1980;11:51-57.
52. Roberts-Thomson IC, Anders RF, Bhathal PS. Granulomatous hepatitis and cholangitis associated with giardiasis. Gastroenterology 1982;83:480-483.
53. Ruel M, Sevestre H, Henry-Biabaud E, et al. Fibrin ring granulomas in hepatitis A. Dig Dis Sci 1992;37:1915-1917.
54. Ruiz-Valverde P, Zafon C, Segarra A, et al. Ticlopidine-induced granulomatous hepatitis. Ann Pharmacother 1995;29:633-634.
55. Saint-Marc Girardin MF, Zafrani ES, Chaumette MT, et al. Hepatic granulomas in Whipple's disease. Gastroenterology 1984;86:753-756.
56. Sartin JS, Walker RC. Granulomatous hepatitis: a retrospective review of 88 cases at the Mayo Clinic. Mayo Clin Proc 1991;66:914-918.
57. Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin. A study of 13 patients. Medicine 1973;52:1-21, 1973.
58. Smith JW, Utz JP. Progressive disseminated histoplasmosis. Ann Intern Med 1972;76: 557-565.
59. Stjernberg V, Silseth C, Ritland S. Granulomatous hepatitis in Yersinia enterocolitica infection. Hepatogastroenterology 1987;34:56-57.
60. Thung SN, Gerber MA, Lebovics E, et al. Granulomatous hepatitis in Q fever. Mt Sinai J Med 1986;53:283-286.
61. ToftE,VybergM, TherkelsenK.Diltiazem-induced granulomatous hepatitis.Histopathology 1991;18:474-475.
62. Vanderstigel M, Zafrani ES, Lejonc JL, et al. Allopurinol hypersensitivity syndrome as a cause of hepatic fibrin-ring granulomas. Gastroenterology 1986;90:188-190.
63. Weitberg AB, Alper JC, Diamond I, et al. Acute granulomatous hepatitis in the course of acquired toxoplasmosis. N Engl J Med 1979;300:1093-1096.
64. Wilkins MJ, Lindley R, Dourakis SP, et al. Surgical pathology of the liver in HIV infection. Histopathology 1991;18:459-464.
65. Yamamoto S, Iguchi Y, Ohomoto K, et al. Epithelioid granuloma formation in type C chronic hepatitis: report of two cases. Hepatogastroenterology 1995;42:291-293.
66. Yamamoto T, Ishii M, Nagura H, et al. Transient hepatic fibrin-ring granulomas in a patient with acute hepatitis A. Liver 1995;15:276-279.
67. Zoutman DE, Ralph ED, Frei JV. Granulomatous hepatitis and fever of unknown origin. J Clin Gastroenterol 1991;13:69-75.
