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Sarcoidosis of the Liver and Bile Ducts
I I
Sarcoidosis of the Liver and Bile Ducts KAMAL G. ISHAK, M.D., PH.D. ductopenia seems to be the underlying pathogenetic mechanism of the chronic cholestatic syndrome of sarcoidosis. Recognition of this syndrome is important in the differential diagnosis of other chronic cholestatic diseases, such as primary biliary cirrhosis or primary sclerosing cholangitis. Other rare complications of sarcoidosis are the Budd-Chiari syndrome and obstructive jaundice attributable to hepatic hilar lymphadenopathy or strictures of the bile ducts. Mayo Clin Proc 1998;73:467-472
In sarcoidosis, granulomas are frequently present in multiple organs, including the liver. Typically, epithelioid granulomas (noncaseating) are scattered throughout the liver, but confluent granulomas can be present in cases with severe hepatic involvement. The characteristic inclusions in giant cells (for example, Schaumann bodies and asteroid bodies) are not seen in all cases and are not pathognomonic. The granulomas of sarcoidosis may heal without a trace, but confluent granulomas can result in extensive, irregular scarring. Occlusion of intrahepatic portal vein branches by the granulomatous inflammation probably accounts for the development of portal hypertension in some cases. A granulomatous cholangitis leading to
I PBC =primary biliary cirrhosis
S
arcoidosis is a systemic disease of unknown cause with protean clinical manifestations, which is characterized histopathologically by epithelioid, typically noncaseating granulomas. It occurs worldwide; the prevalence is high in Scandinavian countries, the United States, and Japan and low in South America and mainland Asia. I Mass radiographic studies in Sweden have shown prevalence rates of 55 (1949 through 1953) and 64 (1953 through 1960) per 100,000 population.' Estimates of the prevalence of sarcoidosis in the United States range from less than 1 case to 40 cases per 100,000 population, with an age-adjusted annual incidence rate of 10.9 per 100,000 for whites and 35.5 per 100,000 for blacks.' Cases of sarcoidosis manifest more commonly in the winter and early spring months than at other times of the year. The disease occurs equally in males and females. It is diagnosed before the age of 40 years in most patients. Less than I % of cases of sarcoidosis occur in patients younger than 20 years of age or older than 60 years.' Sarcoidosis often affects multiple organ systems, but one organ may be predominantly affected. Although granulomas may be demonstrable in liver biopsy specimens in more than 70% of cases of sarcoidosis, hepatic manifestations were documented in one series in only II % and 12.8% of white and black patients, respectively.'
CLINICAL ASPECTS AND COMPLICATIONS
Hepatomegaly and splenomegaly occur in 5 to 10% of patients with sarcoidosis.' Fever is seldom a prominent feature of sarcoidosis, but it may be more common among patients with hepatic involvement.' Jaundice is rare. The chronic cholestatic syndrome of sarcoidosis shares numerous features with primary biliary cirrhosis (PBC)namely, pruritus, jaundice, hepatomegaly, and strikingly increased serum levels of alkaline phosphatase and cholesterol." Unlike PBC, however, no mitochondrial antibodies are found in the serum. Furthermore, the patients have indisputable clinical evidence of sarcoidosis that antedates the onset of cholestasis." In addition to the "pure" variant of chronic cholestasis associated with sarcoidosis.v" sarcoidosis has been found to coexist with PBC1317 and, less often, with primary sclerosing cholangitis.":" Of note, cholestasis in sarcoidosis also may be attributable to extrahepatic biliary obstruction caused by strictures of the bile ducts 20 ,2 ! or enlarged lymph nodes in the porta hepatis." The chronic cholestatic syndrome of sarcoidosis may be accompanied by portal hypertension.s-P-" Alternatively, portal hypertension can complicate sarcoidosis in the absence of chronic cholestasis.I-":" In the cases associated with chronic cholestasis, the portal hypertension is usually a manifestation of biliary fibrosis or cirrhosis. In other cases, it is presinusoidal and probably related to compromise of portal area vessels by the granulomas."
From the Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC. The opinions and assertions herein are those of the author and are not to be construed as official or as reflecting the views of the Department of Army or the Department of Defense.
LABORATORY DATA
The laboratory abnormalities in hepatic sarcoidosis include hyperglobulinemia and moderate increases in serum alkaline phosphatase activity. In the chronic cholestatic syn-
Address reprint requests to Dr. K. G. Ishak, Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000.
Mayo Clin Proc 1998;73:467-472
467
© 1998 Mayo Foundationfor Medical Education and Research
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468
Sarcoidosis of Liver and Bile Ducts
Mayo Clin Proc, May 1998, Vol 73
Fig. 1. Sharply defined sarcoid granuloma of liver,composed of epithelioid cells and surrounded by inflammatory cells. (Hematoxylin-eosin; original magnification, x240.)
Fig. 2. Multiple confluent hepatic sarcoidgranulomas, containing multinucleated giant cells and showing early concentric fibrosis. (Hematoxylin-eosin; original magnification, x120,)
drome, serum bilirubin levels are increased (but usually below 5 mg/dL), whereas alkaline phosphatase values are increased from 2-fold to more than 30-fold. Aminotransferase values are only mildly abnormal. The activity of the serum angiotensin-converting enzyme is increased in sarcoidosisv'? and other conditions, with or without associated granulomas. Serial assays of this enzyme are useful for assessing the response to therapy and warning of impending relapse. Serum collagenase activity (also substantially increased in sarcoidosis) is considered a less sensitive index of sarcoidosis activity than is angiotensin-converting enzyme." Immunologic aspects of sarcoidosis have been reviewed periodically by several investigarors-P:" and will not be further discussed in this report.
epithelioid cells in the granulomas are supported by a delicate network of reticulin fibers." Fibrillogranular (caseation) necrosis is usually absent, but some granulomas may display central fibrinoid necrosis. In one case I recently encountered, fibrin was demonstrated in the necrotic center immunohistochemically. Several types of inclusions may be found in sarcoid granulomas; none is pathognomonic.v" The asteroid body (5 to 20 urn in overall diameter), which resembles a sea anemone, is found in multinucleated giant cells; it often is in a globular vesicle (Fig. 3). Asteroid bodies seem to be
HISTOPATHOLOGIC FEATURES Sarcoid granulomas in the liver are generally scattered widely, but many tend to be portal or periportal. The smallest and presumably earliest lesions are best appreciated within acini and consist of a few loosely arranged epithelioid cells. Older lesions are globular or ovoid and sharply defined (Fig. 1). In cases with severe hepatic involvement, confluence of granulomas is often noted (Fig. 2). One or more multinucleated giant cells may be detected in the granulomas (Fig. 2); angiotensin-converting enzyme has been demonstrated in these cells by immunohistochemical methods." Such cells and the epithelioid cells also express (Xl-antitrypsin and lysozyme. The epithelioid cells, but not the giant cells, express interleukin-L 36 A variable but usually minimal inflammatory cell response is present, with lymphocytes, plasma cells, and eosinophils (Fig. 1). The lymphocytes are CD4+ helper T cells." The
Fig. 3. Asteroid bodies in sarcoid granuloma, "decorated" with anti-ubiquitin antibodies, (Hematoxylin-eosin; original magnification, xnO,) Inset, Asteroid body in Langhans'-typegiantcell. (Hematoxylin-eosin; original magnification, x600.)
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Sarcoidosis of Liver and Bile Ducts
469
Fig. 4. Darkly stained Schaumann bodies (at left) and brightly illuminated calcium oxalate inclusions (arrows), demonstrated in sarcoid granuloma photographed through partially polarized light. (Hematoxylin-eosin; original magnification, x120.)
Fig. 5. Schaumann body with concentric laminations in sarcoid granuloma of liver. X-ray microanalysis of this body revealed an elemental composition of calcium and phosphorus. (Scanning electron micrograph; original magnification, x550.)
composed of noncollagenous filamentsv-" and myelinoid membranes.? Microtubular material derived from the cytoskeleton was described in one ultrastructural study" but not in another." The asteroid bodies in sarcoid granulomas can be immunostained with antibodies to ubiquitin (Fig. 3), similar to asteroid bodies in silicone-induced granulomas." Schaumann ("conchoidal") bodies are large (25 to 200 urn), basophilic, round to roughly oval in configuration, and concentrically laminated (Fig. 4 and 5). They are composed of calcium phosphate or carbonate and iron." In addition, crystals of calcium oxalate, which are colorless and birefringent, have been identified in giant cells (Fig. 4).44,45 Schaumann bodies are more frequently found in the giant cells of sarcoid granulomas in lymph nodes than in the liver. Centrospheres, the third type of inclusion seen in sarcoid granulomas, are small homogeneous vesicles; they can be single or multiple and may displace the nucleus to the cell margin." Sarcoid granulomas heal by fibrosis. Early resolution is characterized by accumulation of fibroblasts that arrange themselves concentrically around the granulomas (Fig. 2). Collagen progressively forms; it may become intensely hyalinized (paramyloid), and the end-stage finding is a focal scar that eventually disappears (Fig. 6). Confluent granulomas are likely to cause residual scars (Fig. 7). The giant cells containing asteroid bodies or Schaumann bodies tend to be the last vestiges of the granulomatous response in the fibrous tissue. Of importance, involvement of the liver in sarcoidosis is not confined to infiltration by noncaseating granulomas. In a series of 100 patients who had sarcoidosis with hepatic
involvement, "cholestatic" morphologic features were found in 58%.46 The changes included duct lesions that resembled those of PBC (Fig. 8) or primary sclerosing cholangitis (Fig. 9), ductopenia, cholestasis and features of chronic cholestasis-such as pseudoxanthomatous transformation (cholate stasis) (Fig. 10)-and copper storage. Necroinflammatory changes in the form of random small foci of necrosis, sinusoidal apoptotic bodies, and mild to moderate portal inflammation were also noted. Cases with extensive involvement by confluent granulomas may exhibit a granulomatous phlebitis, with involvement of termi-
Fig. 6. Focal scar of a healed sarcoid granuloma, adjacent to a terminal hepatic venule. (Hematoxylin-eosin; original magnification, x400.)
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470
Sarcoidosis of Liver and Bile Ducts
Mayo Clin Proc, May 1998,Vol 73
Fig. 7. Extensive fibrosis that resulted from healing of multiple sarcoid granulomas. Darkly stained areas represent disrupted, residual hepatic parenchyma. (Masson trichrome; original magnification,x40.)
Fig. 8. Cholangionecrotic changes (resembling primary biliary cirrhosis) in sarcoidosis. Arrows indicate segments of ducts that have undergone destruction. (Hematoxylin-eosin; original magnification,x240.)
nal hepatic venules or portal vein branches (or both) (Fig. 11); healing can lead to complete obliteration of these veins (Fig. 12). As already noted, severe fibrosis and actual cirrhosis in conjunction with portal hypertension may be present in sarcoidosis. Cirrhosis was noted in 6% of the cases reported by Devaney and associates." Death from hepatic insufficiency as a result of cirrhosis is rare. In one series of 28 fatal cases of sarcoidosis, only 1 death was attributable
to liver failure; 50% of deaths were due to cardiac involvement, and 43% were ascribed to pulmonary involvement." Nodular regenerative hyperplasia has been reported in 9% of cases in one series of hepatic sarcoidosis." Finally, note should be made of the rare complication of the Budd-Chiari syndrome in sarcoidosis.v-" End-stage liver disease in sarcoidosis has been treated successfully by orthotopic liver transplantation; 12 recurrent sarcoidosis has been reported in one such case."
Fig. 9. Severely sclerosed bile duct, surrounded by sarcoid granulomas. (Hematoxylin-eosin; original magnification,
Fig. 10. Foamy pseudoxanthomatouscells, clusterednear a portal area, in sarcoid granuloma. (Hematoxylin-eosin; originalmagnification, x400.)
x75.)
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Sarcoidosis of Liver and Bile Ducts
Mayo Clin Proc, May 1998, Vol 73
Fig. 11. Wall of intrahepatic vein, extensively infiltrated by sarcoid granulomas. (Hematoxylin-eosin; original magnification, x75.)
ETIOLOGIC FACTORS A mycobacterial cause for sarcoidosis has been suggested for many years (see discussion by Popper and associates"). The detection of mycobacterial DNA and RNA in sarcoid lesions by several groups of investigators-'" and the growth of acid-fast L-forms from the blood of patients with sarcoidosis'" lend support to that association. Nevertheless, the role of mycobacteria in sarcoidosis remains a controversial issue." Recently, variant human herpesvirus 8 DNA sequences were found in a wide range of sarcoid but not nonsarcoid tissues. 56 Further studies must be undertaken to determine whether this association is causal.
Fig. 12. A portal vein branch, outlined by its elastica, showing occlusion from healed granulomatous phlebitis. Arrows denote several residual giant cells in lumen. (Hematoxylin-eosin; original magnification, xIOO.)
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Leger L, Lemalgre G, Premont M, Salmon R, Klloua Z, Battesti JP. Hypertension portale au cours de la sarcoidose: trois observations dont une avec foie fibreux et hepatome malin stroma osseux. Presse Med 1980;9:1021-1024 Tekeste H, Latour F, Levitt RE. Portal hypertension complicating sarcoid liver disease: case report and review of the literature. Am J Gastroenterol 1984;79:389-396 Lieberman J. Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. Am J Med 1975;59:365-372 Studdy P, Bird R, James DG. Serum angiotensin-converting enzyme (SACE) in sarcoidosis and other granulomatous disorders. Lancet 1978;2:1331-1334 Lufkin EG, DeRemee RA, Rohrbach MS. The predictive value of serum angiotensin-converting enzyme activity in the differential diagnosis of hypercalcemia. Mayo Glin Proc 1983;58:447-451 Silverstein E, Lockerman Z, Friedland J. Serum and lymph-node collagenase in sarcoidosis: comparison with angiotensin-converting enzyme. Am J Glin Pathol 1978;70:348-351 James DG, Williams WJ. Immunology of sarcoidosis. Am J Med 1982;72:5-8 James DG, Williams WJ. Sarcoidosis and Other Granulomatous Disorders. Philadelphia: Saunders; 1985 Katarla YP. Immunology of sarcoidosis. In: Lieberman J, editor. Sarcoidosis. Orlando (FL): Grune & Stratton: 1985. pp 39-63 Pertschuk LP, Silverstein E, Friedland J. Immunohistologic diagnosis of sarcoidosis: detection of angiotensin-converting enzyme in sarcoid granulomas. Am J Glin Pathol 1981:75:350-354 Chilosi M, Menestrina F, Capelli P, Montagna L, Lestani M, Plzzolo G, et al. Immunohistochemical analysis of sarcoid granulomas: evaluation of Ki67' and interleukin-L' cells. Am J Pathol 1988;131:191198 Klatskin G, Yesner R. Hepatic manifestations of sarcoidosis and other granulomatous diseases: a study based on histological examination of tissue obtained by needle biopsy of the liver. YaleJ BioI Med 1950;23:207-248 Uehllnger E. The sarcoid tissue reaction: the origin and significance of inclusion bodies; differential diagnosis with particular delineation from tuberculosis. Acta Med Scand Suppl 1964;425:713 Cunningham JA. Sarcoidosis. Pathol Annu 1967;2:31-46 Rosen Y, Vuletin JC, Pertschuk LP, Silverstein E. Sarcoidosis: from the pathologist's vantage point. Pathol Annu 1979:14(Part 1):405439 Cain H, Kraus B. Asteroid bodies: derivatives of the cytosphere; an electron microscopic contribution to the pathology of the cytocentre. Virchows Arch 1977;26:119-132
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Kirkpatrick CJ, Curry A, Bisset DL. Light- and electron-microscopic studies on multinucleated giant cells in sarcoid granuloma: new aspects of asteroid and Schaumann bodies. Ultrastruct Pathol 1988; 12:581-597 Okamoto K, Hirai S, Yoshida T, IIzuka T, Tanaka S. Asteroid bodies in silicone-induced granuloma are ubiquinated [letter]. Acta Pathol Jpn 1992;42:688-689 Johnson FB, Pani K. Histochemical identification of calcium oxalate. Arch Pathol 1962;74:347-351 Reid JD, Andersen ME. Calcium oxalate in sarcoid granulomas: with particular reference to the small ovoid body and a note on the finding of dolomite. Am J Glin Pathol 1988;90:545-558 Devaney K, Goodman ZD, Epstein MS, Zimmerman HJ, Ishak KG. Hepatic sarcoidosis: clinicopathologic features in 100 patients. Am J Surg Pathol 1993;17:1272-1280 Perry A, Vultch F. Causes of death in patients with sarcoidosis: a morphologic study of 38 autopsies with clinicopathologic correlations. Arch Pathol Lab Med 1995;119:167-172 Nataline MR, Goyette RE, Owensby LC, Rubin RN. The BuddChiari syndrome in sarcoidosis [letter]. JAMA 1978;239:2657-2658 Russi EW, Bansky G, Pfaltz M, Splnas G, Hammer B, Sennlng A. Budd-Chiari syndrome in saroidosts. Am J Gastroenterol 1986;81:7175 Pescovltz MD, Jones HM, Cummings OW, Lumeng L, Leapman SB, Filo RS. Diffuse retroperitoneal lymphadenopathy following liver transplantation-a case of recurrent sarcoidosis. Transplantation 1995;60:393-396 Popper HH, Winter E, Hofler G. DNA of MycobacterIum tuberculosis in formalin-fixed, paraffin-embedded tissue in tuberculosis and sarcoidosis detected by polymerase chain reaction. Am J Glin Pathol 1994;101:738-741 Saboor SA, Johnson NM, McFadden J. Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction. Lancet 1992;339:1012-1015 MitchelllC, Turk JL, Mitchell DN. Detection of mycobacterial rRNA in sarcoidosis with liquid-phase hybridisation. Lancet 1992;339:10151017 Almenoff PL, Johnson A, Lesser M, Mattman LH. Growth of acid fast L forms from the blood of patients with sarcoidosis. Thorax 1996;51:530-533 Mangiapan G, Hance AJ. Mycobacteria and sarcoidosis: an overview and summary of recent molecular biological data. Sarcoidosis 1995; 12:20-37 Di Alberti L, Plattelli A, Artese L, Favia G, Patel S, Saunders N, et al. Human herpesvirus 8 variants in sarcoid tissues. Lancet 1997; 350:1655-1661
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Sarcoidosis of the Liver and Bile Ducts KAMAL G. ISHAK, M.D., PH.D. ductopenia seems to be the underlying pathogenetic mechanism of the chronic cholestatic syndrome of sarcoidosis. Recognition of this syndrome is important in the differential diagnosis of other chronic cholestatic diseases, such as primary biliary cirrhosis or primary sclerosing cholangitis. Other rare complications of sarcoidosis are the Budd-Chiari syndrome and obstructive jaundice attributable to hepatic hilar lymphadenopathy or strictures of the bile ducts. Mayo Clin Proc 1998;73:467-472
In sarcoidosis, granulomas are frequently present in multiple organs, including the liver. Typically, epithelioid granulomas (noncaseating) are scattered throughout the liver, but confluent granulomas can be present in cases with severe hepatic involvement. The characteristic inclusions in giant cells (for example, Schaumann bodies and asteroid bodies) are not seen in all cases and are not pathognomonic. The granulomas of sarcoidosis may heal without a trace, but confluent granulomas can result in extensive, irregular scarring. Occlusion of intrahepatic portal vein branches by the granulomatous inflammation probably accounts for the development of portal hypertension in some cases. A granulomatous cholangitis leading to
I PBC =primary biliary cirrhosis
S
arcoidosis is a systemic disease of unknown cause with protean clinical manifestations, which is characterized histopathologically by epithelioid, typically noncaseating granulomas. It occurs worldwide; the prevalence is high in Scandinavian countries, the United States, and Japan and low in South America and mainland Asia. I Mass radiographic studies in Sweden have shown prevalence rates of 55 (1949 through 1953) and 64 (1953 through 1960) per 100,000 population.' Estimates of the prevalence of sarcoidosis in the United States range from less than 1 case to 40 cases per 100,000 population, with an age-adjusted annual incidence rate of 10.9 per 100,000 for whites and 35.5 per 100,000 for blacks.' Cases of sarcoidosis manifest more commonly in the winter and early spring months than at other times of the year. The disease occurs equally in males and females. It is diagnosed before the age of 40 years in most patients. Less than I % of cases of sarcoidosis occur in patients younger than 20 years of age or older than 60 years.' Sarcoidosis often affects multiple organ systems, but one organ may be predominantly affected. Although granulomas may be demonstrable in liver biopsy specimens in more than 70% of cases of sarcoidosis, hepatic manifestations were documented in one series in only II % and 12.8% of white and black patients, respectively.'
CLINICAL ASPECTS AND COMPLICATIONS
Hepatomegaly and splenomegaly occur in 5 to 10% of patients with sarcoidosis.' Fever is seldom a prominent feature of sarcoidosis, but it may be more common among patients with hepatic involvement.' Jaundice is rare. The chronic cholestatic syndrome of sarcoidosis shares numerous features with primary biliary cirrhosis (PBC)namely, pruritus, jaundice, hepatomegaly, and strikingly increased serum levels of alkaline phosphatase and cholesterol." Unlike PBC, however, no mitochondrial antibodies are found in the serum. Furthermore, the patients have indisputable clinical evidence of sarcoidosis that antedates the onset of cholestasis." In addition to the "pure" variant of chronic cholestasis associated with sarcoidosis.v" sarcoidosis has been found to coexist with PBC1317 and, less often, with primary sclerosing cholangitis.":" Of note, cholestasis in sarcoidosis also may be attributable to extrahepatic biliary obstruction caused by strictures of the bile ducts 20 ,2 ! or enlarged lymph nodes in the porta hepatis." The chronic cholestatic syndrome of sarcoidosis may be accompanied by portal hypertension.s-P-" Alternatively, portal hypertension can complicate sarcoidosis in the absence of chronic cholestasis.I-":" In the cases associated with chronic cholestasis, the portal hypertension is usually a manifestation of biliary fibrosis or cirrhosis. In other cases, it is presinusoidal and probably related to compromise of portal area vessels by the granulomas."
From the Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC. The opinions and assertions herein are those of the author and are not to be construed as official or as reflecting the views of the Department of Army or the Department of Defense.
LABORATORY DATA
The laboratory abnormalities in hepatic sarcoidosis include hyperglobulinemia and moderate increases in serum alkaline phosphatase activity. In the chronic cholestatic syn-
Address reprint requests to Dr. K. G. Ishak, Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000.
Mayo Clin Proc 1998;73:467-472
467
© 1998 Mayo Foundationfor Medical Education and Research
For personal use, Mass reproduce only with permission from Mayo Clinic Proceedings,
468
Sarcoidosis of Liver and Bile Ducts
Mayo Clin Proc, May 1998, Vol 73
Fig. 1. Sharply defined sarcoid granuloma of liver,composed of epithelioid cells and surrounded by inflammatory cells. (Hematoxylin-eosin; original magnification, x240.)
Fig. 2. Multiple confluent hepatic sarcoidgranulomas, containing multinucleated giant cells and showing early concentric fibrosis. (Hematoxylin-eosin; original magnification, x120,)
drome, serum bilirubin levels are increased (but usually below 5 mg/dL), whereas alkaline phosphatase values are increased from 2-fold to more than 30-fold. Aminotransferase values are only mildly abnormal. The activity of the serum angiotensin-converting enzyme is increased in sarcoidosisv'? and other conditions, with or without associated granulomas. Serial assays of this enzyme are useful for assessing the response to therapy and warning of impending relapse. Serum collagenase activity (also substantially increased in sarcoidosis) is considered a less sensitive index of sarcoidosis activity than is angiotensin-converting enzyme." Immunologic aspects of sarcoidosis have been reviewed periodically by several investigarors-P:" and will not be further discussed in this report.
epithelioid cells in the granulomas are supported by a delicate network of reticulin fibers." Fibrillogranular (caseation) necrosis is usually absent, but some granulomas may display central fibrinoid necrosis. In one case I recently encountered, fibrin was demonstrated in the necrotic center immunohistochemically. Several types of inclusions may be found in sarcoid granulomas; none is pathognomonic.v" The asteroid body (5 to 20 urn in overall diameter), which resembles a sea anemone, is found in multinucleated giant cells; it often is in a globular vesicle (Fig. 3). Asteroid bodies seem to be
HISTOPATHOLOGIC FEATURES Sarcoid granulomas in the liver are generally scattered widely, but many tend to be portal or periportal. The smallest and presumably earliest lesions are best appreciated within acini and consist of a few loosely arranged epithelioid cells. Older lesions are globular or ovoid and sharply defined (Fig. 1). In cases with severe hepatic involvement, confluence of granulomas is often noted (Fig. 2). One or more multinucleated giant cells may be detected in the granulomas (Fig. 2); angiotensin-converting enzyme has been demonstrated in these cells by immunohistochemical methods." Such cells and the epithelioid cells also express (Xl-antitrypsin and lysozyme. The epithelioid cells, but not the giant cells, express interleukin-L 36 A variable but usually minimal inflammatory cell response is present, with lymphocytes, plasma cells, and eosinophils (Fig. 1). The lymphocytes are CD4+ helper T cells." The
Fig. 3. Asteroid bodies in sarcoid granuloma, "decorated" with anti-ubiquitin antibodies, (Hematoxylin-eosin; original magnification, xnO,) Inset, Asteroid body in Langhans'-typegiantcell. (Hematoxylin-eosin; original magnification, x600.)
For personal use, Mass reproduce only with permission from Mayo Clinic Proceedings,
Mayo Clin Proc, May 1998, Vol 73
Sarcoidosis of Liver and Bile Ducts
469
Fig. 4. Darkly stained Schaumann bodies (at left) and brightly illuminated calcium oxalate inclusions (arrows), demonstrated in sarcoid granuloma photographed through partially polarized light. (Hematoxylin-eosin; original magnification, x120.)
Fig. 5. Schaumann body with concentric laminations in sarcoid granuloma of liver. X-ray microanalysis of this body revealed an elemental composition of calcium and phosphorus. (Scanning electron micrograph; original magnification, x550.)
composed of noncollagenous filamentsv-" and myelinoid membranes.? Microtubular material derived from the cytoskeleton was described in one ultrastructural study" but not in another." The asteroid bodies in sarcoid granulomas can be immunostained with antibodies to ubiquitin (Fig. 3), similar to asteroid bodies in silicone-induced granulomas." Schaumann ("conchoidal") bodies are large (25 to 200 urn), basophilic, round to roughly oval in configuration, and concentrically laminated (Fig. 4 and 5). They are composed of calcium phosphate or carbonate and iron." In addition, crystals of calcium oxalate, which are colorless and birefringent, have been identified in giant cells (Fig. 4).44,45 Schaumann bodies are more frequently found in the giant cells of sarcoid granulomas in lymph nodes than in the liver. Centrospheres, the third type of inclusion seen in sarcoid granulomas, are small homogeneous vesicles; they can be single or multiple and may displace the nucleus to the cell margin." Sarcoid granulomas heal by fibrosis. Early resolution is characterized by accumulation of fibroblasts that arrange themselves concentrically around the granulomas (Fig. 2). Collagen progressively forms; it may become intensely hyalinized (paramyloid), and the end-stage finding is a focal scar that eventually disappears (Fig. 6). Confluent granulomas are likely to cause residual scars (Fig. 7). The giant cells containing asteroid bodies or Schaumann bodies tend to be the last vestiges of the granulomatous response in the fibrous tissue. Of importance, involvement of the liver in sarcoidosis is not confined to infiltration by noncaseating granulomas. In a series of 100 patients who had sarcoidosis with hepatic
involvement, "cholestatic" morphologic features were found in 58%.46 The changes included duct lesions that resembled those of PBC (Fig. 8) or primary sclerosing cholangitis (Fig. 9), ductopenia, cholestasis and features of chronic cholestasis-such as pseudoxanthomatous transformation (cholate stasis) (Fig. 10)-and copper storage. Necroinflammatory changes in the form of random small foci of necrosis, sinusoidal apoptotic bodies, and mild to moderate portal inflammation were also noted. Cases with extensive involvement by confluent granulomas may exhibit a granulomatous phlebitis, with involvement of termi-
Fig. 6. Focal scar of a healed sarcoid granuloma, adjacent to a terminal hepatic venule. (Hematoxylin-eosin; original magnification, x400.)
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Fig. 7. Extensive fibrosis that resulted from healing of multiple sarcoid granulomas. Darkly stained areas represent disrupted, residual hepatic parenchyma. (Masson trichrome; original magnification,x40.)
Fig. 8. Cholangionecrotic changes (resembling primary biliary cirrhosis) in sarcoidosis. Arrows indicate segments of ducts that have undergone destruction. (Hematoxylin-eosin; original magnification,x240.)
nal hepatic venules or portal vein branches (or both) (Fig. 11); healing can lead to complete obliteration of these veins (Fig. 12). As already noted, severe fibrosis and actual cirrhosis in conjunction with portal hypertension may be present in sarcoidosis. Cirrhosis was noted in 6% of the cases reported by Devaney and associates." Death from hepatic insufficiency as a result of cirrhosis is rare. In one series of 28 fatal cases of sarcoidosis, only 1 death was attributable
to liver failure; 50% of deaths were due to cardiac involvement, and 43% were ascribed to pulmonary involvement." Nodular regenerative hyperplasia has been reported in 9% of cases in one series of hepatic sarcoidosis." Finally, note should be made of the rare complication of the Budd-Chiari syndrome in sarcoidosis.v-" End-stage liver disease in sarcoidosis has been treated successfully by orthotopic liver transplantation; 12 recurrent sarcoidosis has been reported in one such case."
Fig. 9. Severely sclerosed bile duct, surrounded by sarcoid granulomas. (Hematoxylin-eosin; original magnification,
Fig. 10. Foamy pseudoxanthomatouscells, clusterednear a portal area, in sarcoid granuloma. (Hematoxylin-eosin; originalmagnification, x400.)
x75.)
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Fig. 11. Wall of intrahepatic vein, extensively infiltrated by sarcoid granulomas. (Hematoxylin-eosin; original magnification, x75.)
ETIOLOGIC FACTORS A mycobacterial cause for sarcoidosis has been suggested for many years (see discussion by Popper and associates"). The detection of mycobacterial DNA and RNA in sarcoid lesions by several groups of investigators-'" and the growth of acid-fast L-forms from the blood of patients with sarcoidosis'" lend support to that association. Nevertheless, the role of mycobacteria in sarcoidosis remains a controversial issue." Recently, variant human herpesvirus 8 DNA sequences were found in a wide range of sarcoid but not nonsarcoid tissues. 56 Further studies must be undertaken to determine whether this association is causal.
Fig. 12. A portal vein branch, outlined by its elastica, showing occlusion from healed granulomatous phlebitis. Arrows denote several residual giant cells in lumen. (Hematoxylin-eosin; original magnification, xIOO.)
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