**2. Etiology and histology of hepatic sarcoidosis**

Sarcoidosis is a non-caseating granulomatous disease, of unknown etiology, affecting primarily mediastinum lymph nodes and the lungs. Its diagnosis is mainly an exclusion one, requiring elimination of all infectious and antigen-producing diseases [5]. The pathognomonic histological aspect is of non-caseating granulomas containing epithelioid cells [6]. Typically, sarcoidosis affects the lungs in over 90% of the cases, but several other organs may be involved, including the liver, the skin, the central nervous system, the heart and the eyes [7, 8]. The main peak of incidence is described for the age group 20–39 years for both genders, with women having a second incidence peak at the ages of 65–69 [9].

The main pathophysiological process in sarcoidosis is the immune paradox, with exaggerated inflammation at disease sites and relative anergy in the unaffected regions [10]. Several theories have been suggested as explanation for this paradox [11]. First, there may be an imbalance between regulatory and effector T-cell lymphocytes that accumulate in the periphery of the granuloma and exert inhibiting effects on naïve T cells. Second, the intense immune stimulation at the disease sites causes lymphocytes to converge in these sites and produces a relative peripheral leukopenia. Third, subsequent to disease chronicity, immunosuppressive T cells are more abundant in the peripheral blood, producing anergy to other antigen stimulations.

The result of this immune imbalance is the non-caseous granuloma, probably containing a partially degraded antigen surrounded by macrophages and T-helper cells. [11]. These macrophages will in turn differentiate into epithelioid cells that will eventually fuse to form multinucleate giant cells. The periphery of the granuloma contains CD8+ T cells, regulatory T cells, fibroblasts and B cells.

As mentioned before, a large percentage of patients with sarcoidosis present with typical signs of the disease in liver biopsy specimens, while only 10–30% have abnormal liver tests [12]. Risk factors associated with liver involvement in sarcoidosis include African-American ethnicity, exposure to pegylated interferon and splenomegaly [13].

The histology aspect of liver sarcoidosis is defined by the presence of epithelioid granulomas in both the portal tracts and hepatic lobules [14]. About 30% of patients with liver sarcoidosis have histological chances similar to those in primary biliary cirrhosis or primary sclerosing cholangitis [15]. However, typical granulomas in sarcoidosis are larger, better defined and associated with multinucleate giant cells. Occasionally, the granulomas may conflate resulting in large masses, which can be misdiagnosed for liver tumors on abdominal imaging [15]. Furthermore, granulomas from primary biliary cirrhosis are portal based and are associated with bile duct destruction, unlike sarcoidosis. In sarcoidosis, there are other signs of organ involvement, as it is a systemic disease, and anti-mitochondrial antibodies are always negative. The histological differential diagnosis between liver sarcoidosis and drug-induced liver injury (DILI) takes into account the fact that DILI manifests as granulomatous hepatitis, with small intralobular granulomas with periportal inflammation [16].

The most important aspect of differentiation between sarcoidosis and infectious granulomas is the presence of caseous necrosis, typical for infectious granulomas [17]. As such, caseating granulomas with central necrosis must be considered infections, until serious evidence eliminates the diagnosis. However, histochemical stains have a low sensitivity for infections, and false-negative results are frequent.

The histology aspect of sarcoidosis may vary, thus explaining the differences in symptomatology and evolution [15]. In a report of 100 cases with sarcoidosis and liver biopsy due to abnormal liver test results, all patients presented with liver

**125**

*Particularities of Hepatic Sarcoidosis*

with cirrhosis.

involvement [21].

*DOI: http://dx.doi.org/10.5772/intechopen.90694*

**3. Clinical aspects of hepatic sarcoidosis**

reported in one patient after transplantation.

phy and subsequent liver biopsy.

granulomas, 99% non-caseating, frequently located in the periportal region. None of the patients had serology or cultures suggestive for infectious granulomas. Three types of histologic alterations were encountered: most patients had cholestatic changes (58%), while 41% presented with necroinflammatory changes and 20% presented with vascular alterations. Patients with cholestasis presented with histology aspects similar to those encountered in primary biliary cirrhosis (19 patients with bile duct lesions) or primary sclerosing cholangitis (13 patients with periductal fibrosis). Biliary ductopenia was noted in 37 out of 58 patients with cholestasis. Twelve patients presented with acute cholangitis without signs of biliary obstruction. Necroinflammatory changes consisted of spotty necrosis and chronic portal inflammation, suggesting hepatitis of various etiologies (viral or drug-induced). Vascular alterations encountered in these patients were sinusoidal dilatation and nodular regenerative hyperplasia. Fibrosis was present in 21 patients overall: 13 patients with periportal fibrosis, 2 patients with bridging fibrosis and 6 patients

The spectrum of liver damage in sarcoidosis varies greatly from asymptomatic patients to end-stage liver disease [12]. Commonly, mild liver cytolysis can be observed (in about 30% of patients with positive biopsies for sarcoidosis) [12]. Abdominal imaging reveals hepatomegaly in less than 50% of the cases [18].

Non-specific symptoms are frequently encountered in patients with sarcoidosis, including malaise, fatigue, arthralgias and fever [19]. Symptoms suggesting liver involvement are jaundice, pruritus and abdominal pain in the upper right quadrant, due to chronic cholestasis and distension of the Glisson capsule by hepatomegaly containing granulomas [19, 20]. One report even describes fever and arthralgias in 70% of patients with liver sarcoidosis, as opposed to those without liver

Rarely, the chronic evolution of liver sarcoidosis can lead to portal hypertension

Case reports of liver sarcoidosis show either non-specific general symptomatology or altered liver enzymes at the time of diagnosis. For example, liver sarcoidosis was diagnosed in a 41-year-old patient with a known history of ocular and lung sarcoidosis for 6 years, who presented with an increase in liver enzymes during periodic follow-up [24]. Final diagnosis was based on positron emission tomogra-

Liver sarcoidosis may also appear in association with cutaneous sarcoidosis. In a report of 40 cases of patients with cutaneous sarcoidosis (with positive histology) monitored for a mean period of 9 years, 32 patients developed lung and thoracic

A recent case series of 7 patients with liver sarcoidosis found that the liver was affected in the evolution of known sarcoidosis in 2 cases, while the other 5 had liver involvement at the time of diagnosis [26]. Four patients presented with upper right

lymph node disease; 1 patient developed liver sarcoidosis [25].

and in a minority of cases, end-stage liver disease with the need for liver transplantation [19]. Also, few cases of association between liver sarcoidosis and Budd-Chiari syndrome have been reported [22]. In a report published in 2006 [23], out of 180 patients, 50% had altered liver function associated with sarcoidosis, while 13% of the patients had liver affection without lung sarcoidosis. Fourteen patients presented with liver cirrhosis from the diagnosis of liver involvement, while two patients developed cirrhosis in the course of the disease, despite corticoid therapy. Six patients underwent liver transplantation, and recurrence of liver sarcoidosis was

#### *Particularities of Hepatic Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.90694*

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

**2. Etiology and histology of hepatic sarcoidosis**

having a second incidence peak at the ages of 65–69 [9].

antigen stimulations.

splenomegaly [13].

inflammation [16].

Sarcoidosis is a non-caseating granulomatous disease, of unknown etiology, affecting primarily mediastinum lymph nodes and the lungs. Its diagnosis is mainly an exclusion one, requiring elimination of all infectious and antigen-producing diseases [5]. The pathognomonic histological aspect is of non-caseating granulomas containing epithelioid cells [6]. Typically, sarcoidosis affects the lungs in over 90% of the cases, but several other organs may be involved, including the liver, the skin, the central nervous system, the heart and the eyes [7, 8]. The main peak of incidence is described for the age group 20–39 years for both genders, with women

The main pathophysiological process in sarcoidosis is the immune paradox, with exaggerated inflammation at disease sites and relative anergy in the unaffected regions [10]. Several theories have been suggested as explanation for this paradox [11]. First, there may be an imbalance between regulatory and effector T-cell lymphocytes that accumulate in the periphery of the granuloma and exert inhibiting effects on naïve T cells. Second, the intense immune stimulation at the disease sites causes lymphocytes to converge in these sites and produces a relative peripheral leukopenia. Third, subsequent to disease chronicity, immunosuppressive T cells are more abundant in the peripheral blood, producing anergy to other

The result of this immune imbalance is the non-caseous granuloma, probably containing a partially degraded antigen surrounded by macrophages and T-helper cells. [11]. These macrophages will in turn differentiate into epithelioid cells that will eventually fuse to form multinucleate giant cells. The periphery of the granu-

As mentioned before, a large percentage of patients with sarcoidosis present with typical signs of the disease in liver biopsy specimens, while only 10–30% have abnormal liver tests [12]. Risk factors associated with liver involvement in sarcoidosis include African-American ethnicity, exposure to pegylated interferon and

The histology aspect of liver sarcoidosis is defined by the presence of epithelioid granulomas in both the portal tracts and hepatic lobules [14]. About 30% of patients with liver sarcoidosis have histological chances similar to those in primary biliary cirrhosis or primary sclerosing cholangitis [15]. However, typical granulomas in sarcoidosis are larger, better defined and associated with multinucleate giant cells. Occasionally, the granulomas may conflate resulting in large masses, which can be misdiagnosed for liver tumors on abdominal imaging [15]. Furthermore, granulomas from primary biliary cirrhosis are portal based and are associated with bile duct destruction, unlike sarcoidosis. In sarcoidosis, there are other signs of organ involvement, as it is a systemic disease, and anti-mitochondrial antibodies are always negative. The histological differential diagnosis between liver sarcoidosis and drug-induced liver injury (DILI) takes into account the fact that DILI manifests as granulomatous hepatitis, with small intralobular granulomas with periportal

The most important aspect of differentiation between sarcoidosis and infectious granulomas is the presence of caseous necrosis, typical for infectious granulomas [17]. As such, caseating granulomas with central necrosis must be considered infections, until serious evidence eliminates the diagnosis. However, histochemical stains

The histology aspect of sarcoidosis may vary, thus explaining the differences in symptomatology and evolution [15]. In a report of 100 cases with sarcoidosis and liver biopsy due to abnormal liver test results, all patients presented with liver

have a low sensitivity for infections, and false-negative results are frequent.

loma contains CD8+ T cells, regulatory T cells, fibroblasts and B cells.

**124**

granulomas, 99% non-caseating, frequently located in the periportal region. None of the patients had serology or cultures suggestive for infectious granulomas. Three types of histologic alterations were encountered: most patients had cholestatic changes (58%), while 41% presented with necroinflammatory changes and 20% presented with vascular alterations. Patients with cholestasis presented with histology aspects similar to those encountered in primary biliary cirrhosis (19 patients with bile duct lesions) or primary sclerosing cholangitis (13 patients with periductal fibrosis). Biliary ductopenia was noted in 37 out of 58 patients with cholestasis. Twelve patients presented with acute cholangitis without signs of biliary obstruction. Necroinflammatory changes consisted of spotty necrosis and chronic portal inflammation, suggesting hepatitis of various etiologies (viral or drug-induced). Vascular alterations encountered in these patients were sinusoidal dilatation and nodular regenerative hyperplasia. Fibrosis was present in 21 patients overall: 13 patients with periportal fibrosis, 2 patients with bridging fibrosis and 6 patients with cirrhosis.
