**3. Clinical aspects of hepatic sarcoidosis**

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 involvement [21].

Rarely, the chronic evolution of liver sarcoidosis can lead to portal hypertension 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 reported in one patient after transplantation.

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 tomography and subsequent liver biopsy.

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

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

quadrant abdominal pain and one patient had incidentally discovered altered liver enzymes on routine evaluation. One patient also presented with cutaneous sarcoidosis (erythematous lesions on the scalp), one patient had ocular involvement (Sicca syndrome), while one patient had both skin and ocular manifestations (uveitis and sarcoid nodules). Notably, hepatomegaly was observed in all 7 patients, with 2 patients presenting with concomitant splenomegaly. One of these patients was found to have primary Budd-Chiari syndrome.

Another case report presents the diagnosis of liver sarcoidosis in an asymptomatic 66-year-old woman with abnormal liver function test on routine evaluation [27], requiring extensive evaluation by tomography and magnetic resonance imaging and ultimately liver biopsy for diagnostic confirmation.

In rare instances, necrosis of the sarcoid granulomas may appear [28]. The case of a 37-year-old woman with sudden onset of fever and right abdominal pain is reported. Initially, the patient was treated for suspicion of intra-abdominal infection. The presence of liver and splenic lesions on abdominal CT scan prompted the need for liver biopsy, showing necrotizing granulomas negative for infection, with remission of symptoms after corticoid therapy.

Few cases of typical sarcoidosis have been described under the age of 20 years [29]. One case report [30] presents the diagnosis of pediatric-onset adult sarcoidosis, with lung, liver and lymph nodes involvement. The 9-year-old patient presented with asthenia, weight loss, hepatosplenomegaly and 2 palpable lymph nodes (supraclavicular and inguinal). The major aspect of this case is the emphasis on the differential diagnosis from lymphoproliferative diseases in patients with abdominal organomegaly.

Furthermore, liver sarcoidosis may evolve silently with the development of cirrhosis and portal hypertension. Such a case was reported in 2012 [31] in a 48-year-old patient, complaining of abdominal pain. CT scan in this patient revealed hepatosplenomegaly and increased diameter of portal and splenic vein, suggestive of portal hypertension. In the absence of autoimmune and viral markers, the patient underwent liver biopsy with a positive diagnosis of liver sarcoidosis. Repeated thorax CT scans did not reveal pulmonary or lymph nodes involvement. Splenectomy was required due to severe pancytopenia. The patient's evolution was complicated with the development of ascites; the authors note the absence of esophageal or gastric varices as a sign of portal hypertension in this patient.

A review of 37 patients with sarcoidosis and portal hypertension [20] found a predominance of female patients. All patients presented with hepatosplenomegaly and esophageal varices in different degrees. Direct measurement of pressure in the portal vein was performed in 18 patients, with an average portal pressure of 24.6 mmHg. The authors emphasize the different physiopathological aspects of portal hypertension in sarcoidosis: healing fibrosis, large sarcoid granulomas and small perigranular arteriovenous shunts may increase sinusoidal resistance leading to portal hypertension. A presinusoidal blockage may occur by the direct pressure of the sarcoid granulomas in the portal areas. Another possible explanation is ischemia-induced fibrosis and cirrhosis in the setting of primary granulomatous phlebitis of the portal and hepatic veins [32].

Liver sarcoidosis can be associated with chronic cholestasis, either intrahepatic (mimicking primary biliary cirrhosis or primary sclerosing cholangitis) or extrahepatic (by hilar or ductal compression by adenopathies) [20]. Clinical manifestations of intrahepatic cholestasis reported in 31 patients were pruritus, jaundice and right quadrant abdominal pain. Extrahepatic cholestasis is far rarer [33], and CT scan and endoscopic retrograde cholangiopancreatography are required for the diagnosis.

Acute sarcoidosis rarely presents with liver involvement [20]. Usually, the clinical presentation is dominated by pulmonary symptoms (cough, dyspnea and

**127**

*Particularities of Hepatic Sarcoidosis*

abnormal liver function tests.

**Figure 1.**

tous inflammation [35].

but unrelated to liver involvement.

encountered as a sign of liver disease.

exclude other etiologies of liver disease [36].

**4. Laboratory findings in liver sarcoidosis**

*Summary of clinical aspects encountered in liver sarcoidosis.*

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

chest discomfort) and constitutional symptoms (fever, fatigue, malaise and weight loss). Liver involvement may be suspected in the presence of jaundice, pruritus or

Both cholestasis and hepatocytolysis can appear in liver sarcoidosis. Abnormal liver tests are found in up to 40% of patients with sarcoidosis, with a predominance of cholestasis (increased alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (γGT) and minor increases in bilirubin levels) [34]. ALP can be increased in up to 90% of the patients with symptoms of hepatic disease, up to 10 times the upper normal limit [19]; by contrast, increases in transaminases are mild and less frequent. The severity of the cholestasis is associated with the degree of granuloma-

Peripheral lymphopenia, especially noted in CD4+ positive cells, can be useful in suspecting sarcoidosis [31]. Hypercalcemia and hypercalciuria can also be found,

In cases with portal hypertension, frequent findings are pancytopenia [20, 31] with the predominance of thrombocytopenia. Hypoalbuminemia can also be

Most laboratory determinations are aimed at excluding other causes of liver disease. Most commonly used are viral serology markers for hepatitis B and C infection, serum markers for Wilson's disease and hemochromatosis (especially in young patients), autoantibody determinations for celiac disease, primary biliary cirrhosis and autoimmune hepatitis. **Table 1** summarizes the main serum determinations to

Patients with active disease may present with increased levels of serum inflammation markers (such as erythrocyte sedimentation rate and C-reactive protein), regardless of the organs involved [37]. CRP may also be associated with fatigue in

There are yet no serum markers for the clear diagnosis of sarcoidosis. High serum levels of angiotensin-converting enzyme have been associated with sarcoidosis and are present in about 60% of patients with active disease [19]. Nevertheless, the test is far from pathognomonic, with low positive and negative predicting values

sarcoidosis. However, these tests are not specific in any way to sarcoidosis.

**Figure 1** summarizes possible clinical aspects of liver sarcoidosis.

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

found to have primary Budd-Chiari syndrome.

remission of symptoms after corticoid therapy.

phlebitis of the portal and hepatic veins [32].

organomegaly.

ing and ultimately liver biopsy for diagnostic confirmation.

quadrant abdominal pain and one patient had incidentally discovered altered liver enzymes on routine evaluation. One patient also presented with cutaneous sarcoidosis (erythematous lesions on the scalp), one patient had ocular involvement (Sicca syndrome), while one patient had both skin and ocular manifestations (uveitis and sarcoid nodules). Notably, hepatomegaly was observed in all 7 patients, with 2 patients presenting with concomitant splenomegaly. One of these patients was

Another case report presents the diagnosis of liver sarcoidosis in an asymptomatic 66-year-old woman with abnormal liver function test on routine evaluation [27], requiring extensive evaluation by tomography and magnetic resonance imag-

In rare instances, necrosis of the sarcoid granulomas may appear [28]. The case of a 37-year-old woman with sudden onset of fever and right abdominal pain is reported. Initially, the patient was treated for suspicion of intra-abdominal infection. The presence of liver and splenic lesions on abdominal CT scan prompted the need for liver biopsy, showing necrotizing granulomas negative for infection, with

Few cases of typical sarcoidosis have been described under the age of 20 years [29]. One case report [30] presents the diagnosis of pediatric-onset adult sarcoidosis, with lung, liver and lymph nodes involvement. The 9-year-old patient presented with asthenia, weight loss, hepatosplenomegaly and 2 palpable lymph nodes (supraclavicular and inguinal). The major aspect of this case is the emphasis on the differential diagnosis from lymphoproliferative diseases in patients with abdominal

Furthermore, liver sarcoidosis may evolve silently with the development of cirrhosis and portal hypertension. Such a case was reported in 2012 [31] in a 48-year-old patient, complaining of abdominal pain. CT scan in this patient revealed hepatosplenomegaly and increased diameter of portal and splenic vein, suggestive of portal hypertension. In the absence of autoimmune and viral markers, the patient underwent liver biopsy with a positive diagnosis of liver sarcoidosis. Repeated thorax CT scans did not reveal pulmonary or lymph nodes involvement. Splenectomy was required due to severe pancytopenia. The patient's evolution was complicated with the development of ascites; the authors note the absence of esophageal or gastric varices as a sign of portal hypertension in this patient.

A review of 37 patients with sarcoidosis and portal hypertension [20] found a predominance of female patients. All patients presented with hepatosplenomegaly and esophageal varices in different degrees. Direct measurement of pressure in the portal vein was performed in 18 patients, with an average portal pressure of 24.6 mmHg. The authors emphasize the different physiopathological aspects of portal hypertension in sarcoidosis: healing fibrosis, large sarcoid granulomas and small perigranular arteriovenous shunts may increase sinusoidal resistance leading to portal hypertension. A presinusoidal blockage may occur by the direct pressure of the sarcoid granulomas in the portal areas. Another possible explanation is ischemia-induced fibrosis and cirrhosis in the setting of primary granulomatous

Liver sarcoidosis can be associated with chronic cholestasis, either intrahepatic (mimicking primary biliary cirrhosis or primary sclerosing cholangitis) or extrahepatic (by hilar or ductal compression by adenopathies) [20]. Clinical manifestations of intrahepatic cholestasis reported in 31 patients were pruritus, jaundice and right quadrant abdominal pain. Extrahepatic cholestasis is far rarer [33], and CT scan and endoscopic retrograde cholangiopancreatography are required for the diagnosis. Acute sarcoidosis rarely presents with liver involvement [20]. Usually, the clinical presentation is dominated by pulmonary symptoms (cough, dyspnea and

**126**

**Figure 1.** *Summary of clinical aspects encountered in liver sarcoidosis.*

chest discomfort) and constitutional symptoms (fever, fatigue, malaise and weight loss). Liver involvement may be suspected in the presence of jaundice, pruritus or abnormal liver function tests.

**Figure 1** summarizes possible clinical aspects of liver sarcoidosis.
