**5. Imaging in liver sarcoidosis**

In asymptomatic patients, a routine laboratory testing or abdominal ultrasound can raise suspicion of liver disease, especially in the setting of a known history of sarcoidosis. In fact, some authors recommend routine testing for liver sarcoidosis in the course of the disease [19].

Abdominal ultrasonography frequently reveals hepatomegaly, possibly associated with splenomegaly in the case of splenic involvement or portal hypertension. One review found that 8% of patients with liver sarcoidosis had marked hepatomegaly, with an anteroposterior diameter of over 25 cm [39]. The general aspect of

**129**

**Figure 2.**

*Particularities of Hepatic Sarcoidosis*

liver nodules in sarcoidosis.

hepatitis C.

CEUS (**Figure 3**).

phases [45].

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

the liver is of increased echogenicity, either homogenous or diffusely heterogeneous

Splenomegaly is also reported in almost 60% of patients with liver sarcoidosis [40], with markedly increased dimensions (over 18 cm) in 6% of the cases. In 15% of cases, splenomegaly is associated with hypoechoic splenic nodules. The frequency of nodules appears to vary according to geographical distribution and ethnic characteristics [40]. They are distributed diffusely within the splenic parenchyma, with a medium size of 1 cm [42]; they demonstrate hypovascularization on Doppler analysis. Isolated splenic nodules are more frequent than isolated hepatomegaly or

Up to 76% of patients with liver and splenic nodules also associate with enlarged abdominal lymph nodes [43], with infrequent punctate calcifications. Adenopathies are usually found periportal, celiac, paracaval and para-aortic, with dimensions ranging from 1 cm to 4–6 cm [44, 45]. Larger perihepatic lymph nodes can be associated with advanced liver disease. They raise the need for differential diagnosis to malignant conditions (primarily lymphoproliferative disorders), intra-abdominal infections and benign conditions such as primary biliary cirrhosis or chronic

Contrast-enhanced ultrasonography (CEUS) has emerged as a new, reliable and non-invasive means of evaluation of liver disease [45]. CEUS has proven its greatest utility in differentiating between benign and malignant liver and splenic nodules, with sensitivity and specificity similar to those of CT scans. The use of CEUS in abdominal sarcoidosis has been evaluated in small case series or case reports [45], due to the scarcity of the cases and also to the fact that patients with hepatosplenic sarcoidosis rarely present with focal lesions, making them difficult candidates for

If hypoechoic liver lesions appear on conventional ultrasonography, they have variable arterial enhancement with progressive washout in the portal and late

*Abdominal ultrasonography revealing diffusely heterogeneous hepatomegaly in a patient with liver sarcoidosis.*

[40] (**Figure 2**). The aspect sometimes may resemble fatty liver disease [41]. Focal liver nodules may appear on ultrasonography in the case when sarcoid granulomas conflate and form macroscopic masses. Such nodules have been described in up to 19% of patients [40]. Typically, there are innumerous round nodules, diffusely distributed, with size ranging from 1 to 2 mm to centimeters [39].

Color Doppler ultrasonography reveals hypovascularization of the nodules.

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

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

IgM antibodies for cytomegalovirus

antibodies (SMA)

Antimitochondrial antibodies

Anti-*Saccharomyces cerevisiae*

Antineutrophil cytoplasmic antibodies

Antitissue transglutaminase

**Table 1.**

Antiliver kidney muscle antibodies (LKM-1)

Urinary copper High values

**Determination Result Diagnosis Comments**

HBs antigen Positive Hepatitis B infection Determine HBV-DNA

HCV antibodies Positive Possible hepatitis C infection Confirm infection with

Ceruloplasmin Low values Possible Wilson's disease Confirm with genetic

Serum ferritin High values Possible hemochromatosis Confirm with genetic testing/liver biopsy Transferrin levels High values Antinuclear antibodies Positive Possible autoimmune hepatitis Search for concurrent

other organ involved Antismooth muscle

Positive Possible primary biliary cirrhosis

Positive Possible Wegener's disease, other vasculitis

Positive Possible inflammatory bowel

disease, associated with primary biliary cirrhosis

Positive Possible autoimmune hepatitis

Positive Possible autoimmune hepatitis

testing Serum copper High values

Positive Possible CMV hepatitis Determine viremia

Search for HDV co-infection

abnormal tests and/or

HCV- RNA

(84% and 74%, respectively). Normal ACE levels should not be used for exclusion of sarcoidosis-they can be encountered in patients with chronic disease or patients under corticoid therapy. High values are indicative of sarcoidosis and can be used in excluding other granulomatous diseases. However, inflammatory bowel disease can also manifest with high level of ACE, and the differential diagnosis is difficult, especially when primary biliary cirrhosis is associated. Increased levels of ACE can also be found in pulmonary silicosis, asbestosis, military tuberculosis, diabetes

*Biological parameters required in the etiology of liver disease (adapted from [36]).*

Positive Possible celiac disease

In asymptomatic patients, a routine laboratory testing or abdominal ultrasound can raise suspicion of liver disease, especially in the setting of a known history of sarcoidosis. In fact, some authors recommend routine testing for liver sarcoidosis in

Abdominal ultrasonography frequently reveals hepatomegaly, possibly associated with splenomegaly in the case of splenic involvement or portal hypertension. One review found that 8% of patients with liver sarcoidosis had marked hepatomegaly, with an anteroposterior diameter of over 25 cm [39]. The general aspect of

**128**

mellitus and hyperthyroidism [38].

**5. Imaging in liver sarcoidosis**

the course of the disease [19].

the liver is of increased echogenicity, either homogenous or diffusely heterogeneous [40] (**Figure 2**). The aspect sometimes may resemble fatty liver disease [41].

Focal liver nodules may appear on ultrasonography in the case when sarcoid granulomas conflate and form macroscopic masses. Such nodules have been described in up to 19% of patients [40]. Typically, there are innumerous round nodules, diffusely distributed, with size ranging from 1 to 2 mm to centimeters [39]. Color Doppler ultrasonography reveals hypovascularization of the nodules.

Splenomegaly is also reported in almost 60% of patients with liver sarcoidosis [40], with markedly increased dimensions (over 18 cm) in 6% of the cases. In 15% of cases, splenomegaly is associated with hypoechoic splenic nodules. The frequency of nodules appears to vary according to geographical distribution and ethnic characteristics [40]. They are distributed diffusely within the splenic parenchyma, with a medium size of 1 cm [42]; they demonstrate hypovascularization on Doppler analysis. Isolated splenic nodules are more frequent than isolated hepatomegaly or liver nodules in sarcoidosis.

Up to 76% of patients with liver and splenic nodules also associate with enlarged abdominal lymph nodes [43], with infrequent punctate calcifications. Adenopathies are usually found periportal, celiac, paracaval and para-aortic, with dimensions ranging from 1 cm to 4–6 cm [44, 45]. Larger perihepatic lymph nodes can be associated with advanced liver disease. They raise the need for differential diagnosis to malignant conditions (primarily lymphoproliferative disorders), intra-abdominal infections and benign conditions such as primary biliary cirrhosis or chronic hepatitis C.

Contrast-enhanced ultrasonography (CEUS) has emerged as a new, reliable and non-invasive means of evaluation of liver disease [45]. CEUS has proven its greatest utility in differentiating between benign and malignant liver and splenic nodules, with sensitivity and specificity similar to those of CT scans. The use of CEUS in abdominal sarcoidosis has been evaluated in small case series or case reports [45], due to the scarcity of the cases and also to the fact that patients with hepatosplenic sarcoidosis rarely present with focal lesions, making them difficult candidates for CEUS (**Figure 3**).

If hypoechoic liver lesions appear on conventional ultrasonography, they have variable arterial enhancement with progressive washout in the portal and late phases [45].

**Figure 3.** *CEUS in a patient with liver sarcoidosis—diffuse disease, without focal lesions (late phase).*

Regarding hypoechoic splenic nodules, on CEUS, they appear as progressive hypoenhancing nodules in the arterial and parenchymal phases. As the investigation progresses into the parenchymal phase, the lesion-to-parenchyma contrast diffusion is increased. The mild enhancement in the arterial phase can be homogenous or diffusely heterogeneous, while in the parenchymal phase, it may be homogenous or with a dotted pattern. Sometimes, peripheral blood vessels may be visible and have an irregular aspect. These characteristics may be compatible with malignant conditions; therefore, biopsy is mandatory for a clear diagnosis.

A study performed in 2013 evaluated the efficacy of CEUS in diagnostic abdominal disease in 21 patients with pulmonary sarcoidosis [46]. Eighteen patients had no hepatosplenic disease, one patient had splenic nodules and two patients had liver lesions. CEUS as well as CT scan and abdominal MRI gave concordant results. The authors underline the importance of CEUS in the evaluation of these patients, as it offers the same information without any contraindications that CT or MRI might have including allergy to contrast, contrast-induced nephropathy or the presence of pacemakers or metallic devices. It is also suggested that CEUS should be used in the first evaluation of patients with pulmonary sarcoidosis and in their monitorization during treatment.

The latest review on the importance of CEUS in the evaluation of abdominal involvement in sarcoidosis describes the following characteristics [47]:


Endoscopic ultrasound elastography could also be used to characterize liver sarcoidosis [47]. The lesions may appear as single masses with blue hard patterns within and around.

However, the lack of sufficient data especially from clinical trials or large studies makes it impossible to establish clear recommendations on the use of CEUS in liver sarcoidosis; therefore, other imagistic methods are required for a complete positive diagnosis.

CT scans in liver sarcoidosis may reveal homogenous hepatomegaly (with possible low-density intrahepatic septa) [40] (**Figure 4**). Liver nodules appear as hypoenhanced masses as opposed to the adjacent normal liver parenchyma. There is

**131**

**Figure 5.**

*MRI of a patient with diffuse liver sarcoidosis.*

*Particularities of Hepatic Sarcoidosis*

**Figure 4.**

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

no visible peripheral enhancement. Typically, the nodules have no mass effect. Sometimes, these numerous hypodense nodules with variable dimensions warrant differential diagnosis to metastatic disease of the liver, but also miliary liver tuber-

*Abdominal CT scan of a patient with liver sarcoidosis showing homogeneous hepatomegaly and splenomegaly.*

CT scan is useful in the diagnosis of liver cirrhosis and portal hypertension subsequent to sarcoidosis [49], as rare as they appear. Typical aspects include hypertrophy of the caudate lobe, dilatation of the portal and splenic veins, irregular liver contour, collateral circulation vessels around the digestive tract as well as ascites. MRI evaluation of liver sarcoidosis may reveal hypointense and hypoenhancing nodules relative to the adjacent liver parenchyma [40] (**Figures 5** and **6**). Still, the particularity of the imaging is the lack of mass effect or any impact of the nodules

T2-weighted fat-saturated images are the most conclusive in diagnosing hypointense nodules in liver sarcoidosis. This is an important part in the differential diagnosis from malignancies, as these appear most frequently as hyperintense. Other signs suggestive of sarcoidosis are irregular contour of the liver and high periportal

culosis, fungal infections or Langerhans cell histiocytosis [48].

on the surrounding parenchyma or adjacent vessels.

#### **Figure 4.**

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

Regarding hypoechoic splenic nodules, on CEUS, they appear as progressive hypoenhancing nodules in the arterial and parenchymal phases. As the investigation progresses into the parenchymal phase, the lesion-to-parenchyma contrast diffusion is increased. The mild enhancement in the arterial phase can be homogenous or diffusely heterogeneous, while in the parenchymal phase, it may be homogenous or with a dotted pattern. Sometimes, peripheral blood vessels may be visible and have an irregular aspect. These characteristics may be compatible with malignant

A study performed in 2013 evaluated the efficacy of CEUS in diagnostic abdominal disease in 21 patients with pulmonary sarcoidosis [46]. Eighteen patients had no hepatosplenic disease, one patient had splenic nodules and two patients had liver lesions. CEUS as well as CT scan and abdominal MRI gave concordant results. The authors underline the importance of CEUS in the evaluation of these patients, as it offers the same information without any contraindications that CT or MRI might have including allergy to contrast, contrast-induced nephropathy or the presence of pacemakers or metallic devices. It is also suggested that CEUS should be used in the first evaluation of patients with pulmonary sarcoidosis and in their monitorization during treatment. The latest review on the importance of CEUS in the evaluation of abdominal

conditions; therefore, biopsy is mandatory for a clear diagnosis.

*CEUS in a patient with liver sarcoidosis—diffuse disease, without focal lesions (late phase).*

involvement in sarcoidosis describes the following characteristics [47]:

progressive hypoenhancement in the portal and late phases.

• Liver aspect on CEUS: variable nodular enhancement in the arterial phase,

• Splenic aspect on CEUS: progressive hypoenhancement in the arterial and parenchymal phase. Possible patterns: rim-like, homogenous, dotted.

Endoscopic ultrasound elastography could also be used to characterize liver sarcoidosis [47]. The lesions may appear as single masses with blue hard patterns

CT scans in liver sarcoidosis may reveal homogenous hepatomegaly (with possible low-density intrahepatic septa) [40] (**Figure 4**). Liver nodules appear as hypoenhanced masses as opposed to the adjacent normal liver parenchyma. There is

However, the lack of sufficient data especially from clinical trials or large studies makes it impossible to establish clear recommendations on the use of CEUS in liver sarcoidosis; therefore, other imagistic methods are required for a complete positive

**130**

diagnosis.

**Figure 3.**

within and around.

*Abdominal CT scan of a patient with liver sarcoidosis showing homogeneous hepatomegaly and splenomegaly.*

no visible peripheral enhancement. Typically, the nodules have no mass effect. Sometimes, these numerous hypodense nodules with variable dimensions warrant differential diagnosis to metastatic disease of the liver, but also miliary liver tuberculosis, fungal infections or Langerhans cell histiocytosis [48].

CT scan is useful in the diagnosis of liver cirrhosis and portal hypertension subsequent to sarcoidosis [49], as rare as they appear. Typical aspects include hypertrophy of the caudate lobe, dilatation of the portal and splenic veins, irregular liver contour, collateral circulation vessels around the digestive tract as well as ascites.

MRI evaluation of liver sarcoidosis may reveal hypointense and hypoenhancing nodules relative to the adjacent liver parenchyma [40] (**Figures 5** and **6**). Still, the particularity of the imaging is the lack of mass effect or any impact of the nodules on the surrounding parenchyma or adjacent vessels.

T2-weighted fat-saturated images are the most conclusive in diagnosing hypointense nodules in liver sarcoidosis. This is an important part in the differential diagnosis from malignancies, as these appear most frequently as hyperintense. Other signs suggestive of sarcoidosis are irregular contour of the liver and high periportal

**Figure 5.** *MRI of a patient with diffuse liver sarcoidosis.*

#### **Figure 6.**

*MRI in a patient with liver and splenic sarcoidosis demonstrating hypoattenuation of splenic lesions (A). MRI in the same patient demonstrating hepatosplenomegaly (B).*

signal intensity [50]. However, cases have been described where masses with T2 hyperintensity have proven to be liver sarcoidosis in histology examination [51].

Nodules located in the hilar area need to be differentiated from cholangiocarcinomas. In cases thus located or in the case of hilum adenopathies and subsequent stenosis of biliary ducts, magnetic resonance cholangiopancreatography may reveal the stenosis with dilatation of intrahepatic bile ducts, similar to that in a Klatskin tumor [52]. In this case, the positive diagnosis is set by biopsy, usually obtained by ERCP.
