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Hepatic Sarcoidosis
Sarcoidosis is a systemic granulomatous disease of unknown etiology that primarily affects the lungs and lymphoid tissues of the body. The term sarcoidosis stems from a case report by a Norwegian dermatologist, Caesar Boeck, who in describing “multiple benign sarkoid of the skin” coined the term for skin lesions that resembled sarcoma but were benign. Sarcoid liver disease was first described in detail by Maddrey and colleagues in 1970, when they reported 20 patients with known sarcoidosis who had hepatic granulomas and biochemical or clinical evidence of liver disease. Although a liver affected by sarcoidosis may contain up to 75 million granulomas, the vast majority of patients are asymptomatic or show only minimal biochemical hepatic dysfunction. When symptomatic, the clinical presentation can be very disparate as documented in several studies.
Incidence and Demographics
A population-based study of sarcoidosis in the United States reported an incidence of 5.9 per 100,000 person-years for men and 6.3 per 100,000 person-years for women. In the United States, the incidence is higher in African Americans, and the lifetime risk of sarcoidosis is estimated at 0.85% for Caucasians and 2.4% for African Americans. Most studies show a slight predilection in women. Although the disease may occur in any age group, sarcoidosis is a disease of young adults, with a peak incidence in the second and third decades of life. In Scandinavian countries and Japan, a second peak occurs in women older than 50 years.
Liver involvement by sarcoidosis is common, and it follows lymph nodes and lungs in the frequency of involvement. It is estimated that liver biopsy specimens demonstrate granulomas in up to 90% of patients with systemic sarcoidosis. The reported incidence of liver involvement varies in different series because of differing criteria used to define sarcoid liver disease. In a review of 10 series comprising slightly more than 1200 patients with sarcoidosis, liver involvement as determined by hepatomegaly was found in 21% of cases. A separate study of 125 patients found a 35% incidence of liver involvement, which was defined as abnormal liver tests in patients with known sarcoidosis. A 4% incidence of liver involvement was found among 500 patients with sarcoidosis when defined as presence of granulomas in the liver along with biochemical or clinical evidence of liver disease. Finally, an incidence of 11.5% was reported in a series of 736 patients with liver involvement being defined by a combination of clinical history, physical findings, and laboratory studies. Although a significant number of patients may have abnormal liver tests and even granulomas in the liver, symptomatic liver disease is consistently low in all series and is estimated to be below 5% in patients with sarcoidosis. A predilection for liver disease among African Americans has been reported in some studies but not in others. Sarcoidosis accounts for 8% to 22% of liver biopsies with granulomatous inflammation.
Clinical Manifestations
Liver involvement may be the first manifestation of sarcoidosis or may be discovered several years after the initial diagnosis. In one study, the mean time between the initial diagnosis of sarcoidosis and recognition of liver disease was reported to be 3.3 years. Pulmonary disease may be inactive at presentation of hepatic sarcoidosis, and therefore, a normal chest x-ray (pulmonary stage 0) does not exclude sarcoidosis. Hepatic sarcoidosis is clinically silent in the most cases and often overshadowed by involvement of other organ systems. When liver involvement does come to clinical attention, the presentation of the disease is highly variable. A large number of patients present with liver test abnormalities with or without hepatomegaly or splenomegaly. This has been attributed to inflammatory changes around the hepatic granulomas. In one study, there was a high association of male gender and splenomegaly with liver involvement by sarcoidosis. Splenomegaly in the absence of cirrhosis and portal hypertension reflects the propensity of sarcoidosis to involve lymphatic tissue.
Chronic cholestasis with jaundice, abdominal pain, and elevated alkaline phosphatase levels may rarely occur in hepatic sarcoidosis, resembling primary biliary cholangitis or sclerosing cholangitis. Cirrhosis with portal hypertension and its complications is thought to manifest in about 1% of patients with sarcoidosis. When portal hypertension develops in the absence of cirrhosis, it is thought to be secondary to presinusoidal obstruction as the result of extensive portal tract granulomas, which may be superimposed by sinusoidal block because of fibrosis and/or as the result of nodular regenerative hyperplasia.
Rare manifestations of liver sarcoidosis include extrahepatic biliary obstruction by large granulomatous lymph nodes and the Budd-Chiari syndrome resulting from obstruction of hepatic venous tributaries by granulomatous inflammation.
Liver involvement may present with nonspecific symptoms such as fever and fatigue and is an important differential of fever of unknown origin. In a series of 30 patients who presented with fever of unknown origin and had granulomas on liver biopsy, 15 were subsequently found to have extrahepatic manifestations of sarcoidosis.
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