Sarcoidosis

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Chapter 159 Sarcoidosis

Eveline Y. Wu, Esi Morgan DeWitt

Sarcoidosis is a rare multisystem granulomatous disease of unknown etiology. The name is derived from a Greek word meaning “fleshlike condition,” in reference to the characteristic skin lesions. There appears to be 2 distinct patterns of disease among children with sarcoidosis. The clinical features in older children are similar to those in adults, with frequent pulmonary involvement and lymphadenopathy. In contrast, early-onset sarcoidosis manifesting in children <4 yr of age is characterized by the triad of rash, uveitis, and arthritis.

Etiology

The etiology of sarcoidosis remains obscure but is likely the result of exposure of a genetically susceptible individual to one or more unidentified antigens. This exposure initiates an exaggerated immune response that ultimately leads to the formation of granulomas. The human major histocompatibility complex is located on chromosome 6, and specific human leukocyte antigen class I and class II alleles are associated with disease phenotype. Genetic polymorphisms involving various cytokines and chemokines may also have a role in development of sarcoidosis. Familial clustering supports the contribution of genetic factors to sarcoidosis susceptibility. Environmental and occupational exposures are also associated with disease risk. There are positive associations between sarcoidosis and agricultural employment, occupational exposure to insecticides, and moldy environments typically associated with microbial bioaerosols.

An autosomal dominant familial form of the disease typified by early onset of skin, eye, and joint involvement is described as Blau syndrome. Mutations in the CARD15/NOD2 gene on chromosome 16 have been found in affected family members and appear to be associated with development of sarcoidosis. Similar genetic mutations also have been found in individuals with early-onset sarcoidosis (rash, uveitis, arthritis) but without a family history of disease, suggesting that this nonfamilial disease and Blau syndrome are genetically and phenotypically identical (Chapter 157).

Epidemiology

Sarcoidosis is rare in childhood, and thus the incidence and prevalence are difficult to determine. A nationwide patient registry of childhood sarcoidosis in Denmark estimated the annual incidence to be 0.22 to 0.27 per 100,000 children. The incidence increases with age, and peak onset occurs at 20-39 yr. The most common age of reported childhood cases is 13-15 yr. Annual incidence is about 11/100,000 in adult white Americans and is three times higher in African Americans. There is no clear sex predominance. Within the USA, the majority of childhood sarcoidosis cases are reported in the Southeastern and South Central states.

Pathology and Pathogenesis

Noncaseating, epithelioid granulomatous lesions are a cardinal feature of sarcoidosis. Activated macrophages, epithelioid cells, and multinucleated giant cells as well as CD4+ T lymphocytes accumulate and become tightly packed in the center of the granuloma. The causative agent that initiates this inflammatory process is not known. The periphery of the granuloma contains a loose collection of monocytes, CD4+ and CD8+ T lymphocytes, and fibroblasts. The interaction between the macrophages and CD4+ T lymphocytes is important in the formation and maintenance of the granuloma. The activated macrophages secrete high levels of tumor necrosis factor-α (TNF-α) and other proinflammatory mediators. The CD4+ T lymphocytes differentiate into type 1 helper T cells and release interleukin-2 (IL-2) and interferon-γ (IFN-γ), promoting proliferation of lymphocytes. Granulomas may heal or resolve with complete preservation of the parenchyma. In approximately 20% of the lesions, the fibroblasts in the periphery proliferate and produce fibrotic scar tissue, leading to significant and irreversible organ dysfunction.

The sarcoid macrophage is able to produce and secrete 1,25-(OH)2-vitamin D or calcitriol, an active form of vitamin D typically produced in the kidneys. The hormone’s natural functions are to increase intestinal absorption of calcium and bone resorption and to decrease renal excretion of calcium and phosphate. An excess in vitamin D may result in hypercalcemia and hypercalciuria in patients with sarcoidosis.

Clinical Manifestations

Sarcoidosis is a multisystem disease, and granulomatous lesions may occur in any organ of the body. The clinical manifestations depend on the extent and degree of granulomatous inflammation and are extremely variable. Children may present with nonspecific symptoms, such as fever, weight loss, and general malaise. In adults and older children, pulmonary involvement is most frequent, with infiltration of the thoracic lymph nodes and lung parenchyma. Isolated bilateral hilar adenopathy on chest radiograph is the most common finding, but parenchymal infiltrates and miliary nodules may also be seen (Fig. 159-1

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