Garabed Eknoyan

Sarcoidosis is a clinicopathologic syndrome resulting from dispersed organ involvement by a noncaseating granulomatous process of unknown cause. The clinical manifestations of sar-coidosis are protean, depending on the affected organs; however, the principal targets of sarcoidosis are the lungs and thoracic lymph nodes, which almost always are involved. As a rule, it is a disease of insidious onset that pursues a chronic course, with episodic remissions and exacerbations. The severity and diversity of its clinical manifestations depend on the extent of infiltrating granulomatous lesions of the involved organs and that of the number of affected organs. When diffuse and widespread the disease may pursue an acute fulminant course. Diagnosis depends on demonstration of the characteristic pathologic lesion of noncaseating granulomas within the affected organ.

Sarcoidosis is a common (1 to 40 cases per 100,000 population) disease of the relatively young (mean age 40 years), with a proclivity for racial (3.5 times more in blacks), ethnic (Scandinavian), and seasonal occurrence (summer rather than winter). Reports of community outbreaks, work-related risks, familial clustering, occurrence after organ transplantation, and experimental induction in animals by injection of affected tissue homogenates from humans strongly suggests an infective cause that remains to be identified.

Two associated metabolic abnormalities of diagnostic and clinical import are elevated levels of calcitriol (1,25-dihydroxy-vitamin D3) and angiotensin-converting enzyme (ACE). Neither is unique to sar-coidosis. Elevated levels of calcitriol are consequent to the capacity of the infiltrating macrophages of the granulomas to synthesize calcitriol. Elevated levels of ACE are consequent to that of the multinucleated giant and epithelioid cells that ultimately develop in the granulomas, along with that of the infiltrating macrophages, to produce ACE. Of these, the elevated levels of calcitriol are the more important because they account for the abnormal calcium metabolism that occurs in most patients. Elevated levels of ACE are of no known clinical consequence and are of limited value in diagnosis; however, they can be useful in follow-up of the course of the disease and patient response to treatment.

In symptomatic cases, steroids are highly effective in suppressing the cellular inflammatory reaction of sarcoidosis and in reversing most forms of organ dysfunction caused by granu-lomatous infiltration. Therapy with prednisone (30 to 40 mg/d) for 8 to 12 weeks, with gradual tapering of the dose (10 to 20 mg/d) over 6 to 12 months, is usually sufficient. Persistent dysfunction can result from residual fibrosis after reversal of

FIGURE 8-1 ( see Color Plate)

Pathology of granulomatous lesions in lungs affected by sarcoidosis. The diagnosis of sarcoidosis depends on demonstration of the characteristic lesion of noncaseating granulomas within the affected organs. As with other epithelioid granulomas, the more commonly involved organs are the lungs and liver. A, A section of a normal lung is shown. (Pentachrome stain X 10.) B, Multiple noncaseating granulomas and areas of mononuclear cell infiltration of the lung interstitium charac the active granulomatous lesions. Close monitoring of patients is essential during tapering and after discontinuation of steroid therapy, because 25% of treated patients experience relapse. Other drugs that have been used in cases unresponsive to steroids are methotrexate, chloroquine, azathioprine, and cyclophosphamide. Of these, methotrexate seems to be more effective.

The prognosis is worse in blacks, the elderly, and those patients who fail to respond to steroids or have extensive multiorgan involvement.

teristic of sarcoidosis are shown. (Hematoxylin-eosin stain X 10.) C and D, Lesions in the lung are illustrated, showing their course from a cellular inflammatory response, which may be asymptomatic (panel C), to that of the fibrotic resolution (panel D). The fibrotic response usually accounts for the permanent loss of normal parenchyma and organ function. (Hematoxylin-eosin stain X 10 and pentachrome X 10, respectively.) (From Newman et al. [1]; with permission.)

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