In the latest Case Record of the Massachusetts General Hospital, a 35-year-old man was admitted to this hospital because of dyspnea, anemia, and renal failure. Two days earlier, dyspnea and decreased urine output had developed. Imaging revealed bilateral lung opacities, and bronchoscopy showed pulmonary hemorrhage. Diagnostic tests were performed.
The term Goodpasture’s syndrome is applied to the combination of lung purpura and nephritis, regardless of the underlying pathogenesis. We now recognize that diverse mechanisms underlie Goodpasture’s syndrome, so more precise terminology linked to pathogenesis is now preferred for the specific diseases. There are numerous possible causes of Goodpasture’s syndrome. A useful clinical approach to differential diagnosis involves serologic categorization.
• What are the characteristics of disease mediated by anti-glomerular basement membrane (GBM) antibodies?
Anti-GBM disease is commonly associated with lung hemorrhage, mostly in young men. The severity of the lung hemorrhage varies greatly, but it can be life-threatening. Pulmonary irritants (e.g., cigarette smoke, hydrocarbon fumes, or freebase cocaine) or lung infections can precipitate lung hemorrhage. Systemic manifestations (e.g., fever and hypertension) other than those attributable to uremia or respiratory insufficiency are usually absent. Renal failure is common and usually rapidly progressive. In anti-GBM disease, the renal lesion is most often a necrotizing and crescentic glomerulonephritis, and the pulmonary lesion is most often a bland, noninflammatory alveolar hemorrhage. The diagnostic hallmarks of anti-GBM disease are the presence of autoantibodies (typically IgG and only occasionally IgA) directed to well-defined conformational epitopes expressed on type IV collagen. Approximately 20 to 30% of patients may also be shown to have antineutrophil cytoplasmic autoantibodies.
• What are the characteristics of ANCA-associated disease?
ANCA-associated vasculitis is the single most common cause of the syndrome of lung purpura and nephritis. Approximately 90% of patients with granulomatous polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis have antibodies to neutrophil cytoplasmic constituents (myeloperoxidase or proteinase 3). Systemic features, such as fever, myalgias, arthralgias, and skin lesions (palpable purpura and leukocytoclastic vasculitis), are also common. The pulmonary lesion in ANCA-associated vasculitis is diffuse alveolar damage, hemorrhage, and focal inflammatory vasculitis. In granulomatous polyangiitis, there may also be lesions in the upper airways (e.g., tracheitis, sinusitis, and otitis), necrotic pulmonary lesions, and hilar lymphadenopathy. The serum complement levels are typically normal or elevated and the erythrocyte sedimentation rate and C-reactive protein levels are also elevated.
Morning Report Questions
Q: How often does systemic lupus erythematosus (SLE) present with renal and pulmonary involvement, and what are the typical manifestations?
A: SLE may present with both renal and pulmonary involvement. Pulmonary involvement occurs in only 0.5 to 5% (averaging about 0.2%) of patients with SLE. Diffuse alveolar damage with hemorrhage is among the more common manifestations of pulmonary involvement in SLE, and approximately 50% of patients with pulmonary involvement have overt hemoptysis. Lung hemorrhage in patients with SLE is nearly always associated with lupus nephritis and is commonly associated with antiphospholipid autoantibodies or polyangiitis. The lung lesions can be bland alveolar hemorrhage or a localized inflammatory pulmonary capillaritis, with bland lesions usually predominating over the inflammatory lesions. Other features that may be observed with SLE are hypopigmented and hyperpigmented skin lesions on sun-exposed areas, polyclonal hyperglobulinemia, hypocomplementemia, a positive direct Coomb’s test, biologic false positive tests for syphilis, and positive tests for anticardiolipin antibodies and lupus anticoagulant. Arthritis, arthralgia, serositis, neuropsychiatric involvement, warm-antibody hemolytic anemia, thrombocytopenia, and thrombotic microangiopathy can also be present in SLE.
Q: How can complement assays aid in the differential diagnosis of renal disease?
A: Measurements of complement (C3 and C4 and sometimes total hemolytic complement) may help refine a differential diagnosis. In hepatitis C-related cryoglobulinemia with nephritis, the C4 level is low and the C3 level may be normal. In hemolytic-uremic syndrome due to complement factor H deficiency, the C3 level is low and the C4 level is normal. In lupus nephritis, both the C3 and C4 levels are low. Although these measurements are useful, other evidence must be weighed as well.