eMedicine Specialties > Pediatrics: General Medicine > Pulmonology
Goodpasture Syndrome
Updated: Mar 4, 2009
Introduction
Background
Goodpasture syndrome (GS) is the clinical entity of acute glomerulonephritis and pulmonary alveolar hemorrhage. It is rarely seen in children. The term Goodpasture syndrome is used interchangeably with pulmonary renal syndrome. Goodpasture syndrome has numerous underlying etiologies and often occurs in the setting of a small vessel vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs); examples include Wegener granulomatosis and microscopic polyangiitis.
Goodpasture's name has been used in a more specific clinical condition known as Goodpasture disease, which is the pulmonary renal syndrome specifically associated with anti–glomerular basement membrane (anti-GBM) antibodies.1 These anti-GBM antibodies produce a characteristic linear deposition along the glomerular basement membrane (GBM), one way in which Goodpasture syndrome is differentiated from Wegener granulomatosis. Because pulmonary renal syndrome is discussed extensively in the eMedicine article Wegener Granulomatosis, this article focuses on the specific form of this syndrome associated with anti-GBM antibodies. To avoid confusion between Goodpasture syndrome and Goodpasture disease, the term anti-GBM disease is used.
Anti-GBM disease is defined as the triad of glomerulonephritis (usually rapidly progressive or crescentic), pulmonary hemorrhage, and anti-GBM antibody formation. Despite this triad of clinical findings, patients with anti-GBM disease may present with a spectrum of conditions ranging from pulmonary hemorrhage with minimal or no renal involvement to full-blown renal failure with limited or no pulmonary involvement. Because of limited experience with the disease in children, much of the information presented in this article is derived from the literature about adults.
In 1919, Ernest Goodpasture described an 18-year-old man with a fever and cough, followed by hemoptysis and renal failure. On the basis of this clinical report, Goodpasture's name is often linked to the pulmonary renal syndrome of alveolar hemorrhage and necrotizing and proliferative glomerulonephritis, although vasculitis and not anti-GBM disease is believed to be the cause of the pulmonary renal syndrome in Goodpasture's original patient. The discovery of the role of anti-GBM antibodies by Lerner et al in 1967 helped provide both a better understanding of the pathogenesis for this specific form of pulmonary renal syndrome and a more rational approach to treatment.2
Pathophysiology
Pathogenesis of anti-GBM disease is linked to the presence of autoantibodies that react with the alveolus in the lung and the basement membrane of the glomerulus in the kidney. Anti-GBM autoantibodies that are present in the circulation of patients with anti-GBM disease cross the fenestrated endothelium in the glomerulus and bind with the underlying GBM, inducing renal injury.
Anti-GBM antibodies interact with the GBM glycoproteins, almost exclusively the epitope of the noncollagenous domain (NC1) of the a 3 chain of type IV collagen. This interaction results in complement activation with glomerular infiltration of polymorphonuclear leukocytes and monocytes. Fibrinogen leaks through the damaged GBM into the Bowman space, and it is polymerized to fibrin through procoagulant factors from activated monocytes, resulting in crescent formation. These autoantibodies are believed to cross-react with the alveolar basement membrane and cause similar damage.
The degree of cross-linking of the a 3NC1 hexamer subunits is approximately 3 times greater in the alveolar basement membrane than in the GBM. The Col 4 a 3NC1 epitope is thought to be less accessible for anti-GBM binding in the lung, and partial denaturation of NC1 domains may be required for full exposure of this sequestered epitope to the antibody. If true, this theory may explain why pulmonary hemorrhage is often associated with factors that increase pulmonary capillary permeability, such as active cigarette smoking, infections, recent hydrocarbon inhalation, and hyperoxia.
Etiology of anti-GBM production is not yet well understood. An animal model for anti-GBM disease has demonstrated that a 10 amino acid, nephritogenic, T-cell epitope of Col4alpha3NC1 was capable of inducing an anti-GBM glomerulonephritis in rats. Goodpasture's positive association with human leukocyte antigen (HLA) DRB1*1501 is among the strongest reported for autoimmune diseases. A positive association with HLA-DR4 is also noted. Anti-GBM disease is seen less often with HLA-DR1 and HLA-DR7. Genetic predisposition may be a factor, along with a second environmental insult, such as exposure to cigarette smoke, inhaled hydrocarbons, or viruses.
Frequency
United States
Anti-GBM is rare in adults and children. According to the 2008 United States Renal Data System (USRDS) Annual Data Report, from 2002-2006, Goodpasture syndrome was the underlying cause of end-stage renal disease (ESRD) in 24 pediatric patients younger than 20 years (0.4%).3 Presumably, the term Goodpasture syndrome referred to anti-GBM disease, because other causes for the pulmonary renal syndrome that contributed to ESRD (eg, systemic lupus erythematosus [SLE], Henoch-Schönlein purpura [HSP], Wegener granulomatosis) were all listed separately.
International
The annual incidence is estimated to be 1 case per 2 million population among white Europeans. A recent retrospective study of ESRD in Dutch children from 1987-2001 listed Goodpasture syndrome as the primary cause of renal failure in 4 (1.1%) of 351 cases.4
Mortality/Morbidity
If fulminant pulmonary hemorrhage occurs, it can lead to respiratory failure, which may result in death. Renal disease may be indolent, resulting in advanced and often irreversible disease at the time of presentation. Renal failure usually requires dialysis, and patients requiring dialysis at presentation usually develop ESRD.
The first year mortality for children in the United States with Goodpasture syndrome and ESRD was 4.2%.3
Race
Anti-GBM disease has been described in many racial groups, but whites are affected most often. According to the 2008 USRDS Annual Data Report, 92% of the pediatric patients with ESRD whose primary diagnosis was Goodpasture syndrome were white.3
Sex
Pediatric literature indicates no predilection in either sex. According to the 2008 USRDS Annual Data Report (2002-2006 data), 42% of young patients (<20 y) who developed ESRD (termed Goodpasture syndrome by the USRDS) were male.3
In adults, reports indicate a male-to-female ratio of 2:1 to 9:1. The literature about adults has also shown that anti-GBM disease with pulmonary renal syndrome typically occurs in young men, whereas renal disease that occurs in isolation is more common in elderly women.
Age
In children, anti-GBM disease has been reported in all ages. An 11-month-old infant is the youngest reported patient. The 2008 USRDS Annual Data Report (2002-2006 data) reported the median age of 17 years for patients with ESRD and the primary diagnosis of Goodpasture syndrome.3
In the few pediatric cases of anti-GBM disease reported, some children presented with limited renal disease, and others presented with pulmonary hemorrhage alone. In one child, a diagnosis of pulmonary hemosiderosis was made 4 years before anti-GBM disease was seen. Anti-GBM–mediated renal disease resulted in ESRD in most children.
In adults, the mean age of onset is 20-30 years, with a peak incidence in young men aged 20-30 years. A second peak occurs in those aged 50-70 years, with men and women equally affected.
Clinical
History
Hemoptysis is the most common presenting symptom in Goodpasture syndrome (GS), followed by dyspnea, fatigue or weakness or both, and cough.
- Renal disease may be present in anti–glomerular basement membrane (anti-GBM) disease. When present, it can be isolated or accompanied by pulmonary hemorrhage. Signs include the following:
- Gross hematuria (10-41% of adults)
- Edema (in as many as 25% of patients)
- Pulmonary hemorrhage can range from mild to life threatening. Symptoms include the following:
- Hemoptysis (82-90% of adults)
- Cough (40-60% of adults)
- Exertional dyspnea (57-72% of adults)
- Fatigue and weakness (38-66% of adults)
- Fevers, chills, diaphoresis (15-24% of adults)
- Tachypnea
- Cyanosis
- Inspiratory crackles
- Bronchial breathing
- The general features listed below are more prominent in patients with systemic vasculitis than in others. The following can be the initial signs or symptoms in patients with anti-GBM disease:
- Malaise
- Weight loss
- Arthralgias
- Fever
- Pallor (correlated with degree of anemia present; approximately 51-90% of adults have pallor)
Physical
Physical examination findings in patients with anti-GBM disease are those related to pulmonary hemorrhage, renal failure, and anemia and include pallor (the most common clinical sign), crackles and rhonchi, heart murmur, hepatomegaly, and edema.
- Pulmonary symptoms
- Hemoptysis can vary from blood-tinged sputum to profound bleeding.
- Mild hemoptysis may resolve spontaneously or progress to massive hemorrhage in a short period, resulting in fulminant respiratory failure.
- In approximately two thirds of cases, hemoptysis precedes the onset of renal disease by 8-12 months. This interval can be as long as 12 years before nephritis develops.
- Exertional dyspnea likely reflects both lung parenchymal involvement and anemia from pulmonary hemorrhage.
- In severe cases, clinical signs of pulmonary hemorrhage include tachypnea, inspiratory crackles and rhonchi, and cyanosis.
- Prompt diagnosis of pulmonary hemorrhage is imperative, because it is the principal cause of early death in patients with anti-GBM disease.
- Pulmonary hemorrhage is probably less common in adults than previously reported because of the decreasing prevalence of cigarette smoking.
- Renal symptoms
- Signs and symptoms of disease can vary from hematuria and proteinuria with normal renal function to severe oligoanuric renal failure.
- Hypertension can be present but is an uncommon form of glomerulonephritis, reported in 4-17% of adult patients.
- Similarly, hypertension is unusual in children but has been reported.
- When significant renal disease is present, it usually progresses rapidly.
- Adults presenting with a serum creatinine level greater than 6 mg/dL have a worse prognosis.
- Anemia: Approximately 20-25% of patients have a functional heart murmur because of anemia.
- Generalized vasculitis
- Unlike patients with antineutrophil cytoplasmic autoantibodies (ANCA) disease, patients with anti-GBM disease typically lack symptoms of generalized vasculitis.
- Approximately 20-30% of adults with anti-GBM disease have coexisting ANCA in their circulation. The renal prognosis of these patients is better when both antibodies are present than when anti-GBM is present alone.
Causes
Anti-GBM antibodies cause this autoimmune disorder, usually when a genetically predisposed individual encounters a particular environmental insult.
- Genetic predispositions
- Anti-GBM antibody has been described in identical twins, siblings, and first cousins.
- HLA-DR2 is expressed in 88% of patients with anti-GBM disease compared with 25-32% of a control group of blood donors.
- Simultaneous expression of HLA-B8 and HLA-DR2 is associated with a worse prognosis because of the tendency to form glomerular crescents.
- Anti-GBM antibody is strongly associated with HLA-DR15 and HLA-DR4 alleles.
- HLA-DR7 and HLA-DR1 have strong negative associations; both are highly protective.
- Environmental insults
- Cigarette smoking: Smoking is closely linked with hemoptysis. In one large series, 47 of 51 adult patients with anti-GBM disease had a history of smoking.5 In all, 37 of 37 smokers experienced pulmonary hemorrhage compared with 2 of 10 nonsmokers. Pulmonary hemorrhage is probably less common in adults than previously reported because of the decreasing prevalence of cigarette smoking.
- Inhaled hydrocarbons: Exposure to hydrocarbon solvents has been associated with anti-GBM disease. Gasoline fumes or industrial solvents are believed to induce chemical injury to the lung or kidney, stimulating antibody production. Anti-GBM disease was reported in a 16-year-old adolescent girl who engaged in heavy smoking and glue sniffing.
- Viral infections: Influenza type A2 has been associated with anti-GBM disease. Upper respiratory tract infection or flulike illness occurred before the onset of disease in 20-61% of adults with anti-GBM disease.
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Further Reading
Keywords
Goodpasture syndrome, GS, anti–glomerular basement membrane disease, anti-GBM disease, Goodpasture disease, Goodpasture's disease, pulmonary renal syndrome, Goodpasture's syndrome, Wegener granulomatosis, Wegener's granulomatosis, glomerulonephritis, pulmonary hemorrhage, anti-GBM antibody formation, pulmonary renal syndrome of alveolar hemorrhage, small vessel vasculitis, glomerulonephritis, cigarette smoking, end-stage renal disease, ESRD, systemic lupus erythematosus, SLE, Henoch-Schönlein purpura, HSP, respiratory failure, proteinuria, nephrotic syndrome
