Goodpasture's syndrome

Goodpasture's syndrome, or anti-glomerular basement membrane (anti-GBM) disease, is a rare pulmonary-renal syndrome that results from autoantibody-mediated destruction of alveolar and glomerular basement membranes. It is defined by the triad of pulmonary hemorrhage (hemoptysis), glomerulonephritis (hematuria), and circulating anti-GBM antibodies. Although kidney disease can occur with or without lung involvement, isolated alveolar hemorrhage as an incipient manifestation of the syndrome is rare. We report the case of a patient with anti-GBM disease who initially presented with seronegative hemoptysis and normal urine. It was not until relapse of his condition that we found acute glomerulonephritis and circulating antibodies. In this report, we briefly review the pathogenesis and clinical manifestations of anti-GBM disease and discuss the relevance of isolated alveolar hemorrhage.

Introduction

Anti-glomerular basement membrane (anti-GBM) disease, or Goodpasture's syndrome, is a rare pulmonary-renal syndrome characterized by autoantibody-mediated destruction of alveolar and glomerular basement membranes. The hallmark pathologic finding is linear deposits of immunoglobulin (Ig) G antigen complexes on the basement membrane that are identifiable by immunofluorescent staining.1-3 The anti-GBM antibody plays the primary role in the immunopathogenesis of the disease.4 Therefore, anti-GBM antibody disease is a more accurate name for this disorder and will be used in place of the older term, Goodpasture's syndrome.

The diagnosis is made by demonstrating the triad of diffuse pulmonary hemorrhage, glomerulonephritis, and circulating anti-GBM antibodies. Typically, these three components of the syndrome are present concurrently during an acute flare, although isolated kidney involvement has been observed. The authors present a patient who initially exhibited pulmonary findings suggestive of the syndrome but without detectable autoantibodies or evidence of renal dysfunction. It was not until his second exacerbation that these additional findings were evident, thus confirming the diagnosis of anti-GBM disease. This case emphasizes the concept that anti-GBM disease should not be ruled out after a first presentation of seronegative alveolar hemorrhage.

Case Report

In 1997, a 22-year-old, human immunodeficiency virus-negative white male smoker was referred to the pulmonary clinic at Tripler Army Medical Center for the evaluation of hemoptysis. The patient was a U.S. Army infantryman stationed in Seoul, Korea, who reported a 4-month history of exertional shortness of breath that progressed to dyspnea at rest. He also complained of lightheadedness, fatigue, and feverishness. Three months previously, he had infrequent episodes of coughing up trace amounts of blood. The soldier denied recent weight loss, anorexia, or night sweats. He denied easy bruising or bleeding elsewhere, The patient smoked two packs of cigarettes per day for the preceding 4 years. He denied tuberculosis exposure and had a recent negative tuberculin skin test, He had an excellent functional capacity before the onset of these symptoms.

The soldier's military duties did not expose him to toxic substances. However, six months before enlisting in the Army, the patient worked at a plastics factory and was exposed to various volatile agents, including trimellitic anhydride, a known cause of hemoptysis. He had not worked at this facility for more than 2 years before this presentation. There was no evidence of exposure since leaving this job.

Initially, the patient had a normal physical examination. Spirometry and diffusing capacity of the lungs for carbon dioxide (DL^sub CO^) were within normal limits. A radiograph (Fig. 1) and computer-assisted tomography of the chest revealed bilateral alveolar filling, more prominent in the lower lobes. Blood tests revealed iron-deficiency anemia, an erythrocyte sedimentation rate of 2 mm/h, a serum creatinine of 0.8 mg/dL, and negative serology to include anti-nuclear antibody (ANA), rheumatoid factor, cytoplasmic anti-neutrophil cytoplasmic antibody (C-- ANCA), and anti-GBM antibody. Urinalysis revealed no red cells or casts, and a urine drug screen was negative. IgE titer by radioallergosorbent assay for trimellitic anhydride (Specialty Laboratories, Santa Monica, California) was negative.

Bronchoscopy produced a grossly bloody bronchioloalveolar lavage that did not clear after multiple washes. The transbronchial biopsy and subsequent open lung biopsy demonstrated intra-alveolar and interstitial hemosiderin-laden macrophages and multiple microscopic foci of organizing fibrosis. There was no evidence of vasculitis or infection. Microbiologic stains and cultures on all specimens were negative. Because all other causes of hemoptysis apparently were excluded, we diagnosed the patient with idiopathic pulmonary hemosiderosis. The patient improved with prednisone (1 mg/kg), and he returned to limited duty. Despite our advice, the soldier continued to smoke.

One month later, hemoptysis recurred. The soldier's hemoglobin concentration had decreased from 12 to 8 g/L. A urinalysis showed 137 red blood cells per high-powered field, and a 24-hour urine collection demonstrated 840 mg of protein. The serum creatinine was 0.8 mg/dL. A chest radiograph showed diffuse, nodular airspace disease, consistent with alveolar hemorrhage. Spirometry showed a moderate restrictive pattern, and the DL^sub CO^ was markedly increased at 226% of predicted. Repeat ANA and ANCA were negative; however, the anti-GBM antibody titer was positive (ARUP Laboratories, Salt Lake City, Utah).

We changed our diagnosis to anti-GBM antibody disease. A kidney biopsy was not deemed necessary for further confirmation. We advised the patient to stop smoking, and we continued his corticosteroids. The soldier has since the left the service and is lost to follow-up.

Discussion

In 1919, Ernest Goodpasture described an 18-year-old male patient with massive hemoptysis and acute renal failure during an influenza epidemic.5 In 1958, Stanton and Tange first used the term "Goodpasture's syndrome" to describe a series of patients found to have both pulmonary hemorrhage and glomerulonephritis.6 The role of anti-GBM antibodies in the pathogenesis of this disease was not discovered until 1967.2 Since then, the term Goodpasture's syndrome, or anti-GBM antibody disease, has been has to describe the complex of alveolar hemorrhage, glomerulonephritis, and circulating anti-GBM antibodies. In retrospect, the initial patient described by Goodpasture was found to have vasculitis on autopsy and, ironically, did not have the disease with which the term Goodpasture's syndrome has become synonymous.

Anti-GBM disease affects one in two million people.7,8 It is seen more commonly in whites than blacks (2:1 ratio) and in males than females (9: 1).9 Although the disease has a bimodal age-of-onset distribution, it typically occurs during the second and third decades of life (mean age is 27-35 years).8 In later onsets, the disease affects males and females equally.8

The anti-GBM antibody is an IgG antibody that takes part in a type II cytotoxic antibody-mediated reaction to the NC1 domain of the a-3 chain of type IV collagen in the basement membraves of alveoli and glomeruli.1,10 By an unknown mechanism, macrophages stimulate B cells to produce the IgG. Other basement membranes lack the alpha-3 chain; thus, only lung and kidney tissues tend to be affected in this disorder. In animal studies, circulating anti-GBM antibodies alone seems to be sufficient to result in linear antibody deposits (and subsequent glomerulonephritis) in kidneys, but not in alveolar capillaries. 11,12

There is strong evidence of a genetic predisposition to the development of anti-GBM antibody disease, which has been found to be more common among siblings. Specific histocompatibility locus A (HLA) types, especially the DR subgroups of HLA class II molecules, appear to play a role in the susceptibility of this disease and often result in a worse prognosis. Eighty to 90% of cases have been associated with HIA-DRw2, HLA DRw15, and DR4. In addition, 60% of cases have been associated with HLA-137.1,13

Unlike other autoimmune processes, anti-GBM antibody disease is limited exclusively to the lungs and kidneys, with the majority of patients developing renal disease. Twenty to 30% will have isolated glomerulonephritis.11 In contrast, lung involvement is less common, and isolated alveolar disease is rarely observed.11 Sixty to 80% of patients will have combined manifestations.11 The more common clinical complaints and findings of patients with anti-GBM antibody disease are listed in Table I.14

Patients typically develop iron-deficiency anemia from chronic blood loss attributable to microscopic hematuria and clinically silent alveolar hemorrhage.14 A modest increase in the erythrocyte sedimentation rate is often observed, unlike the marked increase seen in systemic vasculitides. Anti-nuclear antibodies and rheumatoid factor are typically absent. Complement activation is normal. ANCA can be positive in up to onethird of patients with anti-GBM antibody, making it occasionally difficult to distinguish this entity from the more common pulmonary-renal syndrome, Wegener's granulomatosis.15,16

It generally is held that flares of anti-GBM antibody disease require the presence of serum anti-GBM antibodies. More than 90% of patients with this disorder have detectable circulating anti-GBM antibodies, even during periods of remission.17 Current diagnostic assays possess a high positive predictive value and are of high diagnostic sensitivity and specificity. The sensitivity and specificity of the serology are 93.3% and 97%, respectively,18 with the enzyme-linked immunosorbent assay being more sensitive than indirect immunofluorescence. A lack of serologic evidence for this disease may cause the clinician to consider other causes of alveolar hemorrhage and pursue an aggressive, expensive, and potentially harmful diagnostic algorithm, including lung or kidney biopsy. Our case causes us to speculate that an uncommon disease variant exists that relatively spares the kidney but predominantly damages the lung. This variant may not be associated with early detectable autoantibodies.

Renal disease can occur alone or coexist with alveolar hemorrhage. The glomerulonephritis is characterized by hematuria with red cell cast formation, modest proteinuria (

Investigators have shown that the mere presence of antibodies can result in injury to the glomerulus, whereas alveolar damage requires a coexisting insult to cause disease.21 Exacerbating factors, including tobacco use, inhalation of volatile hydrocarbons, and respiratory tract infections, may result in clinical manifestations.22 Increased alveolar permeability found in smokers has been postulated as an important factor leading to diffuse alveolar hemorrhage. In one study, 100% of smokers with circulating anti-GBM antibodies experienced diffuse alveolar hemorrhage, whereas only 20% of nonsmokers had a similar manifestation.23

Pulmonary function tests usually reveal a mild restrictive pattern with an increased DL^sub CO^. The DL^sub CO^ is a measure of the binding of inhaled carbon monoxide to hemoglobin. Hemoglobin is in abundance in the alveoli during a bleeding crisis.11 A 30% increase in the diffusion capacity suggests active diffuse alveolar bleeding.11 In fact, the DL^sub CO^ can be used to follow the progression of disease and detect the recurrence of alveolar hemorrhage. The chest radiograph often reveals scattered or diffuse airspace filling, which suggests alveolar hemorrhage. Rees et al. suggest that recurrent pulmonary hemorrhage can be diagnosed by observing hemoptysis and two of the following findings: fresh alveolar opacities on chest radiographs, an increase in the DL^sub CO^ by 30%, or a decrease in the blood hemoglobin concentration by 2 g/dL in 24 hours in the absence of another source of blood loss.13

Bronchioloalveolar lavage often demonstrates bloody alveolar exudates with hemosiderin-laden macrophages. Lung biopsy is nonspecific, but it can be helpful to rule out other causes of airspace filling and to determine the extent of alveolar damage.

Other causes of hemoptysis to consider include cocaine or crack abuse, arteriovenous malformation, bronchiectasis, lung cancer, occult epistaxis, mitral stenosis, aspergilloma, tuberculosis, cystic fibrosis, foreign body aspiration, catamenial pneumothorax, Wegener's granulomatosis, primary pulmonary hypertension, systemic lupus erythematosus, and vasculitis. In our case, we included an evaluation of trimellitic anhydride-induced hemoptysis, which is the result of an IgEmediated asthma-rhinitis reaction.24 Pulmonary hemorrhage associated with this agent typically occurs after 3 to 10 days and is rarely seen more than 1 month after exposure.24 Given that this patient's last exposure to this agent was 2 years before developing symptoms, it is unlikely that this was the cause of his illness.

The prognosis and overall survival of anti-GBM disease has improved in the past 30 years. This is largely the result of a combination of superior serologic diagnostic testing leading to earlier treatment and aggressive therapy with plasmapheresis and immunosuppression. The treatment goal is to clear the anti-GBM antibodies from the serum while suppressing the formation of new autoantibodies. This, in theory, will halt further destruction of the alveolar and glomerular basement membranes. Currently, plasmapheresis is being used to remove circulating antibodies. Corticosteroids and cyclophosphamide are used in combination to block the formation of new antibodies. In a review of 53 patients, Wilson and Dixon found an 11% disease-free overall survival rate.25 A worse prognosis is associated with massive pulmonary hemorrhage or severe renal disease, which can lead to rapidly progressive glomerulonephritis often requiring hemodialysis.

Anti-GBM antibody disease is the clinical manifestation of an autoimmune process that results in destruction of the alveolar and glomerular basement membranes and should be suspected in any patient presenting with acute glomerulonephritis, especially if accompanied by pulmonary hemorrhage. The initial lack of evidence for renal damage and the absence of circulating anti-GBM antibodies made our patient's presentation atypical. We recommend that any young patient, particularly a male smoker, who presents with hemoptysis should be evaluated with chest radiography, ANA, ANCA, anti-GBM antibodies, and a urinalysis with drug screen. However, because isolated renal or alveolar disease may present initially, repeat testing should be performed during subsequent flares to rule out the syndrome adequately.

References

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2. Duncan DA, Drummond KN, Michael AF, et al: Pulmonary haemorrhage and glomerulonephritis: report of six cases and study of the renal lesion by the fluorescent antibody techniques and electron microscopy. Ann Intern Med 1965; 62: 920-38.

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Guarantor: LTC Joseph Pina, MC USA

Contributors: CPT Christopher Lettieri, MC USA, LTC Joseph Pina, MC USA

Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 96859.

This manuscript was received for review in July 2000. The revised manuscript was accepted for publication in February 2001.

Copyright Association of Military Surgeons of the United States Sep 2001
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