Cryoglobulinemia

A 35-year-old man was admitted to the hospital with the chief complaint of progressive dyspnea on exertion for 3 weeks. He also reported a history of night sweats and weight loss of 2 kg within this time period. He had a cough productive of white, occasionally blood-streaked sputum.

Physical Examination

On hospital admission, the patient's temperature was 37.1[degrees]C, heart rate was 97 beats/min and regular, BP was 109/67 mm Hg, respiratory rate was normal, and the transcutaneous oxygen saturation was 95% on room air. The cardiac and pulmonary examinations were normal. There was no jugular venous distention, lymphadenopathy, cyanosis, clubbing, or edema. The abdomen was soft without evidence of hepatosplenomegaly.

Laboratory and Radiographic Findings

A CBC count revealed normocytic anemia (hemoglobin, 11.4 g/L; mean corpuscular volume, 83 femtoliters) and a leukocytosis of 14.3 x [10.sup.9]/L. Results of serum chemistries, urinalysis, and coagulation were normal. Arterial blood gas analysis on room air showed a mild respiratory alkalosis and an elevated alveolar-arterial [O.sub.2] difference (pH 7.46; PC[O.sub.2], 33.3 mm Hg; P[O.sub.2], 53 mm Hg; HC[O.sub.3], 24.1 mEq/L; and oxygen saturation, 89.3%). ECG showed sinus tachycardia at a rate of 115. Chest radiography (Fig 1) revealed increased opacity throughout both lung fields, which was thought secondary to underpenetration. Three sets of sputum were negative for acid-fast bacilli. Blood culture findings were negative, CD4 count was normal, and an HIV test was not sent. Serum antinuclear antibody, antineutrophil cytoplasmic antibody (ANCA), anti-glomerular basement membrane antibody (anti-GBM), coccidioidomyces, and cryptococcus titers were all negative. Serum C3 and C4 levels were within normal limits.

[FIGURE 1 OMITTED]

A ventilation/perfusion scan of the lungs was low likelihood for pulmonary embolism. CT of the chest (Fig 2) revealed extensive ground-glass opacities with predilection of the perihilar lung areas bilaterally; no lymphadenopathy was noted. Echocardiogram showed trace tricuspid regurgitation without other evidence of valvular abnormality. Pulmonary function tests revealed the following: FE[V.sub.1], 2.39 L (predicted, 3.5 L; 68% of predicted); FE[V.sub.1]/FVC, 81% (predicted, 84%); total lung capacity, 3.49 L (predicted, 5.91 L); and diffusing capacity of the lung for carbon monoxide, 32.2 mL/min/mm Hg (predicted, 25.9 mL/min/mm Hg).

[FIGURE 2 OMITTED]

Bronchoscopy was performed. The lavage specimen was grossly bloody, and numerous hemosiderin-laden macrophages were seen on cytology. The patient then underwent video-assisted thoracoscopic biopsy, with the specimen showing pulmonary hemorrhage with hemosiderosis. Immunofluorescence studies (Fig 3) were positive for linear staining of IgG on the alveolar basement membrane.

[FIGURE 3 OMITTED]

What is the likely diagnosis, and what treatment should be instituted?

Answers: Goodpasture syndrome with negative serum anti-GBM antibody and normal renal function. Treatment should consist of corticosteroids, cyclophosphamide, and plasmapheresis.

This patient presented with clinical and radiographic features of diffuse alveolar hemorrhage, an entity with a broad differential diagnosis and a potentially catastrophic outcome, with an acute mortality of up to 50%. Prompt diagnosis should therefore be pursued concurrently with stabilization of the patient. In this patient, drug use (ie, crack cocaine inhalation, propylthiouracil, diphenylhydantoin, penicillamine, amiodarone, nitrofurantoin) and environmental exposures (ie, hydrocarbons, infection) were excluded. Given the paucity of systemic findings, the differential diagnosis included anti-glomerular basement membrane disease (Goodpasture syndrome) confined to the lung, isolated pulmonary capillaritis with or without autoantibodies, antineutrophil cytoplasmic antibody-associated vasculitides (Wegener granulomatosis with isolated pulmonary involvement, or microscopic polyangiitis), Henoeh-Seh6nlein purpura, and cryoglobulinemia. Less likely syndromes in this ease included systemic lupus erythematosus, collagen vascular diseases such as systemic sclerosis, dermatomyositis, and antiphospholipid syndrome. Sending serum for ANCA, antinuclear antibodies, and anti-GBM antibodies, as well as obtaining a careful history and routine electrolyte, renal function, hematology and coagulation studies, were therefore critical in narrowing the differential diagnosis.

Goodpasture syndrome is a rare autoimmune disease, with an incidence of approximately 0.1 cases per million, which is characterized by pulmonary hemorrhage, crescentic glomeruonephritis, and the presence of circulating anti-GBM antibodies. The antibodies are directed against the noncollagenous domain of the [alpha]-3 chain of type IV collagen ([alpha]-3[IV]NC1), which is the major type of collagen in glomerular and alveolar basement membranes. There is a bimodal age distribution, with peaks of incidence in the fourth and seventh decades of life. Exposure to hydrocarbons in industrial settings has been proposed as a risk factor. Genetic associations with the major histocompatibility complex class II alleles human leukocyte antigen-DR2 and human leukocyte antigen-DR15 have been reported. Multiple theories about the possible pathogenic mechanisms exist; it is currently thought that an inciting process in susceptible individuals initially damages the GBM and exposes the [alpha]3(IV)NC1 epitope, thereby stimulating antibody production and subsequent inflammatory responses.

Hemoptysis is the most common presenting symptom in Goodpasture syndrome, occurring in 65% of patients in one series. Other common symptoms include progressive dyspnea, cough, and fatigue. Fewer than 10% of patients present with gross hematuria, although the incidence of microscopic hematuria on urinalysis is much higher. Physical examination may be notable for pallor and tachycardia secondary to anemia and diffuse crackles on lung auscultation. Routine laboratory studies commonly reveal anemia from chronic blood loss, as well as varying degrees of renal insufficiency. Chest radiography may reveal patchy or diffuse airspace consolidation with air bronchograms, corresponding to areas of hemorrhage. These areas tend to occur in the perihilar region and in the middle and lower lung zones; the apices and costophrenic angles are usually spared. The chest radiograph may be normal in about 20 to 25% of eases. CT may reveal areas of ground-glass attenuation or consolidation with a predilection for dependent lung zones.

The "gold standard" for diagnosing Goodpasture syndrome is the finding of a linear pattern of immunofluorescence on the glomerular or alveolar basement membrane; this requires a lung or kidney biopsy. In the setting of a classic presentation of diffuse alveolar hemorrhage and renal failure, however, a positive serum anti-GBM antibody can establish the diagnosis and preclude the need for biopsy. Some experts still advocate performing a renal biopsy in all suspected cases, because the degree of crescentic glomeruonephritis observed and the number of glomeruli involved can affect the aggressiveness of therapy. Diabetic nephropathy and fibrillary glomerulonephritis are two other conditions characterized by linear deposition of IgG, but in these conditions IgG is nonspecifically absorbed onto the highly permeable capillary wall and onto the fibrils respectively. Moreover, in diabetic nephropathy there is linear deposition of albumin and other plasma proteins. The serum ANCA can be positive in 10 to 38% of patients with positive anti-GBM; their antigen specificities are the same as in patients with anti-GBM alone, but these patients appear to often have more treatable disease.

The prognosis of Goodpasture syndrome was uniformly grim before the development of plasma exchange and powerful immunosuppressive drugs. Treatment consists of oral prednisone, starting at 1 mg/kg/d with a gradual taper, and oral cyclophosphamide, 2.5 mg/kg/d. Daily plasmapheresis should be administered for a total of 14 sessions or until the serum anti-GBM titer is undetectable. Patients should refrain from smoking, and any intercurrent infections should be treated aggressively as they can precipitate relapse. The long-term outcome with treatment depends on the degree of renal involvement. Patients with normal renal function at diagnosis appear to have the best prognosis, although they may still have relapse of pulmonary symptoms. In contrast, many patients who initially present with renal failure will eventually need dialysis despite treatment.

Unusual Features of this Patient's Presentation

Several features of this patient's presentation deserve comment. He was a nonsmoker, and smokers have accounted for 72 to 80% of cases in recent series. Smoking is also associated with a higher risk of pulmonary hemorrhage, as opposed to renal manifestations alone, in patients with anti-GBM disease. This patient also presented with normal renal function and no gross or microscopic hematuria. Urinalysis was normal in 10% of patients in one case series, and several cases of Goodpasture syndrome with normal renal function have been reported. Even in patients who acquire both pulmonary and renal disease, the pulmonary symptoms tend to precede the kidney findings by months to years.

This patient also presented with a negative serum anti-GBM antibody by enzyme-linked immunosorbent assay. Up to 40% of patients with Goodpasture syndrome have a false-negative immunofluorescent antibody test result; radioimmunoassay or enzyme-linked immunosorbent assay using native and recombinant [alpha]-3(IV)NC1 is more sensitive, but the results take longer to return. In a few reported cases, IgA was the main circulating antibody, and was therefore not detected by commercial assays, most of which only test for IgG. Patients with a negative circulating anti-GBM antibody appear to have more benign kidney disease, with lower rates of progression to hemodialysis; the reasons for this are still unclear. Western blot, performed mostly in reference laboratories, is a more sensitive and specific method for detecting circulating anti-GBM, and may be considered if the diagnosis is in doubt; it is usually not necessary unless the patient refuses or has contraindications to biopsy. The development and widespread use of biosensor systems, which are even more sensitive than Western blot, may substantially decrease the rate of seronegative Goodpasture syndrome in the future.

This patient also underwent lung biopsy, rather than renal biopsy, in order to make the definitive diagnosis of Goodpasture syndrome. The sensitivity and specificity of the two approaches have never been compared in a formal trial. The clinical context will determine which technique is used, although in most eases renal biopsy is safer and more convenient for the patient, and it allows an assessment of the degree of glomerular damage.

Follow-up

The patient was discharged without a formal diagnosis. He was started on prednisone, 60 mg/d po, with marked resolution of his symptoms. His biopsy result was consistent with Goodpasture syndrome, and he was readmitted a week after discharge for plasmapheresis. He received nine courses of plasmapheresis, and was also started on cyclophosphamide. The patient continues to feel well with no recurrence of his pulmonary symptoms.

CLINICAL PEARLS

1. In a patient presenting with progressive dyspnea, hemoptysis, radiographic patchy opacities sparing the apices, ground-glass infiltrates on chest CT, and an increased diffusion capacity, diffuse alveolar hemorrhage should be high in the differential diagnosis.

2. Although Goodpasture syndrome is a rare cause of diffuse alveolar hemorrhage, it should be excluded, especially in smokers or those who present with renal insufficiency or hematuria.

3. If there is a high clinical suspicion for Goodpasture syndrome, a negative serum anti-GBM antibody is insufficient to exclude the diagnosis and does no eliminate the need for biopsy.

4. Patients with Goodpasture syndrome who have normal renal function and/or no hematuria on initial presentation appear to have a more benign course.

5. Prompt diagnosis of Goodpasture syndrome is essential, as early therapy with corticosteroids, cyclophosphamide, and plasmapheresis can favorably alter the prognosis.

ACKNOWLEDGMENT: The authors thank Dr. Anton Mlikotic for providing the radiographic images. Dr. Samuel French furnished the pathology specimen. Dr. Harry Prince of Focus Laboratories and Dr. Holly Mason gave insight into the basis of the anti-GBM enzyme-linked immunosorbent assay.

SUGGESTED READINGS

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* From Harbor-UCLA Medical Center, Torrance, CA. Manuscript received January 8, 2004; revision accepted March 31, 2004.

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Correspondence to: Chin lung, MD, Department of Medicine, Box 400, L.A. County Harbor-UCLA Medical Center, Torrance, CA 90509; e-mail: jungc20@hotmail.com

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