Goodpasture Syndrome

By Adil Hasnain

Introduction to disease• Ernest Goodpasture first described the

disorder in 1919. He reported a case of pulmonary hemorrhage and glomerulonephritis during an influenza epidemic.

• rare autoimmune disease • antibodies attack the lungs and kidneys,

leading to bleeding from the lungs and to kidney failure.

• It may quickly result in permanent lung and kidney damage, often leading to death.

• It is treated with immunosuppressant drugs such as corticosteroids and cyclophosphamide, and with plasmapheresis, in which the antibodies are removed from the blood.

Etiology• Causes• Exposure to organic solvents (e.g. chloroform) or hydrocarbons.• Exposure to tobacco smoke.• Infection, such as influenza A.• Bacteraemia.• Sepsis.• High-oxygen environments.• Certain gene mutations (HLA-DR15).• Cocaine inhalation.• Metal dust inhalation.• Treatment with anti-lymphocytic treatment (especially monoclonal antibodies)

• UNDER NORMAL CONDITIONS, THE ALVEOLAR ENDOTHELIUM IS A BARRIER TO THE ANTI–BASEMENT MEMBRANE ANTIBODIES. HOWEVER, WITH INCREASED VASCULAR PERMEABILITY, ANTIBODY BINDING TO THE BASEMENT MEMBRANE OCCURS IN THE ALVEOLI. THEREFORE, FOR THE DEPOSITION OF ANTIBODY, AN ADDITIONAL NONSPECIFIC LUNG INJURY THAT INCREASES ALVEOLAR-CAPILLARY PERMEABILITY IS REQUIRED.

Symptoms

• Tachypnea• Inspiratory crackles over lung bases• Cyanosis• Hepatosplenomegaly (may be present)• Hypertension (present in 20% of cases)• Rash• Edema

Epidemiology

• GPS is rare affecting about 0.5-1.8 per million people per year in Europe and Asia

• Males• Black• 20-30 and 60-70 years

TYPE II HYPERSENSITIVITY

• Cytotoxic hypersensitivity• Affects various organs and tissues• Antigens are normally endogenous• Reactions occurs in hours• Mediated via IgM and IgG antibodies and

complement• Examples include Goodpasture's syndrome

and pemphigus

• Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence. The staining pattern is normally smooth and linear, such as that seen in Goodpasture's nephritis (renal and lung basement membrane) and pemphigus (skin intercellular protein, desmosome)

• Treatment involves anti-inflammatory and immunosuppressive agents.

Immunology of the disease

• GPS causes the abnormal production of anti-GBM antibodies, by the plasma cells of the blood. The anti-GBM antibodies attack the alveoli and glomeruli basement membranes. These antibodies, in turn, bind their reactive epitopes to the basement membranes and activate the compliment cascade, leading to the death of tagged cells. T cells are also implicated. It is generally considered a type II hypersensitivity reaction

Abnormal antibody produced by the plasma cell

• IN MOST PATIENTS, THE AUTOANTIBODY IN GOODPASTURE SYNDROME IS DIRECTED AGAINST ALPHA3 CHAIN OF TYPE IV COLLAGEN

• ALTHOUGH BASEMENT MEMBRANES ARE UBIQUITOUS, ONLY THE ALVEOLAR AND GLOMERULAR BASEMENT MEMBRANES ARE AFFECTED CLINICALLY. THE PREFERENTIAL BINDING TO THE ALVEOLAR AND GLOMERULAR BASEMENT MEMBRANES APPEARS TO BE BECAUSE THEY ARE MORE ACCESSIBLE TO THE CIRCULATING ANTIBODIES.

Diagnosis of GPS• Serologic assays for anti-GBM antibodies , Radioimmunoassays or

enzyme-linked immunosorbent assays (ELISAs) for anti-GBM antibodies are highly sensitive (>95%) and specific (>97%)

• Healthy individuals may have circulating antibodies against GBM belonging to IgG2 and IgG4 subclasses. With onset of clinical disease, IgG1 and IgG3 subclasses increase and levels may correlate with disease severity.

• A study by Yang et al indicated that higher levels of circulating anti-GBM antibodies against the epitopes EA and EB occurred in patients whose renal disease was more severe and that these patients had a worse prognosis. Correlation was noted between the levels of anti-GBM antibodies and the serum creatinine at diagnosis and the presence of oliguria. Correlation existed between the percentage of crescents on biopsy and levels of antibodies,

• At some time during the course of illness, 1/3 of patients with Goodpasture syndrome have circulating antineutrophilic cytoplasmic antibodies (ANCAs) in addition to anti-GBM antibody.most cases, the ANCA antibodies precede the development of anti-GBM antibodies by months to years.

• Cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCA), which can appear in Goodpasture syndrome, are also commonly observed in Wegener granulomatosis and other vasculitides.

• Perinuclear antineutrophilic cytoplasmic antibodies (p-ANCA), which can appear in Goodpasture syndrome, are also observed in Churg-Strauss vasculitis and occasionally in Wegener granulomatosis.In majority of double-positive patients, the ANCAs have specificity for myeloperoxidase (MPO-ANCA).

• In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. The renal survival in these patients is similar to anti-GBM–positive patients and is worse compared with patients with MPO-ANCAs only.

Cytoplasmic ANCA (c-ANCA) and perinuclear ANCA (p-ANCA) are seen in the images below.

• Immunofluorescence stains are confirmatory. These show bright linear deposits of immunoglobulin G (IgG), as seen in the image below, and complement (C3) along the glomerular basement membranes. Subclass IgG-1 predominates.

Treatment• The 3 principles of therapy in anti–glomerular basement membrane (anti-

GBM) disease are (1) to rapidly remove circulating antibody, primarily by plasmapheresis; (2) to stop further production of antibodies using immunosuppression with medications; and (3) to remove offending agents that may have initiated the antibody production

• Plasmapheresis removes whole blood from the body and replaces the plasma with fluid, protein, or donated plasma. Removing harmful antibodies may reduce inflammation in the kidneys and lungs.

• Plasmapheresis is generally instituted after the diagnosis of Goodpasture syndrome is established either by renal biopsy or by detection of anti-GBM antibodies.

• The extent and duration of plasmapheresis is not known, but 4-liter plasma exchanges daily or every other day is usually performed. The plasmapheresis is continued for 2-3 weeks or until the patient's clinical course has improved and serum anti-GBM antibodies are not detected.

• Patients who develop massive hemoptysis or acute respiratory failure should be cared for in an ICU. Transfer to a hospital where plasmapheresis and/or hemodialysis is available may be necessary. Standard indications for dialysis are followed.

• After hospital discharge, patients require long-term regular visits for monitoring of renal function and immunosuppressive therapy. If renal function does not return, dialysis is continued indefinitely and the patient should be referred for renal transplantation.

• Corticosteroid medications (such as prednisone) and other drugs that suppress or quiet the immune system may be used. drops.

• Initial therapy includes cyclophosphamide at 2 mg/kg orally, adjusted to maintain a white blood cell count of approximately 5000, and corticosteroids (eg, prednisone at 1-1.5 mg/kg). Treatment of acute life-threatening alveolar hemorrhage in patients with Goodpasture syndrome is with pulse methylprednisolone at 1 g/day for 3 days, followed by a gradual corticosteroid taper. Intravenous cyclophosphamide is begun concomitantly at 1 g/m2 and repeated 3-4 weeks later, depending on the recovery of bone marrow.

• Controlling blood pressure is the most important way to delay kidney damage. You may get medicines to control high blood pressure, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

• limit salt and fluids to control swelling. A low protein diet may be recommended in some cases.

• If kidney failure becomes severe, you may need dialysis.• kidney transplant. A transplant is not done until the level of harmful antibodies

Thank you• References• http://emedicine.medscape.com/article/240556-

treatment#aw2aab6b6b6aa• http://www.nlm.nih.gov/medlineplus/ency/article/

000142.htm• http://www.ncbi.nlm.nih.gov/books/NBK27155/

figure/A1907/?report=objectonly• http://www.surgical-tutor.org.uk/default-home.htm?

sciences/pathology/hypersensitivity.htm~right• http://www.ncbi.nlm.nih.gov/books/NBK27155/