Transcript Goodpasture Syndrome

Goodpasture Syndrome
By Adil Hasnain
Introduction to disease
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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
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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)
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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
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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
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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 antiGBM 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 antiGBM 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 (antiGBM) 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 antiGBM 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.
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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/240556treatment#aw2aab6b6b6aa
• http://www.nlm.nih.gov/medlineplus/ency/article/000
142.htm
• http://www.ncbi.nlm.nih.gov/books/NBK27155/figure/
A1907/?report=objectonly
• http://www.surgical-tutor.org.uk/defaulthome.htm?sciences/pathology/hypersensitivity.htm~ri
ght
• http://www.ncbi.nlm.nih.gov/books/NBK27155/