Goodpasture’s Disease PDF

Goodpasture’s Disease B e t h a n D a v i e s -J o n e s b .w. d a v i e s -j o n e s @ b a n g o r. a c . u k Disorders of the Bronchi & Lungs Category Conditions Inflammatory Bronchitis; Bronchiolitis. Infective Pneumonia; Tuberculosis, Aspergillosis. Vascular disease Embolism; Arterial hy...

Goodpasture’s Disease B e t h a n D a v i e s -J o n e s b .w. d a v i e s -j o n e s @ b a n g o r. a c . u k Disorders of the Bronchi & Lungs Category Conditions Inflammatory Bronchitis; Bronchiolitis. Infective Pneumonia; Tuberculosis, Aspergillosis. Vascular disease Embolism; Arterial hypertension; Oedema; Haemorrhage. Autoimmune Wegener's granulomatosis; Goodpasture’s syndrome. Obstructive disease Bronchitis; Bronchiectasis; Asthma; Emphysema; COPD; Cystic fibrosis. Restrictive disease Pneumoconiosis; Pulmonary fibrosis; Druga and toxins; Ionising radiation; Sarcoidosis; ARDS; BOOP; Collagen vascular disorders (e.g. SLE); Hypersensitivity pneumonitis (e.g. farmer’s lung); Asbestosis. Malignant Tumours Bronchogenic carcinoma (Squamous cell carcinoma; Adenocarcinoma; Small cell carcinoma; Large cell carcinoma); Neuroendocrine tumours; Metastatic lung tumours. Learning Outcomes • Define Goodpasture's disease; discuss the clinical manifestations and the diagnostic tests and procedures used to diagnose it. • Describe the medical management and treatment options for Goodpasture's disease, as well as the prognosis and follow -up care. • Understand the differential diagnosis of Goodpasture's disease. • Describe the modalities of histopathology examination with regards to kidney biopsies . • Understand the holistic approach to pathology Definition • Also known as anti -glomerular basement membrane antibody (anti -GBM) disease, is an important cause of pulmonary -renal syndrome. • 60 -80% of patients have pulmonary and renal disease, • 20 -40% have renal disease alone, • less than 10% have disease that is limited to the lungs. • Caused by an autoantibody to the alpha -3 chain of type IV collagen. • The specific human leukocyte antigen type ( HLA -DRB1*1501 or HLA -DR4) is considered as a genetic marker for susceptibility. Alveolar and glomerular structure Aetiology • Estimated incidence of 1 to 2 cases per million. • It causes 1% to 2% of all cases of glomerulonephritis. • Between 30% to 50% of patients also have positive anti -neutrophil cytoplasmic antibodies. • There is a male predominance with cases divided approximately 60% male, 40% female. • There are 2 age peaks: at 20 to 30 years, and at 60 to 70 years. • Approximately 83% of cases occur in Caucasians. Diagnosis • Patients with pulmonary renal syndromes or rapidly progressive glomerulonephritis require urgent hospitalisation and consultation with a nephrologist for rapid diagnosis and treatment. • Symptoms may be minimal or include cough, SOB, haemoptysis, fatigue, malaise, dark urine, decreased urine output, and leg oedema. • Treatment may need to begin before the results of diagnostic testing are available if clinical suspicion is high . • Urea, electrolytes, and creatinine levels are useful to assess kidney (renal) function Laboratory Investigations (following renal function tests) • Hepatitis panel • Cryoglobulins • Anti -Nuclear Antibody (ANA ) • Serum Complement Levels (C3 and C4 ) • Anti -Neutrophil Cytoplasmic Antibodies (ANCA ) • 30% of patients positive for MP O • Anti -Streptolysin O • Anti -Glomerular Basement Membrane Antibodies (Anti -GBM) • highly sensitive (> 95%) and specific (> 97%). • Clotting Screen (necessary before preceding with biopsy ) • Renal Biopsy • Immunofluorescence studies are essential, EM studies required to rule out glomerular basement membrane nephropathy. Differentials • Systemic Lupus Erythematosus (SLE) • Granulomatosis with polyangiitis (Wegner’s) • Microscopic Polyangiitis • Churg -Strauss Syndrome • Glomerulonephritis (post -streptococcal) • Cryoglobulinemia • Hepatitis B / C Anti - Neutrophil Cytoplasmic Antibody (ANCA) MYELOPEROXIDASE (MPO) • p -ANCA (indirect -immunofluorescence) • 140kDa cationic protein found predominantly in azurophilic granules of neutrophils and monocytes. • Found in 90% of patients with microscopic polyangiitis and other vasculitis. • Found in 30 -40% of patients with Goodpasture's syndrome. PROTEINASE -3 (PR3) • c-ANCA (indirect -immunofluorescence) • 28kDa protein. The primary function is thought to be the degradation of extracellular proteins at sites of inflammation. • Found in >90% patients with Granulomatosis with polyangiitis (Wegener's granulomatosis). • Levels correlate with disease activity and usually disappear on effective treatment and reappear on re -emergence of the disease. “Our Patient” A 65 -year -old female presented with nausea, vomiting, loss of appetite, malaise and fatigue for 1 week. The patient had noticed decreased urine output for last 3 days, but denied any frequency, urgency or urine colour change. The patient has been having dry cough associated with exertional dyspnoea. No history of smoking. The medical history was notable for coronary artery disease and having previously had a coronary artery bypass graft surgery, also noted was hypothyroidism and hypertension. BP was 150/71, P was 108, RR was 18, temperature was 36.5 oC and oxygen saturation 97% breathing ambient air. The lungs were clear to auscultation. Abdomen was soft and non -tender with no organomegaly. Extremities showed no evidence of oedema. Neurologic examination was normal. Laboratory Results WBC of 9.77 x109/L (4 -11) Hgb of 110 mg/dL (115 -165) PLT of 406x109/L (150 -450) Serum Urea 52 mmol/L (2.5 – 7) Serum Creatinine 117 umol/L (50 – 120) Blood gasses: pH: 7.2, PaCO2: 18 mmHg, PaO2: 130 mmHg Bicarbonate level 7.3 mmol/L (22 -29) Urine analysis: Elevated proteins, blood, red cell casts and granular casts Common indications for renal biopsy: • Nephrotic Syndrome • Acute kidney injury (AKI) • Chronic kidney disease (CKD) • Positive immunology tests with clinical indications of autoimmune renal disease • Abnormal mass detected • Renal transplant dysfunction Kidney ultrasound Dissection Renal biopsy specimen as seen with a dissecting microscope. (a) Renal cortex, note the glomeruli, recognized as round red areas (b) Renal medulla, reddish vasculature is present, but no glomeruli seen Interpretation of the renal biopsy • Sections are examined by light microscopy, Immunofluorescence and electron microscopy. • The interpretation using light microscopy includes the use of multiple sections stained with a variety of stains. • A number of antigens are examined by immunofluorescence. • Careful evaluation of glomeruli, tubules, the interstitium, and the vessels is required. Light microscopy • Tissue fixed in 10% neural buffered formalin. • To avoid specimen loss during processing, the specimen is gently wrapped in biowrap paper. • Sections are cut at around 2µm (thinner than a standard histology section 4µm). • Thinner sections allows for better assessment of the glomerulus for the diagnosis of renal diseases. Roles of histological stains Stain Reason Haematoxylin and Eosin General tissue architecture (morphology) Periodic Acid Schiff Highlight basement membranes and mesangial matrix Jones Methenamine Silver Highlight basement membranes and immune deposits Masson Trichrome To monitor the degree of fibrosis Congo Red To assess amyloid deposition Elastic Van Gieson To monitor the health of blood vessels Thickened glomerular basement membranes The glomerular basement membrane appears thickened and rigid. The silver stain shows typical spikes and 'holes' in the glomerular basement membrane (circled). Amyloid Formed by normally soluble proteins that assemble into insoluble fibers that are resistant to degradation. Can be deposited in any tissue or organ, leading to a rare disease called amyloidosis that can result in life -threatening organ failure. Congo Red is the gold standard test used to identify amyloid in tissues, and the stained tissue sections must be examined using polarised light microscopy to reveal the characteristic 'apple green' birefringence. Direct Immunofluorescence • Best performed on unfixed, frozen tissue • Sections are cut using a cryostat. • The antigens that are examined include: • Immunoglobulins (IgG, IgA and IgM) • Complement components (C3, and C1q) • Fibrin • Kappa and lambda • Accurate localisation of deposits is possible. Electron Microscopy (EM) • Tissue fixed with glutaraldehyde. • EM cannot be performed on tissues exposed to mercury - based fixatives. • Tissue can be recovered from the paraffin block, or from frozen tissue if no glomeruli are available in the EM sample. Micrograph of a glomerulus (EM) • Part of a glomerulus on showing four capillary loops with a podocyte (P) and its foot processes (FP) on the external surface. • The nucleus of an endothelial cell (E) protrudes into a capillary lumen. Also seen is a mesangial cell (M). • Red cells (which appear black on EM) are seen within capillary lumen (L). • The glomerular basement membrane (arrow) forms a prominent part of the capillary wall. Are all modalities necessary? DIAGNOSES OVERLOOKED WITHOUT FLUORESCENCE • Light chain -associated diseases • IgA nephropathy/Henoch –Schoenlein purpura • IgM nephropathy • C1q nephropathy • Goodpasture’s • Humoral (C4d) transplant rejection • Fibronectin glomerulopathy DIAGNOSES OVERLOOKED WITHOUT ELECTRON MICROSCOPY • Fibrillary glomerulopathy/immunotactoid glomerulopathy • Nail –patella syndrome • Lipoprotein glomerulopathy • Dense deposit disease • Alport’s syndrome • Thin glomerular basement membrane nephropathy • Collagen fibrotic glomerulopathy What about our patient? • Patient was started on hemodialysis. • The patient developed progressive worsening of shortness of breath with hypoxemia (decrease in the partial pressure of oxygen in the blood). • High resolution CT of thorax read as diffuse bilateral peribronchial, interlobular septal, and subpleural thickening. • Patient received bronchoscopy. • Bronchoalveolar lavage showed alveolar haemorrhage with clean lung mucosa. Microscopic analysis Kidney biopsy revealed diffuse necrotizing, crescentic and sclerosing glomerulonephritis. Immunofluorescence was also positive for IgG and C3 along the glomerular basement membranes. Kappa and lambda positive matrix. The granular EM densities permeating the GBM and the matrix of the crescent correlate with the immunofluorescence. Immunology test for proteinase -3 (PR3) antibody was negative but positive for myeloperoxidase (MPO). Anti -GBM was also positive. Clinical course Patient had dropped haemoglobin multiple times without any overt bleeding during her stay in the hospital. Patient was transferred to the ICU with worsening of respiratory failure for a trial of plasmapheresis and steroids. Patient’s SOB has significantly improved with plasmapheresis and low dose prednisone . Repeat chest X -ray and CT of thorax showed significant improvement after the treatment. Treatment • Untreated disease has an almost universally poor outcome, with death from renal failure or lung haemorrhage • Plasmapheresis in conjunction with cyclophosphamide and prednisone. • Plasmapheresis removes circulating anti -GBM antibodies and other mediators of inflammation (such as complement), • immunosuppressive agents minimize new antibody formation. • Concern for latent TB should prevent the use of cyclophosphamide. • Treatment has dramatically improved prognosis, and the 5 -year survival rate exceeds 80%. • Patients with advanced renal disease who require dialysis upon hospital presentation have low chances of renal recovery, around 8%. Monitoring • Patients on immunosuppression are monitored at least monthly by a nephrologist. • While on cyclophosphamide, a weekly full blood count is obtained. • After the disease is in remission and off immunosuppression, follow -up may be reduced to every 3 to 6 months for management of residual chronic kidney disease. • Patients may be left with some degree of renal impairment requiring management . • Patients who develop end -stage renal disease may be considered for renal transplantation once the serum anti -GBM antibody becomes undetectable