Presentación de PowerPoint¸าจรบ - Amyloidosis.pdf · Systemic Amyloidosis: an under- &...
Transcript of Presentación de PowerPoint¸าจรบ - Amyloidosis.pdf · Systemic Amyloidosis: an under- &...
Systemic Amyloidosis: an under- & misdiagnosed disorder
Archrob Khuhapinant, MD, PhD Division of Hematology, Department of Medicine,
Faculty of Medicine, Siriraj Hospital Mahidol University
CASE REPORT Male, 75 years-old. Previous history: myocardial infarction (placement 2 stents). Carpal tunnel surgery. Current history: cardiac congestive failure (dyspnea and oedema) MRI: LV and septum hypertrophy, late gadolinium diffuse myocardial enhancement.
IF(s): IgA-lambda IF(u): negative IgA: 1450 mg/dL FLC: kappa 1,07 mg/dL; lambda 2,05 mg/dL; ratio 0,52 24 h proteins (u): 250 mg Pro-BNP: 6108 pg/dL TnT: 0,02 ng/mL Bone marrow smear: plasma cells 7% Skeletal x-ray survey: absence of lytic lesions
Abdominal fat biopsy: Congo Red negative Heart Biopsy: large congo red + amyloid deposits Immunohistochemistry: AA negative, positive for both FLC kappa and lambda AP Diagnosis: Amyloidosis, probably AL
Proteomic (laser microdisection + mass spectrometry): TTR peptides Dx: senile amyloidosis (TTR wild-type) + MGUS
Amyloidosis: protein misfolding disease
Increased conc. Increased synthesis o Monoclonal LC* o SAA
Reduced clearance o β2-microglobulin
Mutations* o Transthyretin o Apolipoprotein AI o Lysozyme, etc.
Aging (inestability) o Transthyretin wt
Amyloid precursor
Proteolysis Lysosomal enzymes Metalloproteases Matrix components
Amyloid fibrils
Interactions with microenvironment of target organs
GAGs
Oligomers
aggregation of normally soluble proteins into soluble β-sheet fibrils which are deposited in target tissues causing progressive organ dysfunction
Organ dysfunction
SAP
The most common types of systemic amyloidoses
Type (abbreviation)
Precursor (site of synthesis)
Organs involved
Heart Kidney Liver/GI
PNS/ ANS
Soft Tissue
Immunoglobulin LC amyloidosis (AL)
Monoclonal LC (BM plasma cells) X X X X X
Reactive amyloidosis (AA)
SAA1 (liver) (X) X X XANS
Senile systemic amyloidosis (SSA)
Transthyretin wild type (liver >90%)
X Transthyretin amyloidosis (ATTR)
Variant transthyretin, (liver >90%) X (X) X (X)
Fibrinogen amyloidosis (AFib)
Variant fibrinogen α-chain (liver)
X Apolipoprotein AI amyloidosis (AApoA-1)
Variant Apo A-1 (liver, intestine)
X X X (X)
Clinically is not possible to distinguish between different amyloidosis
74% 65% 24% 20% 15%
X 50%
Carpal tunnel
Clinical picture: related with affected organ(s)
• Rarely pathognomonic (<10%): periorbital ecchymoses, macroglossia…
The most common types of systemic amyloidoses
Type (abbreviation)
Precursor (site of synthesis)
Established Therapy
Immunoglobulin LC amyloidosis (AL)
Monoclonal LC (BM plasma cells)
Chemotherapy ASCT
novel agents Reactive amyloidosis (AA)
SAA1 (liver) Treat underlying diseases
new drug
Senile systemic amyloidosis (SSA)
Transthyretin wild type (liver >90%)
Supportive
Transthyretin amyloidosis (ATTR)
Variant transthyretin, >100 amyloidogenic mutations (liver >90%)
Liver/heart transplantation new drugs
Fibrinogen amyloidosis (AFib)
Variant fibrinogen α-chain (liver)
Organ transplantation
Apolipoprotein AI amyloidosis (AApoA-1)
Variant Apo A-1 (liver, intestine)
Organ transplantation Supportive
Unequivocal identification of amyloid protein is essential for: • appropriate treatment • assess prognosis • genetic counseling (when appropriate)
• Tissue of choice for histological diagnosis in patients with suspected systemic amyloid disease (S: 60%?)
• Available from virtually all patients, innocuous, fast, inexpensive
• Altenative sites: rectum, bone marrow, salivary glands
Fine-needle abdominal fat aspirate
Biopsy of involved organ
Diagnosis relies on demonstration on tissue biopsy of fibrillar deposits which are congophilic and birefringent under polarized light.
• Antibody availability
• Limited sensitivity and specificity: differences between native and misfolded and aggregated protein
• Contamination with serum proteins, charge interaction amyloid-antibody leading to background staining
Limitations of immunohistochemistry
Typing of amyloid deposits
anti-λ antibody
anti-SAA antibody
anti-κ antibody
anti-TTR antibody
Ultrastructural immunohistochemistry
Theis JD, et al. J Mass Spectrom 2013; 48: 1067-77
Laser microdissection and mass spectrometry-based poteomic analysis of paraffin embedded tissue
Typing of amyloid deposits
Technique Overall (n. 115)
κ clones (n. 30)
λ clones (n. 85)
% positive (95% CI) IFE serum urine serum+urine FLC κ/λ ratio IFE serum + FLC κ/λ IFE serum+urine+FLC κ/λ
80 (72-87) 67 (58-75) 96 (91-98) 88 (68-94) 96 (91-98) 100 (97-100)
60 (42-76) 70 (52-84) 90 (75-97) 97 (85-100) 100 (90-100) 100 (90-100)
87 (79-93) 65 (55-75) 98 (92-100) 82 (69-89) 94 (97-98) 100 (96-100)
IF y FLC in AL amyloidosis
Palladini et al, Clin Chem. 2009;55:499-504.
Diagnostic workup of systemic AL amyloidosis
Palladini G, et al. Blood 2016.
Suspicion
Diagnosis
Unequivocal typing
Staging
AL Amyloidosis • Risk stratification (Mayo staging system): pro-BNP
(>1800 pg/L), cTnT (>0,025 ng/mL), FLC-diff (>18 mg/dL)
Kumar R, et al. JCO 2012; 30: 989-95. Kourelis TV, et al. JCO 2013; 31: 4319-24.
Therapeutic approach to systemic AL amyloidosis
Palladini G, et al. Blood 2016.
Low clonal burden, short courses may be enough
Multidisciplinary approach
MDex vs BMDex
• MDEX: HR76% (CR30%); OS: 7 years • Worse results if reduced dexamethasone
• Bortezomib increases and accelerates response but no impact
on survival so far (interim results of RCT-ASH 2014). • Benefit in patients who can’t tolerate high doses of
dexamethasone.
Palladini G, et al. Leukemia 2014; 28: 2311-6. Palladini G, et al. Haematologica 2014; 99: 743-50.
Kastritis E, et al. ASH 2014. Paladini G, et al. ASH 2015.
Wall JS, et al. PlosOne 2012. Liedtke M, et al. EHA 2015.
Gertz M, et al. J Clin Oncol 2016
NEOD 001