Case 4 -
Primary Systemic Lambda Light Chain Amyloidosis
Massachusetts General Hospital
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The patient is a 37 year-old woman who presented with dyspnea on exertion, fatigue, orthopnea, and
ankle edema. Chest X-ray revealed mild cardiac enlargement. An echocardiogram revealed biatrial
enlargement, moderate left ventricular hypertrophy with mild global dysfunction, mild mitral
regurgitation, moderate tricuspid regurgitation, moderate pulmonary hypertension, and a left ventricular
ejection fraction of 45%. Coronary angiography revealed no significant coronary artery disease. A chest
CT scan showed no evidence of pulmonary emboli or pericardial thickening. A right ventricular
endomyocardial biopsy was performed.
The endomyocardial biopsy revealed deposition of amorphous eosinophilic extracellular material in a
predominantly interstitial and vascular distribution. Congo red stain revealed the material to show
strong orange/pink staining with unpolarized light and green birefringence with polarized light,
indicative of amyloid. Utilization of an immunofluorescence panel on fresh frozen tissue demonstrated
the amyloid deposits to consist of lambda immunoglobulin light chain.
Primary Systemic Lambda Light Chain Amyloidosis
Bone marrow biopsy revealed 6-8% plasma cells with amyloid deposition. Serum protein electrophoresis
(SPEP) and immunofixation revealed a "low concentration" IgG-lambda monoclonal component. The patient
was treated with high-dose melphalan chemotherapy with autologous stem cell transplantion and also
cardiac allograft transplantation. A section from the explanted heart is provided for review.
The amyloidoses are a group of disorders characterized by the formation of proteinaceous amyloid
deposits in tissues. An amyloid deposit is composed of one specific amyloid-prone (amyloidogenic)
protein along with several non-specific proteins. Over 20 distinct types of amyloid deposits are known
to occur based on the specific amyloidogenic protein present. Both prognosis and specific therapies are
based on the type of amyloid deposit present in the tissue. Pathologists are now facing and will
continue to face increasing pressure from our clinical colleagues to subtype the amyloid deposits
observed in tissue sections.
|Common: ||Some forms of amyloidosis affect > 90% of older patients|
Primary AL amyloidosis - annual incidence of 9/million/year
|Serious: ||Some forms have prognoses similar to the most aggressive malignancies. |
Primary AL amyloidosis with cardiac involvement - survival 6 months
|Treatable: ||Immunosuppression with Melphalan and Prednisone for AL amyloidosis. |
Liver transplantation for Familial Amyloidotic Polyneuropathy.
Structure of Amyloid Deposits
- Disorder of protein folding, so-called "conformational disease"
- A particular protein adopts an extended beta-sheet conformation.
- 2-5 extended beta-sheets intertwine to form an amyloid fibril.
- The amyloid fibrils are insoluble and are deposited in tissue.
- The amyloid deposit (amyloid plaque) consists of amyloid fibrils (likely composed entirely of one
protein) along with several non-specifically bound proteins.
- Non-specific proteins, present in most amyloid deposits include:
Serum Amyloid P (SAP), Proteoglycans, Apolipoprotein E, Collagen IV
Classification of Amyloidosis
- Classification based on the identity of the specific protein forming the amyloid fibrils.
- Over 20 such specific proteins now known.
- Systemic vs Localized
Some localized forms have little to no clinical significance
- Acquired vs Hereditary
Different clinical presentation
Senile Systemic Amyloidosis vs Familial Amyloidotic Polyneuropathy
Both result from transthyretin
Impact on treatment options
Factors That Trigger Amyloid Deposition
- Inheritance of an amyloidogenic mutation.
- Transthyretin - Familial Amyloidotic Polyneuropathy
- Cystatin C - Cerebral Amyloid Angiopathy
- Overproduction or accumulation of an amyloidogenic wild-type protein
- Serum Amyloid A - Chronic inflammatory conditions
- Beta-2 microglobulin - Chronic hemodialysis
- Ig light chains - monoclonal gammopathy
- An initial amyloid focus
- Deposition of wild-type transthyretin amyloid in the heart following liver transplantation
for hereditary amyloidosis
- Prion Diseases
- Animal model using serum amyloid A
- Unknown / Multifactorial
- Senile Systemic Amyloidosis
Diagnosis of Amyloidosis
Amorphous eosinophilic material
May be difficult to distinguish from collagen
Heterogeneous, grungy blue staining
Modified Sulfated Alcian Blue:
Amyloid-green, Collagen-red, Cells-yellow
Useful for autopsies with extended post-mortem intervals
Not entirely specific as mucins will stain green
Orange or pink staining (intensity helpful but not diagnostic)
Enhanced (over H&E stain) green birefringence with polarized light
(considered diagnostic for amyloid)
Primary Systemic Ig Light Chain ( AL ) Amyloidosis
- Accounts for 80% of systemic amyloidosis in North America
- 12 to 15% of patients with myeloma develop amyloidosis.
- 90% of Patients with AL amyloidosis have a monoclonal gammopathy.
- May present locally in association with plasmacytoma
- lambda light chains are more amyloidogenic than kappa light chains (3:1).
- Particular gene rearrangements are more highly associated with amyloid formation.
- Almost any organ can be involved.
- Treated with immunosuppression, stem cell transplantation, and cardiac transplantation.
- When cardiac involvement present, survival ~6 months.
Senile Systemic Amyloidosis
- Deposition of wild-type transthyretin
- Etiology Unknown
- 25% of people over age 80 at autopsy
- Clinically significant involvement much less common
- Accounts for ~20% of cases of amyloidosis diagnosed by endomyocardial biopsy
- Most patients diagnosed on biopsy alive after 2 years.
- Heart most severely involved, lungs frequently involved, and subtle involvement of blood vessels in
- Formerly Senile Cardiac Amyloidosis
Sub-typing Amyloid Deposits
Establishing the Presence of a Monoclonal Gammopathy (SPEP / Immunofixation)
- ~10% of patients with a monoclonal gammopathy and systemic amyloidosis actually have a
hereditary amyloidosis, mostly either fibrinogen or transthyretin.
- Monoclonal gammopathies are not uncommon in the elderly and most are not associated with amyloid
- For many of the Hereditary Amyloidoses, multiple mutations have been observed in the culprit
protein, some of which are of low penetrance and late onset.
- Over 80 amyloidogenic mutations in transthyretin identified.
- Ile122 mutation present in 4% of American blacks.
- Newer Serum Free light Chain Analyses may improve sensitivity and specificity over traditional
Direct Sub-Typing of Amyloid Deposits with Immunologic Approaches
- Immunohistochemistry (IHC), Immunofluorescence (IF), Immunoelectron microscopy (IEM)
- Pitfalls and challenges of immunologic techniques
- Not widely utilized with cardiac tissue.
- Very high background staining leading to high false positive rates (IHC).
- Some are prohibitively expensive for routine diagnostic use (IEM).
- The final processed amyloid fragment may lack the antigenic site leading to false negatives.
- Clinical application of an immunofluorescence panel for the subclassification of amyloid in
endomyocardial biopsy specimens.
Ancillary Approaches for Sub-Typing Amyloid Deposits
- Genetic approaches
- May be useful for hereditary amyloidoses.
- An indirect approach that does not definitively subtype the amyloid deposits in the tissue.
- Biochemical approaches
- Amyloid fibril extraction and identification by western-blotting and/or sequencing possible but
- Newer mass spectrometry technologies promising for direct identification of amyloid components.
- Hurdles to achieve routine accurate quantitation.
Table 1: Systemic Acquired Amyloidoses
|Amyloidosis ||Culprit Protein ||Clinical Setting ||Organs Involved|
|Primary Systemic |
|Immunoglobulin light chains (rarely heavy chains) ||Monoclonal gammopathy, myeloma ||Kidney, Heart > other organs, most organs affected|
|Transthyretin ||25% of people over age 80, occasionally clinically significant ||Heart, Lungs, and blood vessels|
|Reactive / Secondary|
|Serum Amyloid A ||Chronic infections or chronic inflammatory diseases ||Spleen > Liver > other organs|
|ABeta2M ||Beta2-Microglobulin ||Chronic Hemodialysis ||Joints, blood vessels, heart|
Table 2: Systemic Hereditary Amyloidoses
|Protein ||Disease, Organs Affected|
|Transthyretin ||Over 80 Mutations known|
Val-122-Ile, 4% American blacks, late onset
Val-30-Met Familial Amyloidotic Polyneuropathy, N. Europeans
Heart, Kidney, Nerves, other (depending on specific mutation).
|Apolipoprotein A-I ||Liver, kidney, heart|
|Apolipoprotein A-II ||Kidney, heart|
|Gelsolin ||Finnish Hereditary Amyloidosis, |
Lattice Corneal Dystrophy Type II, Cornea, nerves
|Lysozyme ||Kidney > other organs|
|Fibrinogen alpha chain ||Kidney > other organs|
|Cystatin C ||Icelandic Hereditary Cerebral Amyloid Angiopathy|
Table 3: Localized Acquired Amyloidoses (Selected)
|Organ ||Protein ||Features|
|Cardiac Atria ||Atrial Natriurtetic Factor (ANF) ||80% autopsies over age 80|
16% of resected atrial appendages
|Cardiac Valves ||unknown || 50% of resected valves|
|Aortic Media ||Lactadherin / medin ||>90% people over age 50, Significance uncertain|
|Islets of the pancreas ||Islet Amyloid Polypeptide / Amylin ||>90% of patients with type 2 diabetes, Insulinomas|
|Thyroid ||Calcitonin ||Associated with medullary carcinoma|
|Brain ||Prion Protein ||CJD, transmissible|
|Brain ||A-beta protein ||sporadic Alzheimer's disease|
Table 4: Localized Hereditary Amyloidoses
|Brain ||A-beta protein ||Cerebral Amyloid Angiopathy, Dutch type Familial Alzheimer's disease|
|Brain ||Prion Protein ||Familial CJD|
|Brain ||ABri Protein ||British Familial Dementia|
|Cornea ||Beta-ig-h3 ||Lattice Corneal Dystrophy, type I|
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