MS4 Amyloidosis

• -resistant to proteolysis
• -beta pleated sheet configuration
• -homogenous protein

• Main Components of Amyloid Deposits
• 1. Fibrillary Protein (95%)
• -each different type of amyloid has a separate protein precursor for its fibrillary protein
• 2. Amyloid P component (5%)
• 3. Glycosoamynoglycan

1. Misfolding of precursor protein to lower thermodynamic state

2. Intermediate takes on more beta-sheet structures

3. Enables aggregation and self-propagation secured by H-bonds

• -Extracellular deposition
• -Unusual stability
• -Damages tissue structure and function
• -Progressive and fatal without treatment

• 1. Macroglossia (almost pathomnemonic)
• 2. Violacious purpura around the eyes
• 3. Amyloid deposits in the muscles
• 4. Hepatomegaly
• 5. Deposits in the lungs
• 6. Submandibular gland enlargement

• Congo red
• -Normal light: brick red
• -Polarized light: apple green birefringence
• **molecules align on the beta pleated sheet

• 1. Primary
• -light chain amyloidosis (AL)
• -underlying plasma cell proliferative disorder

• 2. Secondary
• -AA
• -caused by abnormal deposition of acute phase reactant (increased during inflammation)
• -serum amyloid A (SAA) protein

• 3. Senile/Hereditary
• -most commonly ATTR (transthyretin or prealbumin)
• -sporadically in advanced age (senile)
• -germline ATTR mutation (hereditary)

• 4. Other Proteins (10-15%)
• -more than 28 amyloidgenic proteins

• 5. Localized amyloidosis
• -abnormal accumulation of locally produced proteins in an organ
• -ie: Alzheimer's (amyloid beta protein precursor)
• -ie: Calcitonin in medullary thyroid cancer

• 1. Genetic mutations
• -often AA substitutions
• -ATTR, Afib, ALys, AI and AII (apolipoproteins)

• 2. Wild Type Proteins
• -senile amyloid of WT ATTR
• -other senile from prolactin, calcitonin, amylin

• 3. Acquired Structurally Abnormal Precursor
• -monoclonal immunoglobulin light chain (AL)
• -usually lambda

• 4. Sustained elevated concentrations of inherently amyloidgenic precursor over a very long time
• -increased production: AA in inflammatory syndromes
• -decreased elimination: B2 microglobulin in end stage renal failure
• -injected insulin (amyloidomas)

• 5. Proteolytic Remodeling
• -B-amyloid precursor protein in Alzheimer's

• 6. Transmission by prions
• -act as template for normal host prior protein PrP^c to misfold into pathogenic PrP_^sc

• Visible Tissue Infiltration:
• -bruising: periorbital, general
• -macroglossia
• -muscle pseudohypertrophy

• Renal:
• -proteinuria
• -renal failure

• Cardiac:
• -restrictive cardiomyopathy
• -ECG: low voltage, pseudoinfarct

• Liver:
• -hepatomegaly
• -high ALP
• -rarely liver failure

• Peripheral Neuropathy:
• -carpal tunnel syndrome
• -symmetrical sensorimotor neuropathy

• Autonomic Neuropathy:
• -orthostatic hypotension/arrhythmias
• -gut motility/bladder emptying

• Gastrointestinal:
• -weight loss/anorexia/bloating
• -blood loss-constipation/diarrhea

• Adrenal Axis:
• -hypoadrenalism

• Lymphoreticular System:
• -hyposplenism/splenomegaly
• -lymphadenopathy

• -bladder
• -bronchopulmonary tract
• -prostate
• -conjunctiva
• -other

• Good prognosis
• Local Treatment

• Precursor protein:
• -usually lambda light chain

• Clinical Presentations:
• -cardiac
• -renal
• -hepatic/GI
• -PNS
• -soft tissues

• Clinical Features:
• -nephrotic syndrome
• -renal failure
• -cardiac failure
• -peripheral or autonomic neuropathy (NOT CNS)
• -Carpal Tunnel Syndrome
• -Factor X deficiency
• -periorbital bruising ("raccoon eyes")
• -BM involvement
• -Jaw claudication
• -macroglossia
• -lympadenopathy

• Precursor Protein:
• -mutant transthyretin

• Clinical Presentations:
• -Cardiac
• -PNS

• Precursor Protein:
• -wild-type transthyretin

• Clinical Presentations:
• -Cardiac
• -Pulmonary
• -PNS

• Clinical Features:
• -cardiac isolated disease
• -thick walled LV
• -diastolic dysfunction
• -slowly progressive
• -does NOT respond to chemo
• -mostly elderly white men
• -can be diagnosed as AL in the presence of MGUS/MM

• -Rare in developed world
• -cases still occur in associated with chronic infection, severe gout, UC, metastatic renal cancer

• Precursor Protein:
• -serum amyloid A

• Clinical Presentations:
• -renal

• Clinical Features:
• -primarily renal at presentation
• -liver involvement (sign of advanced disease)
• -adrenal involvement

**almost never cardiac or neurologic

• Precursor Protein:
• -mutant fibrinogen A alpha

• Clinical Presentation:
• -Renal
• -Hepatic

• Precursor Protein:
• -Apolipoprotein A1

• Clinical Presentation:
• -Cardiac
• -renal
• -hepatic/GI
• -PNS
• -Skin

• -can be difficult
• -no blood test to diagnose or exclude
• -usually depends on clinical suspicion

• Supported by:
• 1. underlying chronic inflammatory state (AA)
• 2. underlying plasma cell dyscrasia (AL)
• 3. FHx (hereditary)
• 4. Evidence of organ dysfunction

• -acquired deficiency of Factor X
• -postulated to occur due to absorption of factor X into amyloid fibril

• -screening biopsy
• -rectal: more invasive but better for immunotyping
• -abdominal fat FNA: highly variable sensitivity

• Histology:
• -apple green birefringence on congo red stain
• -AA and hereditary are sensitive and specific
• -AL not often easy (only 50%)

• -highly suggestive of AL amyloidosis
• -bone uptake seen in 25%
• -consistent with AA (but AA protects other amyloid proteins from degradation so it could be any type of systemic amyloidosis)

*essential for deciding treatment

• 1. Spep/upep/IFE/FLC (???)
• 2. bone marrow bx
• 3. mutation analysis for hereditary
• 4. tissue typing (gold standard)
• 5. correlation with clinical features

• Typical Subtle monoclonal gammopathies:
• -subtle monoclonal gammopathies (75-80%)
• -myeloma (20%)
• -clonal disease undetectable (2%)

• MGUS is common in the elderly:
• -monoclonal gammopathy of unknown significance

The presence of clonal dyscracia does not confirm a diagnosis of AL amyloidosis

The absence of detectable clone does NOT exclude AL amyloidosis

• Chemotherapy
• -Melphalan + dex +/- bortezomib
• -plasma cell clone a little too hyperactive → use chemo to shut it down
• -Difficulties: multi-organ involvement (poorly tolerated with high treatment related mortality)
• -optimal treatment contentious

• Autologous HSCT
• -works best early in the course of the disease before too much amyloid has accumulated

• Organ Transplantation:
• 1. Liver: not recommended (poor survival in most)
• 2. Heart: only if cardiac isolated disease, but be followed by ASCT
• 3. Kidneys: viable if clonal disease under good control without significant cardiac disease
• Serum free light chain assay:
• -enables quantitative monitoring of plasma cell dyscracia and response to therapy
• -more difficult in renal failure (retention)
• -excess light chain demonstrable in 95% of patients with AL amyloidosis

• Better Prognosis:
• -renal isolated disease
• -peripheral neuropathy only
• -soft tissue involvement only
• -good response to chemotherapy

• Biomarkers:
• -BNP
• -troponin
• -markers of heart disease (poor prognosis)

• Poorer Prognosis:
• -poor response to chemo
• -cardiac involvement
• -ANS involvement

Suppress underlying inflammation!

• Control underlying inflammatory diseases:
• -RA, JCA, chronic sepsis, crohn's etc

• Immunosuppressants:
• -anti-TNF

Monitor response with serial SAA measurements

Excellent results with kidney transplanation

• Hepato-renal transplant
• -fibrinogen is synthesized in the liver

• Diuretics
• -mainstay (cardiac involvement)

• Diflunisal
• -NSAID
• -stabilizes variant TTRs and prevents unfolding and aggregation

• Tafamidis
• -stabilizing agent
• -inhibits TTR aggregation by stabilizing monomers
• -approved in Europe

• Immunotherapy
• -amyloid fibrils express unique epitopes
• -try to develop antibodies against amyloid fibrils