Amyloidosis Flashcards
Define amyloidosis.
Describes the extracellular deposition of an insoluble fibrillar protein termed amyloid which is derived from many different precursor proteins
How is amyloidosis classified?
- AL - amyloid light chain - contains Ig light chains derived from plasma cells
- AA - serum amyloid A which is an acute-phase reactant produced in inflammation
- A-beta - beta amyloid/APP(amyloid precursor protein) - found in Alzheimer’s disease
- ATTR - transthyretin - TTR is a protein made in the liver which transports thyroxine and retinol binding protein. A mutant form of this protein is deposited in genetically determined familial amyloid neuropathies. TTR is also deposited in the heart —> senile systemic amyloidosis.
Many other types exist.
Effects can be localised or systemic:
- Systemic e.g. AL, AA, A-beta
- Localised e.g. A-beta, isolated atrial amyloidosis.
Also classified as primary or secondary:
- Primary amyloidoses = from a disease with disordered immunity e.g. MM.
- Secondary (reactive) amyloidoses= from complication of chronic inflammatory or tissue-destroying disease e.g. reactive systemic amyloidosis and secondary cutaneous amyloidosis.
Explain the pathophysiology of amyloidosis.
- Amyloid is derived from many different precursor proteins
- In addition to its fibrillar component it has a non-fibrillary protein called amyloid P, derived from the acute phase serum amyloid P
- Other non-fibrillary components include apolipoprotein E and heparan sulfate proteoglycans
- Accumulation of amyloid fibrils → tissue/organ dysfunction
What are the hallmarks of nephrotic syndrome?
- Proteinuria
- Hypoalbuminaemia
- Oedema
- Hyperlipidaemia (occurs because albumins and other proteins usually reduce lipid synthesis)
Describe the pathophysiology of AL amyloidosis.
Plasma cell clones → amyloidogenic monoclonal immunoglobulins → fibrillar light chain deposition → organ failure → death.
This occurs in myeloma (15%), Waldenstrom’s, lymphoma.
- Kidneys: → deposits disrupting glomerular BM → proteinuria and nephrOtic syndrome
- Heart → idiopathic restrictive cardiomyopathy ( looks “sparkling” on echo) arrhythmias, angina.
- Nerves → deposits in vasa nervorum → peripheral and autonomic neuropathy + carpal tunnel.
- Gut → macroglossia, malabsorption, perforation, haemorrhage, obstruction, hepatomegaly.
- Vascular → purpura, especially periorbital, characteristic feature.
Describe the pathophysiology of AA (secondary) amyloidosis.
Derived from serum amyloid A, acute phase protein, e.g. in chronic inflammation in RhA, UC/Crohn’s, FMF, and chronic infections - TB, bronchiectasis, osteomyelitis. *
- Affects kidneys, liver, spleen → proteinuria, nephrotic syndrome, hepatosplenomegaly.
- Macroglossia is NOT seen
- Cardiac involvement is RARE
Describe the pathophysiology of AF amyloidosis/ATTR.
- Most common inheited, systemic form of amyloidosis
- Autosomal dominant - due to mutations in transthyretin (TTR is a transport protein made by the liver) and each variant has a different organ involvement
- Usually causes sensory or autonomic neuropathy, renal impairment, familial cardiomyopathy too.
What is senile systemic amyloidosis (SSA)?
- A form of amyloidosis associated with an unmutated (native/wild-type) TTR
- Occurs in the elderly
- Formely known as senile systemic cardiac amyloidosis
- Deposition occurs exclusively in the heart
Descirbe the epidemiology of amyloidosis.
- RARE - 5-12 cases per million
- Increasing prevalence of AL but decreasing AA due to better anti-inflammatories
- Males>females
- More common in black people
What are the risk factors for amyloidosis?
- MGUS - x8.4 risk
- Inflammatory polyarthropathy e.g. RA, psoriatic arthritis, ankylosing spondylitis
- Chronic infections - bronchiectasis, UTIs, osteomyelitis, decubitus ulcers
- IBD especially Crohn’s
- Familial periodic fever syndromes
- Rare: Castleman’s disease (non-cancerous tumours of lymphoid tissue)
What are the presenting symptoms of amyloidosis?
- Fatigue
- Weight loss
- Dyspnoea on exertion
Less common:
- Paraesthesia (peripheral neuropathy)
- Claudication
- Nausea
- Abdominal cramps
- Alternating bowel habit
- Orthostatic hypotension
- Hepatomegaly
List some signs of amyloidosis on examination.
- Jugular venous distension
- Lower extremity oedema
- Periorbital purpura
- Macroglossia
- Submandibular salivary gland enlargement
- Sensory neuropathy
- Tinel’s sign (tapping carpal nerve → tingling in 1-4th fingers in carpal nerve syndrome)
What invesigations would you do for amyloidosis?
1st
- serum immunofixation –> shows monoclonal protein presence
- urine immunofixation –> same
- immunoglobulin free light chain assay –> abnormal kappa to lambda ratio
- bone marrow biopsy –>clonal plasma cells
Other:
- tissue biopsy –> positive Congo Red staining. Apple-green birefringence is seen when Congo red stained material is viewed under polarised light. Can be taken from rectum or subcutaneous fat.
- genetic testing - sequence for TTR, fibrinogen , lysozyme, TNFR1 etc genes.
- ECG - conduction abnormalities
- 24hr urine - proteinuria (>3g/24hr = nephrotic syndrome)
- echocardiogram - diastolic dysfunction, thickening of interventricular septum
Define AL amyloidosis.
Amyloid light chain amyloidosis
Caused when misfolded free light chains aggregate into amyloid fibrils in target organs
What is the main determinant for AL amyloidosis development?
Amyloidogenic potential of the light chain > their amount
What types of light chain are most commonly involves in AL amyloidosis?
Lambda light chain (60%) e.g. IGLV6-57 in kidney, IGLV1-44 in cardiac.
What are the clinical presentations of AL amyloidosis?
- Nephrotic syndrome (70%) - proteinuria, peripheral oedema
- Unexplained HF
- Sensory neuropathy
- Abnormal liver function tests
- Macroglossia
What investigations may help diagnose AL amyloidosis related HF?
NT-proBNP raised
Abnormal echo
Abnormal cardiac MRI
What are the main two types of amyloidosis?
AA - derived from serum amyloid A e.g. Crohn’s, RhA
AL - derived from light chains of Ig e.g. in MM, B cell lymphoma
Apart from light chains and serum amyloid A, what other proteins can give rise to amyloid?
Transthyretin e.g. mutation
B2-macroglobulin - peritoneal dialysis
AB2 protein - Alzheimer’s
Insulin, calcitonin - endocrine tumours
What is the management of AL amyloidosis?
Referral to specialist amyloidosis centre
Suppress plasma clone responsible e.g.
- Autologous stem cell transplant - if Mayo eligibility criteria are met; induction therapy is usually bortezomib based
- +/- Systemic therapy - e.g. Dara-CyBorD chemotherapy or lenalidomide plus dexamethasone
What is the management of AA amyloidosis?
Control the underlying systemic inflammatory process e.g.
- TNF-alpha inhibitors e.g. infliximab, etanercept
- IL-1 inhibitors e.g. anakinra
- IL-6 inhibitors e.g. tocilizumab
- Specific therapies:
- Resect tumour in Castleman’s disease
- Colchicine in FMF
What are the complications of amyloidosis?
- Treatment related complications e.g. SCT mortality is 2.5%, organ dysfunction post-chemo, infections, fluid-retention
- CKD
- Cardiomyopathy - MOST COMMON CAUSE OF DEATH in amyloidosis; restrictive so responds poorly
- Conduction abnormalities
- Painful peripheral neuropathy
- Macroglossia obstruction
- Factor X deficiency - due to advanced hepatic amyloidosis
- Splenic rupture - as it becomes rigid
What is the prognosis with amyloidosis?
AL - depends on therapeutic suppression of light chains; if suppressed 25% will survive for a decade
AA - also depends on control of disease; serum AA levels are highly predictive or survival e.g. <10mg/L associated with >10yr survival
