amyloidosis Flashcards
definition of amyloidosis
heterogenous group of diseases characterised by extracellular deposition of amyloid fibrils resistant to degradation
can be systemic (generalised) or localised eg in pancreatic islets of Langerhans (t2dm), cerebral cortex (alzheimer’s) cerebral bv (amyloid angiopathy) and in bones and joints (in long-term dialysis caused by B2-microglobin), haemodialysis-related amyloidosis
aetiology of amyloidosis
amyloid fibrils are polymers comprising low molecular weight subunit proteins
these subunits are derived from proteins that undergo conformational changes so are antiparallel B pleated sheet
they associate with glycosaminoglycans and serum amyloid P-component (SAP)
their deposition disrupts structure and function of normal tissue
classification of amyloidosis
classified according to fibril subunit components:
amyloid AA - fibril protein: serum amyloid A protein - underlying disorders: Chronic inflammatory diseases (e.g. rheumatoid arthritis, seronegative arthritides, Crohn’s disease, familial Mediterranean fever); chronic infections(TB, bronchiectasis, osteomyelitis); malignancy (e.g. Hodgkin’s disease, renal cancer)
AL - fibril protein: monoclonal immunoglobin light chains - underlying disorders: Subtle monoclonal plasma cell dyscrasias, multiple myeloma, Waldenstrom’s macroglobulinaemia, B-cell lymphoma
ATTR (familial amyloid polyneuropath) - fibril protein: genetic-varient transthyretin. - underlying disorders: Autosomal dominantly transmitted mutations in the gene for transthyretin (TTR). Variable penetrance. Hereditary amyloidosis is also associated with other variant proteins
AL amyloid
proliferation of plasma cell clone = amyloidogenic monoclonal immunoglobins = amyloidogenic monoclonal immunoglobins - fibrillar light chain protein deposition = organ failure = death
organs involved:
- kidneys - glomerular lesions - proteinuria and nephrotic syndrome
- heart - restrictive cardiomyopathy (looks sparkling on echo), arrhythmias, angina
- nerves - peripheral and autonomic neuropathy, carpal tunnel syndrome
- gut - macroglossia, reduced weight/malabsorption, perf, haemorrhage, obstruction, hepatomegaly
- vascular - purpura, especially periorbital
AA amyloid
amyloid is derived from serum amyloid A, an acute phase protein, reflecting chronic inflammation
affects kidneys, liver and spleen
- proteinuria, nephrotic syndrome or hepatosplenomegaly
cardiac involvement is rare - ventricular hypertrophy and murmurs
familial amyloidosis
(Autosomal dominant, eg from mutations in transthyretin, a transport protein produced by the liver.)
usually causes a sensory or autonomic neuropathy ± renal or cardiac involvement. Liver transplant can cure.
epidemiology of amyloidosis
AA amyloidosis - Lifetime incidence of 1–5 % among patients with chronic inflammatory diseases.
AL amyloidosis - Estimated annual incidence of about 3,000 cases in the United States and300–600 cases in the United Kingdom.
hereditory amyloidosis - Present in5 % of patients with systemic amyloidosis.
renal sx of amyloidosis
Proteinuria, nephrotic syndrome, renal failure
cardiac sx of amyloidosis
Restrictive cardiomyopathy, heart failure, arrhythmia, angina (due to accumulationof amyloid in the coronary arteries).
GI sx of amyloidosis
Macroglossia (characteristic of AL), hepatomegly, splenomegaly, gut dysmotility, mal-absorption, bleeding.
neuro sx of amyloidosis
sensory and motor neuropathy, autonomic neuropathy (symptoms of bowel or bladder dysfunction, postural hypotension), carpal tunnel syndrome.
skin sx of amyloidosis
Waxy skin and easy bruising, purpura around eyes (characteristic of AL), plaques andnodules.
joints sx of amyloidosis
Painful asymmetrical large joints, ‘shoulder pad’ sign (enlargement of the anterior shoulder).
haematological sx of amyloidosis
Bleeding diathesis (factor X deficiency due to binding on amyloid fibrils primarily in the liver and spleen; and reduced synthesis of coagulation factors in patients with advanced liver disease).
Ix for amyloidosis
Tissue biopsy (Congo red stain with apple-green birefringence under polarized light microscopy. , immunohistochemistry): To diagnose amyloidosis and identify amyloid fibril protein. Reliable in AA, often poor for AL. The rectum or subcutaneous fat are relatively non-invasive sites for biopsy and are +ve in 80%.
Urine: Proteinuria, free immunoglobulin light chains in AL
Blood
123I-SAP scan: Radiolabelled SAP localizes to the deposits enabling quantitative imaging of amyloidotic organs throughout the body.
Bone marrow, echocardiography and other investigations including DNA analysis for underlying disorders
