Classification AL amyloid AA amyloid Hereditary amyloidosis § Transthyretin (polyneuropathy, cardiomyopathy) § Fibrinogen A alpha-chain (exclusively renal disease) § Lysozyme § Apolipprotein AI
AL amyloidosis
Pathophysiology § Deposition of monoclonal light chain fragments in an abnormal insoluble fibrillar form. § N terminal consisting of all or part of the VL domain (intact light chains rarely found). § Mol weight 8000 – 30 000 Da § Patially unfolded allowing them to aggregate in beta-sheet secondary structure. § Seeding occurs with amyloid deposition then occurring exponentially as the amyloid template captures further precursor molecules. § Associate with the normal plasma protein serum amyloid P component (SAP). § Evokes little or no local reaction – disrupts normal tissue structure § Poor correlation between amount of amyloid and degree of organ impairment (esp kidneys)
§ Mostly associated with MGUS rather than myeloma § Rare to progress to overt myeloma (probably due to short survival) § 10-15% of myeloma patients have AL amyloid deposits at some point § More rarely occur in Waldenstroms
Prognosis § 20% 2 year survival
Epidemiology § Incidence 5-12 / million / year § 1 in 1500 deaths § 10% age <50 § 60% age 50-70 § Male = female
Clinical features
Nephrotic syndrome (+/- renal failure) (30%) § Glomerular lesion causing nephritic syndrome § Rarely causes progressive renal failure at diagnosis § Pleural / pericardial effusions
Cardiac failure (20%) § Restrictive cardiomyopathy § Low voltages in ECG / CXR often doesn’t show cardiomegaly § Right sided heart failure most common § Atrial thrombi
Sensory / autonomic neuropathy (20%) § Symmetrical paraesthesia / numbness § Motor neuropathy rare § Carpal tunnel syndrome § Autonomic neuropathy more serious § Postural hypotension (definition BP fall 20mmHg on standing for 3-5 mins after lying supine for 5 min), impotence, altered GI motility (early satiety), anhidrosis, gustatory sweating
GI / Hepatic involvement § Hepatomegaly (25% at diagnosis) – may be due to R heart failure rather than amyloid infiltration. § 10% macroglossia (can cause sleep apnoea) § Early satiety, diarrhoea, chronic nausea, malabsorption, weight loss, perforation, GI bleeding
Haemostasis § Haemorrhage (30% at some point) § Abnormal clotting screen (50%) § Purpura common due to vascular fragility (due to endothelial amyloid deposits) – peri-orbital characteristic.
Bone / Joint involvement § Present in 30% of SAP scans § Doesn’t tend to cause lytic lesions (suggestive of myeloma) § X rays may be normal even when there is substantial bone involvement § Painful seronegative arthropathy may occur
Other manifestations § Skin thickening § Vocal cord infiltration § Adrenal / thyroid infiltration § Lymphadenopathy § Pulmonary infiltration § Only brain can’t be involved
Localised AL amyloid § Nodular infiltrate which is usually associated with an infiltrate of clonal cells. § Often in upper respiratory, urogenital, GI, skin or orbit.
Differential AA amyloidosis Hereditary amyloidosis Other paraprotein associated diseases (eg paraprotein associated peripheral neuropathy) Immunoglobulin deposition disorders
Investigations
Establishing diagnosis Biopsy § Fat aspirate / rectal / labial salivary gland – positive in 80% § Affected organ § Bone marrow – involvement highly suggestive of AL amyloidosis § Congo red / red-green birefringence with polarised light § Immunohistochemical staining with a panel of antibodies to amyloid fibril proteins (only establish definitive diagnosis of AL amyloid in 50% due to background immunoglobulin). Confirms AA amyloid in nearly all cases. § Only to determine the diagnosis (not generally helpful to establish extent of organ involvement or monitor disease)
SAP scan § Performed at NAC § Radiolabelled SAP component localises to amyloid deposits § Useful for monitoring extent and distribution of organ involvement § Cardiac amyloid poorly visualised § Bone marrow involvement strongly correlates with AL
Electrophoresis / immunofixation (serum / urine) / § Paraprotein detectable in 80% of AL amyloid § Not det 20% / 30% <10g/dL / 40% 10-20g/dL / 10% >30%
Serum free light chain assay § Positive in 98% of patients with AL amyloid
Ix for myeloma (Bone marrow, skeletal survey, Ca / U&E, Igs- immune paresis?) § NB patients with hereditary amyloid may also have MGUS
DNA analysis § Hereditary amyloid AD with incomplete penetrance § Defects in: o Transthyretin (polyneuropathy, cardiomyopathy) o Fibrinogen A alpha-chain (exclusively renal disease) o Lysozyme o Apolipprotein AI § More common than previously thought most misdiagnosed cases of AL amyloid were due to transthyretin or fibrinogen A alpha-chain defects § Performed at NAC
Amyloid fibril sequencing § Fibrils isolated from tissue biopsy samples and characterised by amino-acid sequencing § Only uniformly definitive method for determining the amyloid fibril type § Performed at NAC
Organ involvement / monitoring § U&E / Albumin / Cholesterol (nephrotic syndrome) § 24h urinary protein (albuminuria present in 90%) / Cr clearance § LFTs (only in advaced liver disease) § Clotting (prolonged TT most common) § FBC (myeloma, chronic renal failure, bleeding)
SAP scanning
ECG / Echo § Cardiac amyloid poorly visualised § ECG (low voltages / ischaemic changes)
CXR Reticulonodular shadowing in pulmonary amyloid
Nerve conduction studies
Nerve biopsy
Synacthen test (orthostatic hypotension)
Thyroid function
Poor prognositic factors 1. Cardiac amyloid (median survival 6 months if substantially involved) 2. Large whole body amyloid load 3. Autonomic neuropathy 4. Hyperbilirubinaemia 5. Multiple myeloma 6. Lack of response to chemotherapy
Good prognostic factors 1. Proteinuria / peripheral neuropathy only 2. Good response to chemotherapy VL germline genes have also recently been correlated with outcome
Treatment Chemotherapy regimes based on myeloma treatment protocols
Low dose Melphalan and Prednisolone § 28% response rate (Kyle et al., 1997) § Survival 18 months cf 8.5 months with colchicines only § Responders survived 89 months cf 14 months in non responders § 20% risk of myelodysplasia § Used in those in whom intermediate or high dose treatment is not appropriate
Combination chemo
VBMCP § 30% response rate
VAD § 60-80% response rate § Rapid reduction in tumour burden § Problems – cardiotoxicity of adriamycin, vincristine related peripheral / autonomic neuropathy, fluid retention caused by dexamethasone § Can be used in patients on dialysis and with cardiac involvement § Considered first line treatment for AL amyloidosis
Thalidomide § Little evidence (phase I/II trial only) § Response rate with dexamethasone around 60% § Problems with thrombosis Bortezomib / Lenalidomide may be used Autografting
Not recommended if: § Symptomatic cardiac amyloid § Symptomatic autonomic neuropathy § History of GI bleeding § Dialysis dependent renal failure § Age >70
Best in § Good risk patients § Non responders / early relapse folloing VAD
Patients with the same reduction in FLC after VAD or IDM have a similar survival to those after autografting therefore current guidelines recommend VAD or IDM first line
Supportive care
Nephrotic syndrome § Diuretics (loop then thiazide / K sparing) § Fluid restriction § Hypertension – treat aggressively (ACE inhibitors especially) § Treatment of hypercholesterolaemia § Prophylactic anticoagulation not recommended due to increased risk of bleeding in amyloid § Dialysis § Renal transplant rarely been used
Cardiac failure § Little evidence specifically relating to cardiac amyloid § Diuretics § Spironolactone § ACEi § BCSH guideline recommends avoidance of Ca channel blockers / beta blockers (ref Gertz 1985).
Orthostatic hypotension § Rule out addisons § Support stockings § Fludrocortisone
Bleeding § Generally due to generalised vasculopathy (amyloid deposition in blood vessels) § Factor X deficiency well recognised § Impaired fibrin polymerisation § Proposed that clotting factors bind to amyloid
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