Haemato-oncology‎ > ‎



AL amyloid

AA amyloid

Hereditary amyloidosis

§   Transthyretin (polyneuropathy, cardiomyopathy)

§   Fibrinogen A alpha-chain (exclusively renal disease)

§   Lysozyme

§   Apolipprotein AI



AL amyloidosis



§   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



§   20% 2 year survival



§   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



§   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.



AA amyloidosis

Hereditary amyloidosis

Other paraprotein associated diseases (eg paraprotein associated peripheral neuropathy)

Immunoglobulin deposition disorders




Establishing diagnosis


§   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)



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



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



§   30% response rate



§   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



§   Little evidence (phase I/II trial only)

§   Response rate with dexamethasone around 60%

§   Problems with thrombosis

Bortezomib / Lenalidomide may be used



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



§   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