AL amyloidosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Suspect AL when apparently unrelated organs fail together. Cardiac clues include breathlessness, oedema, raised NT-proBNP, preserved ejection fraction despite impaired longitudinal strain, increased ventricular thickness, low blood pressure and atrial or ventricular arrhythmia. Renal disease commonly presents with albumin-predominant proteinuria and oedema. Peripheral sensory neuropathy, profound postural hypotension, early satiety, diarrhoea or constipation, weight loss, hepatomegaly, macroglossia, shoulder-pad thickening, carpal tunnel syndrome and periorbital purpura strengthen the pattern. Absence of a large paraprotein does not reassure.

Screen for a clone with serum protein electrophoresis, serum immunofixation, urine immunofixation and serum free light chains. Immunofixation detects small monoclonal proteins that electrophoresis can miss; urine testing adds sensitivity, and the free-light-chain ratio must be interpreted with renal function. Send FBC, renal, liver, calcium, albumin, coagulation, troponin, NT-proBNP, urine albumin-to-creatinine or protein-to-creatinine ratio and a 24-hour urinary protein measurement when required for organ response. A negative complete monoclonal screen makes AL unlikely but does not replace tissue assessment in a compelling phenotype.

Proof requires amyloid in tissue, classically Congo red with apple-green birefringence under polarised light. Abdominal fat aspirate and bone marrow are relatively low-risk first sites and can be sampled together, but negative surrogate biopsies do not exclude disease when organ suspicion remains high. Biopsy the affected organ when benefit exceeds bleeding risk. The reference standard for subtype is laser microdissection followed by mass spectrometry. Immunohistochemistry requires an experienced laboratory. Never type amyloid from the circulating clone alone.

Cardiac assessment determines urgency and prognosis. Obtain ECG, echocardiography with strain, NT-proBNP and troponin; cardiac MRI supports infiltration and quantifies extracellular expansion but does not establish the precursor type. Biomarker staging combines troponin, NT-proBNP and dFLC thresholds. A very high NT-proBNP may also reflect renal dysfunction or atrial fibrillation, so interpret longitudinally and clinically. New syncope, hypotension, conduction disease or ventricular arrhythmia warrants monitored assessment. Bone scintigraphy can support ATTR only after AL has been appropriately excluded.

For newly diagnosed systemic AL, NICE TA959 recommends daratumumab with bortezomib, cyclophosphamide and dexamethasone when its conditions are met. A common 28-day NHS protocol gives daratumumab 1,800 mg subcutaneously weekly in cycles 1 and 2, every two weeks in cycles 3 to 6 and every four weeks thereafter; bortezomib, cyclophosphamide and dexamethasone stop after six cycles, and daratumumab continues to a maximum of 24 cycles. Exact partner doses, steroid attenuation and holds follow the treating centre because advanced cardiac disease, neuropathy, renal impairment and frailty materially change tolerance.

Supportive management is deliberately cautious. Loop diuretics, sometimes with a mineralocorticoid antagonist, relieve congestion but excess diuresis causes renal decline and syncope. Avoid routine fluid challenges in restrictive cardiac disease. Conventional renin-angiotensin blockade, beta blockade and vasodilators often worsen hypotension; retain only when benefit is clear. Manage atrial fibrillation with specialist rhythm and anticoagulation decisions, recognising both intracardiac thrombus and bleeding risk. Treat nephrotic oedema with salt management and carefully titrated diuretics; involve renal services early and prepare for dialysis when required.

Response has separate dimensions. Follow the same involved and uninvolved free light chains, SPEP or immunofixation and marrow where relevant for haematological depth. Cardiac response uses serial NT-proBNP in the appropriate clinical context; renal response uses proteinuria and eGFR. A rapid deep clonal response is the immediate objective, while organ biomarkers may take months to improve. Lack of early clonal fall requires urgent expert review rather than waiting for organ recovery. Relapse decisions consider biochemical trajectory, previous treatment, organ vulnerability and access to trials or subsequent clone-directed therapy.

Key points

AL amyloidosis is a plasma-cell disorder in which misfolded monoclonal light chains deposit as amyloid and damage organs; a small clone can cause lethal disease.
Think AL in otherwise unexplained HFpEF or ventricular thickening, nephrotic proteinuria, peripheral or autonomic neuropathy, macroglossia, periorbital purpura, hepatomegaly or multisystem disease.
Diagnosis requires Congo-red-positive tissue and definitive amyloid typing; laser microdissection with mass spectrometry is the reference standard when available.
Never infer AL solely from a monoclonal band: older patients may have both MGUS and transthyretin cardiac amyloid, which requires completely different therapy.
NICE-supported first-line treatment for newly diagnosed systemic AL is daratumumab plus bortezomib, cyclophosphamide and dexamethasone, individualised for cardiac stage, frailty and organ function.
Daratumumab 1,800 mg subcutaneously is given weekly for eight weeks, every two weeks through week 24, then every four weeks, stopping by 24 cycles under NICE TA959.
Supportive care is active treatment: cautious diuresis, salt review, blood-pressure protection, arrhythmia management, renal and nutritional care can determine whether clone therapy is tolerated.
ACE inhibitors, ARBs, beta blockers and vasodilators are often poorly tolerated in cardiac AL; use only for a clear indication with specialist titration rather than by routine heart-failure habit.
Assess haematological response with involved free light chain or dFLC and assess cardiac and renal response separately; organ improvement lags behind clone suppression.
Urgent specialist assessment is required for syncope, hypotension, arrhythmia, rapidly worsening oedema, acute kidney injury or major bleeding.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Amyloidogenic plasma-cell clone

A usually small bone-marrow plasma-cell clone produces structurally unstable immunoglobulin light chains, most often lambda, that misfold and aggregate in tissues.

Associated plasma-cell disorders

AL can occur with MGUS-sized clones, overt myeloma or another clonal B-cell disorder; organ toxicity depends on protein biology rather than paraprotein concentration.

Acquired clonal disease

The disorder is acquired and incidence rises with age; inherited transthyretin and inflammatory AA amyloidoses are separate aetiologies requiring different treatment.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Light-chain misfolding
Unstable variable-region sequences form oligomers and beta-pleated-sheet fibrils; both circulating precursors and deposits injure cells and extracellular architecture.
2
Cardiac infiltration and toxicity
Myocardial deposition and direct light-chain toxicity produce stiff ventricles, impaired longitudinal function, conduction disease, arrhythmia and exceptionally preload-sensitive heart failure.
3
Glomerular and vascular deposition
Renal amyloid commonly disrupts glomerular filtration barriers, causing albumin-predominant proteinuria and nephrotic syndrome, while vascular or interstitial disease can reduce filtration.
4
Multisystem deposition
Amyloid in peripheral and autonomic nerves, liver, gut, soft tissue and vessels causes neuropathy, dysmotility, hepatomegaly, macroglossia, purpura and bleeding.
5
Treatment response sequence
Rapid suppression of the involved free light chain stops ongoing toxicity; measurable cardiac and renal organ recovery usually follows more slowly than haematological response.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Cardiac pattern

HFpEF, ventricular thickening, impaired longitudinal strain, low voltage, raised biomarkers, hypotension or arrhythmia suggests cardiac amyloid.

Renal pattern

Albumin-predominant proteinuria, nephrotic oedema and declining filtration can be the first manifestation despite a small circulating clone.

Neurological pattern

Painful length-dependent neuropathy with marked postural hypotension, gut dysmotility or erectile and bladder dysfunction suggests amyloid autonomic involvement.

Soft-tissue pattern

Macroglossia, periorbital purpura, carpal tunnel syndrome and shoulder-pad thickening are uncommon but high-specificity clues for systemic AL.

Multisystem mismatch

Unexplained disease across heart, kidney, nerves, liver or gut should trigger one unifying amyloid assessment rather than parallel organ labels.

Red flags requiring action

Heart failure with preserved or mildly reduced ejection fraction, increased ventricular wall thickness, low-voltage ECG, hypotension or unexplained troponin elevation requires urgent amyloid evaluation.
Nephrotic proteinuria, falling eGFR or albumin with a monoclonal protein can represent renal AL despite a small marrow clone and normal calcium.
Macroglossia, periorbital purpura, bilateral carpal tunnel syndrome, autonomic neuropathy or unexplained bruising are high-value multisystem clues.
A monoclonal protein in suspected cardiac amyloid does not prove AL; obtain definitive fibril typing because transthyretin amyloid can coexist with MGUS.
Syncope, ventricular arrhythmia, severe postural hypotension or rapidly worsening congestion indicates high early mortality risk and needs same-day specialist review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: complete monoclonal screenFirst stepFirst line
Why
Find a small plasma-cell clone with maximum non-invasive sensitivity.
Interpretation and limitations
Use SPEP, serum and urine immunofixation and serum free light chains together; interpret the ratio with kidney function and pursue tissue typing rather than assuming causation.
02
Confirmatory: Congo-red-positive biopsyConfirmatory
Why
Demonstrate amyloid deposits in surrogate or affected tissue.
Interpretation and limitations
Fat aspirate plus marrow is low risk but imperfectly sensitive; biopsy the affected organ if both are negative and suspicion remains clinically important.
03
Reference standard: proteomic fibril typingReference standard
Why
Identify the deposited precursor protein and prevent inappropriate chemotherapy.
Interpretation and limitations
Laser microdissection with mass spectrometry distinguishes AL from ATTR, AA and hereditary forms; do not substitute the mere presence of MGUS.
04
Cardiac staging panel
Why
Define involvement, immediate risk and a response baseline.
Interpretation and limitations
Combine ECG, echocardiographic strain, troponin, NT-proBNP and dFLC; cardiac MRI supports infiltration, while biomarker confounders need clinical interpretation.
05
Organ and clone characterisation
Why
Map disease burden and select safe clone-directed treatment.
Interpretation and limitations
Use marrow flow and FISH, renal and urine measurements, liver tests, neurological assessment, coagulation and targeted imaging or biopsy according to symptoms.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Transthyretin cardiac amyloidosis

Wild-type or variant transthyretin causes cardiac and neurological amyloid; an incidental MGUS is common, so mass-spectrometric typing prevents dangerous misclassification.

Hypertrophic or hypertensive heart disease

Ventricular thickening may reflect sarcomeric hypertrophy, hypertension or aortic stenosis, but discordant voltage, strain pattern and multisystem clues favour amyloid.

Diabetic or other renal disease

Diabetes, membranous nephropathy and other glomerulopathies cause proteinuria; renal biopsy establishes whether monoclonal deposits are responsible when uncertainty changes treatment.

POEMS syndrome

Neuropathy plus a lambda clone can suggest POEMS, but osteosclerotic lesions, raised VEGF, organomegaly and endocrinopathy distinguish it from AL.

Other systemic amyloidoses

AA, hereditary fibrinogen, apolipoprotein and gelsolin amyloidoses require proteomic typing and clinical context because chemotherapy would not treat their precursor protein.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected systemic ALScreen clone and organs in parallelFirst stepCardiac, renal, neurological, soft-tissue or multisystem clues suggest amyloid.

1Send serum electrophoresis, serum and urine immunofixation, free light chains and comprehensive cardiac, renal and liver baseline tests.
2Arrange fat and marrow sampling or affected-organ biopsy without allowing a small or absent M-spike to delay investigation.
3Refer early to the amyloidosis service for fibril typing, organ staging and a coordinated treatment decision.

02Amyloid demonstratedType before treatingCongo red confirms amyloid in any sampled tissue.

1Obtain proteomic mass-spectrometric typing through an expert laboratory whenever available.
2Correlate the typed precursor with marrow clone, cardiac imaging and hereditary evaluation rather than inferring type from age or MGUS.
3Start AL-directed therapy only after the diagnosis is secure, except when an expert team manages an immediately life-threatening time-critical pathway.

03Newly diagnosed systemic ALSuppress the light chain rapidlyAL typing, organ involvement and plasma-cell clone are established.

1Assess cardiac stage, blood pressure, neuropathy, renal function, frailty, infection and reproductive considerations before treatment.
2Use NICE-supported daratumumab-bortezomib-cyclophosphamide-dexamethasone with exact centre dosing and early attenuation for vulnerable physiology.
3Measure clonal response early and intensify expert review if the involved light chain does not fall promptly.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

First-line clone suppression for newly diagnosed systemic AL under NICE TA959.

Daratumumab plus VCd

NICE-supported initial therapy uses 28-day cycles. Give daratumumab 1,800 mg subcutaneously weekly in cycles 1–2, every two weeks in cycles 3–6, then every four weeks; stop by 24 cycles. Give exact centre-protocol bortezomib, cyclophosphamide and dexamethasone for six cycles.

Obtain group, screen and extended phenotype or genotype before daratumumab; screen hepatitis B, give required premedication and infection prophylaxis, and monitor reactions and cytopenia. Reduce partner intensity for advanced cardiac disease, frailty, neuropathy, hepatic or renal dysfunction. Apply cyclophosphamide reproductive counselling.

Rapid proteasome-inhibitor suppression of light-chain production.

Bortezomib

A commonly used AL schedule is 1.3 mg/m² subcutaneously on days 1, 8, 15 and 22 of each 28-day cycle for six cycles within VCd; use the authorised amyloid centre protocol for timing and dose modifications.

Assess baseline peripheral and autonomic neuropathy, blood pressure, platelet count and hepatic function. Hold and reduce for neuropathic pain or significant toxicity. Give antiviral prophylaxis against zoster. No routine starting reduction is required solely for renal failure, but coordinate administration around dialysis.

Alkylating partner in first-line VCd to deepen plasma-cell clone suppression.

Cyclophosphamide

A common NHS AL protocol gives 500 mg orally on days 1, 8, 15 and 22 of each 28-day cycle for six cycles; use the centre protocol and reduce for substantial renal impairment or cytopenia.

Monitor FBC, renal function, nausea, infection and haemorrhagic cystitis risk. Encourage appropriate hydration without overloading cardiac AL. Discuss fertility preservation before treatment and use effective contraception during and after therapy for the medicine-specific interval.

Plasma-cell cytotoxic and daratumumab premedication component.

Dexamethasone

One UK AL protocol gives 20 mg orally on days 1, 2, 8, 9, 15, 16, 22 and 23 during cycles 1–6, incorporating pre-daratumumab doses; reduce early for age over 75, low body weight, diabetes, cardiac instability or prior intolerance.

Monitor fluid retention, supine and standing blood pressure, glucose, mood, sleep, muscle weakness, dyspepsia and infection. Steroid-induced volume expansion can destabilise cardiac AL, so a lower schedule may be safer than retrospective rescue after decompensation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cardiac failure and sudden death

Restrictive haemodynamics, conduction disease and ventricular arrhythmia cause congestion, syncope and sudden death; advanced cardiac stage dominates early prognosis.

Nephrotic syndrome and kidney failure

Heavy albumin loss causes oedema, thrombosis and infection risk, while progressive filtration loss may require dialysis despite successful clonal control.

Autonomic and peripheral neuropathy

Painful length-dependent neuropathy, orthostatic hypotension, bladder dysfunction and gut dysmotility impair nutrition, mobility and tolerance of otherwise useful medicines.

Bleeding and thrombosis

Vascular fragility, acquired factor X deficiency and platelet dysfunction increase bleeding, while nephrosis, atrial arrhythmia and immobility also create thrombotic risk.

Treatment-related harm

Daratumumab reactions and transfusion interference, bortezomib neuropathy, steroid fluid retention and infection require anticipatory monitoring in physiologically fragile patients.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure involved and uninvolved free light chains, dFLC, SPEP or immunofixation and quantitative immunoglobulins at each early treatment assessment using the same laboratory method.
Track NT-proBNP, troponin, symptoms, rhythm, weight and diuretic requirement, recognising renal function and atrial fibrillation as biomarker confounders.
Track eGFR, creatinine, albumin and quantified proteinuria; renal response can lag and falling albumin may worsen oedema despite clonal improvement.
Before and during VCd monitor FBC, renal, liver, glucose, blood pressure, neuropathy, infection and treatment-specific toxicity; screen hepatitis B before daratumumab.
Ensure the transfusion laboratory and patient know about daratumumab interference for up to six months after treatment, with baseline phenotype or genotype available.
Reassess organ involvement and supportive-care goals whenever clonal response is inadequate, biomarkers worsen or treatment tolerance declines.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Clone size misleads

A tiny clone can secrete a highly amyloidogenic light chain and cause advanced cardiac disease; tumour burden and organ toxicity are not interchangeable.

Type the tissue

Finding MGUS beside cardiac amyloid does not establish AL. Proteomic typing prevents toxic plasma-cell treatment for transthyretin disease.

Voltage-thickness discordance

Increased ventricular wall thickness with relatively low ECG voltage is a useful clue, although normal voltage does not exclude cardiac amyloid.

Response clocks differ

Free light chains can fall within days or weeks, whereas cardiac and renal recovery takes months; judge both domains separately.

Support determines delivery

Meticulous diuresis, blood-pressure protection, infection control and nutrition often determine whether a patient can receive enough clone-directed treatment.

Transfusion preparation matters

Anti-CD38 treatment masks compatibility testing; pre-treatment phenotype or genotype and an alert card prevent dangerous delays during later emergencies.

11Common pitfallsFrequent interpretation and management errors.

01
Do not reassure because the paraprotein or marrow clone is small when cardiac, renal, neurological or soft-tissue clues are present.
02
Do not label amyloid AL solely because serum immunofixation is positive; obtain definitive fibril typing.
03
Do not exclude AL with serum electrophoresis alone; combine serum and urine immunofixation with free light chains.
04
Do not accept negative fat or marrow sampling as final when affected-organ suspicion remains high and biopsy is feasible.
05
Do not use routine heart-failure vasodilators without considering profound preload dependence and autonomic hypotension.
06
Do not wait for organ biomarkers to improve before recognising an inadequate early free-light-chain response.
07
Do not begin daratumumab without baseline transfusion testing, hepatitis B assessment, reaction prophylaxis and patient identification.
08
Do not overlook ATTR, POEMS, MGRS or hereditary amyloid when phenotype and protein type are discordant.