Amyloidosis
Amyloidosis is a group of disorders characterized by extracellular deposition of misfolded fibrillar proteins (amyloid) in various tissues and organs, leading to progressive organ dysfunction.
Amyloidosis
Amyloidosis is a group of disorders characterised by the extracellular deposition of insoluble fibrillar proteins (amyloid fibrils) in organs and tissues, leading to progressive organ dysfunction through pressure atrophy of adjacent cells [1][2].
Let's break down the name:
- Amyloid → from Latin amylum ("starch") + Greek -eidos ("resemblance"). Rudolf Virchow coined the term in 1854 because the deposits stained blue with iodine, resembling starch. In reality, amyloid is protein, not carbohydrate — the name is a historical misnomer.
- -osis → a condition or process.
So "amyloidosis" literally means "a condition of starch-like deposits," but what it really means is: misfolded proteins aggregate into β-pleated sheet fibrils that deposit extracellularly and destroy organs.
Core Concept – What Makes a Protein 'Amyloid'?
All amyloid fibrils, regardless of the precursor protein, share a common structural motif: cross-β-pleated sheet conformation. This is what gives them their characteristic staining properties (Congo red → apple-green birefringence under polarised light). The precursor protein determines the type of amyloidosis and therefore the clinical phenotype, but the final common pathway is always misfolded protein → β-sheet aggregation → extracellular deposition → organ damage.
Key mechanistic points:
- Amyloid does NOT evoke a significant inflammatory response — it causes damage primarily by mechanical disruption and pressure atrophy of parenchymal cells [2]. This is why amyloid-laden organs enlarge silently before function fails.
- All amyloid deposits contain three components: (1) the fibrillar protein itself (~95%), (2) serum amyloid P component (SAP) — a normal plasma glycoprotein that stabilises the fibrils, and (3) glycosaminoglycans (heparan sulfate proteoglycans) that help scaffold the deposits.
2. Epidemiology
- AL (primary) amyloidosis is the MOST common type of systemic amyloidosis in developed countries [3][2].
- Incidence: approximately 10–14 cases per million person-years (US/UK data).
- Median age at diagnosis: ~65 years. Rare before age 40.
- Slight male predominance (~60–65% male).
- AA (secondary) amyloidosis is more common in developing countries, likely due to a higher burden of chronic infection such as tuberculosis, leprosy and osteomyelitis [3]. In the developed world, AA amyloidosis has declined as these infections are better controlled; the main causes of AA in Western settings are now rheumatoid arthritis, inflammatory bowel disease, and familial Mediterranean fever.
- ATTR amyloidosis (transthyretin-related):
- Wild-type ATTR (ATTRwt), formerly called "senile systemic amyloidosis," is increasingly recognised as a cause of heart failure in elderly men (>75 years). Autopsy studies suggest it is far more common than previously appreciated — amyloid deposits found in up to 25% of hearts in individuals >80 years.
- Hereditary ATTR (ATTRv): prevalence depends on the specific TTR mutation. The Val30Met variant is endemic in Portugal, Sweden, and Japan. The Val122Ile variant is carried by ~3–4% of African Americans.
- In Hong Kong, AL amyloidosis is the most commonly diagnosed systemic form, encountered mainly in the context of plasma cell dyscrasias (MGUS, smouldering myeloma, multiple myeloma).
- AA amyloidosis is seen in patients with chronic inflammatory conditions — notably rheumatoid arthritis and chronic infections (tuberculosis still has a significant burden in HK).
- ATTRwt cardiac amyloidosis is likely under-diagnosed in the elderly HK population. With increasing use of cardiac MRI and bone scintigraphy, more cases are being identified.
- Dialysis-related amyloidosis (Aβ2M) is relevant given HK's significant dialysis population.
| Risk Factor | Type of Amyloidosis | Mechanism |
|---|---|---|
| Age >60 | AL, ATTRwt | Clonal plasma cell disorders increase with age; wild-type TTR misfolding accumulates over decades |
| Plasma cell dyscrasia (MGUS, MM) | AL | Overproduction of monoclonal light chains (usually λ) that misfold |
| Chronic inflammatory disease (RA, IBD, FMF, chronic infections) | AA | Persistent elevation of serum amyloid A (SAA), an acute-phase reactant, provides substrate for AA fibril formation |
| Long-term haemodialysis (>8–10 years) | Aβ2M | β2-microglobulin is normally cleared by the kidney; dialysis membranes clear it poorly → accumulation |
| TTR gene mutations | ATTRv (hereditary) | Destabilising mutations in transthyretin make the protein prone to misfolding |
| Family history | ATTRv, AA (if FMF) | Autosomal dominant TTR mutations; MEFV mutations in FMF |
| African American descent | ATTRv (Val122Ile) | 3–4% carrier rate of the Val122Ile TTR mutation |
4. Anatomy & Function of Key Target Organs
Understanding why specific organs are affected requires knowing the anatomy of the extracellular compartment where amyloid deposits:
- The glomerular basement membrane (GBM) and mesangium are classic sites of amyloid deposition (AL and AA).
- Amyloid deposits in the glomerulus disrupt the filtration barrier → massive proteinuria (nephrotic syndrome).
- Tubular and vascular deposition also occur, contributing to renal failure.
- Amyloid infiltrates the myocardial interstitium between cardiomyocytes → walls become stiff and non-compliant → restrictive cardiomyopathy (impaired diastolic filling with preserved or mildly reduced systolic function until late).
- Deposits in the conduction system → arrhythmias, heart block.
- Deposits in coronary microvasculature → microvascular ischaemia.
- Peripheral nerves: amyloid deposits in the endoneurium and vasa nervorum → axonal degeneration → length-dependent sensorimotor neuropathy (starts distally).
- Autonomic nerves: deposits disrupt autonomic ganglia and nerve fibres → autonomic neuropathy (orthostatic hypotension, GI dysmotility, bladder dysfunction, erectile dysfunction).
- Carpal tunnel: amyloid deposition in the flexor retinaculum → carpal tunnel syndrome (often bilateral, can precede systemic diagnosis by years — this is a clinical pearl for ATTR amyloidosis).
- Deposits in the muscularis propria and myenteric (Auerbach's) plexus → dysmotility, pseudo-obstruction.
- Mucosal and submucosal deposits → malabsorption, GI bleeding (vascular fragility).
- Amyloid in the space of Disse (hepatic sinusoidal space between hepatocytes and sinusoidal endothelium) → hepatomegaly, mild cholestatic LFT derangement.
- Splenic deposits → splenomegaly.
- Tongue: infiltration of lingual muscles → macroglossia (pathognomonic of AL amyloidosis — AA does NOT cause macroglossia).
- Skin and subcutaneous tissue: deposits cause waxy thickening, purpura (periorbital ecchymoses, "pinch purpura" from vascular fragility).
5. Etiology and Pathophysiology
All types of amyloidosis share the same fundamental mechanism:
Two mechanisms by which amyloid damages tissues:
- Mechanical disruption: fibrils physically displace and compress parenchymal cells → pressure atrophy (this is the dominant mechanism for most organ damage).
- Direct cytotoxicity: soluble pre-fibrillar oligomers (especially in AL) can be directly toxic to cells, particularly cardiomyocytes — this is why AL cardiac amyloidosis has a worse prognosis than ATTR cardiac amyloidosis despite often having less amyloid bulk.
5.2 Specific Types
AL most common type of systemic amyloidosis [4]
- Precursor protein: Monoclonal immunoglobulin free light chains (usually λ > κ, ~3:1 ratio — this is the opposite of normal serum light chain distribution which is κ-predominant).
- Source: Clonal plasma cells in the bone marrow. These are the same cells that cause multiple myeloma, but in AL amyloidosis, the clone is usually small (often <10% BM plasma cells).
- One of the plasma cell dyscrasias, distinct from myeloma → but also some relationship, with AL amyloidosis possibly arising as a complication of myeloma in ~10% of cases [4].
Relationship to the Plasma Cell Dyscrasia Spectrum:
AL amyloidosis is a differential diagnosis of MGUS — especially if the patient has suggestive symptoms [5][1]. This is a critical clinical point: a patient labelled as "MGUS" who develops nephrotic syndrome, cardiomyopathy, or neuropathy must be evaluated for AL amyloidosis. The paraprotein level may be small, but the light chains are inherently "amyloidogenic" (prone to misfolding).
The pathophysiology:
- A clonal plasma cell population (may be tiny — even <5% BM involvement) produces excess monoclonal free light chains.
- These light chains have an inherent propensity to misfold into β-pleated sheet structure (this depends on the specific variable region sequence of the light chain — some sequences are more "amyloidogenic" than others).
- The misfolded light chains polymerise into fibrils and deposit in extracellular spaces of target organs.
- Organ tropism depends on the specific light chain variable region: some target the heart, some the kidneys, some the nerves.
- In addition to mechanical disruption, soluble light chain oligomers are directly cardiotoxic — they increase oxidative stress and cause cardiomyocyte apoptosis. This explains why cardiac AL amyloidosis can be rapidly fatal even with relatively modest amyloid burden.
Organs affected (in order of frequency): Kidney (most common), Heart, Liver, Soft tissue (tongue, skin), Peripheral/autonomic nerves, GI tract.
- Precursor protein: Serum amyloid A (SAA) — an acute-phase reactant produced by the liver in response to IL-1, IL-6, and TNF-α during inflammation.
- Cause: Any condition causing chronic, sustained inflammation → persistently elevated SAA → SAA fragments are cleaved by macrophages into AA protein → AA fibrils deposit in tissues.
- Common causes in HK:
- Rheumatoid arthritis (most common cause in developed countries)
- Inflammatory bowel disease (Crohn's > UC)
- Chronic infections: tuberculosis (important in HK), bronchiectasis, osteomyelitis, chronic abscesses
- Familial Mediterranean fever (FMF) — less common in HK but important globally
- Ankylosing spondylitis
- Castleman disease
Organs affected: Kidney (dominant — nearly always presents with nephrotic syndrome), Liver, Spleen, Adrenals. AA amyloidosis does NOT typically affect the heart or peripheral nerves (important distinguishing feature from AL).
Key pathophysiology point: If you can control the underlying inflammation and bring SAA levels to normal, AA amyloid deposits can actually regress — making this the most "reversible" form of systemic amyloidosis.
- Precursor protein: Transthyretin (TTR) — a transport protein for thyroxine (T4) and retinol-binding protein, produced mainly by the liver.
- Name etymology: Transports Thyroxine and Retinol → "Transthyretin."
- TTR is normally a homotetramer (four identical subunits). Amyloidosis occurs when the tetramer dissociates into monomers that misfold and aggregate.
Two subtypes:
| Feature | ATTRv (Variant/Hereditary) | ATTRwt (Wild-type/Senile) |
|---|---|---|
| Cause | Point mutations in TTR gene (>150 known mutations) destabilise the tetramer | Age-related misfolding of normal TTR protein |
| Inheritance | Autosomal dominant | Not inherited (sporadic) |
| Age of onset | 30–70 years (depending on mutation) | >65–70 years (predominantly elderly men) |
| Organ tropism | Peripheral + autonomic neuropathy (Val30Met), cardiomyopathy (Val122Ile, Thr60Ala) | Predominantly cardiac (restrictive CMP), carpal tunnel syndrome |
| Epidemiology | Endemic in Portugal, Sweden, Japan; Val122Ile in 3–4% African Americans | Increasingly recognised; autopsy prevalence up to 25% in >80y |
Senile systemic amyloidosis: transthyretin accumulation [2].
- Precursor protein: β2-microglobulin — a component of MHC class I molecules, present on the surface of all nucleated cells.
- Mechanism: β2-microglobulin is normally filtered and catabolised by the kidney. In end-stage renal disease, it accumulates because:
- The kidneys cannot clear it.
- Conventional dialysis membranes (especially older cuprophane membranes) are poor at removing β2-microglobulin (MW ~11.8 kDa — too large for some membranes).
- Dialysis itself may stimulate β2-microglobulin production via chronic inflammatory activation.
- Onset: typically after >8–10 years of haemodialysis. Less common with high-flux membranes and essentially absent after successful renal transplantation (the transplanted kidney clears β2-microglobulin).
Dialysis-associated amyloidosis: long-term haemodialysis → β2-microglobulin accumulation [2].
Organs affected: Almost exclusively musculoskeletal — carpal tunnel syndrome (earliest and most common), destructive arthropathy (shoulders, hips, knees), bone cysts, pathological fractures, spondyloarthropathy.
| Type | Precursor Protein | Key Association |
|---|---|---|
| Aβ (Amyloid-β) | Amyloid precursor protein (APP) | Alzheimer's disease — localised cerebral amyloidosis |
| AIAPP | Islet amyloid polypeptide (amylin) | Type 2 diabetes mellitus — localised to pancreatic islets |
| ACal | Calcitonin | Medullary thyroid carcinoma — localised |
| AFib | Fibrinogen Aα-chain | Hereditary renal amyloidosis |
| ALys | Lysozyme | Hereditary systemic amyloidosis |
| AApoAI | Apolipoprotein A-I | Hereditary — renal, hepatic, cardiac |
6. Classification
| Category | Definition | Examples |
|---|---|---|
| Systemic | Multiple organs involved | AL, AA, ATTR, Aβ2M |
| Localised | Confined to a single organ or tissue | Alzheimer's disease [amyloid β], MTC [calcitonin] [2], bladder amyloidosis, tracheobronchial amyloidosis, cutaneous amyloidosis |
The International Society of Amyloidosis (ISA) classifies amyloidosis by the precursor fibril protein using the prefix "A" (for amyloid) followed by the protein abbreviation:
| Abbreviation | Precursor Protein | Type | Main Organs |
|---|---|---|---|
| AL | Immunoglobulin light chain | Systemic (primary) | Kidney, heart, liver, nerve, soft tissue |
| AH | Immunoglobulin heavy chain | Systemic (rare) | Similar to AL |
| AA | Serum amyloid A | Systemic (secondary/reactive) | Kidney, liver, spleen |
| ATTR | Transthyretin (wild-type or variant) | Systemic | Heart, nerve, carpal tunnel |
| Aβ2M | β2-microglobulin | Systemic (dialysis-related) | Musculoskeletal |
| Aβ | Amyloid-β peptide | Localised (cerebral) | Brain |
| AIAPP | Islet amyloid polypeptide | Localised | Pancreatic islets |
AL vs AA vs β2-microglobulin vs transthyretin — these are the four major systemic types to know [4].
| Feature | AL | AA | ATTR (wt + v) | Aβ2M |
|---|---|---|---|---|
| Precursor | Light chain (λ > κ) | Serum amyloid A | Transthyretin | β2-microglobulin |
| Underlying condition | Plasma cell dyscrasia | Chronic inflammation | Age (wt) / mutation (v) | Long-term dialysis |
| Kidney | +++ | +++ | Rare | - |
| Heart | +++ | Rare | +++ | - |
| Nerve | ++ (peripheral + autonomic) | Rare | +++ (ATTRv) | - |
| MSK | + (shoulder pad, CTS) | - | + (CTS) | +++ |
| Macroglossia | Pathognomonic | No | No | No |
| Periorbital purpura | Pathognomonic | No | No | No |
| Liver/Spleen | ++ | ++ | + | - |
7. Clinical Features
7.1 Symptoms (with Pathophysiological Basis)
- Frothy urine / leg swelling → Amyloid deposited in glomeruli disrupts the filtration barrier (podocyte foot process effacement and GBM thickening/disruption) → massive proteinuria → nephrotic syndrome (proteinuria >3.5 g/day, hypoalbuminaemia, oedema, hyperlipidaemia). Kidney (MC): nephrotic syndrome [2].
- Why nephrotic and not nephritic? Because amyloid deposits cause non-inflammatory damage to the GBM — there is no significant glomerular inflammation, no RBC casts. The damage is structural, not immunological.
- Reduced urine output / symptoms of uraemia → Progressive amyloid deposition eventually causes CKD → ESRD.
- Exertional dyspnoea, orthopnoea, PND → Amyloid infiltrates the myocardial interstitium → walls stiffen → restrictive physiology → impaired diastolic filling → pulmonary congestion and elevated filling pressures → congestive heart failure symptoms. CVS: restrictive cardiomyopathy [2].
- Fatigue, exercise intolerance → Reduced cardiac output because the stiff ventricle cannot fill adequately.
- Palpitations → Amyloid deposits in the conduction system → arrhythmias (especially atrial fibrillation, which is very common in cardiac amyloidosis).
- Pre-syncope / syncope → Can be from arrhythmia (heart block, VT), low cardiac output, or autonomic neuropathy causing orthostatic hypotension.
- Dizziness on standing → Autonomic neuropathy (AL, ATTRv) → impaired baroreceptor reflex → orthostatic hypotension.
Amyloidosis affects the whole body … New would be affecting nerves → autonomic neuropathy, postural hypotension caused by amyloidosis [4].
- Numbness, tingling, burning pain in feet/hands → Amyloid deposits in peripheral nerves (endoneurial deposits + vasa nervorum ischaemia) → length-dependent sensorimotor polyneuropathy (starts distally in lower limbs, "stocking-glove" pattern). Pain and temperature sensation affected first (small fibres), then light touch and proprioception (large fibres).
- Carpal tunnel syndrome (wrist pain, hand numbness, thenar wasting) → Amyloid deposits in the flexor retinaculum compress the median nerve. This is an early and often the first manifestation, particularly in ATTR amyloidosis. Bilateral CTS in an elderly patient should raise suspicion for amyloidosis.
- Postural dizziness, early satiety, constipation/diarrhoea alternating, urinary retention, erectile dysfunction → Autonomic neuropathy from amyloid infiltration of autonomic ganglia and nerve fibres.
- Early satiety, nausea, vomiting, abdominal distension → Amyloid deposition in GI tract smooth muscle and myenteric (Auerbach's) plexus → GI dysmotility → intestinal pseudo-obstruction [3].
- Chronic diarrhoea, steatorrhoea → Mucosal infiltration + autonomic neuropathy → malabsorption.
- Haematemesis, melaena → Amyloid in vessel walls → vascular fragility + loss of vasomotor responses to injury → GI bleeding [3].
- Dysphagia, dysphonia → Macroglossia (tongue infiltration, pathognomonic of AL) → difficulty swallowing and altered speech.
- Abdominal fullness / right upper quadrant discomfort → Hepatomegaly from amyloid infiltration of the liver (space of Disse).
- Shoulder pain with visible enlargement → Amyloid infiltration of glenohumeral synovium and periarticular structures → "Shoulder pad" sign — visible enlargement of the anterior shoulder [3]. Almost pathognomonic of AL amyloidosis.
- Joint stiffness, arthralgia → Amyloid arthropathy (AL, Aβ2M in dialysis patients).
- Jaw claudication / difficulty opening mouth → Macroglossia and submandibular infiltration.
- Easy bruising around the eyes → Periorbital ecchymoses ("Raccoon eyes") — purpura in the periorbital distribution, classically elicited by Valsalva manoeuvre, coughing, or proctoscopy [3]. Caused by amyloid deposition in dermal blood vessel walls → vascular fragility.
- Bruising from minimal trauma → Pinch purpura — skin bleeds with minimal trauma (e.g., skin pinch, blood pressure cuff) [3]. Same vascular fragility mechanism.
- Waxy skin thickening, subcutaneous nodules → Direct amyloid infiltration of the dermis and subcutaneous tissue.
- Easy bruising, prolonged bleeding → Factor X deficiency in AL amyloidosis [3]. Factor X binds to amyloid fibrils and is adsorbed/sequestered out of the circulation → acquired coagulation factor deficiency. Additionally, vascular amyloid infiltration contributes to bleeding tendency.
- Dyspnoea (not solely cardiac) → Pleural effusion (often bilateral, recurrent, and sometimes the presenting feature of AL amyloidosis) [3]. Also tracheobronchial infiltration can cause airway narrowing.
- Weight loss, fatigue, anorexia → Multi-organ involvement, malabsorption, and heart failure collectively cause cachexia.
| System | Sign | Pathophysiological Basis |
|---|---|---|
| General | Macroglossia | Amyloid infiltration of tongue muscles; pathognomonic of AL (does not occur in AA or ATTR) [2][3] |
| Weight loss, cachexia | Multi-organ disease, malabsorption, reduced oral intake | |
| Skin | Periorbital ecchymoses ("Raccoon eyes") | Amyloid in dermal vessels → vascular fragility; classic for AL [3] |
| Pinch purpura | Same mechanism; skin bleeds with minimal trauma [3] | |
| Waxy thickening, subcutaneous nodules/plaques | Direct dermal/subcutaneous amyloid infiltration [3] | |
| Nail dystrophy | Amyloid deposition in nail bed | |
| Cardiovascular | Elevated JVP (non-collapsing / Kussmaul sign) | Restrictive physiology → impaired RV filling → elevated RA pressure; RV cannot accommodate increased venous return with inspiration → Kussmaul sign |
| Hepatojugular reflux | Poor RV compliance | |
| S3 gallop | Rapid ventricular filling halted by stiff ventricle | |
| Low-volume pulse | Reduced stroke volume | |
| Peripheral oedema | Right heart failure → elevated systemic venous pressure | |
| Ascites | Hepatic venous congestion + possible hepatic amyloid infiltration | |
| Neurological | Stocking-glove sensory loss | Length-dependent peripheral neuropathy from endoneurial amyloid |
| Orthostatic hypotension (>20/10 mmHg drop) | Autonomic neuropathy → impaired baroreceptor-mediated vasoconstriction | |
| Reduced reflexes (ankle > knee) | Peripheral neuropathy | |
| Thenar/hypothenar wasting | Carpal tunnel syndrome → median nerve compression | |
| Abdominal | Hepatomegaly | Amyloid in space of Disse → massive, firm, non-tender liver enlargement [2] |
| Splenomegaly | Splenic amyloid infiltration [2] | |
| Pseudohypertrophy of muscles | Amyloid deposition between muscle fibres mimics muscular enlargement [2] | |
| Musculoskeletal | "Shoulder pad" sign | Periarticular amyloid infiltration around shoulder [3] |
| Bilateral carpal tunnel (Tinel's/Phalen's positive) | Flexor retinaculum amyloid deposition → median nerve compression | |
| Respiratory | Reduced breath sounds / stony dull percussion at bases | Pleural effusion |
When to Think of Amyloidosis
Think of amyloidosis when you see unexplained multi-system disease that doesn't fit a single common diagnosis:
- Heart failure with preserved EF + thick walls but low voltage on ECG (voltage-mass mismatch — the walls are thick on echo but the ECG shows low voltage because amyloid is electrically inert, unlike true LVH where voltage is high)
- Nephrotic syndrome in an older adult without diabetes
- Bilateral carpal tunnel syndrome (especially if preceding cardiac symptoms by years)
- Peripheral neuropathy + cardiomyopathy (think ATTR)
- Macroglossia + periorbital purpura (virtually diagnostic of AL)
- Unexplained autonomic neuropathy (orthostatic hypotension, GI dysmotility)
- Any patient with known MGUS or myeloma who develops organ dysfunction
This deserves special emphasis because it is a classic exam point:
ECG: low voltage (amyloidosis) → those toxic deposits + effusion dampens the voltage [6].
In hypertrophic cardiomyopathy, thick walls produce high voltage on ECG. In cardiac amyloidosis, despite the walls being thick on echocardiography, the ECG shows low voltage (limb leads <5mm, precordial leads <10mm). Why?
- The "thickening" in amyloidosis is NOT due to myocyte hypertrophy — it is due to amyloid protein deposition in the interstitium. Amyloid is electrically inert (it doesn't generate electrical activity).
- The myocytes themselves are actually being compressed and lost (pressure atrophy).
- Additionally, pericardial effusion (common in cardiac amyloidosis) further attenuates the voltage.
This voltage-mass mismatch (low ECG voltage + increased wall thickness on echo) is a hallmark of cardiac amyloidosis and distinguishes it from true LVH.
Other ECG findings in cardiac amyloidosis:
- Pseudo-infarct pattern: Q waves in anterior leads (from amyloid replacing myocardium, not from true infarction)
- Conduction abnormalities: AV block, bundle branch block (amyloid in conduction system)
- Atrial fibrillation: very common due to atrial amyloid infiltration
Restrictive cardiomyopathy — Aetiology: Myocardial: amyloidosis (most common) [7].
This is the single most important cause of restrictive cardiomyopathy. The clinical distinction from constrictive pericarditis is a classic exam question:
| Feature | Restrictive CMP (Amyloidosis) | Constrictive Pericarditis |
|---|---|---|
| History | Infiltrative disease | Previous pericarditis |
| Auscultation | S3 | Pericardial knock (slightly before S3) |
| ECG | BBB, LVH/RVH, pathological Q wave, AV blocks | Low voltage, isolated repolarisation abnormalities |
| CXR | Normal pericardium | Calcified pericardium |
| Echo | Ventricular wall thickening, abnormal echotexture | Increased pericardial thickness |
| BNP | Elevated (due to myocardial stretching) | Normal or mildly elevated |
| Definitive | Endomyocardial biopsy | Pericardial biopsy |
Congo red stain, salmon pink color → indicative of amyloid deposition [4].
- Light microscopy: Amyloid deposits appear as amorphous, eosinophilic, acellular material on H&E staining.
- Congo red stain: The definitive histochemical test. Amyloid stains salmon pink under ordinary light.
- Polarised light microscopy: Congo red-stained amyloid shows apple-green birefringence [2][8]. This is the gold standard for confirming amyloid.
- Thioflavin T: Fluorescent dye that binds amyloid fibrils → bright fluorescence under UV light [8].
- Electron microscopy: non-branching fibrils (7–13 nm diameter) in the extracellular compartment [4]. These are randomly arranged, rigid, non-branching — distinguishing amyloid from collagen (which has a banded periodicity) and from immune complex deposits (which are electron-dense but amorphous).
- Immunohistochemistry / mass spectrometry: Used to type the amyloid (identify the precursor protein — AL vs AA vs ATTR etc.). This is critical because treatment differs entirely based on type.
Diagnosis
A common student mistake: diagnosing "amyloidosis" without typing it. Identifying amyloid is not enough — you MUST determine the type. Treatment for AL (chemotherapy targeting plasma cells) is completely different from AA (treat underlying inflammation) and ATTR (tafamidis, liver transplant). Using chemotherapy in ATTR amyloidosis would be harmful and futile. Always send tissue for mass spectrometry or immunohistochemistry for typing.
- Abdominal fat pad aspiration: Minimally invasive screening test. Sensitivity ~70–80% for AL, lower for other types. Infiltration of subcutaneous fat is generally asymptomatic but is a convenient site for biopsy [3].
- Rectal biopsy (submucosal vessels): ~75% sensitivity.
- Bone marrow biopsy: Can detect amyloid AND simultaneously assess for underlying plasma cell dyscrasia.
- Affected organ biopsy: Renal biopsy, endomyocardial biopsy, liver biopsy — highest sensitivity but more invasive.
- Renal biopsy for acute renal failure — histopathological diagnosis when there is nephrotic-range proteinuria and suspected amyloidosis [9].
- Endomyocardial biopsy is diagnostic for cardiac amyloidosis when non-invasive tests are equivocal.
Serum Protein Electrophoresis in the Context of Amyloidosis
Indications for serum protein electrophoresis include: suspected AL amyloidosis [10]. When evaluating any patient with suspected amyloidosis, you should order:
- Serum protein electrophoresis (SPEP) + immunofixation
- Serum free light chain assay (κ and λ with ratio)
- 24-hour urine protein electrophoresis (UPEP) + immunofixation
The combination of these three tests detects an abnormal monoclonal protein in >95% of AL amyloidosis cases. An abnormal free light chain ratio is the most sensitive single test.
High Yield Summary
-
Definition: Amyloidosis = extracellular deposition of misfolded protein in β-pleated sheet conformation → organ dysfunction via pressure atrophy (not inflammation).
-
Classification by precursor protein: AL (light chain — most common systemic), AA (serum amyloid A — secondary to chronic inflammation), ATTR (transthyretin — hereditary or wild-type/senile), Aβ2M (β2-microglobulin — dialysis-related).
-
AL amyloidosis: Plasma cell dyscrasia produces amyloidogenic light chains (λ > κ). Can arise from MGUS, SMM, or MM (~10%). Affects kidney (nephrotic syndrome — MC), heart (restrictive CMP), nerves, liver, soft tissues. Macroglossia and periorbital purpura are pathognomonic.
-
AA amyloidosis: Chronic inflammation → persistent SAA elevation → AA fibrils. Mainly affects kidneys. Does NOT cause cardiac or neurological disease. Potentially reversible if inflammation controlled.
-
ATTR amyloidosis: Wild-type (elderly men, cardiac dominant) vs hereditary (TTR mutations, neuropathy ± cardiomyopathy). Bilateral CTS may precede diagnosis by years.
-
Cardiac amyloidosis hallmark: Low voltage on ECG + increased wall thickness on echo = "voltage-mass mismatch." Amyloidosis is the most common cause of restrictive cardiomyopathy.
-
Diagnosis: Congo red stain → apple-green birefringence under polarised light. Must type the amyloid (immunohistochemistry / mass spectrometry) because treatment differs completely by type.
-
Biopsy: Abdominal fat pad aspiration (screening), rectal biopsy, or organ biopsy (definitive). Bone marrow biopsy simultaneously assesses for plasma cell clone in AL.
-
Key labs for AL: SPEP + immunofixation, serum free light chains (κ/λ ratio), UPEP + immunofixation — combination sensitivity >95%.
-
Albumin < 30 is critical in AL amyloidosis → must work fast [4]. Low albumin reflects nephrotic losses or cardiac cachexia and is a poor prognostic marker.
Active Recall - Amyloidosis
[1] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf, p19 (MGUS definition and AL amyloidosis as DDx) [2] Senior notes: Maksim Medicine Notes.pdf, p182 (Amyloidosis overview, types, clinical features, diagnosis) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, p1777–1779 (Clinical manifestation table, epidemiology) [4] Senior notes: Block A - Hematology Data Interpretation.pdf, p1 (AL vs AA vs β2M vs TTR, Congo red stain, autonomic neuropathy, albumin prognostic significance) [5] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf, p12 (MGUS definition, AL amyloidosis as DDx) [6] Senior notes: Block A - Inherited Cardiac conditions.pdf, p13 (ECG low voltage in amyloidosis) [7] Senior notes: Ryan Ho Cardiology.pdf, p170 (Restrictive cardiomyopathy, amyloidosis as most common cause, comparison with constrictive pericarditis) [8] Senior notes: Block A - Deterioration of eyesight in a diabetic patient_ diabetic complications.pdf, p28 (Congo red staining, apple-green birefringence, thioflavin T) [9] Senior notes: Block A – Nephrology Data Interpretation.pdf, p5 (Renal biopsy for amyloidosis, myeloma kidney pathophysiology) [10] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf, p27 (Indications for SPEP including suspected AL amyloidosis)
Differential Diagnosis of Amyloidosis
Amyloidosis is a great mimicker. Because amyloid can deposit in virtually any organ, the initial presentation is often organ-specific — and the real clinical challenge is recognising that the organ problem is caused by amyloidosis rather than a more common disease. The differential diagnosis therefore needs to be approached from two complementary angles:
- "I suspect amyloidosis — what else could mimic it?" (i.e., differentiating amyloidosis from conditions that present similarly)
- "I have confirmed amyloid — what type is it?" (i.e., differentiating between the types of amyloidosis, because treatment is completely different)
A. Differential Diagnosis by Presenting Syndrome
The key principle: amyloidosis rarely presents as "amyloidosis." It presents as nephrotic syndrome, heart failure, neuropathy, hepatomegaly, or bleeding. Your job is to include amyloidosis in the DDx of these common presentations.
Kidney (MC): nephrotic syndrome [2]. The kidney is the most commonly affected organ in both AL and AA amyloidosis. When a patient — especially one >50 years — presents with heavy proteinuria and nephrotic syndrome, amyloidosis must be on the list.
Differential diagnosis of nephrotic syndrome (non-proliferative glomerular diseases):
| Diagnosis | Key Distinguishing Features | Why It Mimics Amyloidosis |
|---|---|---|
| Diabetic nephropathy | Long history of DM, retinopathy usually present, gradual onset | Both cause heavy proteinuria with non-proliferative histology; both can cause large kidneys initially |
| Membranous nephropathy | Anti-PLA2R antibodies (primary); secondary to HBV, malignancy, drugs | Heavy proteinuria; can co-exist with malignancy (like amyloidosis) |
| Minimal change disease | More common in children; steroid-responsive; selective proteinuria | Heavy proteinuria; normal-appearing glomeruli on LM (but NO amyloid on Congo red) |
| Focal segmental glomerulosclerosis (FSGS) | May be primary or secondary (HIV, reflux, obesity) | Heavy proteinuria; segmental sclerosis on biopsy |
| Light and heavy chain deposition disease | Monoclonal gammopathy present; nodular glomerulosclerosis on biopsy; Congo red NEGATIVE | Both are complications of monoclonal gammopathy; BUT LCDD deposits are granular (NOT fibrillar), Congo red negative [9][11] |
| Myeloma cast nephropathy | AKI with bland urine sediment; tubular casts on biopsy; usually presents with AKI rather than nephrotic syndrome | Both associated with plasma cell dyscrasia; but cast nephropathy causes AKI by tubular obstruction, not glomerular damage [9][11] |
| Lupus nephritis | Young female, multi-system features, anti-dsDNA, low C3/C4 | Proteinuria + multi-system disease |
Amyloidosis is classified as a secondary, non-proliferative glomerular disease — it causes nephrotic syndrome without significant glomerular cellularity increase [12][13].
Renal diseases associated with monoclonal light chains include: Amyloidosis (AL type), Light chain deposition disease, Light chain proximal tubulopathy, Type I cryoglobulinaemic glomerulonephritis [11]. This is an important DDx cluster — all are complications of monoclonal gammopathy but have different pathology and treatment.
High Yield — DDx of Nephrotic Syndrome with Monoclonal Gammopathy
Differential diagnosis includes: Light and heavy chain deposition disease – complication of monoclonal gammopathy; Amyloidosis; NSAID-induced AKI [9]. When you find a monoclonal band AND nephrotic-range proteinuria, you must differentiate between these entities. The renal biopsy is the arbiter:
- AL amyloidosis: Congo red positive, apple-green birefringence, non-branching fibrils on EM
- LCDD: Congo red NEGATIVE, granular punctate deposits on EM (not fibrillar), nodular glomerulosclerosis
- Cast nephropathy: Tubular casts with giant cell reaction, lambda/kappa light chain restriction on IHC
Restrictive cardiomyopathy — Aetiology: Myocardial: amyloidosis (most common), idiopathic, scleroderma, sarcoidosis, haemochromatosis, glycogen storage disease, Gaucher's disease [7].
| Diagnosis | Key Distinguishing Features | Why It Mimics Cardiac Amyloidosis |
|---|---|---|
| Constrictive pericarditis | History of pericarditis/TB/radiation; calcified pericardium on CXR; pericardial knock; normal wall thickness on echo; ↑pericardial thickness | Both cause diastolic HF with elevated filling pressures, Kussmaul sign [7] |
| Hypertrophic cardiomyopathy (HCM) | HIGH voltage on ECG (vs LOW in amyloidosis); asymmetric septal hypertrophy; LVOTO; family history of sudden death | Both cause thick LV walls on echo; but HCM has HIGH ECG voltage (true myocyte hypertrophy) vs LOW voltage in amyloidosis (electrically inert amyloid) [6] |
| Hypertensive heart disease | Long history of hypertension; concentric LVH; ECG shows LVH voltage criteria | Thick walls on echo; but hypertensive LVH shows high ECG voltage and responds to BP control |
| Sarcoidosis (cardiac) | AV block, lymphadenopathy, ↑ACE; FDG-PET positive; patchy LGE on CMR | Infiltrative cardiomyopathy; but sarcoid shows non-caseating granulomas (not amyloid) |
| Haemochromatosis | Elevated ferritin/transferrin saturation; bronze skin; DM; liver cirrhosis; T2* MRI shows iron loading | Restrictive physiology; but iron deposition has distinct T2* MRI signal |
| Fabry disease | X-linked; angiokeratomas, acroparesthesias, cornea verticillata; low α-galactosidase A | Concentric LVH; but genetic + enzyme assay distinguishes |
| Endomyocardial fibrosis | Tropical regions; eosinophilia; apical obliteration | Restrictive physiology |
Major d/dx of restrictive cardiomyopathy = constrictive pericarditis → similar clinical and haemodynamic features [7]. The table distinguishing these two is a classic exam question (see Part 1 for the comparison table).
Patient presents with DCM with small QRS complex voltages on ECG, with a very thickened wall on echo → Classical for amyloidosis [6]. This "voltage-mass mismatch" should immediately trigger further workup.
Amyloidosis: sensorimotor + autonomic involvement; a/w plasma cell dyscrasia or chronic inflammation; a/w renal disease and cardiomyopathy [14].
| Diagnosis | Key Distinguishing Features |
|---|---|
| Diabetic neuropathy | Most common cause; history of long-standing DM; distal symmetric sensorimotor ± autonomic |
| CIDP | Chronic demyelinating; proximal + distal weakness; palpable thickened nerves; NCS shows demyelinating pattern; treatable with IVIg/steroids |
| Paraproteinaemic neuropathy (non-amyloid) | MGUS-associated; often IgM anti-MAG; predominantly sensory with ataxia; demyelinating on NCS |
| Hereditary neuropathies (CMT) | Young onset; family history; pes cavus; slow progression |
| B12 deficiency | Megaloblastic anaemia; subacute combined degeneration of cord (dorsal columns + corticospinal tracts) |
| Uraemic neuropathy | CKD with Cr >300; improves with dialysis |
| Vasculitic neuropathy | Mononeuropathy multiplex → confluent; associated systemic vasculitis features |
| AL amyloid neuropathy | Distinguished from the above by: multi-system involvement (cardiac, renal, hepatic), monoclonal protein on SPEP/sFLC, and Congo red positive tissue biopsy |
Clinical Pearl — Bilateral Carpal Tunnel Syndrome
Bilateral CTS in an older patient — especially if preceding cardiac symptoms — should raise suspicion for ATTR amyloidosis. The amyloid deposits in the flexor retinaculum years before systemic disease becomes clinically apparent. If a patient has bilateral CTS AND unexplained HFpEF with thick walls, think ATTR.
Differential diagnosis of hepatomegaly — Infiltrative lesions: HCC, metastasis, haematological causes (chronic leukaemia, lymphoma, MPD), infiltration e.g. amyloidosis [15][16].
The liver in amyloidosis is characteristically firm, smooth, massively enlarged, and non-tender — sometimes reaching the pelvis. ALP and GGT are disproportionately elevated compared to transaminases (cholestatic pattern). This is because amyloid deposits in the space of Disse compress bile canaliculi.
Macroglossia is relatively uncommon. When present, the DDx is short:
- AL amyloidosis (pathognomonic in the context of systemic disease)
- Hypothyroidism (myxoedema)
- Acromegaly
- Down syndrome
- Beckwith-Wiedemann syndrome (paediatric)
- Lymphangioma / haemangioma (paediatric)
Mouth: gum bleeding and macroglossia (classical for amyloidosis) [17].
Periorbital ecchymoses and pinch purpura are almost pathognomonic of AL amyloidosis, but the DDx of purpura / bleeding tendency in general includes:
- Thrombocytopenia (ITP, TTP/HUS, BM failure, DIC)
- Coagulation factor deficiency (haemophilia, liver disease, DIC)
- Vascular fragility (scurvy, Ehlers-Danlos, senile purpura)
- AL amyloidosis (acquired Factor X deficiency + vascular amyloid)
Differential diagnosis of a large kidney: Polycystic kidney disease (PKD); Infiltration → amyloidosis [18]. Most causes of CKD produce small kidneys. Finding large kidneys with renal impairment narrows the DDx significantly:
- ADPKD (cystic architecture on imaging)
- Diabetic nephropathy (especially early — kidneys enlarge before shrinking)
- Amyloidosis (homogeneous enlargement from infiltration)
- HIV-associated nephropathy
- Obstructive uropathy (hydronephrosis)
Once amyloid is confirmed histologically (Congo red positive, apple-green birefringence), you must type it — because management is entirely different. This is the second critical DDx exercise.
If suspecting amyloidosis, have to differentiate between the transthyretin, AL/primary (associated with increase in immunoglobulins), AA/secondary type [6].
| Feature | AL | AA | ATTR (wt/v) | Aβ2M |
|---|---|---|---|---|
| Age | ~65y | Any (depends on underlying disease) | >65 (wt); 30-70 (v) | After >8-10y dialysis |
| Underlying condition | Plasma cell dyscrasia (MGUS, MM, WM) | Chronic inflammation (RA, IBD, FMF, TB, chronic infection) | None (wt); TTR mutation (v) | ESRD on dialysis |
| Monoclonal protein | Present (>95% by SPEP + sFLC + UPEP) | Absent | Absent | Absent |
| Kidney | +++ (nephrotic) | +++ (nephrotic) | Rare | - |
| Heart | +++ (RCMP) | Rare | +++ (RCMP) | - |
| Nerve | ++ (sensorimotor + autonomic) | Rare | +++ in ATTRv | - |
| Macroglossia | Pathognomonic | No | No | No |
| Periorbital purpura | Pathognomonic | No | No | No |
| MSK | + (shoulder pad, CTS) | - | + (CTS) | +++ (CTS, arthropathy, bone cysts) |
| Elevated SAA | No | Yes (↑↑) | No | No |
| 99mTc-PYP / DPD scan | Negative (or grade ≤1) | Negative | Strongly positive (grade 2-3) | N/A |
| Biopsy IHC / Mass spec | κ or λ light chain | AA protein | Transthyretin | β2-microglobulin |
Approach to monoclonal gammopathy — look for features of AL amyloidosis: macroglossia, pseudohypertrophy of muscles, periorbital purpura, hepatomegaly, RCMP with HF, peripheral neuropathy, nephrotic syndrome [19].
AL amyloidosis is a DDx of MGUS — especially if the patient has suggestive symptoms [1][5]. A patient with MGUS who develops any of these features must be urgently evaluated for AL amyloidosis. The paraprotein may be small, but the light chains are "amyloidogenic."
Key points in the algorithm:
-
Serum and urine immunofixation and serum free light chain ratio analysis — Primary amyloidosis and light chain deposition disease are associated with a monoclonal gammopathy [20]. This is the first branching point after confirming amyloid.
-
99mTc-PYP scan (technetium pyrophosphate scintigraphy): This is a game-changing non-invasive test for cardiac ATTR amyloidosis. 99m Tc-PYP scan for transthyretin (TTR) amyloidosis [6]. Grade 2-3 uptake (equal to or greater than bone) in the absence of a monoclonal protein is virtually diagnostic of ATTR cardiac amyloidosis, potentially avoiding endomyocardial biopsy.
-
If monoclonal protein is absent AND bone scintigraphy is negative AND there is no chronic inflammatory disease, consider rarer hereditary forms (AFib, ALys, AApoAI) → mass spectrometry of the biopsy specimen is required.
Don't Forget — RA Can Cause BOTH AA Amyloidosis AND Cardiac Disease
Rheumatoid arthritis resulting in cardiac amyloidosis [21]. In a patient with RA who develops heart failure, the DDx includes:
- AA amyloidosis (secondary to chronic inflammation — but AA rarely affects the heart)
- AL amyloidosis (if co-existent MGUS — always check monoclonal protein)
- Drug-related cardiomyopathy (e.g., NSAIDs causing fluid retention)
- Valvular disease (RA-associated)
- Ischaemic heart disease (accelerated atherosclerosis in RA)
The teaching point: AA amyloidosis from RA very rarely causes clinically significant cardiac disease. If a RA patient has cardiac amyloidosis, think AL or ATTR as the amyloid type, not AA.
| Presentation | Top DDx (non-amyloid) | Clue That Points to Amyloidosis |
|---|---|---|
| Nephrotic syndrome, age >50 | Membranous nephropathy, diabetic nephropathy, FSGS | Monoclonal protein on SPEP/sFLC; multi-system involvement; Congo red + biopsy |
| HFpEF with thick walls + low ECG voltage | HCM, hypertensive heart disease, Fabry, sarcoidosis | Voltage-mass mismatch; 99mTc-PYP uptake (ATTR); monoclonal protein (AL) |
| Bilateral CTS + HFpEF in elderly man | Idiopathic CTS + hypertensive heart disease | Consider ATTRwt; 99mTc-PYP scan |
| Painful length-dependent neuropathy + autonomic features | Diabetic neuropathy, CIDP, B12 deficiency | Concurrent cardiac/renal involvement; monoclonal protein (AL); TTR mutation (ATTRv) |
| Massive hepatomegaly + cholestatic LFTs | Metastatic cancer, haematological malignancy | Smooth firm liver; monoclonal protein; Congo red + on liver/fat biopsy |
| Macroglossia | Hypothyroidism, acromegaly | Virtually pathognomonic of AL when combined with systemic features |
| Periorbital purpura | Trauma, vascular fragility | Virtually pathognomonic of AL after Valsalva / coughing |
| MGUS with organ dysfunction | Smouldering myeloma progressing to MM | AL amyloidosis is the most important DDx of MGUS with suggestive symptoms [1][5] |
| Large kidneys + renal failure | ADPKD, diabetic nephropathy, obstructive uropathy | Homogeneous enlargement without cysts; nephrotic-range proteinuria [18] |
| Recurrent bilateral pleural effusions | Heart failure, malignancy, TB, nephrotic syndrome | Exudative or transudative; associated features of multi-system amyloid involvement |
High Yield Summary — Differential Diagnosis of Amyloidosis
-
Think of amyloidosis in the DDx of: nephrotic syndrome (especially age >50 without DM), restrictive cardiomyopathy (especially with low ECG voltage + thick walls), unexplained peripheral/autonomic neuropathy, massive hepatomegaly, macroglossia, periorbital purpura, and bilateral CTS in the elderly.
-
Once amyloid is confirmed, the critical DDx is BETWEEN types: AL vs AA vs ATTR vs Aβ2M. This determines treatment.
-
AL vs LCDD vs cast nephropathy: All are monoclonal light chain-related renal diseases. Congo red positivity distinguishes AL; LCDD is Congo red negative with granular deposits; cast nephropathy shows tubular casts with giant cell reaction.
-
Cardiac amyloidosis vs HCM: Voltage-mass mismatch (low ECG voltage + thick walls) = amyloidosis. High ECG voltage + thick walls = HCM. 99mTc-PYP scan differentiates ATTR from AL.
-
AL amyloidosis is the most important DDx of MGUS — any patient with MGUS developing organ dysfunction must be evaluated for AL amyloidosis.
-
Restrictive CMP vs constrictive pericarditis: History of infiltrative disease, S3, wall thickening, ↑BNP → RCMP. History of pericarditis, pericardial knock, calcification, ↑pericardial thickness → constrictive pericarditis.
Active Recall - Amyloidosis Differential Diagnosis
References
[1] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf, p19 (MGUS definition; AL amyloidosis as DDx of MGUS) [2] Senior notes: Maksim Medicine Notes.pdf, p182 (Amyloidosis types, clinical features, diagnosis) [5] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf, p12 (MGUS definition; AL amyloidosis as most important DDx) [6] Senior notes: Block A - Inherited Cardiac conditions.pdf, p7–8 (Low voltage ECG + thick walls = amyloidosis; 99mTc-PYP scan; differentiation between amyloid types) [7] Senior notes: Ryan Ho Cardiology.pdf, p170 (Restrictive CMP aetiology; amyloidosis most common; RCMP vs constrictive pericarditis table) [9] Senior notes: Block A – Nephrology Data Interpretation.pdf, p5 (DDx of nephrotic syndrome with monoclonal gammopathy; LCDD, amyloidosis, NSAID-AKI) [11] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p15 (Renal diseases associated with monoclonal light chains) [12] Senior notes: Adrian Lui Pediatrics Notes.pdf, p313 (Classification of GN; amyloidosis as secondary non-proliferative) [13] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, p402 (GN classification table) [14] Senior notes: Ryan Ho Neurology.pdf, p181 (Amyloidosis in DDx of chronic axonal polyneuropathy) [15] Senior notes: Ryan Ho Fundamentals.pdf, p73 (DDx of hepatomegaly; amyloidosis as infiltrative cause) [16] Senior notes: Ryan Ho GI.pdf, p21 (DDx of hepatomegaly; amyloidosis as infiltrative cause) [17] Senior notes: Adrian Lui Pediatrics Notes.pdf, p383 (Macroglossia classical for amyloidosis) [18] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf, p13 (Large kidney DDx: PKD, amyloidosis) [19] Senior notes: Ryan Ho Haemtology.pdf, p103 (Approach to monoclonal gammopathy; AL amyloidosis features) [20] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf, p415 (Serum and urine immunofixation for amyloidosis and LCDD) [21] Senior notes: Block A - Hematology Interactive Tutorial.pdf, p2 (RA resulting in cardiac amyloidosis)
Diagnostic Criteria, Diagnostic Algorithm & Investigations for Amyloidosis
1. Diagnostic Criteria
There is no single set of "diagnostic criteria" for amyloidosis the way there is for SLE or rheumatoid arthritis. Instead, the diagnosis rests on a two-step process mandated by all major guidelines (ASH, ISA, ESC):
Step 1 — Confirm the presence of amyloid in tissue Step 2 — Determine the type of amyloid (precursor protein)
Both steps are essential. Confirming amyloid without typing it is like confirming "anaemia" without checking the MCV — it tells you there is a problem, but not how to treat it.
Congo red stain, salmon pink color → indicative of amyloid deposition. Electron microscopy to show non-branching fibrils in the extracellular compartment, clusters which are characteristic of light chain deposition [4].
| Criterion | Finding | Why This Works |
|---|---|---|
| Congo red stain (light microscopy) | Salmon pink deposits | Congo red dye intercalates between β-pleated sheets of amyloid fibrils in a highly ordered fashion |
| Polarised light microscopy | Apple-green birefringence | The ordered binding of Congo red to the cross-β structure creates birefringence — the ability to rotate polarised light into green wavelength. This is unique to amyloid and is the gold standard confirmatory test [2][8] |
| Thioflavin T (fluorescence microscopy) | Bright green-yellow fluorescence | Thioflavin T binds β-sheet-rich structures and fluoresces; highly sensitive but less specific than Congo red [8] |
| Electron microscopy | Non-branching fibrils, 7–13 nm diameter, randomly arranged in the extracellular space | Fibrils are rigid, non-branching — distinguishes from collagen (banded, 60–70 nm) and immune complex deposits (amorphous, electron-dense) [4] |
High Yield — The Histological 'Triad' for Amyloid Confirmation
- Congo red positive (salmon pink under ordinary light)
- Apple-green birefringence under polarised light
- Non-branching fibrils (7–13 nm) on electron microscopy
If all three are present, amyloid is confirmed. Proceed immediately to typing.
If suspecting amyloidosis, have to differentiate between the transthyretin, AL/primary (associated with increase in immunoglobulins), AA/secondary type [6].
| Method | Principle | When to Use |
|---|---|---|
| Immunohistochemistry (IHC) | Antibodies against specific amyloid proteins (AA, TTR, κ, λ) applied to tissue section | First-line typing in many centres; good for AA and ATTR; can be unreliable for AL due to background staining |
| Laser microdissection + mass spectrometry (LMD-MS) | Amyloid deposits are laser-dissected from tissue, digested, and analysed by tandem mass spectrometry to identify the constituent protein | Gold standard for typing — identifies the protein with >98% accuracy; essential when IHC is equivocal or rare types suspected |
| Immunoelectron microscopy | EM combined with immunogold labelling against specific amyloid proteins | High specificity; labour-intensive; used in specialised centres |
Why Is Typing Non-Negotiable?
Treatment for AL (chemotherapy ± stem cell transplant targeting the plasma cell clone) is completely different from ATTR (tafamidis, patisiran) or AA (control underlying inflammation). Giving chemotherapy to an ATTR patient is futile and toxic. Every biopsy-proven amyloid case must be typed, preferably by mass spectrometry [4][6].
For AL amyloidosis specifically, diagnosis requires ALL of the following:
- Biopsy-proven amyloid with Congo red positivity ± apple-green birefringence
- Amyloid typed as AL (immunohistochemistry or mass spectrometry showing light chain composition)
- Evidence of a monoclonal plasma cell proliferative disorder: at least ONE of:
- Evidence of amyloid-related organ involvement (at least one organ affected — see organ-specific criteria below)
| Organ | Criteria for Involvement |
|---|---|
| Kidney | 24h urine protein ≥ 0.5 g/day (predominantly albumin) |
| Heart | Echo: mean LV wall thickness >12 mm with no other cause; OR NT-proBNP >332 pg/mL in absence of renal failure or AF |
| Liver | Total liver span >15 cm (imaging) in absence of HF; OR ALP >1.5× ULN |
| Nerve | Clinical peripheral neuropathy (symmetric, lower extremity) or autonomic neuropathy not attributable to other causes |
| GI tract | Direct biopsy verification with symptoms |
| Soft tissue | Macroglossia, arthropathy, skin involvement, myopathy, lymphadenopathy (with biopsy proof) |
Albumin anything lower than 30 is critical, have to work fast [4]. In AL amyloidosis, serum albumin < 30 g/L reflects either severe nephrotic losses, hepatic amyloid infiltration, or both — and is an adverse prognostic marker in the Mayo staging system.
The following algorithm integrates clinical suspicion, tissue diagnosis, and amyloid typing into a logical stepwise pathway:
Key decision points explained:
-
Screening biopsy first: Abdominal fat pad aspiration is preferred because it is minimally invasive (bedside procedure, local anaesthetic, fine-needle aspiration of periumbilical subcutaneous fat). Sensitivity ~70–80% for AL, lower for ATTR and AA. If negative but suspicion remains high → proceed to target organ biopsy.
-
Congo red is the gatekeeper: No Congo red positivity = no amyloidosis (with the caveat that sampling error exists, hence repeat biopsy from the affected organ if needed).
-
99m Tc-PYP scan for transthyretin (TTR) amyloidosis [6]: This is a non-invasive diagnostic pathway for cardiac ATTR amyloidosis. Grade 2-3 cardiac uptake (equal to or greater than rib bone) in the absence of a monoclonal protein is diagnostic of ATTR cardiac amyloidosis with >99% specificity — potentially avoiding endomyocardial biopsy entirely. This has revolutionised the diagnosis of cardiac ATTR.
-
Monoclonal protein workup runs in parallel: While awaiting typing, you simultaneously screen for a plasma cell clone (SPEP + UPEP + immunofixation + serum FLC). This is because the monoclonal protein workup results often come back faster than the mass spectrometry and help guide the differential.
High Yield — The Non-Invasive Diagnosis of Cardiac ATTR
Nuclear imaging (technetium-labeled bisphosphonates) for ATTR-cardiac amyloidosis → TTR amyloidosis actually quite common, 10% of patients with HFpEF have this → have to know since there are treatments [22].
A patient with HFpEF + thick LV walls + low ECG voltage can be diagnosed with ATTR cardiac amyloidosis without endomyocardial biopsy if:
- 99mTc-PYP/DPD bone scintigraphy shows Grade 2 or 3 cardiac uptake, AND
- No monoclonal protein is detected (SPEP, UPEP, immunofixation, sFLC all negative)
If monoclonal protein IS present, you cannot exclude AL amyloidosis non-invasively → must proceed to tissue typing (because AL and ATTR can co-exist, and the treatment implications are critical).
3. Investigation Modalities — Detailed Breakdown
| Biopsy Site | Sensitivity | Invasiveness | When to Use |
|---|---|---|---|
| Abdominal subcutaneous fat pad aspiration | ~70–80% for AL; ~60% for AA; lower for ATTR | Minimal (bedside, LA, FNA) | First-line screening — recommended as initial sampling technique due to less invasiveness [3] |
| Rectal biopsy (submucosal) | ~75% for AL | Low (endoscopic) | Alternative to fat pad if GI symptoms |
| Bone marrow biopsy | ~50–60% for AL | Moderate | Simultaneously detects amyloid AND assesses for plasma cell clone — efficient in suspected AL [3] |
| Renal biopsy | >95% for renal amyloidosis | Moderate-high | Should do a renal biopsy — to know the cause of acute renal failure — histopathological diagnosis [9] |
| Endomyocardial biopsy | >95% for cardiac amyloidosis | High (invasive, catheter-based) | When non-invasive tests (echo, CMR, bone scan) are equivocal; endomyocardial biopsy is diagnostic for RCMP [7] |
| Liver biopsy | High | Moderate-high (bleeding risk in amyloid liver) | Only if liver involvement suspected and diagnosis unclear; risk of bleeding due to vascular fragility |
| Nerve biopsy (sural nerve) | Variable | Moderate | Nerve biopsy findings: infiltration, e.g. amyloidosis [23]; used when neuropathy is the dominant presentation |
Histopathological assessment showed amorphous eosinophilic deposits, positive Congo red staining, and apple-green birefringence under polarized light. The specimen also stained positive for thioflavin T under fluorescence [8]. These are the hallmark findings on any amyloid biopsy.
The combination of these three tests detects an abnormal monoclonal protein in >95% of AL amyloidosis cases:
a) Serum Protein Electrophoresis (SPEP) + Immunofixation
Indications for serum protein electrophoresis: suspected AL amyloidosis, unexplained raised ESR, investigation of unexplained neuropathy, heavy proteinuria, or renal impairment [10].
- SPEP separates serum proteins by electrophoresis → allows detection and quantification of an M protein (monoclonal spike in the γ-globulin region) [19].
- Monoclonal gammopathy: single, narrow peak at γ-globulin area → a/w plasma cell neoplasms
- Polyclonal gammopathy: broad-based peak at γ-globulin area → a/w infectious/inflammatory disease [19]
- Immunofixation follows a positive SPEP → identifies the type of M protein (e.g., IgG-κ, IgA-λ, free λ etc.) [19].
- Method: each sample electrophoresed in 5 lanes, each overlaid with specific Ab (anti-γ, anti-μ, anti-α, anti-κ, anti-λ) [19]
- Important caveat: In AL amyloidosis, the M protein is often small (may be < 1 g/dL). SPEP alone misses ~20–30% of cases → must always pair with immunofixation and serum FLC.
4 patterns of serum protein electrophoresis: Normal Ig pattern (absence of paraprotein); Pan-immunoparesis; Raised immunoglobulin (absence of paraprotein); Presence of paraprotein +/- immunoparesis [10].
b) Urine Protein Electrophoresis (UPEP) + Immunofixation
- Detects monoclonal light chains (Bence Jones protein) in urine.
- ~50% light chain MM is SPEP negative but UPEP positive → must do UPEP [19]. The same applies to AL amyloidosis — always check both serum AND urine.
- 24-hour urine collection preferred for quantification.
c) Serum Free Light Chain (sFLC) Assay
Serum free light chain: can detect low concentration of monoclonal free light chains in the serum. More sensitive than urine immunofixation for monoclonal FLCs [19].
| Parameter | Normal Range |
|---|---|
| Free κ light chains | 3.3–19.4 mg/L |
| Free λ light chains | 5.7–26.3 mg/L |
| κ:λ FLC ratio | 0.26–1.65 |
- An abnormal κ:λ ratio strongly suggests monoclonal light chain production.
- The difference between involved and uninvolved free light chain (dFLC) is used for staging (Mayo 2012 staging) and monitoring treatment response.
- In AL amyloidosis, the sFLC is abnormal in ~98% of cases — it is the single most sensitive test for detecting a clonal light chain.
d) Serum Immunoglobulin Levels (IgG, IgA, IgM)
- Look for immunoparesis — suppression of the uninvolved immunoglobulin classes by the dominant plasma cell clone.
- Example: If the clone produces IgA-λ, you expect ↑IgA with ↓IgG and ↓IgM.
- This patient had immunoparesis [4] — suggests significant clonal expansion.
Bone marrow biopsy to look for abnormal monoclonal plasma cells [9].
- BM aspirate and trephine with:
- Plasma cell enumeration — in AL amyloidosis, BM plasma cells are often <10% (unlike MM where they are ≥10%). Even a small clone can produce enough amyloidogenic light chains.
- Biopsy should be stained specifically for amyloid [3] — Congo red stain on the trephine to detect BM amyloid deposits.
- Immunohistochemistry and flow cytometry with antibodies to κ and λ light chains to look for clonality [3].
- FISH cytogenetics — prognostic (e.g., t(11;14) associated with better response to venetoclax in AL; gain 1q, t(4;14), del(17p) are high-risk features).
| Investigation | Key Finding in Cardiac Amyloidosis | Why |
|---|---|---|
| ECG | Low voltage (limb leads < 5 mm, precordial < 10 mm); pseudo-infarct pattern (Q waves); AV block; AF | Amyloid is electrically inert → doesn't generate voltage despite thick walls; conduction system infiltration → blocks [6] |
| Echocardiography | Biventricular thickening with granular sparkling appearance [3]; diastolic dysfunction (restrictive filling pattern); small LV cavity; biatrial dilation; pericardial effusion; valvular thickening | Amyloid infiltration of myocardial interstitium → wall thickening + stiffness; atria dilate because they must generate higher pressures to fill stiff ventricles |
| Cardiac MRI (CMR) | Late gadolinium enhancement (LGE) — diffuse, subendocardial or transmural; difficulty nulling the myocardium; elevated native T1 mapping and ECV (extracellular volume fraction) | LGE reflects expanded extracellular space from amyloid deposition; T1 mapping and ECV are quantitative and highly sensitive even before LGE appears |
| 99mTc-PYP / DPD / HMDP bone scintigraphy | Grade 2-3 cardiac uptake (heart-to-contralateral ratio ≥ 1.5) | Technetium-labelled bisphosphonates bind preferentially to ATTR fibrils (mechanism unclear, likely calcium content); negative or Grade ≤1 in AL [6][22] |
| NT-proBNP / BNP | Markedly elevated | Myocardial stretch from amyloid infiltration → BNP release; used in Mayo staging; ↑BNP due to myocardial stretching [7] |
| Troponin (hsTnT/hsTnI) | Chronically mildly elevated | Ongoing low-grade cardiomyocyte injury from amyloid compression + direct toxicity (especially in AL); used in staging |
| Right heart catheterisation | Restrictive haemodynamic pattern: elevated and equalised diastolic pressures in all chambers; "dip-and-plateau" (square-root sign) | Right heart catheterization — a must, since restrictive physiology is easy to see on cath [22] |
Exam Classic — Voltage-Mass Mismatch
Patient presents with DCM/RCMP with small QRS complex voltages on ECG, with a very thickened wall on echo → Classical for amyloidosis, indicates further investigations: 99mTc-PYP scan for transthyretin amyloidosis; immunofixation electrophoresis on bloods or 24-hour urine [6].
This is the "trigger finding" that should launch the amyloid workup in any cardiac case.
| Investigation | Key Finding | Interpretation |
|---|---|---|
| Urinalysis (dipstick) | Proteinuria | Serum, urine protein electrophoresis → amyloidosis-related nephropathy [24][25] |
| Urine microscopy | Bland sediment (no RBC casts, no dysmorphic RBCs) | Amyloid causes non-inflammatory damage → no nephritic sediment |
| 24-hour urine protein | ≥ 3.5 g/day = nephrotic range | Urine protein ≥ 3.5 gram/day = nephrotic change; normal < 0.15 gram/day [9] |
| Spot urine protein-to-creatinine ratio (uPCR) | Elevated | Alternative to 24h collection for screening |
| RFT | Elevated creatinine, reduced eGFR | Progressive renal insufficiency |
| Serum albumin | Low (< 30 g/L) | Urinary loss (nephrotic syndrome) ± reduced hepatic synthesis; albumin < 30 is critical [4] |
| Lipid profile | ↑↑ Cholesterol, ↑↑ LDL | Nephrotic syndrome → hepatic lipoprotein overproduction as compensation for albumin loss |
| Renal ultrasound | Normal or large kidneys (unlike most CKD which shows small kidneys) | Amyloid infiltration → kidney enlargement; large kidney DDx: PKD, infiltration → amyloidosis [18] |
| Renal biopsy | Congo red positive deposits in glomeruli (mesangium, GBM); IF/IHC for light chain typing | Definitive; should do renal biopsy for AKI/nephrotic syndrome — histopathological diagnosis [9] |
| Investigation | Purpose | Key Finding |
|---|---|---|
| SAA level | Identify AA amyloidosis; monitor inflammatory activity | Markedly elevated in AA; correlates with risk of progression and can be used to monitor treatment response |
| CRP / ESR | Assess inflammatory burden (AA context) | ↑↑ in AA; ESR also raised in AL due to M protein (rouleaux) |
| LFT | Hepatic involvement | Cholestatic pattern: ↑ALP, ↑GGT disproportionate to transaminases; hepatomegaly on imaging |
| Coagulation studies | Bleeding tendency | Prolonged PT (Factor X deficiency — adsorbed onto amyloid fibrils); normal platelets |
| β2-microglobulin | Prognostic in MM; elevated in dialysis-related amyloidosis | Serum beta-2 microglobulin — important for prognosis [19]; also the precursor protein in Aβ2M amyloidosis |
| TTR gene sequencing | Distinguish ATTRv from ATTRwt | Identifies >150 known TTR mutations; essential once ATTR is confirmed |
| SAP scintigraphy | Map amyloid distribution throughout the body | IV injection of radiolabelled SAP (serum amyloid P component) → localises to amyloid deposits; available only in specialised centres (e.g., Royal Free, London) |
| Nerve conduction studies / EMG | Characterise neuropathy | Axonal pattern in amyloid neuropathy (vs demyelinating in CIDP and anti-MAG neuropathy) [14] |
| Skeletal survey / PET-CT | Exclude concurrent myeloma (lytic lesions) | Skeletal survey – hypermetabolic lesions with PET/CT [9]; important because ~10% of AL patients have co-existing MM |
| Autonomic function testing | Quantify autonomic neuropathy | Tilt-table test (orthostatic hypotension), HRV analysis, sudomotor function |
Name all the investigations that could be ordered in the work-up for a patient with paraprotein: History and Physical Examination; CBC; Renal function and calcium, albumin, ALP, LDH; SPEP +/- immunofixation; Urine for protein; UPEP; Serum free light chain level and ratio; Serum beta-2 immunoglobulin; Bone marrow aspirate and trephine + FISH analysis; Skeletal survey / whole-body PET-CT or MRI or low-dose CT [5].
The following table organises the investigation battery by clinical purpose:
| Purpose | Investigations |
|---|---|
| Confirm amyloid | Tissue biopsy (fat pad, rectal, organ) → Congo red / polarised light / EM |
| Type the amyloid | IHC on biopsy; mass spectrometry (gold standard); 99mTc-PYP/DPD if cardiac ATTR |
| Detect monoclonal protein | SPEP + immunofixation; UPEP + immunofixation; serum FLC (κ, λ, ratio) |
| Assess plasma cell clone | BM aspirate + trephine (morphology, flow cytometry κ/λ, FISH) |
| Organ involvement — Heart | ECG, echo, CMR, NT-proBNP, hsTnT, 99mTc-PYP scan |
| Organ involvement — Kidney | RFT, 24h urine protein, urine microscopy, renal US, renal biopsy |
| Organ involvement — Liver | LFT (ALP pattern), liver US/CT, ± liver biopsy |
| Organ involvement — Nerve | NCS/EMG, autonomic function tests, ± sural nerve biopsy |
| Staging and prognosis | NT-proBNP, hsTnT, dFLC, serum albumin, β2-microglobulin |
| Exclude concurrent myeloma | Calcium, CBC, RFT, skeletal imaging (PET-CT / whole-body low-dose CT) |
| Genetic testing | TTR gene sequencing (if ATTR confirmed) |
4. Staging Systems (Brief — for Prognosis, Not Diagnosis)
Uses three biomarkers to stratify prognosis:
| Parameter | Threshold |
|---|---|
| NT-proBNP | ≥ 1800 pg/mL |
| hsTnT | ≥ 0.025 ng/mL |
| dFLC (difference between involved and uninvolved FLC) | ≥ 180 mg/L |
| Stage | Criteria | Median OS |
|---|---|---|
| I | All three below threshold | ~95 months |
| II | One above threshold | ~60 months |
| III | Two above threshold | ~16 months |
| IV | All three above threshold | ~6 months |
Why these markers? NT-proBNP and troponin quantify the degree of cardiac damage (the main determinant of survival in AL), while dFLC quantifies the burden of the toxic light chain being produced by the clone. Higher values = more cardiac injury + more toxin production = worse prognosis.
| Stage | Criteria | 2-year Renal Survival |
|---|---|---|
| I | eGFR ≥ 50 AND proteinuria < 5 g/day | ~85% |
| II | Neither I nor III | ~60% |
| III | eGFR < 50 AND proteinuria ≥ 5 g/day | ~15% |
High Yield Summary — Diagnostics for Amyloidosis
-
Histological confirmation: Congo red stain → apple-green birefringence under polarised light. EM shows non-branching fibrils 7–13 nm.
-
Typing is mandatory: IHC or mass spectrometry on the biopsy. Never treat without knowing the type.
-
AL workup triad: SPEP + immunofixation, UPEP + immunofixation, serum FLC assay → combined sensitivity >95% for detecting a monoclonal protein.
-
Fat pad aspiration is the recommended initial biopsy (minimally invasive, ~70–80% sensitivity for AL). If negative with high suspicion → organ biopsy.
-
99mTc-PYP/DPD scan: Non-invasive diagnosis of cardiac ATTR — Grade 2-3 uptake WITHOUT monoclonal protein = diagnostic (avoids endomyocardial biopsy).
-
Voltage-mass mismatch (low ECG voltage + thick echo walls) is the trigger for cardiac amyloid workup.
-
Staging: Mayo 2012 uses NT-proBNP, hsTnT, dFLC. Stage IV (all elevated) has median survival of only ~6 months.
-
Always exclude concurrent myeloma: ~10% of AL patients have co-existing MM → check CRAB criteria, skeletal imaging, BM plasma cell percentage.
Active Recall - Amyloidosis Diagnosis and Investigations
References
[2] Senior notes: Maksim Medicine Notes.pdf, p182 (Amyloidosis diagnosis: Congo red, apple-green birefringence) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, p1776–1778 (Classification table; biopsy approach; SIEP/UIEP; FLC; echo findings; BM biopsy staining) [4] Senior notes: Block A - Hematology Data Interpretation.pdf, p1 (Congo red stain; EM fibrils; albumin < 30 critical; immunoparesis; AL vs AA vs β2M vs TTR) [5] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf, p20 (Workup for paraprotein: SPEP, UPEP, FLC, BM, imaging) [6] Senior notes: Block A - Inherited Cardiac conditions.pdf, p7–8 (Low voltage + thick wall = amyloidosis; 99mTc-PYP scan; immunofixation electrophoresis) [7] Senior notes: Ryan Ho Cardiology.pdf, p170 (RCMP aetiology; RCMP vs constrictive pericarditis; ↑BNP; endomyocardial biopsy diagnostic) [8] Senior notes: Block A - Deterioration of eyesight in a diabetic patient_ diabetic complications.pdf, p28 (Congo red, apple-green birefringence, thioflavin T) [9] Senior notes: Block A – Nephrology Data Interpretation.pdf, p5 (Renal biopsy; DDx with monoclonal band; urine protein thresholds) [10] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf, p27 (SPEP indications; 4 patterns; immunofixation) [14] Senior notes: Ryan Ho Neurology.pdf, p181 (Amyloid neuropathy: axonal, sensorimotor + autonomic) [18] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf, p13 (Large kidney DDx: PKD, amyloidosis) [19] Senior notes: Ryan Ho Haemtology.pdf, p103, p106–107 (Approach to monoclonal gammopathy; SPEP/UPEP method; immunofixation; sFLC normal ranges; β2-microglobulin; skeletal survey) [22] Senior notes: Block A - Inherited Cardiac conditions.pdf, p18 (Restrictive CMP workup: RHC, CMR, nuclear imaging for ATTR, endomyocardial biopsy; TTR amyloidosis 10% of HFpEF) [23] Senior notes: Ryan Ho Neurology.pdf, p44 (Nerve biopsy: indication and findings including amyloid infiltration) [24] Senior notes: Adrian Lui Pediatrics Notes.pdf, p314 (Investigations for glomerular disease: serum/urine protein electrophoresis for amyloidosis-related nephropathy) [25] Senior notes: Ryan Ho Urogenital.pdf, p55 (Investigations: serum/urine protein electrophoresis for amyloidosis-related nephropathy)
Management Algorithm and Treatment Modalities for Amyloidosis
The fundamental management principle is straightforward from first principles: stop the supply of the amyloidogenic precursor protein, support the damaged organs, and — where possible — promote regression of existing deposits. Because each type of amyloidosis has a completely different precursor protein, each requires a completely different treatment strategy. Treating amyloidosis without knowing the type is like giving insulin to every patient with polyuria — you may help some and kill others.
| Principle | Rationale |
|---|---|
| 1. Eliminate or reduce the precursor protein | If you stop the supply of the misfolding protein, no new fibrils form. Existing deposits may even slowly regress (demonstrated in AA and ATTR). |
| 2. Support the failing organs | Heart failure management, dialysis for ESRD, nutritional support for malabsorption — these keep the patient alive while disease-directed therapy takes effect. |
| 3. Treat the underlying condition (if applicable) | In AA: treat the chronic inflammation. In AL: target the clonal plasma cells. |
| 4. Monitor response | Serial biomarkers (sFLC/dFLC, NT-proBNP, proteinuria) to assess haematological and organ response. |
| 5. Manage complications | Thrombosis prophylaxis, infection prophylaxis, autonomic neuropathy management, nutritional support. |
3. Treatment by Type — Detailed
3.1 AL Amyloidosis Management
AL amyloidosis is a haematological malignancy — the treatment targets the underlying clonal plasma cell population, not the amyloid deposits directly. The logic: kill the clone → no more amyloidogenic light chains → no new amyloid → organ recovery (if caught early enough).
AL amyloidosis possibly arising as a complication of myeloma in ~10% of cases [4]. When AL co-exists with MM, the management framework follows MM protocols but with important dose modifications for organ fragility.
HSCT candidates: Melphalan → Autologous hematopoietic stem cell transplantation (HSCT) [3].
Why autologous HSCT? High-dose melphalan (HDM) is the most potent way to eradicate the plasma cell clone. But it causes profound and prolonged bone marrow aplasia → you need to rescue the patient with their own previously harvested stem cells. This is the same principle used in myeloma HSCT.
| Step | Detail |
|---|---|
| Eligibility assessment | Age < 70 (flexible); adequate cardiac function (typically NT-proBNP < 5000 pg/mL, troponin < 0.06 ng/mL, systolic BP ≥ 90 mmHg); ≤ 2 major organs involved; eGFR > 30 (not on dialysis); ECOG PS 0-2. Only ~20-25% of newly diagnosed AL patients are eligible. |
| Stem cell mobilisation & harvest | G-CSF → peripheral blood stem cell collection via apheresis |
| Induction chemotherapy (optional, increasingly recommended pre-transplant) | Bortezomib-based induction (e.g., CyBorD × 2-4 cycles) to reduce the clone before HDM |
| Conditioning | High-dose Melphalan 140-200 mg/m² (dose-adjusted based on organ function — 140 mg/m² if eGFR < 30 or significant cardiac involvement) |
| Autologous HSCT | Infusion of cryopreserved autologous stem cells |
| Post-transplant consolidation | Consider bortezomib-based consolidation if < VGPR (very good partial response) achieved |
Expected outcomes: Haematological complete response (CR) in ~40% with HSCT; organ response in 50-70% over 12-24 months. Median OS > 10 years for transplant-eligible patients who achieve CR.
Transplant-related mortality (TRM): Has decreased from ~20% in early studies to < 5% in experienced centres (2020s data) with careful patient selection and supportive care. However, this is still higher than myeloma HSCT TRM (~1-2%) because AL patients have fragile, amyloid-infiltrated organs.
Why Not Transplant Everyone?
The majority of AL amyloidosis patients (~75%) are NOT eligible for HSCT because of advanced cardiac involvement, multi-organ disease, or poor functional status. Pushing a patient with Mayo Stage IIIb or IV cardiac disease through HSCT carries unacceptable TRM. These patients need non-transplant chemotherapy regimens.
Non-HSCT candidates: Melphalan + Dexamethasone (OR) Cyclophosphamide + Bortezomib + Dexamethasone [3].
Current standard of care (2024–2026):
| Regimen | Components | Mechanism | When to Use |
|---|---|---|---|
| DaraCyBorD (ANDROMEDA regimen — now considered standard 1st-line) | Daratumumab + Cyclophosphamide + Bortezomib + Dexamethasone | Daratumumab = anti-CD38 monoclonal antibody → targets plasma cells; Bortezomib = proteasome inhibitor → disrupts protein degradation in plasma cells; Cyclophosphamide = alkylating agent; Dexamethasone = lymphocytotoxic + anti-inflammatory | Standard first-line for transplant-ineligible AL (ANDROMEDA trial showed superior haematological CR rate ~53% vs ~18% with CyBorD alone) |
| CyBorD | Cyclophosphamide + Bortezomib + Dexamethasone | As above minus daratumumab | If daratumumab not available or contraindicated |
| Melphalan + Dexamethasone (MDex) | Melphalan + Dexamethasone | Melphalan = alkylating agent targeting dividing plasma cells | Older regimen; still used if bortezomib contraindicated (e.g., severe neuropathy). Being superseded by bortezomib-based regimens. |
Mechanism of key drugs — explained from first principles:
-
Bortezomib ("borte-zomib" — proteasome inhibitor):
- Proteasome = the cell's protein shredder. It degrades ubiquitin-tagged proteins that are misfolded or no longer needed.
- Plasma cells produce enormous quantities of immunoglobulin → they are uniquely dependent on the proteasome to handle the folding and quality-control burden (called the "unfolded protein response").
- Inhibition of 26S proteasome → prevent proteolysis of ubiquitin-tagged protein → cytotoxic to myeloma/plasma cells by affecting multiple signaling cascades [26].
- Why particularly effective in AL? The amyloidogenic clone is a plasma cell producing excess misfolded light chains → already under proteotoxic stress → proteasome inhibition tips them over the edge into apoptosis.
- Main side effect: Peripheral neuropathy (dose-limiting — problematic in AL where neuropathy may already exist). Subcutaneous route preferred over IV to reduce neuropathy risk.
-
Daratumumab ("dara-tumumab" — "dara" from the development programme, "-tu-" = fully human, "-mab" = monoclonal antibody):
- Targets CD38, a glycoprotein highly expressed on the surface of plasma cells.
- Mechanism: antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and direct apoptosis of CD38+ cells.
- Game-changing drug in AL amyloidosis — the ANDROMEDA trial (2020) showed DaraCyBorD produced haematological CR in ~53% vs ~18% with CyBorD, with improved organ response rates.
-
Cyclophosphamide ("cyclo-phosphamide" — cyclic phosphoramide):
- Alkylating agent → cross-links DNA strands in dividing cells → prevents replication → apoptosis.
- Well-tolerated orally; synergistic with bortezomib.
-
Dexamethasone ("dexa-methasone"):
- Potent glucocorticoid → directly lymphocytotoxic to plasma cells + reduces inflammation.
- Used at lower doses in AL than in MM (20 mg weekly rather than 40 mg) because AL patients tolerate steroids poorly due to autonomic neuropathy, fluid retention, and cardiac fragility.
| Setting | Options |
|---|---|
| Relapse after HSCT | Repeat bortezomib-based therapy; daratumumab-based therapy if not used upfront; lenalidomide-dexamethasone |
| Relapse after DaraCyBorD | Lenalidomide + dexamethasone; pomalidomide + dexamethasone; ixazomib-based regimens; venetoclax (if t(11;14) present) |
| Refractory disease | Novel agents: daratumumab, venetoclax (BCL-2 inhibitor), CAR-T cell therapy [26]; clinical trials |
| Anti-amyloid immunotherapy | Birtamimab (anti-SAP antibody in trials), CAEL-101 (anti-fibril antibody targeting AL deposits directly — Phase 3 ongoing). These aim to actively remove deposited amyloid rather than just stopping production. |
Haematological response (how well the clone is being suppressed):
| Response Level | Definition |
|---|---|
| Complete Response (CR) | Negative serum/urine immunofixation + normal sFLC ratio + normal BM plasma cells |
| Very Good Partial Response (VGPR) | dFLC < 40 mg/L |
| Partial Response (PR) | ≥ 50% decrease in dFLC |
| No Response (NR) | Less than PR |
Organ response (is the organ recovering? — takes 6-12+ months):
| Organ | Response Criteria |
|---|---|
| Kidney | ≥ 30% decrease in proteinuria or drop to < 0.5 g/24h (without ≥ 25% decline in eGFR) |
| Heart | ≥ 30% decrease in NT-proBNP (and ≥ 300 pg/mL decrease) |
| Liver | ≥ 50% decrease in ALP |
The critical teaching point: haematological response must come first → organ response follows months later. The amyloid deposits themselves take time to resorb. If the clone is not suppressed, organs will continue to deteriorate regardless of supportive care.
Treatment of AA amyloidosis: Treatment of underlying conditions. Biologics such as tocilizumab and anakinra for rheumatological associated disease [3].
The logic here is beautifully simple: SAA (serum amyloid A) is an acute-phase reactant produced by the liver in response to inflammatory cytokines (mainly IL-6). If you eliminate the inflammation, SAA levels normalise → no new AA fibrils are formed → existing deposits can actually regress.
| Approach | Detail |
|---|---|
| Treat the underlying inflammatory disease | RA → DMARDs (MTX, biologics); IBD → anti-TNF, vedolizumab; FMF → colchicine (gold standard — dramatically reduces AA amyloidosis risk in FMF); Chronic infections → antibiotics/anti-TB; Surgical drainage of chronic abscesses |
| Target SAA directly | Biologics that suppress IL-6 (the main driver of SAA): Tocilizumab (anti-IL-6R) — especially effective in RA-associated AA; Anakinra (IL-1 receptor antagonist) — especially effective in FMF and autoinflammatory syndromes |
| Monitoring target | SAA < 10 mg/L — sustained suppression below this threshold is associated with stabilisation or improvement of organ function and amyloid regression |
| Anti-SAA therapy | Eprodisate was studied (GAG mimetic that interferes with SAA fibril formation) but is not widely available. No specific anti-AA fibril immunotherapy is currently approved. |
Key point: AA amyloidosis is the most "reversible" form. With adequate control of the underlying disease and SAA suppression, renal function can stabilise and even improve, and amyloid deposits demonstrably regress on SAP scintigraphy.
Colchicine in FMF-associated AA:
- FMF (familial Mediterranean fever) is the prototypical cause of AA amyloidosis globally (especially in Mediterranean populations).
- Colchicine 1–2 mg/day prevents FMF attacks → prevents SAA elevation → prevents AA amyloid deposition.
- If colchicine-resistant: anakinra or canakinumab (anti-IL-1β).
3.3 ATTR Amyloidosis Management
This is the most rapidly evolving area in amyloidosis therapeutics. The key insight is that TTR is a liver-produced protein → you can either (a) stabilise the TTR tetramer so it doesn't dissociate and misfold, (b) silence TTR gene expression in the liver, or (c) remove the source organ (liver transplant).
TTR amyloidosis actually quite common, 10% of patients with HFpEF have this → have to know since there are treatments [22].
| Treatment | Mechanism | Indication | Key Evidence |
|---|---|---|---|
| Tafamidis 80 mg daily (or tafamidis meglumine 20 mg) | TTR stabiliser — binds to thyroxine-binding sites on the TTR tetramer → prevents dissociation into monomers → prevents misfolding | First-line for ATTR cardiomyopathy (both ATTRwt and ATTRv); NYHA I-III | ATTR-ACT trial: reduced all-cause mortality by 30%, cardiovascular hospitalisations by 32% over 30 months |
| Patisiran (IV q3w) | RNA interference (RNAi) — double-stranded siRNA packaged in lipid nanoparticles → delivered to hepatocytes → binds and degrades TTR mRNA → reduces TTR production by ~80% | ATTRv with polyneuropathy; also now approved for ATTR cardiomyopathy (APOLLO-B trial) | APOLLO trial: improved neuropathy scores and quality of life at 18 months |
| Inotersen (SC weekly) or Eplontersen (SC monthly) | Antisense oligonucleotide (ASO) — binds TTR mRNA in hepatocytes → promotes RNase H-mediated degradation → reduces TTR production | ATTRv with polyneuropathy; eplontersen also for cardiomyopathy | NEURO-TTR trial: slowed neuropathy progression |
| Vutrisiran (SC q3mo) | Next-gen RNAi (GalNAc-conjugated siRNA) — more convenient dosing than patisiran | ATTR with polyneuropathy; cardiomyopathy data emerging (HELIOS-B) | HELIOS-A: non-inferior to patisiran; HELIOS-B: reduced mortality + CV events in ATTR cardiomyopathy |
| Liver transplant | Removes the source organ producing mutant TTR | Selected young ATTRv patients with early neuropathy (Val30Met) | Historical gold standard for ATTRv before gene-silencing era; declining use as pharmacotherapy improves |
How tafamidis works — from first principles:
- TTR normally exists as a homotetramer (4 identical subunits). At the centre of this tetramer are two funnel-shaped thyroxine-binding sites (TTR transports thyroxine).
- In amyloidosis, the tetramer is thermodynamically unstable (due to mutation in ATTRv, or due to age-related changes in ATTRwt) → it dissociates into monomers → monomers misfold → aggregate into amyloid fibrils.
- Tafamidis binds to the thyroxine-binding sites → acts as a molecular "glue" or "kinetic stabiliser" → prevents tetramer dissociation → no monomers → no fibrils.
- Think of it like putting a rubber band around a stack of books — the individual books (monomers) can't fall apart.
How patisiran works — from first principles:
- RNA interference (RNAi) is a natural cellular mechanism where small double-stranded RNA molecules (siRNAs) guide the RISC (RNA-induced silencing complex) to target and degrade complementary mRNA.
- Patisiran is a synthetic siRNA that targets the 3'-UTR of TTR mRNA.
- It is packaged in lipid nanoparticles (LNPs) → taken up by hepatocytes via apolipoprotein E receptor-mediated endocytosis → released into the cytoplasm → incorporated into RISC → finds and degrades TTR mRNA → ~80% reduction in circulating TTR protein.
- Less TTR = less substrate for amyloid formation.
Tafamidis — A Paradigm Shift in Cardiac Amyloidosis
Before tafamidis, cardiac ATTR amyloidosis had no disease-modifying therapy — patients just received heart failure management and died. The ATTR-ACT trial (2018) was the first to demonstrate a survival benefit with a disease-specific treatment in cardiac amyloidosis. Tafamidis is now standard of care for all symptomatic ATTR cardiomyopathy (NYHA I-III).
- First-line: Patisiran, inotersen, vutrisiran, or eplontersen (gene-silencing agents)
- Alternative: Tafamidis (especially if also cardiac involvement)
- Liver transplant: Still considered in young Val30Met patients diagnosed early, particularly in endemic regions (Portugal, Japan) — but increasingly superseded by pharmacotherapy
- Supportive: Neuropathic pain management (gabapentin, pregabalin, duloxetine), physiotherapy, orthotics
| Approach | Rationale |
|---|---|
| Switch to high-flux or super high-flux dialysis membranes | Modern high-flux membranes can clear β2-microglobulin more effectively than older cuprophane membranes → reduced accumulation |
| Increase dialysis frequency/duration | More clearance time → lower β2M levels |
| Renal transplantation | Definitive treatment — a functioning transplant kidney clears β2-microglobulin normally. Symptoms (CTS, arthropathy) typically improve or stabilise after successful transplant. |
| Surgical decompression | Carpal tunnel release for symptomatic CTS; joint surgery for destructive arthropathy |
| Online haemodiafiltration (HDF) | Better β2M clearance than conventional HD; now the standard modality in many centres |
4. Supportive and Organ-Specific Management
Regardless of amyloid type, organ support is critical. Many patients die from organ failure before disease-directed therapy has time to work.
| Consideration | Management | Rationale / Pitfalls |
|---|---|---|
| Heart failure | Loop diuretics (furosemide) — often high doses needed; cautious fluid restriction | The stiff ventricle has a narrow window of optimal filling — too much fluid → pulmonary oedema; too little → catastrophic drop in CO |
| Avoid β-blockers | Generally contraindicated in cardiac amyloidosis | In a stiff ventricle that cannot increase stroke volume, cardiac output is entirely heart-rate dependent. β-blockers slow the heart rate → CO drops → patient decompensates. This is the opposite of HFrEF! |
| Avoid ACE inhibitors/ARBs | Use with extreme caution or avoid | Patients with cardiac amyloidosis often have autonomic neuropathy → already vasodilated and hypotensive → ACEi/ARB can precipitate dangerous hypotension |
| Avoid digoxin | Contraindicated | Digoxin binds to amyloid fibrils → accumulates in tissue → toxicity at "therapeutic" serum levels |
| Avoid CCBs (esp. verapamil, diltiazem) | Contraindicated | Bind to amyloid fibrils similarly to digoxin → can cause profound hypotension and heart block |
| Rate control for AF | Amiodarone often the only tolerable option | β-blockers, CCBs, digoxin all problematic as above |
| Anticoagulation for AF | Standard indications | High thromboembolic risk; DOACs or warfarin as per usual AF guidelines |
| Pacemaker | For symptomatic high-degree AV block | Common in cardiac amyloidosis due to conduction system infiltration |
| ICD | Controversial — not routine | VT/VF occurs but is often PEA/asystole → ICD may not benefit |
Critical Exam Point — Why Standard HF Drugs Are Dangerous in Cardiac Amyloidosis
No medication exists for idiopathic restrictive cardiomyopathy [22]. For amyloid-specific RCMP, the mainstay drugs used in HFrEF (β-blockers, ACEi/ARBs) are often harmful because:
- The ventricle is stiff (not dilated) → cannot compensate for rate-lowering or vasodilation
- Autonomic neuropathy → already at risk of hypotension
- Digoxin and CCBs bind to amyloid fibrils → toxicity at normal doses
Diuretics are the only safe standard HF drug. Disease-directed therapy (tafamidis, chemotherapy) is the real treatment.
| Consideration | Management |
|---|---|
| Nephrotic syndrome | Dietary sodium restriction; loop diuretics; albumin infusions (temporary); ACEi/ARB may be used if tolerating (reduce proteinuria) but caution with hypotension |
| CKD progression | Standard CKD management (BP control, avoid nephrotoxins); prepare for renal replacement therapy if progressing |
| Dialysis | Haemodialysis or peritoneal dialysis — both feasible. Peritoneal dialysis may be preferred in patients with autonomic neuropathy (avoids intradialytic hypotension). |
| Renal transplant | Considered in patients who achieve complete haematological response from AL treatment and have isolated renal failure |
| Symptom | Management |
|---|---|
| Neuropathic pain | Gabapentin, pregabalin, duloxetine, amitriptyline (caution: anticholinergic side effects) |
| Orthostatic hypotension | Midodrine (α1-agonist), fludrocortisone (mineralocorticoid → volume expansion), compression stockings, slow postural changes, adequate hydration + salt intake |
| GI dysmotility | Prokinetics (metoclopramide, domperidone); small frequent meals; post-pyloric feeding if severe |
| Urinary retention | Intermittent self-catheterisation |
| Erectile dysfunction | PDE5 inhibitors (caution with hypotension) |
| Carpal tunnel syndrome | Surgical decompression if symptomatic |
- Malabsorption from GI amyloid infiltration + autonomic neuropathy → malnutrition is common and undertreated.
- Enteral nutrition preferred; parenteral nutrition if enteral route fails.
- Dietician involvement essential.
- Patients with nephrotic syndrome lose antithrombin III in the urine → hypercoagulable state → venous thromboembolism prophylaxis may be needed.
- Paradoxically, AL patients can also have a bleeding tendency from acquired Factor X deficiency (Factor X adsorbed onto amyloid fibrils) + vascular fragility.
- Balance thrombotic and bleeding risk carefully.
| Type | Disease-Directed Therapy | Key Drugs | Supportive Care |
|---|---|---|---|
| AL | Target plasma cell clone | DaraCyBorD (1st-line non-transplant); HDM + auto-HSCT (transplant-eligible); MDex (if bortezomib-intolerant) [3] | Cardiac: diuretics (avoid β-blockers, digoxin, CCBs); Renal: sodium restriction, RRT; Neuro: neuropathic pain Mx |
| AA | Suppress inflammation → reduce SAA | Colchicine (FMF); Tocilizumab / Anakinra (RA, auto-inflammatory); DMARDs; anti-infectives | Renal support; nutrition |
| ATTRwt | TTR stabilisation | Tafamidis 80 mg daily | Cardiac: diuretics; pacing for AV block |
| ATTRv | TTR silencing or stabilisation | Patisiran / Vutrisiran / Inotersen / Eplontersen; Tafamidis; liver transplant | Neuropathic pain Mx; autonomic support; cardiac support |
| Aβ2M | Remove/reduce β2M accumulation | High-flux dialysis; renal transplant (definitive) | CTS surgery; joint Mx |
| Parameter | Frequency | Purpose |
|---|---|---|
| Serum FLC + dFLC | Every cycle during treatment; q3-6 months during surveillance | Haematological response monitoring (AL) |
| SPEP + immunofixation | Every 2-3 cycles; q6-12 months in remission | M protein quantification |
| NT-proBNP | q3-6 months | Cardiac organ response |
| hsTnT | q3-6 months | Cardiac damage monitoring |
| 24h urine protein | q3-6 months | Renal organ response |
| eGFR / Creatinine | q1-3 months | Renal function |
| SAA (in AA) | q3-6 months | Inflammatory activity; target < 10 mg/L |
| Echo | q6-12 months | Structural cardiac assessment |
| NCS/EMG (if neurological) | q12 months | Neuropathy progression |
High Yield Summary — Management of Amyloidosis
-
AL amyloidosis:
- Transplant-eligible → bortezomib-based induction → high-dose melphalan → autologous HSCT.
- Transplant-ineligible → DaraCyBorD is the new standard first-line (ANDROMEDA trial); alternatives include CyBorD or MDex.
- Key drugs: bortezomib (proteasome inhibitor), daratumumab (anti-CD38), cyclophosphamide (alkylator), dexamethasone.
- Goal: complete haematological response (negative immunofixation + normal sFLC ratio) → organ response follows.
-
AA amyloidosis: Treat underlying inflammation. Biologics (tocilizumab, anakinra) for rheumatological causes. Colchicine for FMF. Target SAA < 10 mg/L. Most "reversible" form.
-
ATTR amyloidosis: Tafamidis (TTR stabiliser) is first-line for cardiac ATTR. Gene-silencing agents (patisiran, vutrisiran, inotersen, eplontersen) for neurological ATTR and increasingly for cardiac ATTR.
-
Aβ2M: High-flux dialysis membranes; renal transplantation is definitive.
-
Cardiac amyloidosis pitfalls: Standard HF drugs (β-blockers, ACEi/ARBs, digoxin, CCBs) are harmful. Only diuretics + disease-directed therapy. CO is heart-rate dependent in a stiff ventricle.
-
Response assessment: Haematological response (sFLC, immunofixation) + organ response (NT-proBNP for heart, proteinuria for kidney). Haematological response must precede organ response.
Active Recall - Amyloidosis Management
References
[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, p1778 (Treatment of AL: HSCT candidates - melphalan + auto-HSCT; Non-HSCT: MDex or CyBorD; Treatment of AA: biologics tocilizumab and anakinra) [4] Senior notes: Block A - Hematology Data Interpretation.pdf, p1 (AL amyloidosis as complication of myeloma in 10%; albumin < 30 critical) [5] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf, p12, p16 (MGUS definition; AL amyloidosis as DDx of paraproteinaemia) [22] Senior notes: Block A - Inherited Cardiac conditions.pdf, p18 (RCMP causes; 10% of HFpEF is TTR amyloidosis; nuclear imaging for ATTR; no medication for idiopathic RCMP) [26] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf, p27 (Proteasome inhibitors: bortezomib, carfilzomib, ixazomib — mechanism of 26S proteasome inhibition; novel agents: daratumumab, venetoclax, CAR-T)
Complications of Amyloidosis
Complications in amyloidosis arise directly from the progressive, irreversible deposition of amyloid fibrils in organs. The beauty — and the tragedy — of this disease is that the complications are entirely predictable from the anatomy of deposition. If you understand where the amyloid goes and what it does to the local tissue (pressure atrophy, vascular fragility, functional disruption of specialised cells), every complication follows logically.
We can organise complications into:
- A. Organ-specific complications (from amyloid deposition in that organ)
- B. Complications of the underlying disease (e.g., complications of the plasma cell clone in AL, complications of chronic inflammation in AA)
- C. Treatment-related complications (chemotherapy, HSCT, immunosuppression)
A. Organ-Specific Complications
Cardiac involvement is the leading cause of death in AL amyloidosis and the dominant determinant of prognosis.
| Complication | Pathophysiology | Clinical Consequence |
|---|---|---|
| Restrictive cardiomyopathy | Amyloid infiltrates the myocardial interstitium → stiff, non-compliant ventricles → impaired diastolic filling → normal systolic function but abnormal diastolic function; rigid ventricular walls impeding ventricular filling [7] | Progressive heart failure (dyspnoea, oedema, ascites); median survival without treatment: ~6 months for Mayo Stage IV AL |
| Congestive heart failure | Restrictive physiology → elevated filling pressures in both ventricles → systemic and pulmonary congestion | Congestive HF: pulmonary rales, distended veins, ascites, peripheral oedema; Kussmaul sign/hepatojugular reflux positive (due to poor RV compliance) [7] |
| Atrial fibrillation | Amyloid deposits in atrial walls → structural remodelling → electrical heterogeneity → re-entrant circuits | AF is extremely common in cardiac amyloidosis (~70% in ATTR); increases thromboembolic risk; difficult to rate-control (β-blockers/CCBs/digoxin contraindicated) |
| Conduction system disease | Amyloid infiltrates the AV node, His bundle, and bundle branches → progressive conduction block | First-degree AV block → higher-degree AV block → complete heart block → pacemaker requirement |
| Sudden cardiac death | Electromechanical dissociation (PEA), VT/VF, complete heart block | A major cause of death; note that VT/VF is less common than PEA — this is why ICD implantation is controversial (ICD cannot treat PEA) |
| Pericardial effusion | Amyloid in pericardium + elevated filling pressures → transudation of fluid into pericardial space | Often small-to-moderate; contributes to low ECG voltage; rarely causes tamponade |
| Intracardiac thrombus | Atrial dysfunction (mechanical standstill even in sinus rhythm) + AF → blood stasis in atria | Systemic embolism (stroke, peripheral embolism); LA appendage thrombus common even without AF on telemetry |
Amyloidosis: low voltage, despite echo being very thick → associated with pericardial effusion; amyloid is toxic, damaging myocardium, and infiltrating and insulating the myocardium, resulting in dampening of voltage (limb leads less than 5, chest leads all less than 10) [27].
High Yield — Why Cardiac Amyloidosis is So Lethal
In AL amyloidosis, cardiac involvement determines survival. The toxic light chain oligomers are directly cardiotoxic (inducing oxidative stress and apoptosis in cardiomyocytes) ON TOP of the mechanical disruption from fibril deposition. This dual mechanism explains why AL cardiac amyloidosis has a worse prognosis than ATTR cardiac amyloidosis, even when ATTR has a greater amyloid burden on imaging. Without treatment, median survival with cardiac AL is only 6-12 months.
Kidney (MC): nephrotic syndrome [2]. The kidney is the most commonly affected organ overall.
| Complication | Pathophysiology | Clinical Consequence |
|---|---|---|
| Nephrotic syndrome | Amyloid deposits in glomeruli (mesangium, GBM) → disrupts filtration barrier → massive proteinuria (>3.5 g/day) | Oedema, hypoalbuminaemia, hyperlipidaemia; frothy urine |
| Chronic kidney disease → ESRD | Progressive amyloid accumulation in glomeruli, tubules, and vasculature → nephron loss → fibrosis | Need for renal replacement therapy (HD or PD); renal transplant in selected cases |
| Nephrotic syndrome complications [4] | Heavy proteinuria → loss of plasma proteins with specific consequences: | See below |
| — Loss of globulin → infection | Immunoglobulins (especially IgG) are lost in the urine → acquired hypogammaglobulinaemia → immunodeficiency | Recurrent bacterial infections (pneumonia, UTI, cellulitis); similar to myeloma-associated immunoparesis |
| — Loss of antithrombin → thrombosis | Antithrombin III (MW ~58 kDa) is small enough to be lost in urine → hypercoagulable state | Renal vein thrombosis, deep vein thrombosis, pulmonary embolism |
| — Hyperlipidaemia | Liver compensates for albumin loss by increasing lipoprotein production (especially LDL) | Accelerated atherosclerosis |
| Renal tubular acidosis | Amyloid in renal tubules disrupts acid-base handling | Metabolic acidosis (type 1 or type 4 RTA) |
| Nephrogenic diabetes insipidus | Amyloid in collecting ducts disrupts aquaporin function → inability to concentrate urine | Polyuria, polydipsia |
Nephrotic syndrome complications: Loss of globulin → infection; Loss of antithrombin → thrombosis; Hyperlipidemia [4].
Amyloidosis as a Cause of Renal Failure in Myeloma
Other mechanisms of kidney injury in myeloma include: hypercalcaemia, dehydration, amyloidosis and direct myeloma deposition (the last two are rare) [28][29].
In the context of multiple myeloma, cast nephropathy (myeloma kidney) is the predominant cause of renal failure, not amyloidosis. However, AL amyloidosis presents with nephrotic syndrome (heavy albuminuria), whereas cast nephropathy presents with AKI and bland sediment. The clinical distinction matters because management differs entirely.
Amyloidosis affects the whole body … New would be affecting nerves → autonomic neuropathy, postural hypotension caused by amyloidosis [4].
| Complication | Pathophysiology | Clinical Consequence |
|---|---|---|
| Peripheral sensorimotor neuropathy | Amyloid deposits in endoneurium + vasa nervorum ischaemia → axonal degeneration (length-dependent) | Painful paresthesias, numbness (small fibre first → then large fibre), foot drop, muscle wasting, difficulty walking |
| Autonomic neuropathy | Amyloid infiltrates autonomic ganglia and nerve fibres → disrupts sympathetic/parasympathetic function | Orthostatic hypotension (dangerous — can cause syncope, falls, head injury); gastroparesis; early satiety; alternating constipation/diarrhoea; urinary retention; erectile dysfunction; anhidrosis |
| Carpal tunnel syndrome | Amyloid deposition in flexor retinaculum → median nerve compression | Hand numbness, thenar wasting; often bilateral; may precede systemic diagnosis by years (especially ATTR) |
| Gastroparesis | Amyloid in myenteric (Auerbach's) plexus + smooth muscle → GI dysmotility | Gastroparesis causes include neurological disease (e.g. Parkinsonism, amyloidosis) [30] — nausea, vomiting, early satiety, abdominal distension |
Causes of mononeuritis multiplex include: amyloidosis, diabetes mellitus, RA, SLE, PAN, Wegener's, leprosy, carcinomatosis, Churg-Strauss [31]. Amyloid neuropathy can occasionally present as mononeuritis multiplex rather than the more typical symmetric polyneuropathy.
| Complication | Pathophysiology | Clinical Consequence |
|---|---|---|
| GI bleeding | Amyloid in submucosal vessel walls → vascular fragility + loss of vasomotor responses to injury | Occult or overt GI bleeding (haematemesis, melaena, haematochezia); can be life-threatening |
| Malabsorption | Mucosal amyloid infiltration + autonomic neuropathy → villous atrophy + dysmotility → impaired nutrient absorption | Chronic diarrhoea, steatorrhoea, weight loss, nutritional deficiencies |
| Intestinal pseudo-obstruction | Amyloid in muscularis propria and myenteric plexus → loss of coordinated peristalsis | Abdominal distension, vomiting, obstipation; mimics mechanical obstruction but no structural block present |
| Hepatomegaly | Amyloid in space of Disse → massive liver enlargement | Firm, smooth, non-tender hepatomegaly; cholestatic LFT pattern (↑ALP, ↑GGT disproportionate to transaminases); rarely progresses to hepatic failure (amyloid liver function is surprisingly preserved until very late) |
| Splenic involvement | Amyloid in splenic sinusoids and red pulp | Splenomegaly; functional hyposplenism (leading to susceptibility to encapsulated organisms — Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) |
| Complication | Pathophysiology | Clinical Consequence |
|---|---|---|
| Acquired Factor X deficiency | Factor X binds avidly to amyloid fibrils in tissues → sequestered out of circulation → reduced plasma Factor X activity | Prolonged PT/aPTT; mucocutaneous bleeding; life-threatening haemorrhage; almost unique to AL amyloidosis |
| Vascular fragility / purpura | Amyloid weakens vessel walls → loss of structural integrity and vasomotor tone | Periorbital ecchymoses ("raccoon eyes"), pinch purpura; spontaneous bruising |
| Immunoparesis | In AL: clonal plasma cells suppress normal immunoglobulin production; nephrotic syndrome adds urinary Ig loss | Recurrent infections — pneumonia, UTI, cellulitis |
| Hyperviscosity (rare in AL; more common in WM-associated amyloidosis) | Very high M protein → increased serum viscosity | Visual disturbance, headache, confusion, bleeding |
| Complication | Pathophysiology | Clinical Consequence |
|---|---|---|
| Pleural effusion | Cardiac amyloidosis → elevated filling pressures → transudative effusion; OR direct pleural amyloid → exudative effusion | Dyspnoea; often bilateral, recurrent, difficult to manage; sometimes the presenting feature of AL amyloidosis |
| Tracheobronchial amyloidosis | Localised amyloid deposition in the airway submucosa | Airway narrowing, stridor, recurrent pneumonia; may be localised or part of systemic disease |
| Pulmonary parenchymal nodules | Amyloid nodules within lung parenchyma | Usually asymptomatic; incidental finding on imaging; DDx with malignancy |
| Complication | Pathophysiology | Clinical Consequence |
|---|---|---|
| Primary adrenal insufficiency | Amyloid deposition → adrenal gland degeneration [32] | Fatigue, hypotension, hyperkalaemia, hyponatraemia, hypoglycaemia; requires cortisol replacement |
| Thyroid infiltration | Amyloid in thyroid gland | Goitre, hypothyroidism (rare clinically significant) |
| Complication | Type | Pathophysiology |
|---|---|---|
| Carpal tunnel syndrome | AL, ATTR, Aβ2M | Amyloid in flexor retinaculum compresses median nerve |
| Destructive arthropathy | Aβ2M (dialysis-related) | β2-microglobulin amyloid deposits in synovium and periarticular structures → joint destruction |
| Bone cysts / pathological fractures | Aβ2M | Amyloid deposits weaken bone → cystic lesions → fractures |
| "Shoulder pad" sign | AL | Periarticular amyloid infiltration around glenohumeral joint |
| Macroglossia → dysphagia, airway compromise | AL | Progressive tongue enlargement can cause obstructive sleep apnoea, difficulty swallowing, and in severe cases, airway obstruction |
Dialysis-related amyloidosis: due to inability to clear β2-microglobulin; risk increases with prolonged PD/HD [33][34].
This is listed as a specific complication of long-term haemodialysis:
- Dialysis-related amyloidosis is a recognised long-term complication of haemodialysis [34].
- Manifests after >8–10 years on dialysis (less common with modern high-flux membranes and haemodiafiltration).
- Predominantly musculoskeletal: bilateral CTS (earliest), destructive spondyloarthropathy, bone cysts (femoral neck, acetabulum, humerus), pathological fractures.
- Prevention: use high-flux/super-flux membranes, online haemodiafiltration; ultimately renal transplantation halts and may partially reverse the process.
B. Complications of the Underlying Disease
These are complications of the cause of the amyloidosis, not the amyloid deposits themselves:
| Complication | Mechanism |
|---|---|
| Progression to overt multiple myeloma | ~10% of AL patients have co-existing MM at diagnosis; the plasma cell clone can evolve to fulfil CRAB criteria |
| Recurrent infections | Immunoparesis (suppression of normal Ig classes by the dominant clone) + urinary Ig losses from nephrotic syndrome |
| Hypercalcaemia (if concurrent MM) | Osteoclast activation by myeloma-derived cytokines → bone resorption → hypercalcaemia → confusion, constipation, polyuria, nephrocalcinosis |
| Anaemia | BM infiltration by clonal plasma cells; chronic disease; renal failure (reduced EPO); dilutional |
Cardiac failure: secondary to amyloidosis / anaemia / hyperviscosity [19]. Multiple mechanisms can contribute to heart failure in myeloma-related AL amyloidosis.
| Complication | Mechanism |
|---|---|
| Complications of the underlying inflammatory disease | RA joint destruction, IBD strictures/fistulae, FMF serositis attacks, TB dissemination |
| Drug side effects | Long-term DMARD/biologic therapy → infections, hepatotoxicity, cytopenias |
| Amyloidosis as a complication of JIA | Others: amyloidosis listed as a complication of juvenile idiopathic arthritis [35]. Chronic childhood inflammation → decades of elevated SAA → AA amyloid deposition in young adulthood |
C. Treatment-Related Complications
| Complication | Agent | Mechanism |
|---|---|---|
| Peripheral neuropathy | Bortezomib | Dose-limiting neurotoxicity; problematic because amyloid neuropathy may already exist → additive damage. Subcutaneous route and weekly (rather than twice-weekly) dosing reduce risk. |
| Myelosuppression (cytopenias, neutropenic sepsis) | Melphalan, cyclophosphamide | Alkylating agents damage haematopoietic progenitors |
| Infusion reactions | Daratumumab | First-dose reaction common (~50%); pre-medication with steroids + antihistamine + antipyretic |
| Hyperglycaemia, infection, insomnia, psychosis | Dexamethasone | Glucocorticoid side effects |
| Secondary MDS/AML | Melphalan (especially cumulative high-dose) | Alkylating agent-induced DNA damage to HSCs → myelodysplasia/leukaemia years later |
Post-transplant recovery: protective isolation, G-CSF, antibacterial/antiviral/antifungal prophylaxis, revaccination (infection); immunosuppressant e.g. steroid (rejection) [2].
| Timing | Complication | Detail |
|---|---|---|
| Early (< 100 days) | Neutropenic infections: bacteria, Candida, Aspergillus, HSV reactivation [2] | BM aplasia from conditioning → profound neutropenia → susceptible to opportunistic infections |
| Mucositis | Conditioning regimen damages rapidly dividing mucosal cells → painful oral/GI ulceration | |
| Cardiac arrhythmias / sudden death | Patients with cardiac amyloidosis are at highest risk during peri-transplant period due to fluid shifts and cytokine release → this is why careful cardiac selection criteria exist | |
| Engraftment syndrome | Fever, rash, pulmonary infiltrates during neutrophil recovery | |
| Late (> 100 days) | Encapsulated bacterial infection, VZV [2] | Reconstitution of humoral immunity is slow → susceptible to pneumococcus, H. influenzae, VZV reactivation |
| Secondary malignancy (MDS/AML) | From alkylating agent conditioning | |
| Relapse of AL amyloidosis | Clone not fully eradicated → light chain production resumes |
| Type | Main Determinant of Prognosis | Median Survival (Untreated/Historical) | Median Survival (With Modern Therapy) |
|---|---|---|---|
| AL — no cardiac involvement | Haematological response depth | ~4 years | >10 years (if complete haematological response achieved) |
| AL — cardiac involvement | Mayo cardiac stage | Stage IIIb: ~6 months; Stage IV: ~3–4 months | Stage IIIb: ~2 years with DaraCyBorD; Stage IV remains poor |
| AA | Control of SAA | ~10 years (if SAA suppressed) | Excellent if underlying disease controlled; renal transplant if ESRD |
| ATTRwt | Degree of cardiac involvement | ~3.5 years from diagnosis (historical) | >5 years with tafamidis |
| ATTRv | Mutation type, organ involvement | Variable (Val30Met: ~10 years from symptom onset) | Improving with gene-silencing therapy |
| Aβ2M | Duration of dialysis | Does not usually cause death directly | Excellent after renal transplant |
Albumin anything lower than 30 is critical, have to work fast [4]. In AL amyloidosis, hypoalbuminaemia reflects the severity of nephrotic losses and/or hepatic infiltration and is an independent adverse prognostic marker in multiple staging systems.
High Yield Summary — Complications of Amyloidosis
-
Cardiac complications are the leading cause of death in AL amyloidosis. Restrictive cardiomyopathy, AF, conduction disease, and sudden cardiac death (often PEA, not shockable VT/VF) dominate the clinical course.
-
Renal complications: Nephrotic syndrome is the most common presentation. Downstream complications include infection (loss of immunoglobulins), thrombosis (loss of antithrombin III), and hyperlipidaemia.
-
Neurological complications: Length-dependent sensorimotor neuropathy + autonomic neuropathy (orthostatic hypotension, gastroparesis, erectile dysfunction). Bilateral CTS may precede systemic disease by years.
-
GI complications: Bleeding (vascular fragility), malabsorption, pseudo-obstruction, massive hepatomegaly.
-
Haematological complications: Acquired Factor X deficiency (unique to AL) → bleeding tendency; immunoparesis → infection.
-
Dialysis-related amyloidosis (Aβ2M): CTS, destructive arthropathy, bone cysts — a complication of prolonged haemodialysis.
-
Treatment complications: Bortezomib neuropathy, melphalan-related MDS/AML, post-HSCT neutropenic infections, cardiac decompensation peri-transplant.
-
Amyloidosis as a complication of other diseases: ~10% of MM develop AL; AA complicates RA, IBD, JIA, FMF, chronic infections; adrenal amyloidosis → primary adrenal insufficiency.
Active Recall - Complications of Amyloidosis
References
[2] Senior notes: Maksim Medicine Notes.pdf, p182 (Amyloidosis types, clinical features; HSCT complications: infection early/late, graft rejection, GVHD) [4] Senior notes: Block A - Hematology Data Interpretation.pdf, p1 (Nephrotic syndrome complications: loss of globulin, antithrombin, hyperlipidaemia; autonomic neuropathy; albumin < 30 critical) [7] Senior notes: Ryan Ho Cardiology.pdf, p170 (RCMP definition, signs of congestive HF, Kussmaul sign) [19] Senior notes: Ryan Ho Haemtology.pdf, p106 (MM complications: bleeding, amyloidosis, cardiac failure secondary to amyloidosis/anaemia/hyperviscosity) [27] Senior notes: Block A - Introduction to CVS investigations (including ECG).pdf, p10 (Amyloidosis low voltage despite thick echo walls; pericardial effusion; toxic damage and insulation of myocardium) [28] Lecture slides: GC 030. An old man with bone pain and anaemia.pdf, p29 (Myeloma renal complications: cast nephropathy predominant; amyloidosis rare mechanism) [29] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf, p19 (Myeloma kidney complications; amyloidosis as rare cause) [30] Senior notes: Block A - Indigestion and 'heartburn'_ nausea and vomiting; gastric motility problems; benign esophageal lesions.pdf, p26 (Gastroparesis causes: amyloidosis listed under neurological disease) [31] Senior notes: Ryan Ho Neurology.pdf, p180 (Causes of mononeuritis multiplex and polyneuropathy including amyloidosis) [32] Senior notes: Ryan Ho Chemical Path.pdf, p32 (Major causes of primary adrenal insufficiency: amyloidosis listed under degeneration) [33] Senior notes: Ryan Ho Urogenital.pdf, p115 (Dialysis-related amyloidosis: inability to clear β2-microglobulin; risk with prolonged PD/HD) [34] Senior notes: Block A - Renal Replacement Therapies.pdf, p25 (Dialysis-related amyloidosis listed as complication of haemodialysis) [35] Senior notes: Adrian Lui Pediatrics Notes.pdf, p454 (Amyloidosis listed as complication of JIA)
High Yield Summary
-
Definition: Amyloidosis = extracellular deposition of misfolded protein in β-pleated sheet conformation → organ dysfunction via pressure atrophy (not inflammation).
-
Classification by precursor protein: AL (light chain — most common systemic), AA (serum amyloid A — secondary to chronic inflammation), ATTR (transthyretin — hereditary or wild-type/senile), Aβ2M (β2-microglobulin — dialysis-related).
-
AL amyloidosis: Plasma cell dyscrasia produces amyloidogenic light chains (λ > κ). Can arise from MGUS, SMM, or MM (~10%). Affects kidney (nephrotic syndrome — MC), heart (restrictive CMP), nerves, liver, soft tissues. Macroglossia and periorbital purpura are pathognomonic.
-
AA amyloidosis: Chronic inflammation → persistent SAA elevation → AA fibrils. Mainly affects kidneys. Does NOT cause cardiac or neurological disease. Potentially reversible if inflammation controlled.
-
ATTR amyloidosis: Wild-type (elderly men, cardiac dominant) vs hereditary (TTR mutations, neuropathy ± cardiomyopathy). Bilateral CTS may precede diagnosis by years.
-
Cardiac amyloidosis hallmark: Low voltage on ECG + increased wall thickness on echo = "voltage-mass mismatch." Amyloidosis is the most common cause of restrictive cardiomyopathy.
-
Diagnosis: Congo red stain → apple-green birefringence under polarised light. Must type the amyloid (immunohistochemistry / mass spectrometry) because treatment differs completely by type.
-
Biopsy: Abdominal fat pad aspiration (screening), rectal biopsy, or organ biopsy (definitive). Bone marrow biopsy simultaneously assesses for plasma cell clone in AL.
-
Key labs for AL: SPEP + immunofixation, serum free light chains (κ/λ ratio), UPEP + immunofixation — combination sensitivity >95%.
-
Albumin < 30 is critical in AL amyloidosis → must work fast [4]. Low albumin reflects nephrotic losses or cardiac cachexia and is a poor prognostic marker.
High Yield Summary — Differential Diagnosis of Amyloidosis
-
Think of amyloidosis in the DDx of: nephrotic syndrome (especially age >50 without DM), restrictive cardiomyopathy (especially with low ECG voltage + thick walls), unexplained peripheral/autonomic neuropathy, massive hepatomegaly, macroglossia, periorbital purpura, and bilateral CTS in the elderly.
-
Once amyloid is confirmed, the critical DDx is BETWEEN types: AL vs AA vs ATTR vs Aβ2M. This determines treatment.
-
AL vs LCDD vs cast nephropathy: All are monoclonal light chain-related renal diseases. Congo red positivity distinguishes AL; LCDD is Congo red negative with granular deposits; cast nephropathy shows tubular casts with giant cell reaction.
-
Cardiac amyloidosis vs HCM: Voltage-mass mismatch (low ECG voltage + thick walls) = amyloidosis. High ECG voltage + thick walls = HCM. 99mTc-PYP scan differentiates ATTR from AL.
-
AL amyloidosis is the most important DDx of MGUS — any patient with MGUS developing organ dysfunction must be evaluated for AL amyloidosis.
-
Restrictive CMP vs constrictive pericarditis: History of infiltrative disease, S3, wall thickening, ↑BNP → RCMP. History of pericarditis, pericardial knock, calcification, ↑pericardial thickness → constrictive pericarditis.
High Yield Summary — Diagnostics for Amyloidosis
-
Histological confirmation: Congo red stain → apple-green birefringence under polarised light. EM shows non-branching fibrils 7–13 nm.
-
Typing is mandatory: IHC or mass spectrometry on the biopsy. Never treat without knowing the type.
-
AL workup triad: SPEP + immunofixation, UPEP + immunofixation, serum FLC assay → combined sensitivity >95% for detecting a monoclonal protein.
-
Fat pad aspiration is the recommended initial biopsy (minimally invasive, ~70–80% sensitivity for AL). If negative with high suspicion → organ biopsy.
-
99mTc-PYP/DPD scan: Non-invasive diagnosis of cardiac ATTR — Grade 2-3 uptake WITHOUT monoclonal protein = diagnostic (avoids endomyocardial biopsy).
-
Voltage-mass mismatch (low ECG voltage + thick echo walls) is the trigger for cardiac amyloid workup.
-
Staging: Mayo 2012 uses NT-proBNP, hsTnT, dFLC. Stage IV (all elevated) has median survival of only ~6 months.
-
Always exclude concurrent myeloma: ~10% of AL patients have co-existing MM → check CRAB criteria, skeletal imaging, BM plasma cell percentage.
High Yield Summary — Management of Amyloidosis
-
AL amyloidosis:
- Transplant-eligible → bortezomib-based induction → high-dose melphalan → autologous HSCT.
- Transplant-ineligible → DaraCyBorD is the new standard first-line (ANDROMEDA trial); alternatives include CyBorD or MDex.
- Key drugs: bortezomib (proteasome inhibitor), daratumumab (anti-CD38), cyclophosphamide (alkylator), dexamethasone.
- Goal: complete haematological response (negative immunofixation + normal sFLC ratio) → organ response follows.
-
AA amyloidosis: Treat underlying inflammation. Biologics (tocilizumab, anakinra) for rheumatological causes. Colchicine for FMF. Target SAA < 10 mg/L. Most "reversible" form.
-
ATTR amyloidosis: Tafamidis (TTR stabiliser) is first-line for cardiac ATTR. Gene-silencing agents (patisiran, vutrisiran, inotersen, eplontersen) for neurological ATTR and increasingly for cardiac ATTR.
-
Aβ2M: High-flux dialysis membranes; renal transplantation is definitive.
-
Cardiac amyloidosis pitfalls: Standard HF drugs (β-blockers, ACEi/ARBs, digoxin, CCBs) are harmful. Only diuretics + disease-directed therapy. CO is heart-rate dependent in a stiff ventricle.
-
Response assessment: Haematological response (sFLC, immunofixation) + organ response (NT-proBNP for heart, proteinuria for kidney). Haematological response must precede organ response.
High Yield Summary — Complications of Amyloidosis
-
Cardiac complications are the leading cause of death in AL amyloidosis. Restrictive cardiomyopathy, AF, conduction disease, and sudden cardiac death (often PEA, not shockable VT/VF) dominate the clinical course.
-
Renal complications: Nephrotic syndrome is the most common presentation. Downstream complications include infection (loss of immunoglobulins), thrombosis (loss of antithrombin III), and hyperlipidaemia.
-
Neurological complications: Length-dependent sensorimotor neuropathy + autonomic neuropathy (orthostatic hypotension, gastroparesis, erectile dysfunction). Bilateral CTS may precede systemic disease by years.
-
GI complications: Bleeding (vascular fragility), malabsorption, pseudo-obstruction, massive hepatomegaly.
-
Haematological complications: Acquired Factor X deficiency (unique to AL) → bleeding tendency; immunoparesis → infection.
-
Dialysis-related amyloidosis (Aβ2M): CTS, destructive arthropathy, bone cysts — a complication of prolonged haemodialysis.
-
Treatment complications: Bortezomib neuropathy, melphalan-related MDS/AML, post-HSCT neutropenic infections, cardiac decompensation peri-transplant.
-
Amyloidosis as a complication of other diseases: ~10% of MM develop AL; AA complicates RA, IBD, JIA, FMF, chronic infections; adrenal amyloidosis → primary adrenal insufficiency.
Diabetic Nephropathy
Diabetic nephropathy is a progressive kidney disease caused by long-standing diabetes mellitus, characterized by glomerular hyperfiltration, thickening of the glomerular basement membrane, mesangial expansion, and nodular glomerulosclerosis (Kimmelstiel-Wilson lesions), ultimately leading to proteinuria and declining renal function.
Membranoproliferative Glomerulonephritis
Membranoproliferative glomerulonephritis is a pattern of glomerular injury characterized by mesangial cell proliferation, mesangial matrix expansion, and thickening of the glomerular basement membrane due to subendothelial immune complex deposits or complement dysregulation, resulting in a lobular appearance on light microscopy and a "tram-track" double-contour pattern on silver stain.