• 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.

• 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).

All types of amyloidosis share the same fundamental mechanism:

Two mechanisms by which amyloid damages tissues:

1. Mechanical disruption: fibrils physically displace and compress parenchymal cells → pressure atrophy (this is the dominant mechanism for most organ damage).
2. 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.

The International Society of Amyloidosis (ISA) classifies amyloidosis by the precursor fibril protein using the prefix "A" (for amyloid) followed by the protein abbreviation:

AL vs AA vs β2-microglobulin vs transthyretin — these are the four major systemic types to know ^[4].

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:

^[7]

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):

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.

Restrictive cardiomyopathy — Aetiology: Myocardial: amyloidosis (most common), idiopathic, scleroderma, sarcoidosis, haemochromatosis, glycogen storage disease, Gaucher's disease ^[7].

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].

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)

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].

If suspecting amyloidosis, have to differentiate between the transthyretin, AL/primary (associated with increase in immunoglobulins), AA/secondary type ^[6].

For AL amyloidosis specifically, diagnosis requires ALL of the following:

1. Biopsy-proven amyloid with Congo red positivity ± apple-green birefringence
2. Amyloid typed as AL (immunohistochemistry or mass spectrometry showing light chain composition)
3. Evidence of a monoclonal plasma cell proliferative disorder: at least ONE of:
   • Monoclonal protein on serum protein electrophoresis +/- immunofixation ^[10]
   • Abnormal serum free light chain (FLC) ratio ^[3]
   • Monoclonal plasma cells on bone marrow biopsy ^[3]
4. Evidence of amyloid-related organ involvement (at least one organ affected — see organ-specific criteria below)

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.

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].

• 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).

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:

Uses three biomarkers to stratify prognosis:

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.

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.

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).

• 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.

Cardiac involvement is the leading cause of death in AL amyloidosis and the dominant determinant of prognosis.

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].

Kidney (MC): nephrotic syndrome ^[2]. The kidney is the most commonly affected organ overall.

Nephrotic syndrome complications: Loss of globulin → infection; Loss of antithrombin → thrombosis; Hyperlipidemia ^[4].

Amyloidosis affects the whole body … New would be affecting nerves → autonomic neuropathy, postural hypotension caused by amyloidosis ^[4].

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.

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.

Cardiac failure: secondary to amyloidosis / anaemia / hyperviscosity ^[19]. Multiple mechanisms can contribute to heart failure in myeloma-related AL amyloidosis.

Post-transplant recovery: protective isolation, G-CSF, antibacterial/antiviral/antifungal prophylaxis, revaccination (infection); immunosuppressant e.g. steroid (rejection) ^[2].