Medicine – Amyloidosis

Amyloidosis is a group of disorders in which abnormal misfolded proteins aggregate into insoluble fibrils and are deposited in extracellular tissues. These deposits can progressively disrupt the structure and function of affected organs.

The kidney is one of the most important organs involved, but amyloid may also affect the heart, liver, spleen, gastrointestinal tract, peripheral nerves, and soft tissues.

1. What Amyloid Is

Amyloid is not one single protein.

Instead, the term describes a characteristic fibrillar protein structure that can be formed by several different precursor proteins.

The fibrils share a common appearance and staining pattern despite arising from different proteins.

2. General Mechanism

The basic sequence is:

Abnormal precursor protein → protein misfolding → fibril formation → extracellular deposition → organ dysfunction.

The exact precursor protein determines the type of amyloidosis and therefore the underlying disease and treatment.

3. Major Classification of Amyloidosis

Important systemic forms include:

AL amyloidosis.

AA amyloidosis.

ATTR amyloidosis.

Dialysis-related amyloidosis.

These categories are more useful than the older terms “primary,” “secondary,” and “senile” alone.

4. AL Amyloidosis

AL amyloidosis is caused by deposition of:

Immunoglobulin light chains.

The abnormal light chains are usually produced by a clonal population of:

Plasma cells.

This is why AL amyloidosis is strongly associated with plasma-cell disorders.

5. Primary Amyloidosis

The older term:

Primary amyloidosis

usually refers to:

AL amyloidosis.

It may occur with a relatively small plasma-cell clone or alongside a more obvious plasma-cell malignancy.

6. Multiple Myeloma and AL Amyloidosis

Multiple myeloma is associated with:

AL amyloidosis.

Therefore, myeloma should not be listed as a cause of secondary AA amyloidosis.

This is an important correction to the original notes.

The association is:

Myeloma → monoclonal immunoglobulin light chains → AL amyloid.

7. AA Amyloidosis

AA amyloidosis is the classic form of:

Secondary amyloidosis.

It occurs as a complication of chronic inflammatory or infectious disease.

The precursor protein is:

Serum amyloid A protein.

Serum amyloid A is an:

Acute-phase reactant

produced mainly by the liver during persistent inflammation.

8. Important Correction to the Original Classification

The original note states:

“Secondary amyloid – AA or AL.”

This is incorrect.

The classic pattern is:

Primary/plasma-cell-associated amyloidosis → AL.

Secondary inflammatory amyloidosis → AA.

9. Chronic Inflammation and AA Amyloidosis

Persistent inflammation causes prolonged elevation of:

Serum amyloid A.

If this continues for years, abnormal fragments can accumulate as amyloid fibrils in tissues.

The kidneys are especially vulnerable.

10. Rheumatoid Arthritis

Rheumatoid arthritis is a classical cause of AA amyloidosis.

Historically, chronic uncontrolled RA was an important cause.

With modern anti-inflammatory and biologic therapy, AA amyloidosis has become less frequent in many populations.

11. Seronegative Inflammatory Arthritis

Chronic inflammatory arthropathies can also produce AA amyloidosis.

Examples include selected cases of:

Ankylosing spondylitis.

Psoriatic arthritis.

Other chronic inflammatory arthritides.

The risk is related mainly to persistent inflammatory activity.

12. Systemic Sclerosis

Older lists sometimes include:

Scleroderma/systemic sclerosis

among causes of secondary amyloidosis.

However, it is not one of the strongest classical modern associations.

More important causes to remember are:

Chronic inflammatory arthritis.

Inflammatory bowel disease.

Chronic infections.

Autoinflammatory disorders.

13. Inflammatory Bowel Disease

Both:

Crohn disease

and

Ulcerative colitis

may be associated with chronic inflammation and AA amyloidosis.

The risk is greater when inflammatory activity is:

Severe and prolonged.

14. Tuberculosis

Chronic:

Tuberculosis

is a classical infectious cause of AA amyloidosis.

Before effective antimicrobial therapy, chronic infections such as TB were major causes of secondary amyloid deposition.

15. Chronic Osteomyelitis

Long-standing:

Osteomyelitis

can maintain persistent systemic inflammation.

This can produce sustained serum amyloid A elevation and eventually:

AA amyloidosis.

16. Bronchiectasis

Chronic suppurative lung disease such as:

Bronchiectasis

is another classical cause.

Repeated infection and inflammation may lead to:

AA amyloid deposition.

17. Other Causes of AA Amyloidosis

Important additional causes include:

Familial Mediterranean fever.

Other autoinflammatory syndromes.

Chronic inflammatory diseases.

Long-standing chronic infection.

Familial Mediterranean fever is a particularly high-yield modern association.

18. ATTR Amyloidosis

ATTR amyloidosis is caused by deposition of:

Transthyretin.

Transthyretin was historically called:

Prealbumin.

It is mainly produced in the liver.

19. Wild-Type ATTR Amyloidosis

The older term:

Senile systemic amyloidosis

has largely been replaced by:

Wild-type transthyretin amyloidosis, or wild-type ATTR.

It mainly affects older adults, particularly men.

The heart is commonly involved.

20. Wild-Type ATTR and the Heart

Wild-type ATTR can cause:

Restrictive/infiltrative cardiomyopathy.

Typical features may include:

Heart failure with preserved ejection fraction.

Increased ventricular wall thickness.

Conduction abnormalities.

Atrial arrhythmias.

It may also be associated with:

Carpal tunnel syndrome.

21. Hereditary ATTR Amyloidosis

Mutations in the transthyretin gene can produce:

Hereditary ATTR amyloidosis.

Depending on the mutation, patients may develop:

Peripheral neuropathy.

Autonomic neuropathy.

Cardiomyopathy.

Mixed neurological and cardiac disease.

22. Dialysis-Related Amyloidosis

Long-term dialysis may cause deposition of:

β2-microglobulin.

This is called:

Dialysis-related amyloidosis.

β2-microglobulin is normally filtered and metabolised by healthy kidneys.

23. Sites of β2-Microglobulin Deposition

Dialysis-related amyloid particularly affects:

Joints.

Bones.

Tendons.

Patients may develop:

Carpal tunnel syndrome.

Chronic arthropathy.

Bone cysts.

It is less characteristically a cause of nephrotic renal amyloidosis than AL or AA disease.

24. Renal Involvement in Amyloidosis

The kidneys are very commonly affected in:

AL

and

AA amyloidosis.

Amyloid commonly deposits within the:

Glomeruli.

It may also involve renal vessels and interstitial structures.

25. Proteinuria

One of the most common renal presentations is:

Proteinuria.

This may range from:

Mild asymptomatic albuminuria

to

Heavy nephrotic-range proteinuria.

26. Nephrotic Syndrome

Amyloid deposition in glomeruli can cause marked disruption of the filtration barrier.

The result may be:

Nephrotic syndrome.

Features include:

Heavy proteinuria.

Hypoalbuminaemia.

Peripheral oedema.

Hyperlipidaemia.

27. Chronic Kidney Disease

Progressive renal amyloid deposition may lead to:

Chronic kidney disease.

The older term:

CRF

is better replaced with:

CKD.

Advanced disease may eventually progress to:

End-stage kidney disease.

28. Haematuria

Unlike many inflammatory glomerulonephritides, prominent haematuria is not usually the dominant feature.

The renal pattern is more commonly:

Proteinuria + nephrotic syndrome + progressive renal impairment.

29. Hepatomegaly

Amyloid can deposit in the liver and produce:

Hepatomegaly.

Liver function may be relatively preserved despite marked enlargement, although alkaline phosphatase can be elevated.

30. Splenomegaly

The spleen may also be affected.

This can produce:

Splenomegaly.

Therefore, amyloidosis may present with:

Hepatosplenomegaly.

31. Macroglossia

Macroglossia is a classic feature, particularly of:

AL amyloidosis.

The tongue may become enlarged and firm because of amyloid deposition.

32. Periorbital Purpura

Another characteristic clue to AL amyloidosis is:

Periorbital purpura.

This can occur because of vascular fragility.

The combination:

Macroglossia + periorbital purpura

should strongly suggest AL amyloidosis.

33. Gastrointestinal Involvement

Amyloid deposition in the gastrointestinal tract may cause:

Malabsorption.

Diarrhoea.

Constipation.

Weight loss.

GI dysmotility.

Bleeding in some cases.

34. Peripheral Neuropathy

Amyloidosis may affect peripheral nerves.

This can cause:

Sensory neuropathy.

Painful neuropathy.

Motor weakness in advanced disease.

It is especially important in hereditary ATTR and AL amyloidosis.

35. Autonomic Neuropathy

Amyloid involvement of autonomic nerves may cause:

Postural hypotension.

Diarrhoea or constipation.

Erectile dysfunction.

Bladder dysfunction.

This can be a major feature in certain forms of amyloidosis.

36. Cardiac Amyloidosis

Amyloid deposition in the myocardium causes an:

Infiltrative cardiomyopathy.

Traditionally this is described as:

Restrictive cardiomyopathy.

Important forms include:

AL cardiac amyloidosis

and

ATTR cardiac amyloidosis.

37. Cardiac Features

Possible findings include:

Heart failure.

Exertional dyspnoea.

Peripheral oedema.

Conduction disease.

Arrhythmias.

Low blood pressure.

Syncope.

Cardiac involvement is a major determinant of prognosis.

38. ECG and Echocardiographic Pattern

A classic teaching clue is:

Increased ventricular wall thickness on echocardiography

combined with unexpectedly:

Low-voltage QRS complexes on ECG.

This mismatch can suggest cardiac amyloidosis, although it is not present in every patient.

39. Diagnosis – Tissue Biopsy

The definitive demonstration of amyloid usually requires:

Tissue sampling.

Possible sites include:

Abdominal subcutaneous fat aspiration.

Bone marrow biopsy.

Rectal biopsy, historically.

Affected-organ biopsy.

40. Abdominal Fat Pad Aspiration

A commonly used relatively low-risk test is:

Abdominal fat pad aspiration.

If positive, this can establish the presence of amyloid without requiring biopsy of a vital organ.

However, sensitivity varies according to amyloid type.

41. Organ Biopsy

If non-invasive or low-risk tissue sampling is negative but clinical suspicion remains high, biopsy may be taken from the affected organ.

Examples include:

Kidney.

Liver.

Heart.

Organ biopsy usually has high diagnostic yield but carries greater procedural risk.

42. Congo Red Staining

The classic histological stain is:

Congo red.

Amyloid deposits stain:

Salmon-pink or red

on ordinary microscopy.

43. Apple-Green Birefringence

When Congo-red-stained tissue is viewed under:

Polarised light,

amyloid demonstrates:

Apple-green birefringence.

This is the classic pathological hallmark.

44. Why Typing Amyloid Is Essential

Simply identifying amyloid is not enough.

The exact amyloid protein must be determined because treatment differs dramatically between:

AL.

AA.

ATTR.

Other rare forms.

Therefore, modern diagnosis includes:

Amyloid typing.

45. Serum and Urine Monoclonal Protein Testing

When AL amyloidosis is suspected, investigation includes looking for a monoclonal plasma-cell disorder.

Tests commonly include:

Serum free light chains.

Serum immunofixation.

Urine immunofixation.

These are more sensitive than routine serum protein electrophoresis alone.

46. Serum Amyloid P Scintigraphy

The original note lists:

Serum amyloid protein scan.

This usually refers to:

Serum amyloid P component scintigraphy, or SAP scintigraphy.

It can assess the distribution and overall burden of systemic amyloid in centres where available.

47. Limitation of SAP Scanning

SAP scintigraphy can help assess amyloid in organs such as:

Liver.

Spleen.

Kidneys.

However, it is not a complete substitute for:

Tissue diagnosis and amyloid typing.

Cardiac assessment generally requires other imaging techniques.

48. Cardiac Imaging

Cardiac amyloidosis may be investigated with:

Echocardiography.

Cardiac MRI.

Nuclear scintigraphy using bone-avid tracers in suspected ATTR.

The exact pathway depends on whether AL or ATTR is suspected.

49. Treatment Principle

Treatment depends entirely on the amyloid type.

The main objectives are:

Stop production of the amyloid precursor protein.

Treat the underlying disease.

Support affected organs.

50. Treatment of AL Amyloidosis

Because AL amyloidosis is caused by a plasma-cell clone, treatment aims to suppress:

Abnormal light-chain production.

This uses plasma-cell-directed therapy.

51. Plasma-Cell-Directed Therapy

Modern regimens may include combinations involving:

Proteasome inhibitors such as bortezomib.

Monoclonal antibody therapy such as daratumumab.

Other anti-plasma-cell drugs.

Treatment is individualised according to disease severity and organ involvement.

52. Cytotoxic Therapy

Older notes refer broadly to:

Cytotoxic therapy.

This reflects the use of chemotherapy directed against the abnormal plasma-cell clone.

Modern treatment is more targeted and often uses specific myeloma-style regimens.

53. Autologous Stem Cell Transplantation

Selected patients with AL amyloidosis may undergo:

High-dose chemotherapy followed by autologous stem cell transplantation.

This was historically referred to as:

Bone marrow transplantation.

It is suitable only for carefully selected patients because severe cardiac involvement can make the procedure high risk.

54. Treatment of AA Amyloidosis

The central treatment of AA amyloidosis is:

Aggressive control of the underlying inflammatory or infectious disease.

This reduces:

Serum amyloid A production

and may slow or sometimes partially reverse amyloid accumulation.

55. Examples of Treating the Underlying Cause

Examples include:

Effective antimicrobial treatment for chronic infection.

Biologic or disease-modifying therapy for inflammatory arthritis.

Control of inflammatory bowel disease.

Colchicine in familial Mediterranean fever.

Thus:

Control inflammation → reduce SAA → reduce further AA deposition.

56. Treatment of ATTR Amyloidosis

ATTR treatment depends on whether disease is:

Hereditary

or

Wild-type.

Modern therapy may include transthyretin stabilisers such as:

Tafamidis

for selected patients with ATTR cardiomyopathy.

Gene-silencing treatments may also be used in selected hereditary ATTR disease.

57. Treatment of Dialysis-Related Amyloidosis

For dialysis-related β2-microglobulin amyloidosis, strategies include:

Optimised high-flux dialysis.

Improved β2-microglobulin clearance.

Kidney transplantation in suitable patients.

Successful transplantation markedly reduces continued β2-microglobulin accumulation.

58. Supportive Renal Treatment

Renal amyloidosis may require:

Control of oedema.

Blood-pressure management.

Management of proteinuria.

Treatment of CKD complications.

Dialysis if kidney failure develops.

59. Prognosis

Prognosis varies greatly according to:

Amyloid type.

Degree of cardiac involvement.

Renal function.

Response to treatment.

Extent of systemic organ involvement.

The presence of significant cardiac amyloidosis is particularly important because it can markedly worsen prognosis.

60. AL Amyloidosis – Note Form

Precursor:

Immunoglobulin light chains.

Underlying problem:

Clonal plasma-cell disorder.

Associations:

Plasma-cell dyscrasia.

Multiple myeloma.

Typical clinical clues:

Proteinuria/nephrotic syndrome.

Restrictive cardiomyopathy.

Macroglossia.

Periorbital purpura.

Peripheral/autonomic neuropathy.

Treatment:

Plasma-cell-directed therapy.

Selected patients may undergo autologous stem cell transplantation.

61. AA Amyloidosis – Note Form

Precursor:

Serum amyloid A.

Cause:

Chronic inflammation or chronic infection.

Classical associations:

Rheumatoid arthritis.

Other chronic inflammatory arthritides.

Inflammatory bowel disease.

Tuberculosis.

Chronic osteomyelitis.

Bronchiectasis.

Familial Mediterranean fever.

Major renal presentation:

Proteinuria.

Nephrotic syndrome.

Progressive CKD.

Treatment:

Control the underlying inflammatory or infectious disease.

62. ATTR Amyloidosis – Note Form

Precursor:

Transthyretin.

Older name:

Prealbumin.

Wild-type ATTR:

Formerly called senile systemic amyloidosis.

Mainly affects older adults.

Often causes cardiomyopathy.

Hereditary ATTR:

Due to transthyretin gene variants.

May cause neuropathy, autonomic dysfunction, and cardiomyopathy.

63. Dialysis-Related Amyloidosis – Note Form

Precursor:

β2-microglobulin.

Association:

Long-term dialysis.

Common sites:

Joints.

Bones.

Tendons.

Clinical features:

Carpal tunnel syndrome.

Arthropathy.

Bone cysts.

64. Diagnosis – Note Form

Tissue sampling:

Abdominal fat aspiration.

Bone marrow.

Rectal biopsy historically.

Affected-organ biopsy if necessary.

Histology:

Congo red positive.

Polarised light:

Apple-green birefringence.

Further investigation:

Amyloid typing.

Serum free light chains.

Serum and urine immunofixation for AL.

SAP scintigraphy in selected centres.

Cardiac imaging where appropriate.

65. Important Corrections to the Original Notes

The original statement:

“Secondary amyloid = AA or AL”

is incorrect.

Remember:

AL = plasma-cell/light-chain amyloidosis.

AA = secondary chronic inflammatory amyloidosis.

The original list includes:

Myeloma as a cause of secondary amyloidosis.

This should be corrected to:

MULTIPLE MYELOMA → AL AMYLOIDOSIS.

The older term:

“Senile amyloid – prealbumin”

is better written as:

WILD-TYPE ATTR AMYLOIDOSIS → TRANSTHYRETIN.

The protein historically called:

Prealbumin

is now generally called:

Transthyretin.

The original term:

“Bone marrow transplantation”

is better described in appropriate AL patients as:

Autologous stem cell transplantation following high-dose chemotherapy.

The older term:

CRF

is better replaced by:

CKD – chronic kidney disease.

Key Clinical Pattern

Think of amyloidosis as:

MISFOLDED PROTEIN → EXTRACELLULAR DEPOSITION → ORGAN DYSFUNCTION.

For the major types:

AL = LIGHT CHAINS = PLASMA CELLS / MYELOMA.

AA = SERUM AMYLOID A = CHRONIC INFLAMMATION.

ATTR = TRANSTHYRETIN = HEREDITARY OR WILD-TYPE CARDIAC/NEUROLOGICAL DISEASE.

β2-MICROGLOBULIN = LONG-TERM DIALYSIS.

For the kidney:

AMYLOID → PROTEINURIA → NEPHROTIC SYNDROME → CKD.

For pathology:

CONGO RED + APPLE-GREEN BIREFRINGENCE = AMYLOID.

And a particularly high-yield clue is:

MACROGLOSSIA + PERIORBITAL PURPURA + NEPHROTIC PROTEINURIA / CARDIOMYOPATHY → THINK AL AMYLOIDOSIS.