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PH-FD16

Amyloidosis

How misfolded proteins stack into insoluble fibrils that collect between cells: where the precursor proteins come from, the main types, how amyloid is recognised under the microscope, and why it stiffens the heart and makes the kidneys leak protein.

By the end, you can

  • Explain how a soluble precursor protein misfolds into cross-β fibrils that resist breakdown.
  • Relate the main types (AL, AA, ATTR, β2-microglobulin and localised forms) to their precursor proteins and causes.
  • Describe the gross and microscopic appearance of amyloid, including Congo red staining.
  • Explain how amyloid in the kidney, heart, nerves and other organs produces their typical findings.
  • Distinguish systemic from localised amyloidosis.
  • Recognise the classic gross and microscopic appearances and the tests that confirm and type amyloid, and explain how cutting the supply of each precursor protein treats it.

What it is

Amyloidosis is the deposition, between cells, of amyloid: insoluble fibrils formed when a precursor protein misfolds into a cross-β-pleated sheet structure. More than 30 different proteins can do this. Each type is named after its precursor (AL from immunoglobulin light chains, AA from serum amyloid A, ATTR from transthyretin). Amyloidosis is systemic when the precursor circulates and deposits in many organs, and localised when it is made and deposited in one tissue.

4 types to tell apart
AL (light-chain) amyloidosis
A clone of plasma cells makes a misfolding immunoglobulin light chain; sometimes with myeloma. Kidney, heart, nerves, gut, tongue and skin.
AA amyloidosis
Long-standing inflammation keeps serum amyloid A high: rheumatoid arthritis, inflammatory bowel disease, chronic infection, inherited fever syndromes. Kidney first.
ATTR amyloidosis
Transthyretin misfolds: the normal (wild-type) protein in older people, mainly the heart; or an inherited variant, with neuropathy, heart disease or both.
Dialysis-related and localised forms
β2-microglobulin in joints after years of dialysis; Aβ in Alzheimer disease, islet amyloid in type 2 diabetes, calcitonin-derived amyloid in medullary thyroid carcinoma.

Normal function

Proteins fold, work and are cleared

A new protein chain made on must fold into one precise shape to work. Proteins for export fold in the , helped by chaperone proteins, and pass through the ; chains that misfold are recognised and destroyed.

Some proteins circulate in large amounts. Plasma cells make antibodies, each built of heavy and light chains, and release a small excess of free light chains, which the kidneys filter and break down. In inflammation, cytokines drive the liver to make the acute-phase protein serum amyloid A. The liver also makes transthyretin, a four-part carrier of thyroid hormone and vitamin A.

Folded proteins are stable, but not permanently: proteins that are made in excess, that carry a mutation or that are long-lived can partly unfold. Normally the unfolded ones are cleared before they can stick together.

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