Amyloid

What is amyloid?

A pathologic proteinaceous substance deposited between cells in various tissue and organs of the body in wide variety of clinical settings.

What happens in amyloid?

Proteins polymerise and form insoluble aggregates of fibrils (deposits)

What does the deposition of the various types of amyloid in tissues lead to? what is it called?

Leads to organ malfunction

Amyloidosis

How many different types of proteins are implicated in amyloid diseases?

over 35 different proteins

Is amyloid diseases herediatry?

Hereditary or non-hereditary

Is amyloid diseases localised?

Localised or systemic

What is amyloidosis?

A group of diseases having in common the deposition of amyloid protein

What does amyloidosis appear like on H&E?

Appears amorphous, eosinophilic hyaline extracellular substance. Characteristic appearance under polarised light.

What are the 3 components of amyloid composition?

Non branching fibrils

Non fibrillar pentagonal glycoprotein

Proteoglycans

Nonbranching fibrils are in a ?

Beta pleated sheet conformation. Varies depending on underlying disease

Nonfibrillar pentagonal glycoprotein (amyloid P component) is derived from?

A circulating serum protein called serum amyloid P (SAP)

What does the diagnosis of amyloid depend on?

On morphologic identification of amyloid deposits in appropriate biopsy specimens (histological diagnosis)

With the light microscope and standard tissue stain (H&E) amyloid is?

amorphous, eosinophilic, extracellular subsatnce, that with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells.

What is a biopsy taken of?

Directly on affected organ or on an abdominal fat pad biopsy

What are the 2 specific stains for amyloid?

Congo red

Sirius red stain

What does congo red/sirius red stain (under ordinary light impart? How?

A pink or red colour to amyloid deposits. It binds to amyloid by hydrogen bonds.

What is there on the stained amyloid when observed by polarising microscopy?

Green birefringence

What other thing can be used for certain protein?

Immunohistochemistry

What are some addition investigations that may be required with amylosis?

FBC, LFTs

Renal function tests- creatinine, eGFR, 24h proteinuria

Cardiac tests: troponin, ECG, ECHO, MRI

SPEP, light chain quantifictaion

Bone marrow biopsy

Skeletal imaging

Genetic sequencing

Historically, amyloid used to classified as?

Systemic or localised

What is systemic amyloidosis?

Generalised, involving several organ systems

What are the 2 types of systemic amyloidosis?

Primary and secondary

What is primary amyloidosis?

Associated with some immunocyte dyscrasia

What is secondary amyloidosis?

Complication of underlying chronic inflammatory or destructive tissue process

What is localised amyloidosis?

Deposits in a single organ

What is hereditary or familial amyloidosis?

Seperate yet distinctive pattern or organ involvement that is usually systemic

Current classification systems are based on?

The protein that produces the majority of the deposits, usually abbreviated starting with the letter A followed usually by first letter of what is misfolded.

Other forms are due to?

Different diseases causing over abundant or abnormal protein production

What are the most common types of amyloidosis?

AL (amyloid light chain)

AA (amyloid-associated)

Abeta amyloid

ATTR

What is AL due to?

An overproduction of immunoglobulin light chains derived from plasma cells

What is AA due to?

Continuous overproduction of acute phase proteins in chronic inflammation

What is abeta amyloid found in?

Cerebral lesions of Alzheimer's disease. Deposited in brain

What. is ATTR?

Transthyretin deposited in heartm lung, tenosynovium, ligaments

Is AL amyloid rare?

Yes minimum incidence of 8/million

What is the precursor protein of AL amyloid?

Immunoglobulin light chains derived from plasma cells (or other B cells)

Many patients have some form of what with AL amyloid?

Of a monoclonal B cell proliferation, which synthesises abnormal amounts of immunoglobulin

AL amyloid is seen in how many patients with multiple myeloma?

5-15%

The increase amounts of immunoglobulin will produce?

An M protein spike on serum electrophoresis

What are the most involved organs in AL amyloid?

Kidneys and heart

Patients with myeloma and AL amyloidosis generally follow what course?

Unremitting and ultimately fatal course , either from malignancy or from cardiac/renal complications of amyloid

What are some tx options for AL amyloid?

Bone marrow transplant or chemotherapy

What age does amyloid happen?

50-60 years

What are the symptoms?

No single set of symptoms points unequivocally to amyloidosis as a diagnosis.

WHat do symptoms depend on?

Depends very much on the subtype

• The symptomatology is governed by the underlying disease and the magnitude and site(s) of deposits.

What happens when the kidneys are involved?

commonly involved. Signs include protein in the urine, may develop nephrotic syndrome, renal insufficiency

What happens when the heart are involved?

can present with heart failure, restrictive cardiomyopathy

What happens when the liver are involved?

raised LFTs, hepatomegaly

What happens when the GIT are involved?

malabsorption

What happens when the spleen are involved?

dysfunction, abnormal erythrocytes

What would the morphology be in the kidney?

- Large, pale, grey, firm.

- Microscopic amyloid deposits principally in glomeruli and interstitial peritubular tissue, as well as walls of blood vessels. Eventual obliteration of the glomerulus.

What would the morphology be in the spleen?

- Moderate enlargement, pale, grey, waxy

- Microscopically deposits in splenic follicles (sago spleen) or involve the splenic sinuses in large sheet like deposits (lardaceous spleen)

What would the morphology be in the liver?

- Massive enlargement up to 9000g.

- Microscopic deposits in space of Disse, then hepatic parenchyma and sinusoids

- Trapped hepatocytes undergo compression atrophy and get replaced by amyloid

What would the morphology be in the heart?

- Mild to moderate enlargement, grey pink subendocardial

elevations especially in the atria

- Microscopically,depositsthroughoutmyocardium,first between myocardial fibres, then causing pressure atrophy

What would the morphology be in the endocrine system?

What would the morphology be in the GIT?

What would the morphology be in the Tongue?

What would the morphology be in the synovial tissue?

-

-

what are the 3 most common forms of amyloidosis?

AA, AL (90%) and ATTR

How can you diagnose it?

A biopsy followed by confirmation with Congo Red staining is the most

important tool in the diagnosis.

- This is usually done in an organ suspected to be involved - e.g. kidney, gingival, rectal, or abdominal 'fat pad' biopsy

- Immunohistochemistry may also be used

For AL, what could also. be performed?

For AL, serum and urinary protein electrophoresis may be performed

The outlook for patient presenting late with generalised amyloidosis is?

poor with a mean survival time of 1-3yrs after diagnosis.

In AA amyloidosis, prognosis depends on?

Controlling underlying condition

In AA amyloid, deposits are composed of?

Deposits are composed of AA amyloid, derived from a larger serum precursor synthesized in the liver called SAA (serum amyloid- associated) protein.

In AA amyloid, deposits are ---- in distribution.

systemic

What is AA amyloid also known as?

Sometimes known as secondary amyloidosis as it is associated with inflammatory conditions, eg RA, TB, osteomyelitis, inflammatory bowel disease, ankylosing spondylitis.

What is SAA?

SAA is a normal plasma protein synthesised in the liver, under influence of cytokines such as IL6 and IL1, as part of the physiologic acute phase response.

If AA is untreated, it is associated with?

If untreated, it is associated with significant mortality due to end- stage renal disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding

Why is active management of the underlying inflammatory process critical?

Active management of the underlying inflammatory process is critical in lowering the hepatic production of the SAA proteins (eg biologic agents in RA)

AL and AA amyloid tend to deposit where?

AL and AA amyloid tend to deposit systemically. Some forms of amyloid however are localised.

What are examples of endocrine amyloid produced by certain tumours?

- Islet cell tumours of the pancreas.

- Thyroid medullary carcinoma.