Amyloid

Amyloid is one of those things clinicians can put in many differential diagnoses. The pathologist can diagnose it.

Amyloid
Diagnosis in short
Cardiac amyloidosis. H&E stain.
LM	typically extracellular, amorphous (no specific shape), acellular and pink (on H&E stain) -- cotton candy like, classically has a "cracked" appearance
Subtypes	multiple subclassifications: Robbins (AL amyloidosis, AA amyloidosis, non-AA and non-AL), set of six subtypes (primary (AL amyloidosis), secondary (AA amyloidosis, hemodialysis-related, localized), hereditary, senile systemic amyloidosis)
LM DDx	fibrin, collagen, smooth muscle
Stains	Congo red +ve
EM	non-branching fine fibrils - usually 8-12 nm in diameter (accepted range 8-15 nm)
Molecular	beta sheet
Gross	waxy appearance
Site	pretty much anywhere, blood vessels
Associated Dx	very many
Clinical history	variable
Prevalence	uncommon
Prognosis	dependent on subtype

This article is a general overview of the topic. Links are provided to articles that deal with amyloidosis at specific sites, see site specific section below.

Overview

Definition

• Disorder of protein folding - structure: beta sheet.

Appearance

Light microscopy

Features:

• Pink (on H&E stain).
• Extracellular location.
• Amorphous - no specific shape.
• May have a "cracked" appearance.^{[citation needed]}

Classic DDx - ABCs of pink:

• Amyloid.
• Blood (fibrin).
• Collagen.
• Smooth muscle.

Other considerations:

• Foreign material, e.g. lifting agent "O'rise".

Images

• 

  Amyloid - H&E stain. (WC)

• 

  Amyloid - congo red stain. (WC)

Electron microscopy

Features:

• Fine fibrils, non-branching.
  • Usually 8-12 nm in diameter; accepted range 8-15 nm.

Images:

• Amyloid (fondazionedamico.org).
• Amyloid (fondazionedamico.org).

DDx

• CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).
  • Typically has basophilic granularity in the blood vessels.

Stains

• Congo red +ve.
  • Positive:
    • Orange/light red (non-polarized light).
    • Apple green birefringence (polarized light).
  • Negative:
    • Blue birefringence (polarized light) = collagen fibers.
• Thioflavin T stain.
• Sodium sulphate-Alcian Blue stain +ve.

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BONE LESION, RIGHT ILIAC, BIOPSY:
- AMYLOID ASSOCIATED WITH HISTOCYTES, GIANT CELLS AND A FEW LYMPHOCYTES
  AND PLASMA CELLS.

COMMENT:
The presence of amyloid is confirmed with congo red staining and polarization.

There are no histomorphologic findings suggestive of a plasma cell neoplasm
in this biopsy.

Clinical correlation with serum protein electrophoresis, urine protein electrophoresis
and bone marrow sampling is suggested.

Associations - DDx

• Infections:
  • Tuberculosis.
  • Leprosy.
  • Chronic osteomyelitis.
  • Bronchiectasis.
• Idiopathic conditions:
  • Rheumatoid arthritis - relatively common (compared to others below).
  • Anklyosing spondylitis - renal amyloidosis.
  • Crohn's disease.
  • Familial Mediterranean fever.
• Malignancy.
  • Plasmacytoma.
    • 5-15% of patients with multiple myeloma develop amyloidosis - some say 10-20%.
  • Medullary thyroid carcinoma.
  • Renal cell carcinoma.
• Many other conditions...

Classification

Amyloidosis can be classified a number of different ways.

Six subtypes classification

Amyloid classified into six groups:

1. Primary (AL amyloidosis).
   • Monoclonal light chains in serum and/or urine, may be due to plasma cell dyscrasia.
2. Secondary (AA amyloidosis).
   • Infections (osteomyelitis), neoplasia (Hodgkin's lymphoma).
3. Hemodialysis-related.
   • Beta-2 microglobulin.
4. Localized.
   • Abeta amyloid found in Alzheimer's disease.
   • Pancreatic amyloid deposition associated with diabetes mellitus type 2.
     • Image: Amyloid in DM (med.utah.edu).
5. Hereditary.
6. Senile systemic amyloidosis.

How to remember: Two As = secondary amyloidosis.

Three main types - Robbins classification

Amyloid classified into three groups:

1. AL amyloidosis - "AL" = Amyloid Light chain.
   • Primary amyloidosis.
   • Bence Jones protein (light chains -- kappa or lambda) +ve -- necessary for amyloidosis but not sufficient.
2. AA amyloidosis - "AA" = Amyloid Associated.
   • Secondary amyloidosis.
3. Abeta amyloid - found in Alzheimer's disease.

Additional types:

• ATTR = Amyloid Transthyretin (TTR)
  • Transthyretin - serum protein that transport thyroxine and retinol; transthyretin AKA prealbumin.

Treatment

The very short version:

• AL - chemotherapy & stem cell transplant.
• AA - treat underlying cause.

Classification of amyloid - differentiation

Biochemical techniques

• Pre-treated with potassium permanganate, to obliterate congo red reactivity, was though be definitive for AA amyloidosis; this is now generally considered to be unreliable.

Immunohistochemistry

• IHC may be useful for the subclassification of amyloidoses.
  • The reliability of IHC for the subclassification of amyloidoses is thought to be low.
    • Extreme caution is advised when interpreting IHC results.

Possibly useful immunostains:

• Kappa.
• Lambda.
• Transthyretin.
  • The name transthyretin is from transports thyroxine and retinol (previous unknown as prealbumin).

Mass spectroscopy

• Can be typed using mass spectroscopy.
  • Considered to be the definitive test.
    • High specificity and sensitivity vis-à-vis clinicopathologic correlation.
  • May be done on formalin-fixed paraffin embedded (FFPE) material.

Types

Secondary amyloidosis

• AKA AA amyloidosis.
• Pathophysiology: acute-phase reactant serum amyloid A (SAA) - degraded + deposits.

Cerebral amyloid angiopathy

Main article: Cerebral amyloid angiopathy

A common cause of lobar hemorrhage (cerebral cortex, cerebellar cortex) in the elderly.

Senile systemic amyloidosis

• Abbreviated SSA.

General

• Previously known as senile cardiac amyloidosis.
• May be referred to as ATTR = amyloidosis TTR; in SSA the TTR is not mutated, some call it: wt transthyretin amyloidosis (ATTR).
  • There is a hereditary form of amyloidosis with mutated TTR deposition known as ATTR type FAP = ATTR type Familial Amyloid Polyneuropathy.
    • Hereditary TTR: deposits in the heart, nerves and leptomeningeal amyloidosis.

Epidemiology:

• Common in the elderly, as the word senile suggests.
• Found in approx. 25% of elderly over 80 years old, and in upto 65% of patients over 90 years old.

Treatment:

• Liver transplantation, RNAi therapy (patisiran) and antisense oligonucleotides (inotersen).

Gross pathology

• Grey/black "peppering" of left atrial endocardium - in fixed specimens.
  • "Peppering" should be present if severe.

Microscopic

Features:

• Heart most commonly involved, followed by lungs and then by kidney (renal papilla).
• DDx of pink of H&E is important to remember: amyloid, muscle, collagen, clotted blood.
  • Amyloid vs. Fibrosis? Subendocardial fibrosis may have rim of (diffusion) preserved myocytes. (???)
• Amyloid often present in the subepicardial tissue - less commonly affected by ischemia.

Images

• 

  Senile systemic amyloidosis - H&E. (WC)

• 

  Senile systemic amyloidosis - congo red. (WC)

• 

  Senile systemic amyloidosis - Movat's. (WC)

Site specific

Abdomen

Abdominal fat pad biopsy redirects here.

General

• Abdominal fat pad biopsy - common screen for amyloidosis.
  • May be done with FNA.
    • Suffers for poor sensitivity.

Microscopic

Features:

• Small-to-intermediate sized arteries with a thickened amorphous eosinophilic media.
  • Thickening classically nodular.
  • Apple green-birefringence -- with polarization.

Note:

• Evaluation of at least 15 small blood vessels is recommended.

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SOFT TISSUE, ABDOMEN, BIOPSY:
- AMYLOIDOSIS.

Negative

SOFT TISSUE, ABDOMEN, BIOPSY:
- BENIGN FIBROADIPOSE TISSUE.
- NEGATIVE FOR AMYLOIDOSIS WITH CONGO RED STAINING AND POLARIZED LIGHT.

COMMENT:
Correlation with serum protein electrophoresis, urine protein electrophoresis
and bone marrow sampling should be considered within the clinical context.

Cardiac amyloidosis

General

• Common cause of restrictive cardiomyopathy.

Cardiac amyloidosis - subtypes:

1. AL amyloidosis - associated with plasma cell dyscrasia - most common cardiac amyloidosis.
2. Senile systemic amyloidosis - TTR-related amyloidosis (unmutated TTR).
3. Hereditary amyloidosis.
4. AA amyloidosis is uncommon.

Clinical:

• CHF, conduction abnormalities.
• Kidney disease (proteinuria) - associated with AL amyloidosis.

Pulmonary amyloidosis

Main article: Pulmonary amyloidosis

• Very rare.

Renal amyloidosis

Main article: Medical kidney diseases

General

• Both AL and AA amyloidosis can affect the kidney.

Clinical:

• Usually Nephrotic range proteinuria.

Microscopic

Features:

• Paucicellular mesangial expansion.
• Fluffy hyaline material in medium-sized blood vessels.

DDx:

• Diabetic nephropathy.
• Idiopathic nodular glomerulosclerosis.
• Light chain deposition disease.
• Fibrillary glomerulopathy.
• Immunotactoid glomerulopathy.

Images

• 

  Renal amyloidosis - high mag. (WC)

• 

  Renal amyloidosis - high mag. (WC)

• 

  Renal amyloidosis - very high mag. (WC)

www:

• Renal amyloidosis - several images (upmc.edu).

Urinary bladder amyloidosis

Main article: Urinary bladder amyloidosis

GI amyloidosis

• GI amyloidosis can lead to obstruction and usually is greatest in the small bowel.

Liver amyloidosis

Main article: Liver amyloidosis

Features:

• Parenchymal deposition (common).
• Portal triad deposition (less common).

Gastric amyloidosis

Main article: Amyloidosis of the stomach

Bone

Amyloid is reported in association with:

• Multiple myeloma ~40% of patients in one series.
• Chronic osteomyelitis ~10% of patients in one series.
• Diabetes (one case).

See also

• Basics.
• Neuropathology.
• Fibrillary glomerulonephritis.

External links

• Amyloidosis - wikipedia.org.