Amyloidosis

• Amyloid is a pathologic proteinaceous substance, deposited between cells in various tissues and organs of the body in a wide variety of clinical settings
• Disease can be systemic or localised
• Diagnosis depends of morphology seen in biopsies
• With the light microscope and standard tissue stains, amyloid appears as a amorphous, eosinophilis, hyaline, extracellular substance that with progressive accumulation encroaches on and produces pressure atophy of adjacent cells
• Congo red is the most widely used stain – under ordinary light imparts a pink or red colour to tissue deposits but under polarised light produces a green bifrigence
• Amyloid is not a chemically distinct entity, there are three major and several minor biochemical forms

 

• Physical nature of amyloid
  • Non-branching fibrils which form characteristic beta-pleated sheets
  • Structure is identical in all types of amyloidosis

 

• Chemical nature of amyloid
  • 95% of amyloid material consists of fibril proteins, the remaining 5% is the P-component and other glycoproteins
  • Of the 15 distinct forms of amyloid, the 3 most common are;
  • AL – amyloid light chain derived from plasma cells and containing Ig-light chains (mostly l). Associated with some form of B cell monoclonal proliferation
  • AA – amyloid associated, a unique non-Ig protein synthesised by the liver. Found in clinical settings described as secondary amyloidosis. Derived from a larger serum precursor, SAA (serum amyloid-associated) protein
  • Ab – found in the cerebral lesions of Alzheimer disease. It is derived from the precursor, amyloid precursor protein
  • Other forms of amyloidosis are;
  • Transthyretin – a serum protein which binds and transports thryoxine and retinol. A mutant form is deposited in a group of genetically determined disorders called familial amyloid polyneuropathies
  • b2 microglobumin has been identified in amyloidosis and complicates the course of patients on long term haemodialysis

 

Classification of Amyloidosis

 

Immunocyte dyscrasia with amyloidosis

• Usually systemic and of the AL type
• Most common form of amyloidosis
• Associated with multiple myeloma whereby the amyloid deposits contain Bence-Jones proteins
• The majority of cases are not associated with any B cell neoplasm and are classified as primary amyloidosis. In these patients there is an underlysing B cell dyscrasia which manifests itself with production of abnormal protein rather than neoplasia

 

Reactive systemic amyloidosis

• Amyloid distribution systemic and composed of AA protein
• Considered secondary to an associated inflammatory condition
• Due to chronic inflammatory conditions
• Most commonly complicates, RA, alkylosing spondylitis and IBD
• May also occur in non-immunocyte-derived tumours such as renal cell carcinoma and Hodkin disease
• Also seen in heroine abusers who inject subcutaneously

 

Haemodialysis-associated Amyloidosis

• b2-microglobulin is found in high levels in patients with renal disease and is retained in the circulation because it cannot be filtered through dialysis membranes
• Amyloid deposits in the joints, synovium and tendon sheaths

 

Heredofamilial Amyloidosis

• Wide variety of familial varieties have been described;
• They include familial Mediterranean fever, an autosomal recessive condition associated with systemic amyloidosis of AA origin
• Familial amyloidotic polyneuropathies, autosomal dominant whereby fibrils are made up of mutant transthyretins

 

Localised Amyloidosis

• Deposits produce nodular masses and are most often encountered in the lung, larynx, skin, bladder, tongue and regions of the eye
• In the periphery of these lesions are infiltrates of lymphocytes and plasma cells – responsible or a response to amyloid?

 

Endocrine Amyloid

• Microscopic deposits of amyloid may be found in certain endocrine tumours such as medullary carcinoma of the thyroid, islet tumours of the pancreas, pheochromocytomas, undifferentiated tumours of the stomach and the islets of Langerhans in Type II diabetics
• In this setting amyloid is derived from either polypeptide hormones or unique proteins such as islet amyloid polypeptide

 

Amyloid of Aging

Senile systemic amyloidosis generally involves the heart resulting in restrictive cardiomyopathy or arrhythmias

The amyloid in this form is composed of the abnormal transthyretin molecule

 

Pathogenesis

 

• Amyloidosis results from abnormal folding of proteins
• The proteins that form amyloid are either;
• Normal proteins that have an inherent tendency to fold improperly and do so when they are produced in increased amounts
• Mutant proteins that are structurally unstable and prone to misfolding and aggregation
• Normally misfolded proteins are degraded by proteosomes or extracellularly by macrophages. In affected individuals it is possible that there may be some kind of failure in this degradation either due to defective degradation mechanisms or resistance of the amyloid to proteolysis

 

Morphology

 

• Secondary amyloidosis tends to yield the most severe systemic involvement
• Mostly it affects;
  • Kidneys
  • Liver
  • Spleen
  • Lymph nodes
  • Adrenals
  • Thyroid
• Immunocytes-associated amyloidosis more often involves;
  • Heart
  • Kidney
  • GI tract
  • Peripheral nerves
  • Skin
  • Tongue

 

Kidney

• Kidneys may be enlarged or shrunken owing to vascular narrowing induced by amyloidosis of the vessel walls
• Histological amyloid is deposited primarily in the glomeruli but the peritubular areas, arteries and arterioles are also involved

 

Spleen

• Two patterns of deposition can be seen;
• Deposits are limited to the splenic follicles producing a pattern known as sago spleen
• Deposition in the splenic sinuses and CT framework in the red pulp. Fusion of plaques results in large map-like areas of amyloidosis termed lardaceous spleen

 

 

Liver

• Amyloid first appears in the space of Disse and then progressively encroaches on the hepatic parenchymal cells and the sinusoids
• In time, deformity, pressure atrophy and disappearance of hepatocytes causes total replacement of large areas of liver parenchyma

 

Heart

• Histologically the deposits begin in subendocardial accumulations and within the myocardium between the muscle fibres
• Expansion of the deposits causes pressure atrophy of the myocardial fibres

 

Clinical correlation

 

• Symptoms depend on the magnitude of deposits and the particular organs affected
• Clinical manifestations are often non-specific and include;
  • Weakness
  • Weight loss
  • Light headedness
  • Synocope
• More specific findings related to renal, cardiac, GI involvement

 

• Renal involvement gives rise to proteinuria and nephrotic syndrome
• Progressive obliteration of glomeruli can lead to renal failure and uraemia
• Cardiac amyloidosis may present are congestive heart failure, arrthymias
• Gastrointestinal involvement may manifest with;
• Amyloidosis of the tongue may cause sufficient enlargement to hamper speech and swallowing
• Deposition in the stomach or intestine may lead to malabsorption or diarrhoea